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Zheng J, Zhou C, Li Z, Jin X, Zou Y, Bai S, Zheng H, Ling W, Zhao Y, Wang Y, Zhang R, Liu Z, Lu L. Alcaligenes faecalis promotes colitis to colorectal cancer transition through IgA+ B cell suppression and vinculin acetylation. Gut Microbes 2025; 17:2473511. [PMID: 40047249 PMCID: PMC11901412 DOI: 10.1080/19490976.2025.2473511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 12/24/2024] [Accepted: 02/21/2025] [Indexed: 03/14/2025] Open
Abstract
Lymphoid tissue-resident commensal bacteria (LRC), a subtype of gut microbiota essential for inflammation-associated carcinogenesis, predominantly attribute to colorectal cancer(CRC), whereas its role was largely unknown. Herein, we found Alcaligenes faecalis (A. faecalis), the main LRC embedded in Peyer's patches, was abundantly enriched in colitis, adenoma, and stage-dependently observed in CRC tissues. Interestingly, A. faecalis alone can not affect intestinal homeostasis, while during colitis, A. faecalis significantly translocated from Peyer's patches to colon, remarkably attenuated immune response abilities of B cells, T cells, and DC cells in PPs, consequently impeded IgA+ B cells homing. Meanwhile, during colitis, the ectopia of A. faecalis in colon tissues, promoted vinculin acetylation by A. faecalis-derived metabolite acetic acid, which impeded intestinal barrier via hindering the binding of vinculin to β-catenin. Our study revealed A. faecalis not only suppress mucosal immune responses via reducing IgA+ B cells in Peyer's patches but also disrupt intestinal barrier via increasing vinculin acetylation, ultimately promoting inflammation-to-cancer transition in CRC.
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Affiliation(s)
- Jing Zheng
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chishun Zhou
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zizheng Li
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xin Jin
- Department of Colorectal Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yihua Zou
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shasha Bai
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Huanjin Zheng
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Weichao Ling
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yiru Zhao
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ying Wang
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Rong Zhang
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhongqiu Liu
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Linlin Lu
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
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Sun Y, Wang Q, Jiang Y, He J, Jia D, Luo M, Shen W, Wang Q, Qi Y, Lin Y, Zhang Y, Wang L, Wang L, Chen S, Fan L. Lactobacillus intestinalis facilitates tumor-derived CCL5 to recruit dendritic cell and suppress colorectal tumorigenesis. Gut Microbes 2025; 17:2449111. [PMID: 39773173 PMCID: PMC11730368 DOI: 10.1080/19490976.2024.2449111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 11/11/2024] [Accepted: 12/23/2024] [Indexed: 01/11/2025] Open
Abstract
Gut microbes play a crucial role in regulating the tumor microenvironment (TME) of colorectal cancer (CRC). Nevertheless, the deep mechanism between the microbiota-TME interaction has not been well explored. In this study, we for the first time discovered that Lactobacillus intestinalis (L. intestinalis) effectively suppressed tumor growth both in the AOM/DSS-induced CRC model and the ApcMin/+ spontaneous adenoma model. Our investigation revealed that L. intestinalis increased the infiltration of immune cells, particularly dendritic cells (DC), in the TME. Mechanically, the tumor-derived CCL5 induced by L. intestinalis recruited DC chemotaxis through the NOD1/NF-κB signaling pathway. In clinical samples and datasets, we found positive correlation between L. intestinalis, CCL5 level, and the DC-related genes. Our study provided a new strategy for microbial intervention for CRC and deepened the understanding of the interaction between tumor cells and the immune microenvironment modulated by gut microbes.
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Affiliation(s)
- Yong Sun
- Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Qiwen Wang
- Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Yao Jiang
- Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Jiamin He
- Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Dingjiacheng Jia
- Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Man Luo
- Department of Nutrition, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Wentao Shen
- Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Qingyi Wang
- Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Yadong Qi
- Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Yifeng Lin
- Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Ying Zhang
- Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Lan Wang
- Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Liangjing Wang
- Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China
- Prevention and Treatment Research Center of Senescent Disease, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Shujie Chen
- Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Prevention and Treatment Research Center of Senescent Disease, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Lina Fan
- Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China
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Dong Y, Meng F, Wang J, Wei J, Zhang K, Qin S, Li M, Wang F, Wang B, Liu T, Zhong W, Cao H. Desulfovibrio vulgaris flagellin exacerbates colorectal cancer through activating LRRC19/TRAF6/TAK1 pathway. Gut Microbes 2025; 17:2446376. [PMID: 39718561 DOI: 10.1080/19490976.2024.2446376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 11/22/2024] [Accepted: 12/18/2024] [Indexed: 12/25/2024] Open
Abstract
The initiation and progression of colorectal cancer (CRC) are intimately associated with genetic, environmental and biological factors. Desulfovibrio vulgaris (DSV), a sulfate-reducing bacterium, has been found excessive growth in CRC patients, suggesting a potential role in carcinogenesis. However, the precise mechanisms underlying this association remain incompletely understood. We have found Desulfovibrio was abundant in high-fat diet-induced Apcmin/+ mice, and DSV, a member of Desulfovibrio, triggered colonocyte proliferation of germ-free mice. Furthermore, the level of DSV progressively rose from healthy individuals to CRC patients. Flagella are important accessory structures of bacteria, which can help them colonize and enhance their invasive ability. We found that D. vulgaris flagellin (DVF) drove the proliferation, migration, and invasion of CRC cells and fostered the growth of CRC xenografts. DVF enriched the epithelial-mesenchymal transition (EMT)-associated genes and characterized the facilitation of DVF on EMT. Mechanistically, DVF induced EMT through a functional transmembrane receptor called leucine-rich repeat containing 19 (LRRC19). DVF interacted with LRRC19 to modulate the ubiquitination of tumor necrosis factor receptor-associated factor (TRAF)6, rather than TRAF2. This interaction drove the ubiquitination of pivotal molecule TAK1, further enhancing its autophosphorylation and ultimately contributing to EMT. Collectively, DVF interacts with LRRC19 to activate the TRAF6/TAK1 signaling pathway, thereby promoting the EMT of CRC. These data shed new light on the role of gut microbiota in CRC and establish a potential clinical therapeutic target.
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Affiliation(s)
- Yue Dong
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Fanyi Meng
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Jingyi Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Jingge Wei
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Kexin Zhang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Siqi Qin
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Mengfan Li
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Fucheng Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Tianyu Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Weilong Zhong
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
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Lin H, Chen Y, Zhou M, Wang H, Chen L, Zheng L, Wang Z, Zheng X, Lu S. Comprehensive analysis of faecal metagenomic and serum metabolism revealed the role of gut microbes and related metabolites in detecting colorectal lateral spreading tumours. Virulence 2025; 16:2489154. [PMID: 40223231 DOI: 10.1080/21505594.2025.2489154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 02/07/2025] [Accepted: 03/26/2025] [Indexed: 04/15/2025] Open
Abstract
Colorectal lateral spreading tumours (LST), early-stage lesions of colorectal cancer (CRC), are associated with gut microbiota dysbiosis. However, the functional alterations in gut microbiota and their metabolic pathways remain inadequately understood. This study employed propensity score matching to compare 35 LST patients with 35 healthy controls. Metagenomic and metabolomic analyses revealed notable differences in gut microbiota composition and metabolic pathways. LST patients exhibited a marked reduction in short-chain fatty acid (SCFA)-producing probiotics, such as Roseburia, Clostridium, and Butyricicoccus sp-OF13-6, alongside anti-inflammatory metabolites. In contrast, potential intestinal pathogens linked to inflammatory bowel disease (IBD), including Escherichia and Citrobacter amalonaticus, were significantly enriched. Orthogonal partial least squares discriminant analysis (OPLS-DA) highlighted significant metabolic disparities between the groups, with enrichment in pathways associated with cholesterol metabolism, choline metabolism in cancer, and amino acid metabolism - all relevant to cancer progression. Key biomarkers identified for LST included fumarate, succinate, glutamic acid, glycine, and L-aspartic acid, which were closely linked to these pathways. Functional studies demonstrated that these metabolites promoted the proliferation and invasion of HCT-116 and SW480 human colorectal cancer cells in vitro. Metagenomic and metabolomic analysis revealed a strong positive correlation between Escherichia and Ruminococcus sp-AM41-2AC abundance and the enriched pathways, whereas reductions in Roseburia species, including Roseburia-OF03-24 and Roseburia intestinalis_CAG13-exhibited negative correlations. These results suggest that gut microbiota and metabolite alterations in LST contribute to intestinal inflammation and CRC development, underscoring their potential as biomarkers for early detection and therapeutic targets.
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Affiliation(s)
- Hao Lin
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Gastroenterology, Fujian Provincial Hospital, Fuzhou, China
- Department of Gastroenterology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Yudai Chen
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Gastroenterology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
- Department of Digestive Endoscopy, Fujian Provincial Hospital, Fuzhou, China
| | - Ming Zhou
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Gastroenterology, Fujian Provincial Hospital, Fuzhou, China
- Department of Gastroenterology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Hongli Wang
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Gastroenterology, Fujian Provincial Hospital, Fuzhou, China
- Department of Gastroenterology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Lichun Chen
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Gastroenterology, Fujian Provincial Hospital, Fuzhou, China
- Department of Gastroenterology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Li Zheng
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Gastroenterology, Fujian Provincial Hospital, Fuzhou, China
- Department of Gastroenterology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Zhixin Wang
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Gastroenterology, Fujian Provincial Hospital, Fuzhou, China
- Department of Gastroenterology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Xiaoling Zheng
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Gastroenterology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
- Department of Digestive Endoscopy, Fujian Provincial Hospital, Fuzhou, China
| | - Shiyun Lu
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Gastroenterology, Fujian Provincial Hospital, Fuzhou, China
- Department of Gastroenterology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
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Liu W, Yang X, Zhou Y, Huang Z, Huang J. Gut microbiota in melanoma: Effects and pathogeneses. Microbiol Res 2025; 296:128144. [PMID: 40120565 DOI: 10.1016/j.micres.2025.128144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 03/13/2025] [Accepted: 03/14/2025] [Indexed: 03/25/2025]
Abstract
The gut microbiota exhibits intricate connections with the body's immune system and holds significant implications for various diseases and cancers. Currently, accumulating evidence suggests a correlation between the composition of the gut microbiota and the development, treatment, and prognosis of melanoma. However, the underlying pathogenesis remains incompletely elucidated. In this comprehensive review, we present an in-depth review of the role played by gut microbiota in melanoma tumorigenesis, growth, metastasis, treatment response, and prognosis. Furthermore, we discuss the potential utility of gut microbiota as a promising prognostic marker. Lastly, we summarize three routes through which gut microbiota influences melanoma: immunity, aging, and the endocrine system. By modulating innate and adaptive immunity in patients with melanoma across different age groups and genders, the gut microbiota plays a crucial role in anti-tumor immune regulation from tumorigenesis to prognosis management, thereby impacting tumor growth and metastasis. This review also addresses current study limitations while highlighting future research prospects.
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Affiliation(s)
- Wenwen Liu
- Department of Clinical Laboratory, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Xin Yang
- Department of Clinical Laboratory, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yuwei Zhou
- Department of Clinical Laboratory, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Ziru Huang
- Department of Clinical Laboratory, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Jian Huang
- Department of Clinical Laboratory, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, China; School of Healthcare Technology, Chengdu Neusoft University, Chengdu, Sichuan, China.
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Gong T, Lu X, Zhang H, Su W, Jin Y, He H, Yao B, Jin M, Wang Y, Cheng Y. Intestinal microbiota-derived d-(+)-malic acid promotes pBD1 expression via p-p38/ATF1 signaling pathway to maintain porcine intestinal health. Int Immunopharmacol 2025; 154:114552. [PMID: 40186905 DOI: 10.1016/j.intimp.2025.114552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/20/2025] [Accepted: 03/22/2025] [Indexed: 04/07/2025]
Abstract
This study aims to identify nutrients that enhance the expression of host defense peptides (HDPs) and to evaluate their application effects and regulatory mechanisms, thereby advancing the exploring of nutritional regulation of HDPs. To achieve this, we constructed 16 stable fluorescent reporter porcine epithelial cell lines, driven by promoters targeting eight porcine intestinal HDPs genes, using IPEC-1 and IPEC-J2 cells. Through untargeted metabolomics sequencing and high-throughput screening, 15 metabolites were identified as potential enhancers of pBD1 expression, with d-(+)-malic acid (DMA) emerged as the most effective candidate. Transcriptomic and western blot analysis suggested that DMA enhances pBD1 expression primarily via the p-p38/ATF1 signaling pathways. Functional studies demonstrated that DMA significantly improved intestinal barrier integrity and alleviated intestinal damage. Overall, this work successfully established promoter-driven fluorescent reporter cell lines and identified microbiota-derived metabolites enhancing pBD1 expression, such as DMA, as promising alternatives to antibiotics for maintaining porcine intestinal health.
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Affiliation(s)
- Tao Gong
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; National Engineering Laboratory of Biological Feed Safety and Pollution Prevention and Control, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China
| | - Xiaoxi Lu
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; National Engineering Laboratory of Biological Feed Safety and Pollution Prevention and Control, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China
| | - Hong Zhang
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; National Engineering Laboratory of Biological Feed Safety and Pollution Prevention and Control, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China
| | - Weifa Su
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; National Engineering Laboratory of Biological Feed Safety and Pollution Prevention and Control, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China
| | - Yuanli Jin
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; National Engineering Laboratory of Biological Feed Safety and Pollution Prevention and Control, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China
| | - Huan He
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; National Engineering Laboratory of Biological Feed Safety and Pollution Prevention and Control, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China
| | - Bin Yao
- Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Mingliang Jin
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; National Engineering Laboratory of Biological Feed Safety and Pollution Prevention and Control, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China
| | - Yizhen Wang
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; National Engineering Laboratory of Biological Feed Safety and Pollution Prevention and Control, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China
| | - Yuanzhi Cheng
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; National Engineering Laboratory of Biological Feed Safety and Pollution Prevention and Control, College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China.
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Liu Y, Zhang Q, Lu L, Qian Y, Wu Y, Hu D, Xu Y, Xu H, Ji G. Huang-qin decoction alleviates deoxycholic acid-induced colorectal cancer in mice by regulating gut microbiota. JOURNAL OF ETHNOPHARMACOLOGY 2025; 346:119715. [PMID: 40158829 DOI: 10.1016/j.jep.2025.119715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 03/17/2025] [Accepted: 03/27/2025] [Indexed: 04/02/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Huangqin Decoction (HQD), a traditional Chinese medicine (TCM) formula documented in Shang Han Lun, has demonstrated safety and efficacy in the treatment of ulcerative colitis (UC). Recent studies also suggest that HQD exerts therapeutic effects on colorectal cancer (CRC). However, the underlying mechanisms remain unclear. AIMS OF THE STUDY This study aimed to investigate the therapeutic effects of HQD on CRC and explore its potential mechanisms of action. METHODS The active ingredients and potential targets of HQD were identified through network pharmacology-based analyses. The CRC-related targets were compared with those of HQD. Shared targets were subjected to Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and a protein-protein interaction (PPI) network was constructed. Additionally, APCmin/+ mice were treated with 0.2 % deoxycholic acid (DCA) and gavaged with low or high doses of HQD. Tumor morphology was assessed using hematoxylin and eosin (HE) staining. Immunohistochemical staining was performed to evaluate the expression of Ki-67, Caspase-3, and MUC2 in the intestine. Periodic acid-Schiff (PAS) and PAS-alcian blue (PAS-AB) staining were utilized to detect mucin distribution and the number of goblet cells in the intestines of the mice. The mRNA expression levels of interleukin 6 (IL-6), mitogen-activated protein kinase 8 (MAPK8), vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor (EGFR), albumin (ALB), and Caspase 3 (CASP3) were quantified using quantitative reverse-transcription PCR (qRT-PCR). Immunofluorescence was employed to assess the degree of apoptosis. Additionally, 16S ribosomal RNA gene sequencing, sequence curation and annotation, and metagenomic sequencing were performed to analyze changes in the composition of the mouse intestinal microbiota and related functions and signaling pathways. RESULTS The active ingredients of HQD were identified. GO and KEGG pathway enrichment analyses indicated that the shared targets were primarily involved in tumor suppression. HQD effectively treated DCA-induced CRC in mice. Furthermore, positive PAS and PAS-AB staining was significantly increased in the intestines of mice treated with HQD. HQD enhanced the abundance of Lachnospiraceae, Firmicutes, Fusobacteria, and Clostridium, while reducing the abundance of Eggerthellales. Additionally, HQD modulated secondary bile acid metabolism, carbohydrate synthesis, and other energy metabolism pathways, which may underlie its therapeutic effects. CONCLUSION HQD effectively treated CRC in mice, and its mechanisms of action may be related to the regulation of the gut microbiota.
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Affiliation(s)
- Yujing Liu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Xuhui District, Shanghai, 200032, China; Shanghai Frontier Research Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation, 725 South Wanping Road, Xuhui District, Shanghai, 200032, China
| | - Qiang Zhang
- Department of Digestive Endoscopy, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, No. 155, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu, 210029, China
| | - Lu Lu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Xuhui District, Shanghai, 200032, China; Shanghai Frontier Research Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation, 725 South Wanping Road, Xuhui District, Shanghai, 200032, China
| | - Yufan Qian
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Xuhui District, Shanghai, 200032, China; Shanghai Frontier Research Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation, 725 South Wanping Road, Xuhui District, Shanghai, 200032, China
| | - Yuanmin Wu
- Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, 399 Pingchuan Road, Pudong New Area, Shanghai, 2001205, China
| | - Dan Hu
- Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, 399 Pingchuan Road, Pudong New Area, Shanghai, 2001205, China
| | - Yangxian Xu
- Department of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Xuhui District, Shanghai, 200032, China
| | - Hanchen Xu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Xuhui District, Shanghai, 200032, China; Department of Digestive Endoscopy, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, No. 155, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu, 210029, China; Shanghai Frontier Research Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation, 725 South Wanping Road, Xuhui District, Shanghai, 200032, China.
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Xuhui District, Shanghai, 200032, China; Department of Digestive Endoscopy, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, No. 155, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu, 210029, China; Shanghai Frontier Research Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation, 725 South Wanping Road, Xuhui District, Shanghai, 200032, China.
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8
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Liu YL, Liu J. Gut microbiota plays a key role in the development of colorectal cancer. World J Gastroenterol 2025; 31:105420. [DOI: 10.3748/wjg.v31.i14.105420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 03/05/2025] [Accepted: 03/10/2025] [Indexed: 04/11/2025] Open
Abstract
This letter addresses the recently published manuscript by Darnindro et al, which investigates the diversity and composition of colonic mucosal microbiota in Indonesian patients with and without colorectal cancer (CRC). Although the analysis revealed no statistically significant differences in alpha diversity between the CRC and non-CRC groups, the authors identified notable distinctions in the composition and diversity of colonic mucosal microbiota among patients with CRC compared to those without. At the genus level, a statistically significant difference in microbiota composition was documented between the two cohorts. Specifically, the genera Bacteroides, Campylobacter, Peptostreptococcus, and Parvimonas were found to be elevated in individuals with CRC, while Faecalibacterium, Haemophilus, and Phocaeicola were more prevalent in the non- CRC group.
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Affiliation(s)
- Ying-Ling Liu
- Department of Gastroenterology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
| | - Jie Liu
- Department of Gastroenterology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
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9
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Qiu X, Gao Q, Wang J, Zhang Z, Tao L. The microbiota-m 6A-metabolism axis: Implications for therapeutic strategies in gastrointestinal cancers. Biochim Biophys Acta Rev Cancer 2025:189317. [PMID: 40222422 DOI: 10.1016/j.bbcan.2025.189317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 04/06/2025] [Accepted: 04/06/2025] [Indexed: 04/15/2025]
Abstract
Gastrointestinal (GI) cancers remain a leading cause of cancer-related mortality worldwide, with metabolic reprogramming recognized as a central driver of tumor progression and therapeutic resistance. Among the key regulatory layers, N6-methyladenosine (m6A) RNA modification-mediated by methyltransferases (writers such as METTL3/14), RNA-binding proteins (readers like YTHDFs and IGF2BPs), and demethylases (erasers including FTO and ALKBH5), plays a pivotal role in controlling gene expression and metabolic flux in the tumor context. Concurrently, the gut microbiota profoundly influences GI tumorigenesis and immune evasion by modulating metabolite availability and remodeling the tumor microenvironment. Recent evidence has uncovered a bidirectional crosstalk between microbial metabolites and m6A methylation: microbiota-derived signals dynamically regulate m6A deposition on metabolic and immune transcripts, while m6A modifications, in turn, regulate the stability and translation of key mRNAs such as PD-L1 and FOXP3. This reciprocal interaction forms self-reinforcing epigenetic circuits that drive tumor plasticity, immune escape, and metabolic adaptation. In this review, we dissect the molecular underpinnings of the microbiota-m6A-metabolism axis in GI cancers and explore its potential to inform novel strategies in immunotherapy, metabolic intervention, and microbiome-guided precision oncology.
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Affiliation(s)
- Xiuxiu Qiu
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qi Gao
- Institute of Acupuncture and Moxibustion, Chinese Academy of Traditional Chinese Medicine, Beijing, China
| | - Jiahui Wang
- Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhanxia Zhang
- Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Li Tao
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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10
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Wang M, Liu K, Bao W, Hang B, Chen X, Zhu X, Li G, Liu L, Xiang H, Hu H, Lu Y, Song Z, Chen J, Wang Y. Gut microbiota protect against colorectal tumorigenesis through lncRNA Snhg9. Dev Cell 2025; 60:1008-1017.e7. [PMID: 39755115 DOI: 10.1016/j.devcel.2024.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 09/30/2024] [Accepted: 12/05/2024] [Indexed: 01/06/2025]
Abstract
The intestinal microbiota is a key environmental factor in the development of colorectal cancer (CRC). Here, we report that, in the context of mild colonic inflammation, the microbiota protects against colorectal tumorigenesis in mice. This protection is achieved by microbial suppression of the long non-coding RNA (lncRNA) Snhg9. Snhg9 promotes tumor growth through inhibition of the tumor suppressor p53. Snhg9 suppresses p53 activity by dissociating the p53 deacetylase sirtuin 1 (SIRT1) from the cell cycle and apoptosis regulator 2 (CCAR2). Consequently, the depletion of the microbiota by antibiotics causes upregulation of Snhg9 and accelerates CRC progression. Moreover, Snhg9 is functionally conserved. Human SNHG9 promotes tumor growth via the same mechanism as mouse Snhg9, despite their low sequence similarity.
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Affiliation(s)
- Meng Wang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, Zhejiang, China
| | - Kailin Liu
- Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, Zhejiang, China
| | - Wu Bao
- Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, Zhejiang, China
| | - Bingqing Hang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, Zhejiang, China
| | - Xianjiong Chen
- Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, Zhejiang, China
| | - Xinyi Zhu
- Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, Zhejiang, China
| | - Guifang Li
- Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, Zhejiang, China
| | - Lihong Liu
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China
| | - Haoyi Xiang
- Department of Colorectal Surgery and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang, China
| | - Hai Hu
- Breast Cancer Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou 310022, Zhejiang, China
| | - Yanhui Lu
- School of Nursing, Peking University, Beijing 100191, China
| | - Zhangfa Song
- Department of Colorectal Surgery and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang, China.
| | - Jiaxin Chen
- Department of Breast Surgery and Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China.
| | - Yuhao Wang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou 310029, Zhejiang, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou 310029, Zhejiang, China.
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11
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Leigh J, Skidmore B, Wong A, Maleki Vareki S, Ng TL. Exploring the Microbiome's Impact on Glioma and Brain Metastases: Insights into Development, Progression, and Treatment Response-A Scoping Review. Cancers (Basel) 2025; 17:1228. [PMID: 40227812 DOI: 10.3390/cancers17071228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2025] [Revised: 03/29/2025] [Accepted: 04/03/2025] [Indexed: 04/15/2025] Open
Abstract
Background: The human microbiome plays a crucial role in health and disease. Dysbiosis, an imbalance of microorganisms, has been implicated in cancer development and treatment response, including in primary brain tumors and brain metastases, through interactions mediated by the gut-brain axis. This scoping review synthesizes current evidence on the relationship between the human microbiome and brain tumors. Methods: A systematic search of five electronic databases was conducted by an expert librarian, using controlled vocabulary and keywords. A targeted grey literature search in Google Scholar and clinical trial registries was also undertaken. Eligible studies included primary research involving human patients, or in vivo, or in vitro models of glioma or brain metastasis, with a focus on the microbiome's role in tumor development, treatment response, and outcomes. Results: Out of 584 citations screened, 40 studies met inclusion criteria, comprising 24 articles and 16 conference abstracts. These included 12 human studies, 16 using mouse models, 7 combining both, and 5 employing large datasets or next-generation sequencing of tumor samples. Thirty-one studies focused on primary brain tumors, six on brain metastases, and three on both. Of the 20 studies examining dysbiosis in tumor development, 95% (n = 19) found an association with tumor growth. Additionally, 71.4% (n = 5/7) of studies reported that microbiome alterations influenced treatment efficacy. Conclusions: Although the role of the gut-brain axis in brain tumors is still emerging and is characterized by heterogeneity across studies, existing evidence consistently supports a relationship between the gut microbiome and both brain tumor development and treatment outcomes.
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Affiliation(s)
- Jennifer Leigh
- Division of Medical Oncology, Department of Medicine, The Ottawa Hospital Cancer Centre, Ottawa, ON K1Y 4E9, Canada
- Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
| | - Becky Skidmore
- Skidmore Research & Information Consulting Inc., Ottawa, ON, Canada
| | - Adrian Wong
- Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Saman Maleki Vareki
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
- Verspeeten Family Cancer Centre, London Health Sciences Research Institute, London, ON N6A 5W9, Canada
- Department of Oncology, Western University, London, ON N6A 3K7, Canada
- Department of Medical Biophysics, Western University, London, ON N6A 3K7, Canada
| | - Terry L Ng
- Division of Medical Oncology, Department of Medicine, The Ottawa Hospital Cancer Centre, Ottawa, ON K1Y 4E9, Canada
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12
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Wang ML, Zhang YJ, Xiao H, Lu XL, Chen L, Ma ZW, Chen A, Yin Q. Probiotic effects of Clostridium cellabutyricum against Pseudomonas aeruginosa infection in antibiotic-induced gut microbial dysbiosis mice model. Int J Antimicrob Agents 2025:107503. [PMID: 40187664 DOI: 10.1016/j.ijantimicag.2025.107503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 03/16/2025] [Accepted: 03/28/2025] [Indexed: 04/07/2025]
Abstract
Gut microbiota dysbiosis induced by antibiotic use weakens its colonization resistance against opportunistic pathogens, increasing the risk of invasion and infection. While probiotics have the potential to restore the impaired gut microbial structure and prevent respiratory tract infections, the effectiveness of specific strains and the underlying mechanisms remain largely unexplored. In this study, the preventive effects of a novel butyrate-producing bacterium, Clostridium cellabutyricum YQ-FP-027T against Pseudomonas aeruginosa infection after antibiotic exposure were investigated in antibiotic-pretreated mice model. Phenotypic characterizations including the bacterial load in the lung, the assessment of gene expression of immune factors in lung tissue using qPCR, and detection of gut microbial composition using 16S rRNA sequencing were conducted. Pulmonary bacterial load and expression levels of immune factors of lung tissue, and gut microbial composition were evaluated. Our results demonstrated that YQ-FP-027T ameliorated lung tissue integrity, significantly reduced pulmonary bacterial burden, and decreased the expression of IL-1β and TNF-α, while enhancing the expression of IL-10 and CRAMP. Furthermore, YQ-FP-027T increased the abundance of Lachnospiraceae in the gut and reduced the abundance of opportunistic pathogens such as Enterococcaceae and Helicobacteraceae. These results suggest YQ-FP-027T exerts probiotic effects by restoring gut microbiota balance, enhancing intestinal barrier function, and positively influencing pulmonary immune responses through the gut-lung axis. This study reveals the preventive potential of YQ-FP-027T against P. aeruginosa infection in the context of gut microbiota dysbiosis, offering a novel preventive strategy.
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Affiliation(s)
- Meng-Ling Wang
- College of Public Health, Chongqing Medical University, No. 61 Daxuecheng Middle Road, Shapingba District, Chongqing 401334, PR China
| | - Yuan-Jie Zhang
- College of Public Health, Chongqing Medical University, No. 61 Daxuecheng Middle Road, Shapingba District, Chongqing 401334, PR China
| | - Hong Xiao
- College of Public Health, Chongqing Medical University, No. 61 Daxuecheng Middle Road, Shapingba District, Chongqing 401334, PR China
| | - Xiao-Ling Lu
- College of Public Health, Chongqing Medical University, No. 61 Daxuecheng Middle Road, Shapingba District, Chongqing 401334, PR China
| | - Li Chen
- College of Public Health, Chongqing Medical University, No. 61 Daxuecheng Middle Road, Shapingba District, Chongqing 401334, PR China
| | - Zhi-Wen Ma
- College of Public Health, Chongqing Medical University, No. 61 Daxuecheng Middle Road, Shapingba District, Chongqing 401334, PR China
| | - Anyi Chen
- College of Public Health, Chongqing Medical University, No. 61 Daxuecheng Middle Road, Shapingba District, Chongqing 401334, PR China
| | - Qi Yin
- College of Public Health, Chongqing Medical University, No. 61 Daxuecheng Middle Road, Shapingba District, Chongqing 401334, PR China.
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13
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Luan B, Yang Y, Yang Q, Li Z, Xu Z, Chen Y, Wang M, Chen W, Ge F. Gut microbiota, blood metabolites, & pan-cancer: a bidirectional Mendelian randomization & mediation analysis. AMB Express 2025; 15:59. [PMID: 40175810 PMCID: PMC11965084 DOI: 10.1186/s13568-025-01866-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 03/14/2025] [Indexed: 04/04/2025] Open
Abstract
We propose using Mendelian randomization analysis on GWAS data and MetaboAnalyst to model gut microbiota, metabolic pathways, blood metabolites, and cancer risk. We examined 473 gut microbiota, 205 pathways, 1400 metabolites, and 8 cancers. Results were validated through bidirectional two-sample Mendelian Randomization (MR), heterogeneity tests, and pathway enrichment, leading to a mediation pathway model. We identified 129 gut microbiota, 57 pathways, and 463 metabolites linked to cancer, and 34 significant plasma pathways. 15 microbiota, 8 pathways, and 58 metabolites implicated in multiple cancers. Eight plasma metabolic pathways are involved in the development of multiple types of cancer. Through Multivariate Mendelian Randomization (MVMR) and mediation analysis, we found 9 mediation pathways, offering novel targets and research directions for cancer pathogenesis and treatment.
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Affiliation(s)
- Biqing Luan
- Department of Breast Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yang Yang
- Yunnan Key Laboratory of Breast Cancer Precision Medicine, Department of breast surgery, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, Kunming, Yunnan, China
| | - Qizhi Yang
- Department of Breast Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Zhiqiang Li
- Department of Breast Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Zhihui Xu
- Department of Breast Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yaqin Chen
- Department of Breast Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Meiting Wang
- Department of Breast Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Wenlin Chen
- Yunnan Key Laboratory of Breast Cancer Precision Medicine, Department of breast surgery, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, Kunming, Yunnan, China.
| | - Fei Ge
- Department of Breast Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
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14
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Chang Y, Long M, Shan H, Liu L, Zhong S, Luo JL. Combining gut microbiota modulation and immunotherapy: A promising approach for treating microsatellite stable colorectal cancer. Crit Rev Oncol Hematol 2025; 208:104629. [PMID: 39864533 DOI: 10.1016/j.critrevonc.2025.104629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/20/2025] [Accepted: 01/21/2025] [Indexed: 01/28/2025] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent and lethal cancers worldwide, ranking third in incidence and second in mortality. While immunotherapy has shown promise in patients with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), its effectiveness in proficient mismatch repair (pMMR) or microsatellite stable (MSS) CRC remains limited. Recent advances highlight the gut microbiota as a potential modulator of anti-tumor immunity. The gut microbiome can significantly influence the efficacy of immune checkpoint inhibitors (ICIs), especially in pMMR/MSS CRC, by modulating immune responses and systemic inflammation. This review explores the role of the gut microbiota in pMMR/MSS CRC, the mechanisms by which it may enhance immunotherapy, and current strategies for microbiota modulation. We discuss the potential benefits of combining microbiota-targeting interventions with immunotherapy to improve treatment outcomes for pMMR/MSS CRC patients.
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Affiliation(s)
- Yujie Chang
- The Cancer Research Institute and the Second Affiliated Hospital, Hengyang Medical School, University of South China (USC), Hunan 421001, China; MOE Key Lab of Rare Pediatric Diseases, Hengyang Medical School, USC, Hunan 421001, China
| | - Min Long
- The Cancer Research Institute and the Second Affiliated Hospital, Hengyang Medical School, University of South China (USC), Hunan 421001, China; MOE Key Lab of Rare Pediatric Diseases, Hengyang Medical School, USC, Hunan 421001, China
| | - Hanguo Shan
- The Cancer Research Institute and the Second Affiliated Hospital, Hengyang Medical School, University of South China (USC), Hunan 421001, China; Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, USC, Hunan 421001, China
| | - Logen Liu
- Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, USC, Hunan 421001, China
| | - Shangwei Zhong
- The Cancer Research Institute and the Second Affiliated Hospital, Hengyang Medical School, University of South China (USC), Hunan 421001, China; MOE Key Lab of Rare Pediatric Diseases, Hengyang Medical School, USC, Hunan 421001, China
| | - Jun-Li Luo
- The Cancer Research Institute and the Second Affiliated Hospital, Hengyang Medical School, University of South China (USC), Hunan 421001, China; Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, USC, Hunan 421001, China; MOE Key Lab of Rare Pediatric Diseases, Hengyang Medical School, USC, Hunan 421001, China; National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, USC, Hunan 410008, China.
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15
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Liu Z, Jiang X, Ke Z, Wang W, Tang J, Dai Y. PAR2 deficiency impairs antitumor immunity and attenuates anti-PD1 efficacy in colorectal cancer. Pharmacol Res 2025:107721. [PMID: 40174816 DOI: 10.1016/j.phrs.2025.107721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 03/28/2025] [Accepted: 03/28/2025] [Indexed: 04/04/2025]
Abstract
A T cell-inflamed tumor microenvironment is predictive of better prognosis and clinical response to immunotherapy. Proteinase-activated receptor 2 (PAR2), a member of G-protein coupled receptors is involved in inflammatory process and the progression of various cancers. However, the role of PAR2 in modulating the tumor microenvironment remains unclear. Here, we found that PAR2 high-expression was associated with a favorable prognosis in patients with colorectal cancer. Intriguingly, PAR2 expression in human colorectal cancer was mainly confined to tumor cells and was significantly associated with CD8+ T cell infiltration. Tumor-intrinsic PAR2 deficiency blunted antitumor immune responses to promote tumor growth and attenuated the therapeutic efficacy of anti-PD1 in a mouse model of colon cancer. Tumors with downregulated PAR2 showed decreased CD8+ T cell infiltration and impaired effector function. Mechanistically, PAR2 activation in tumor cells induced CXCL9 and CXCL10 production via PI3K/AKT/mTOR signaling, thereby enhancing CD8+ T cell recruitment in the tumor microenvironment. In addition, PAR2 was essential for dendritic cell activation and differentiation towards conventional type 1 subset. PAR2 deficiency in dendritic cells markedly impaired their ability to prime CD8+ T cells and control tumor growth in vivo. Thus, our findings identify new roles for PAR2 in promoting antitumor immunity and provide a promising target to improve immunotherapy efficacy in colorectal cancer.
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Affiliation(s)
- Zilin Liu
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Xuehui Jiang
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Ziliang Ke
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Weihong Wang
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Jianqiang Tang
- Department of General Surgery, Peking University First Hospital, Beijing, China.
| | - Yun Dai
- Department of Gastroenterology, Peking University First Hospital, Beijing, China.
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16
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Sousa MGC, Brasino DSK, Krieger M, Dindar DA, Duhen R, Zhang Z, Franca CM, Bertassoni LE. Host-microbe-cancer interactions on-a-chip. Front Bioeng Biotechnol 2025; 13:1505963. [PMID: 40230461 PMCID: PMC11994592 DOI: 10.3389/fbioe.2025.1505963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 03/11/2025] [Indexed: 04/16/2025] Open
Abstract
The tumor microbiota has emerged as a pivotal contributor to a variety of cancers, impacting disease development, progression, and therapeutic resistance. Due to the complexity of the tumor microenvironment, reproducing the interactions between the microbes, tumor cells, and the immune system remains a great challenge for both in vitro and in vivo studies. To this end, significant progress has been made toward leveraging tumor-on-a-chip model systems to replicate critical hallmarks of the native disease in vitro. These microfluidic platforms offer the ability to mimic essential components of the tumor microenvironment, including controllable fluid flow conditions, manipulable extracellular matrix dynamics, and intricate 3D multi-cellular communication. The primary objective of this review is to discuss recent challenges and advances in engineering host-microbiota and tumor interactions on-a-chip. Ultimately, overcoming these obstacles will help us gain deeper insights into tumor-microbe interactions and enhance avenues for developing more effective cancer therapies.
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Affiliation(s)
- Mauricio G. C. Sousa
- Knight Cancer Precision Biofabrication Hub, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR, United States
- Department of Biomaterial and Biomedical Sciences, School of Dentistry, Oregon Health & Science University, Portland, OR, United States
| | - Danielle S. K. Brasino
- Department of Microbiology and Molecular Genetics, Robert Larner College of Medicine at the University of Vermont, Burlington, VT, United States
| | - Madeline Krieger
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR, United States
| | - Duygu A. Dindar
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR, United States
| | - Rebekka Duhen
- Knight Cancer Precision Biofabrication Hub, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR, United States
| | - Zhenzhen Zhang
- Division of Oncological Sciences, Oregon Health & Science University, Portland, OR, United States
| | - Cristiane Miranda Franca
- Knight Cancer Precision Biofabrication Hub, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR, United States
- Department of Biomaterial and Biomedical Sciences, School of Dentistry, Oregon Health & Science University, Portland, OR, United States
| | - Luiz E. Bertassoni
- Knight Cancer Precision Biofabrication Hub, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR, United States
- Department of Biomaterial and Biomedical Sciences, School of Dentistry, Oregon Health & Science University, Portland, OR, United States
- Division of Oncological Sciences, Oregon Health & Science University, Portland, OR, United States
- Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR, United States
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Song Q, Jin Z, Zhang H, Hong K, Zhu B, Yin H, Yu B. Fusobacterium nucleatum-derived 3-indolepropionic acid promotes colorectal cancer progression via aryl hydrocarbon receptor activation in macrophages. Chem Biol Interact 2025; 414:111495. [PMID: 40174685 DOI: 10.1016/j.cbi.2025.111495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 03/15/2025] [Accepted: 03/26/2025] [Indexed: 04/04/2025]
Abstract
An increasing body of research indicates that Fusobacterium nucleatum (F. nucleatum) significantly influences the onset and progression of colorectal cancer (CRC). Our previous study has shown that F. nucleatum exerts pro-tumorigenic effects through aryl hydrocarbon receptor (AhR) activation. However, the role of its microbial metabolites in regulating immune responses remains unclear. Here, we report for the first time that F. nucleatum-derived 3-Indolepropionic acid (IPA) activates AhR in macrophages, driving M2 polarization and tumor-promoting immunosuppression. We discovered that culture supernatant of F. nucleatum (CSF) robustly activates AhR in macrophages. In co-culture systems, CSF upregulated the expression of the M2 marker CD206 and elevated mRNA levels of CD163, TGF-β, IL-10, and VEGF. In a subcutaneous allograft model, CSF induced an elevated number of CD206+ macrophages and decreased presence of CD8+ T cells within the tumor microenvironment, thereby promoting tumor growth. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed IPA as a novel major AhR-activating metabolite in CSF. Strikingly, IPA recapitulated CSF's effects in promoting tumor cell migration and immunosuppression, both in vitro and in vivo. Critically, the AhR inhibitor CH223191 abolished both IPA-mediated M2 polarization and tumor growth. Our study revealed a novel mechanism by which F. nucleatum-derived IPA reprograms macrophages through AhR activation to fuel CRC progression, providing potential therapeutic targets for CRC treatment and prognosis improvement.
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Affiliation(s)
- Qi Song
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China; Key Laboratory of Hubei Province for Digestive System Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China; Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China
| | - Zhiliang Jin
- Department of Oncology, The Second Clinical Medical College, Yangtze University, Jingzhou, 434000, Hubei Province, People's Republic of China
| | - Han Zhang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China; Key Laboratory of Hubei Province for Digestive System Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China
| | - Kunqiao Hong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China; Key Laboratory of Hubei Province for Digestive System Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China
| | - Beibei Zhu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China; Key Laboratory of Hubei Province for Digestive System Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China
| | - Haisen Yin
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China.
| | - Baoping Yu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China.
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Yue J, Fang H, Yang Q, Feng R, Ren G. Integrating multi-omics and machine learning methods reveals the metabolism of amino acids and derivatives-related signature in colorectal cancer. Front Oncol 2025; 15:1565090. [PMID: 40206583 PMCID: PMC11978647 DOI: 10.3389/fonc.2025.1565090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 02/28/2025] [Indexed: 04/11/2025] Open
Abstract
Objective The metabolism of amino acids and derivatives (MAAD) is closely related to the occurrence and development of colorectal cancer (CRC), but the specific regulatory mechanisms are not yet clear. This study aims to explore the role of MAAD in the progression of colorectal cancer and ultimately identify key molecules that may become potential therapeutic targets for CRC. Methods This study integrates bulk transcriptome and single-cell transcriptome to analyze and identify key MAAD-related genes from multiple levels. Subsequently, numerous machine learning methods were incorporated to construct MAAD-related prognostic models, and the infiltration of immune cells, tumor heterogeneity, tumor mutation burden, and potential pathway changes under different modes were analyzed. Finally, key molecules were identified for experimental validation. Results We successfully constructed prognostic models and Nomograms based on key MAAD-related molecules. There was a notable survival benefit observed for low-risk patients when contrasted with their high-risk counterparts. In addition, the high-risk group had a poorer response to immunotherapy and stronger tumor heterogeneity compared with the low-risk group. Further research found that by knocking down the MAAD-related gene. LSM8, the malignant characteristics of colorectal cancer cell lines were significantly alleviated, suggesting that LSM8 may become a potential therapeutic target. Conclusion The MAAD-related gene LSM8 is likely involved in the progression of CRC and could be a hopeful target for therapeutic intervention.
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Affiliation(s)
- Jian Yue
- Department of Breast and Thyroid Surgery, Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Breast Surgery, Gaozhou People’s Hospital, Gaozhou, Guangdong, China
| | - Huiying Fang
- Department of Breast Cancer Center, Chongqing Key Laboratory for Intelligent Oncology in Breast Cancer (iCQBC), Chongqing University Cancer Hospital, Chongqing, China
| | - Qian Yang
- Department of Breast and Thyroid Surgery, Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Institute for Brain Science and Disease, Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China
| | - Rui Feng
- Department of Breast and Thyroid Surgery, Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guosheng Ren
- Department of Breast and Thyroid Surgery, Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Jiang GH, Li HY, Xie LJ, Fan JY, Li SY, Yu WQ, Xu YT, He ML, Jiang Y, Bai X, Zhou J, Wang X. Changes in Intestinal flora is associated with chronic diseases. World J Gastroenterol 2025; 31:103507. [PMID: 40124279 PMCID: PMC11924013 DOI: 10.3748/wjg.v31.i11.103507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 12/26/2024] [Accepted: 02/24/2025] [Indexed: 03/13/2025] Open
Abstract
BACKGROUND The intestinal flora (IF) has been linked to risks of non-communicable diseases, especially various cancers, stroke, and Alzheimer’s disease. However, many uncertainties of these associations during different stages of growth, development, and aging still exist. Therefore, further in-depth explorations are warranted.
AIM To explore the associations of the human IF with disease risks during different stages of growth, development, and aging to achieve more accurate and convincing conclusions.
METHODS Cohort, cross-sectional, case-control, and Mendelian randomization studies published in the PubMed and Web of Science databases until December 31, 2023 were systematically reviewed to clarify the associations of the IF at the genus level with the risks of various non-communicable diseases, which were grouped in accordance with the 10th revision of the International Classification of Diseases.
RESULTS In total, 57 studies were included to quantitatively examine the influence of the IF on the risks of 30 non-communicable diseases during different stages of growth, development, and aging. Population studies and Mendelian randomization studies confirmed positive associations of the abundances of Bifidobacterium and Ruminococcus with multiple sclerosis.
CONCLUSION These findings contribute to a deeper understanding of the roles of the IF and provide novel evidence for effective strategies for the prevention and treatment of non-communicable diseases. In the future, it will be necessary to explore a greater variety of research techniques to uncover the specific mechanisms by which gut microbiota trigger diseases and conduct in-depth studies on the temporal relationship between microbiota alterations and diseases, so as to clarify the causal relationship more accurately.
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Affiliation(s)
- Guo-Heng Jiang
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hong-Yu Li
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lin-Jun Xie
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jing-Yuan Fan
- China Tobacco Sichuan Industry Co. Ltd., Technology Center, Chengdu 610101, Sichuan Province, China
| | - Shi-Yi Li
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wen-Qian Yu
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yi-Ting Xu
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Meng-Lin He
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yi Jiang
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xuan Bai
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jin Zhou
- Department of Anorectal Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Xin Wang
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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20
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Qin Y, Wang Q, Lin Q, Liu F, Pan X, Wei C, Chen J, Huang T, Fang M, Yang W, Pan L. Multi-omics analysis reveals associations between gut microbiota and host transcriptome in colon cancer patients. mSystems 2025; 10:e0080524. [PMID: 40013792 PMCID: PMC11915798 DOI: 10.1128/msystems.00805-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 01/31/2025] [Indexed: 02/28/2025] Open
Abstract
Colon cancer (CC) is one of the most common cancers globally, which is associated with the gut microbiota intimately. In current research, exploring the complex interaction between microbiomes and CC is a hotspot. However, the information on microbiomes in most previous studies is based on fecal, which does not fully display the microbial environment of CC. Herein, we collected mucosal and tissue samples from both the tumor and normal regions of 19 CC patients and clarified the composition of mucosal microbiota by 16S rRNA and metagenomic sequencing. Additionally, RNA-Seq was also conducted to identify the different expression genes between tumor and normal tissue samples. We revealed significantly different microbial community structures and expression profiles to CC. Depending on correlation analysis, we demonstrated that 1,472 genes were significantly correlated with CC tumor microbiota. Our study reveals a significant enrichment of Campylobacter jejuni in the mucosa of CC, which correlates with bile secretion. Additionally, we observe a negative correlation between C. jejuni and immune cells CD4+ Tem and mast cells. Finally, we discovered that metabolic bacterial endosymbiont of Bathymodiolus sp., Bacillus wiedmannii, and Mycobacterium tuberculosis had a significant survival value for CC, which was ignored by previous research. Overall, our study expands the understanding of the complex interplay between microbiota and CC and provides new targets for the treatment of CC. IMPORTANCE This study contributes to our understanding of the interaction between microbiota and colon cancer (CC). By examining mucosal and tissue samples rather than solely relying on fecal samples, we have uncovered previously unknown aspects of CC-associated microbiota. Our findings reveal distinct microbial community structures and gene expression profiles correlated with CC progression. Notably, the enrichment of Campylobacter jejuni in CC mucosa, linked to bile secretion, underscores potential mechanisms in CC pathogenesis. Additionally, observed correlations between microbial taxa and immune cell populations offer new avenues for immunotherapy research in CC. Importantly, this study introduces CC-associated microbiota with survival implications for CC, expanding therapeutic targets beyond conventional strategies. By elucidating these correlations, our study not only contributes to uncovering the potential role of gut microbiota in colon cancer but also establishes a foundation for mechanistic studies of gut microbiota in colon cancer, emphasizing the broader impact of microbiota research on cancer biology.
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Affiliation(s)
- Yuling Qin
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Qiang Wang
- Guangxi Clinical Research Center for Anesthesiology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Qiumei Lin
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Fengfei Liu
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xiaolan Pan
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Caibiao Wei
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Junxian Chen
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Taijun Huang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Min Fang
- Guangxi Clinical Research Center for Anesthesiology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Weilong Yang
- Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
- Institute of Advanced Biotechnology and School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Linghui Pan
- Guangxi Clinical Research Center for Anesthesiology, Guangxi Medical University Cancer Hospital, Nanning, China
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21
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Chan C, Coffey M, Murphy C, McKay I, Abdu J, Paida K, Tam RY, Wrigley-Carr H, Prentice B, Owens L, Belessis Y, Chuang S, Jaffe A, van Dorst J, Ooi CY. The Prevalence of Polyketide Synthase-Positive E. coli in Cystic Fibrosis. Microorganisms 2025; 13:681. [PMID: 40142573 PMCID: PMC11944406 DOI: 10.3390/microorganisms13030681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 03/14/2025] [Accepted: 03/14/2025] [Indexed: 03/28/2025] Open
Abstract
Cystic fibrosis (CF) patients experience higher risks of colorectal cancer but the pathogenesis is unclear. In the general population, polyketide synthase-positive (pks+) E. coli is implicated in intestinal carcinogenesis via the production of colibactin; however, the relevance in CF is unknown. In this study, we investigate pks+E. coli prevalence in CF and potential associations between pks+E. coli, gastrointestinal inflammation, and microbiome dynamics with fecal calprotectin and 16SrRNA gene taxonomic data. Cross-sectional analysis demonstrated no difference in pks+E. coli carriage between CF patients and healthy controls, 21/55 (38%) vs. 26/55 (47%), p = 0.32. Pks+E. coli was not associated with significant differences in mean (SD) calprotectin concentration (124 (154) vs. 158 (268) mg/kg; p = 0.60), microbial richness (159 (76.5) vs. 147 (70.4); p = 0.50) or Shannon diversity index (2.78 (0.77) vs. 2.65 (0.74); p = 0.50) in CF. Additionally, there was no association with exocrine pancreatic status (p = 0.2) or overall antibiotic use (p = 0.6). Longitudinally, CF subjects demonstrated intra-individual variation in pks+E. coli presence but no significant difference in overall prevalence. Future investigation into the effects of repeat exposure on risk profile and analysis of older CF cohorts is necessary to identify if associations with colorectal cancer exist.
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Affiliation(s)
- Christopher Chan
- School of Clinical Medicine, Discipline of Paediatrics & Child Health, UNSW Medicine & Health, University of New South Wales, Sydney, NSW 2031, Australia; (C.C.); (M.C.); (C.M.); (I.M.); (J.A.); (H.W.-C.); (B.P.); (S.C.); (A.J.); (C.Y.O.)
| | - Michael Coffey
- School of Clinical Medicine, Discipline of Paediatrics & Child Health, UNSW Medicine & Health, University of New South Wales, Sydney, NSW 2031, Australia; (C.C.); (M.C.); (C.M.); (I.M.); (J.A.); (H.W.-C.); (B.P.); (S.C.); (A.J.); (C.Y.O.)
- Department of Gastroenterology, Sydney Children’s Hospital, Randwick, NSW 2031, Australia
| | - Caitlin Murphy
- School of Clinical Medicine, Discipline of Paediatrics & Child Health, UNSW Medicine & Health, University of New South Wales, Sydney, NSW 2031, Australia; (C.C.); (M.C.); (C.M.); (I.M.); (J.A.); (H.W.-C.); (B.P.); (S.C.); (A.J.); (C.Y.O.)
| | - Isabelle McKay
- School of Clinical Medicine, Discipline of Paediatrics & Child Health, UNSW Medicine & Health, University of New South Wales, Sydney, NSW 2031, Australia; (C.C.); (M.C.); (C.M.); (I.M.); (J.A.); (H.W.-C.); (B.P.); (S.C.); (A.J.); (C.Y.O.)
| | - Jumaana Abdu
- School of Clinical Medicine, Discipline of Paediatrics & Child Health, UNSW Medicine & Health, University of New South Wales, Sydney, NSW 2031, Australia; (C.C.); (M.C.); (C.M.); (I.M.); (J.A.); (H.W.-C.); (B.P.); (S.C.); (A.J.); (C.Y.O.)
| | - Keerti Paida
- School of Clinical Medicine, Discipline of Paediatrics & Child Health, UNSW Medicine & Health, University of New South Wales, Sydney, NSW 2031, Australia; (C.C.); (M.C.); (C.M.); (I.M.); (J.A.); (H.W.-C.); (B.P.); (S.C.); (A.J.); (C.Y.O.)
| | - Rachel Y. Tam
- School of Clinical Medicine, Discipline of Paediatrics & Child Health, UNSW Medicine & Health, University of New South Wales, Sydney, NSW 2031, Australia; (C.C.); (M.C.); (C.M.); (I.M.); (J.A.); (H.W.-C.); (B.P.); (S.C.); (A.J.); (C.Y.O.)
| | - Hannah Wrigley-Carr
- School of Clinical Medicine, Discipline of Paediatrics & Child Health, UNSW Medicine & Health, University of New South Wales, Sydney, NSW 2031, Australia; (C.C.); (M.C.); (C.M.); (I.M.); (J.A.); (H.W.-C.); (B.P.); (S.C.); (A.J.); (C.Y.O.)
| | - Bernadette Prentice
- School of Clinical Medicine, Discipline of Paediatrics & Child Health, UNSW Medicine & Health, University of New South Wales, Sydney, NSW 2031, Australia; (C.C.); (M.C.); (C.M.); (I.M.); (J.A.); (H.W.-C.); (B.P.); (S.C.); (A.J.); (C.Y.O.)
- Department of Respiratory Medicine, Sydney Children’s Hospital, Randwick, NSW 2031, Australia; (L.O.); (Y.B.)
| | - Louisa Owens
- Department of Respiratory Medicine, Sydney Children’s Hospital, Randwick, NSW 2031, Australia; (L.O.); (Y.B.)
| | - Yvonne Belessis
- Department of Respiratory Medicine, Sydney Children’s Hospital, Randwick, NSW 2031, Australia; (L.O.); (Y.B.)
| | - Sandra Chuang
- School of Clinical Medicine, Discipline of Paediatrics & Child Health, UNSW Medicine & Health, University of New South Wales, Sydney, NSW 2031, Australia; (C.C.); (M.C.); (C.M.); (I.M.); (J.A.); (H.W.-C.); (B.P.); (S.C.); (A.J.); (C.Y.O.)
- Department of Respiratory Medicine, Sydney Children’s Hospital, Randwick, NSW 2031, Australia; (L.O.); (Y.B.)
| | - Adam Jaffe
- School of Clinical Medicine, Discipline of Paediatrics & Child Health, UNSW Medicine & Health, University of New South Wales, Sydney, NSW 2031, Australia; (C.C.); (M.C.); (C.M.); (I.M.); (J.A.); (H.W.-C.); (B.P.); (S.C.); (A.J.); (C.Y.O.)
- Department of Respiratory Medicine, Sydney Children’s Hospital, Randwick, NSW 2031, Australia; (L.O.); (Y.B.)
| | - Josie van Dorst
- School of Clinical Medicine, Discipline of Paediatrics & Child Health, UNSW Medicine & Health, University of New South Wales, Sydney, NSW 2031, Australia; (C.C.); (M.C.); (C.M.); (I.M.); (J.A.); (H.W.-C.); (B.P.); (S.C.); (A.J.); (C.Y.O.)
| | - Chee Y. Ooi
- School of Clinical Medicine, Discipline of Paediatrics & Child Health, UNSW Medicine & Health, University of New South Wales, Sydney, NSW 2031, Australia; (C.C.); (M.C.); (C.M.); (I.M.); (J.A.); (H.W.-C.); (B.P.); (S.C.); (A.J.); (C.Y.O.)
- Department of Gastroenterology, Sydney Children’s Hospital, Randwick, NSW 2031, Australia
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Liu Y, Zhong Y, Sang Y, Zhu S, Xu K, Zhu X, Cui X, Liu X, Wang X, Chen H, Jing C, Chong W, Li L. Molecular characteristics and cancer immunity of LRP1B and its relationship with the Hedgehog signaling pathway in colorectal cancer. Front Immunol 2025; 16:1567102. [PMID: 40170839 PMCID: PMC11959038 DOI: 10.3389/fimmu.2025.1567102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Accepted: 02/21/2025] [Indexed: 04/03/2025] Open
Abstract
Background Colorectal cancer (CRC) is a malignant tumor of the digestive tract that significantly impacts human health. LDL receptor-related protein 1B (LRP1B) may play a crucial role in tumorigenesis and disease progression. Methods We performed a comparative analysis of differential gene expression, mutation patterns, drug sensitivity, and cellular phenotypes across different subgroups with varying LRP1B expression levels. Cellular and molecular experiments were conducted to validate our findings. Results Our analysis implicated LRP1B as a tumor suppressor gene. Experimental results confirmed that LRP1B expression was reduced in CRC and its knockdown was associated with poor prognosis. Molecular mechanism studies revealed that LRP1B negatively regulated the Hedgehog (Hh) signaling pathway, influencing cell cycle and apoptosis processes. Single-cell analysis showed significant differences in the infiltration of T cells, B cells, epithelial cells, and myeloid cells between high and low LRP1B expression groups. Immune cell infiltration and drug sensitivity analyses demonstrated that LRP1B plays a crucial role in immunotherapy and targeted therapy, suggesting that restoring LRP1B function could be a promising treatment strategy for CRC. Conclusion Our results indicate that LRP1B may function as a tumor suppressor factor in CRC, playing a significant role in mutation, therapy, and immune infiltration. Knockdown of LRP1B activates the Hh pathway in tumor cells, leading to the inhibition of several malignant biological behaviors.
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Affiliation(s)
- Yuan Liu
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Yang Zhong
- Department of Epidemiology and Health Statistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Clinical Research Center of Shandong University, Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Yaodong Sang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Siqiang Zhu
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Kang Xu
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Xingyu Zhu
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Xiaoling Cui
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Xinyu Liu
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Xiaohan Wang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Hao Chen
- Clinical Research Center of Shandong University, Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Changqing Jing
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Wei Chong
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Leping Li
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
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23
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Keung WS, Zhang WH, Luo HY, Chan KC, Chan YM, Xu J. Correlation between the structures of natural polysaccharides and their properties in regulating gut microbiota: Current understanding and beyond. Carbohydr Polym 2025; 352:123209. [PMID: 39843110 DOI: 10.1016/j.carbpol.2024.123209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/23/2024] [Accepted: 12/30/2024] [Indexed: 01/24/2025]
Abstract
Natural polysaccharides have complex structural properties and a wide range of health-promoting effects. Accumulating evidence suggests that the effects are significantly mediated through fermentation by gut microbiota. In recent years, the relationship between the structures of natural polysaccharides and their properties in regulating gut microbiota has garnered significant research attention as researchers attempt to precisely understand the role of gut microbiota in the bioactivities of natural polysaccharides. Progress in this niche, however, remains limited. In this review, we first provide an overview of current research investigating this structure-property relationship. We then present a detailed correlation analysis between the structural characteristics of 159 purified natural polysaccharides and their effects on gut microbiota reported over the past two decades. The analysis revealed that diverse gut bacteria show specific correlations with the molecular weight, glycosidic linkages, and monosaccharide composition of natural polysaccharides. Multifaceted molecular mechanisms, including carbohydrate binding, enzymatic degradation, and cross-feeding, were proposed to be collectively involved in these correlations. Finally, we offer our perspective on future studies to further improve our understanding of the relationship between polysaccharide structure and gut microbiota regulation.
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Affiliation(s)
- Wing-Shan Keung
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong
| | - Wei-Hao Zhang
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong
| | - Han-Yan Luo
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong
| | - Kam-Chun Chan
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong
| | - Yui-Man Chan
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong
| | - Jun Xu
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong.
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24
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Zhang X, Chen Y, Xia Y, Lin S, Zhou X, Pang X, Yu J, Sun L. Oral microbiota in colorectal cancer: Unraveling mechanisms and application potential. Life Sci 2025; 365:123462. [PMID: 39947314 DOI: 10.1016/j.lfs.2025.123462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/31/2025] [Accepted: 02/10/2025] [Indexed: 02/17/2025]
Abstract
Colorectal cancer (CRC), with a rising prevalence, is the third most commonly diagnosed cancer and the third leading cause of cancer-related death. Studies have shown that a complex interplay between the development of CRC and alterations in the oral microbiome. Recent advancements in genomics and metagenomics have highlighted the significant roles of certain oral microbes, particularly Porphyromonas gingivalis (P. gingivalis) and Fusobacterium nucleatum (F. nucleatum), in the progression of CRC. However, the detailed mechanisms by which the oral microbiota influence CRC development remain unclear. This review aims to elucidate the role of oral microbiota in CRC progression, evaluate their potential as biomarkers, and explore therapeutic strategies targeting these microbes. This review offers insights into the mechanisms underlying the interaction between oral microbiota and CRC, underscoring the potential of oral microbes as diagnostic and prognostic biomarkers, as well as therapeutic targets. Future research should focus on clarifying the exact pathways and developing innovative therapeutic strategies to enhance the diagnosis and treatment.
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Affiliation(s)
- Xinran Zhang
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, China
| | - Yixin Chen
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, China
| | - Yuwei Xia
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, China
| | - Shenghao Lin
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, China
| | - Xinlei Zhou
- The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Xi Pang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
| | - Jieru Yu
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Leitao Sun
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, China; Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou 310053, China; Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
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25
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Sun YY, Liu NN. Mycobiome: an underexplored kingdom in cancer. Microbiol Mol Biol Rev 2025:e0026124. [PMID: 40084887 DOI: 10.1128/mmbr.00261-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2025] Open
Abstract
SUMMARYThe human microbiome, including bacteria, fungi, archaea, and viruses, is intimately linked to both health and disease. The relationship between bacteria and disease has received much attention and intensive investigation, while that of the fungal microbiome, also known as mycobiome, has lagged far behind bacteria. There is growing evidence showing mycobiome dysbiosis in cancer patients, and certain cancer-specific fungi may contribute to cancer progression by interacting with both host and bacteria. It was also demonstrated that the role of fungi-derived products in cancer should also not be underestimated. Therefore, investigating how fungal pathogenesis contributes to the onset and spread of cancer would yield crucial information for cancer diagnosis, prevention, and anti-cancer therapy.
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Affiliation(s)
- Yan-Yan Sun
- State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ning-Ning Liu
- State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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26
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Liu QL, Zhou H, Wang Z, Chen Y. Exploring the role of gut microbiota in colorectal liver metastasis through the gut-liver axis. Front Cell Dev Biol 2025; 13:1563184. [PMID: 40181829 PMCID: PMC11965903 DOI: 10.3389/fcell.2025.1563184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Accepted: 02/26/2025] [Indexed: 04/05/2025] Open
Abstract
Colorectal liver metastasis (CRLM) represents a major therapeutic challenge in colorectal cancer (CRC), with complex interactions between the gut microbiota and the liver tumor microenvironment (TME) playing a crucial role in disease progression via the gut-liver axis. The gut barrier serves as a gatekeeper, regulating microbial translocation, which influences liver colonization and metastasis. Through the gut-liver axis, the microbiota actively shapes the TME, where specific microbial species and their metabolites exert dual roles in immune modulation. The immunologically "cold" nature of the liver, combined with the influence of the gut microbiota on liver immunity, complicates effective immunotherapy. However, microbiota-targeted interventions present promising strategies to enhance immunotherapy outcomes by modulating the gut-liver axis. Overall, this review highlights the emerging evidence on the role of the gut microbiota in CRLM and provides insights into the molecular mechanisms driving the dynamic interactions within the gut-liver axis.
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Affiliation(s)
- Qiu-Luo Liu
- Colorectal Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
- Institute of Digestive Surgery, Institute of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Huijie Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Health Management Center, General Practice Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ziqiang Wang
- Colorectal Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Chen
- Department of Gastrointestinal Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
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27
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Pani G. Bacteria, stem cells and cancer. Cancer Gene Ther 2025; 32:269-272. [PMID: 39915606 DOI: 10.1038/s41417-025-00876-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 01/16/2025] [Accepted: 01/29/2025] [Indexed: 03/28/2025]
Affiliation(s)
- Giovambattista Pani
- Department of Translational Medicine and Surgery, Faculty of Medicine, Università Cattolica del Sacro Cuore, Rome, Italy.
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
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28
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Richter KM, Wrage M, Krekeler C, De Oliveira T, Conradi LC, Menck K, Bleckmann A. Model systems to study tumor-microbiome interactions in early-onset colorectal cancer. EMBO Mol Med 2025; 17:395-413. [PMID: 39948421 PMCID: PMC11903813 DOI: 10.1038/s44321-025-00198-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 01/13/2025] [Accepted: 01/24/2025] [Indexed: 03/14/2025] Open
Abstract
Colorectal cancer (CRC) is a major health problem, with an alarming increase of early-onset CRC (EO-CRC) cases among individuals under 50 years of age. This trend shows the urgent need for understanding the underlying mechanisms leading to EO-CRC development and progression. There is significant evidence that the gut microbiome acts as a key player in CRC by triggering molecular changes in the colon epithelium, leading to tumorigenesis. However, a comprehensive collection and comparison of methods to study such tumor-microbiome interactions in the context of EO-CRC is sparse. This review provides an overview of the available in vivo, ex vivo as well as in vitro approaches to model EO-CRC and assess the effect of gut microbes on tumor development and growth. By comparing the advantages and limitations of each model system, it highlights that, while no single model is perfect, each is suitable for studying specific aspects of microbiome-induced tumorigenesis. Taken together, multifaceted approaches can simulate the human body's complexity, aiding in the development of effective treatment and prevention strategies for EO-CRC.
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Affiliation(s)
- Katharina M Richter
- Department of Medicine A, University of Muenster, 48149, Muenster, Germany
- West German Cancer Center, University Hospital Muenster, 48149, Muenster, Germany
| | - Marius Wrage
- Department of Medicine A, University of Muenster, 48149, Muenster, Germany
- West German Cancer Center, University Hospital Muenster, 48149, Muenster, Germany
| | - Carolin Krekeler
- Department of Medicine A, University of Muenster, 48149, Muenster, Germany
- West German Cancer Center, University Hospital Muenster, 48149, Muenster, Germany
| | - Tiago De Oliveira
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075, Goettingen, Germany
| | - Lena-Christin Conradi
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075, Goettingen, Germany
| | - Kerstin Menck
- Department of Medicine A, University of Muenster, 48149, Muenster, Germany
- West German Cancer Center, University Hospital Muenster, 48149, Muenster, Germany
| | - Annalen Bleckmann
- Department of Medicine A, University of Muenster, 48149, Muenster, Germany.
- West German Cancer Center, University Hospital Muenster, 48149, Muenster, Germany.
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29
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Tardy KJ, Kwak HV, Tieniber AD, Mangold AK, Perez JE, Do K, Zeng S, Rossi F, DeMatteo RP. Intratumoral Bacteria are Uncommon in Gastrointestinal Stromal Tumor. Ann Surg Oncol 2025; 32:1504-1510. [PMID: 39578323 PMCID: PMC11811456 DOI: 10.1245/s10434-024-16526-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 10/30/2024] [Indexed: 11/24/2024]
Abstract
BACKGROUND Gastrointestinal stromal tumor (GIST) is the most common human sarcoma with over 5000 new patients diagnosed in the USA each year. The tumor originates from the interstitial cells of Cajal and forms an intramural lesion most commonly in the stomach or small intestine. The gut microbiome has been linked to other gastrointestinal cancers and a recent paper purported that GISTs contain substantial intratumoral bacteria. The purpose of this study is to further evaluate the presence of bacteria in GISTs. PATIENTS AND METHODS We collected 25 tumor samples of varying size and location from 24 patients under sterile conditions in the operating room immediately following surgical resection. 16S quantitative polymerase chain reaction (qPCR) and 16S ribosomal RNA (rRNA) gene amplicon sequencing were performed to evaluate the bacterial species present in each tumor. Retrospective chart review was performed to determine tumor characteristics, including tumor size, location, imatinib exposure, and mucosal involvement. RESULTS In 23 of the 25 tumor samples, there were fewer than 100 copy numbers of 16S rRNA per uL, indicating an absence of a significant bacterial load. 16S rRNA gene amplicon sequencing of the remaining two samples, one gastric tumor and one duodenal tumor, revealed the presence of normal intestinal bacteria. These two tumors, along with three others, had disruption of the mucosal lining. CONCLUSIONS GISTs generally lack substantial bacteria, except in some cases when the tumor disrupts the mucosa.
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Affiliation(s)
- Katherine J Tardy
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Hyunjee V Kwak
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Andrew D Tieniber
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Alina K Mangold
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Juan E Perez
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kevin Do
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Shan Zeng
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ferdinando Rossi
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ronald P DeMatteo
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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30
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Li P, Zhang H, Chen L, Gao X, Hu Y, Xu Q, Liu W, Chen W, Chen H, Yuan S, Wang M, Liu S, Dai M. Oral and fecal microbiota as accurate non-invasive tools for detection of pancreatic cancer in the Chinese population. Cancer Lett 2025; 612:217456. [PMID: 39800212 DOI: 10.1016/j.canlet.2025.217456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 01/02/2025] [Accepted: 01/10/2025] [Indexed: 01/15/2025]
Abstract
Pancreatic cancer (PCA), a leading cause of cancer-related deaths, has limited non-invasive diagnostic methods. We aimed to identify oral and fecal microbiome biomarkers and construct diagnostic classifiers. Oral and fecal samples from 97 PCA patients and 90 healthy controls underwent 16S rRNA sequencing. Samples were randomly divided into training and validation cohorts in a 7:3 ratio. Random forest models were constructed using training cohort and validated internally and externally in Chinese, Japanese, and Spanish populations. Results revealed significant dysbiosis of the oral and fecal microbiota of PCA patients. Most of the differential taxa shared between oral and fecal samples showed similar changes. Relative abundances of Streptococcus in oral samples, and of Bifidobacterium, Klebsiella and Akkermansia in fecal samples, were enriched in PCA. The fecal Firmicutes to Bacteroidota ratio was higher in PCA patient samples. Oral and fecal microbiome classifiers based on the top 20 contributing genera were constructed, and internal validation showed that the area under the curve (AUC) values were 0.963 and 0.890, respectively. The fecal microbiome classifier performed well in the external Chinese population, with an AUC of 0.878, but poorly in the Japanese and Spanish populations. Furthermore, fecal microbiomes could predict metastasis status in PCA patients, with an AUC of 0.804. In conclusion, oral and fecal microbiota were dysbiotic in PCA patients. Fecal microbiome classifier provides a feasible, non-invasive, and cost-effective tool with high precision for PCA screening in China; oral microbiome classifier requires further validation in external populations sampled with the same simple and convenient methods.
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Affiliation(s)
- Pengyu Li
- Department of General Surgery, Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China
| | - Hanyu Zhang
- Department of General Surgery, Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China
| | - Lixin Chen
- Department of General Surgery, Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China
| | - Xingyu Gao
- Department of General Surgery, Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China
| | - Ya Hu
- Department of General Surgery, Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China
| | - Qiang Xu
- Department of General Surgery, Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China
| | - Wenjing Liu
- Department of General Surgery, Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China
| | - Weijie Chen
- Department of General Surgery, Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China
| | - Haomin Chen
- Department of General Surgery, Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China
| | - Shuai Yuan
- Department of General Surgery, Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China
| | - Mingfei Wang
- Department of General Surgery, Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China
| | - Shili Liu
- Department of Medical Microbiology, School of Basic Medical Sciences, Cheelo College of Medicine, Shandong University, No.44 Wenhuaxi Road, Lixia District, Jinan, Shandong, 250012, China
| | - Menghua Dai
- Department of General Surgery, Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China.
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31
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Devall MA, Eaton S, Hu G, Sun X, Jakum E, Venkatesh S, Powell SM, Yoshida C, Weisenberger DJ, Cooper GS, Willis J, Ebrahim S, Zoellner J, Casey G, Li L. Association between dietary fructose and human colon DNA methylation: implication for racial disparities in colorectal cancer risk using a cross-sectional study. Am J Clin Nutr 2025; 121:522-534. [PMID: 39788295 PMCID: PMC11923427 DOI: 10.1016/j.ajcnut.2025.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 12/28/2024] [Accepted: 01/06/2025] [Indexed: 01/12/2025] Open
Abstract
BACKGROUND An increasing body of evidence has linked fructose intake to colorectal cancer (CRC). African-American (AA) adults consume greater quantities of fructose and are more likely to develop right-side colon cancer than European American (EA) adults. OBJECTIVES We examined the hypothesis that fructose consumption leads to epigenomic and transcriptomic differences associated with CRC tumor biology. METHODS Deoxyribonucleic acid methylation data from this cross-sectional study was obtained using the Illumina Infinium MethylationEPIC kit (GSE151732). Right and left colon differentially methylated regions (DMRs) were identified using DMRcate through analysis of Food Frequency Questionnaire data on fructose consumption in normal colon biopsies (n = 79) of AA adults undergoing screening colonoscopy. Secondary analysis of CRC tumors was carried out using data derived from The Cancer Genome Atlas Colon Adenocarcinoma, GSE101764, and GSE193535. Right colon organoids derived from AA (n = 5) and EA (n = 5) adults were exposed to 4.4 mM of fructose for 72 h. Differentially expressed genes (DEGs) were identified using DESeq2. RESULTS We identified 4263 right colon fructose-associated DMRs [false-discovery rates (FDR) < 0.05]. In contrast, only 24 DMRs survived multiple testing corrections (FDR < 0.05) in matched, left colon. Almost 50% of right colon fructose-associated DMRs overlapped regions implicated in CRC in ≥1 of 3 data sets. Highly significant enrichment was also observed between genes corresponding to right colon fructose-associated DMRs and DEGs associated with fructose exposure in right colon organoids of AA individuals (P = 3.28E-30). Overlapping and significant enrichments for fatty acid metabolism, glycolysis, and cell proliferation pathways were also found. Cross-referencing genes within these pathways to DEGs in CRC tumors reveal potential roles for ankyrin repeat domain containing protein 23 and phosphofructokinase, platelet in fructose-mediated CRC risk for AA individuals. CONCLUSIONS Our data support that dietary fructose exerts a greater CRC risk-related effect in the right than left colon among AA adults, alluding to its potential role in contributing to racial disparities in CRC.
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Affiliation(s)
- Matthew A Devall
- Department of Family Medicine, University of Virginia, Charlottesville, VA, United States; University of Virginia Comprehensive Cancer Center, University of Virginia, Charlottesville, VA, United States
| | - Stephen Eaton
- Department of Family Medicine, University of Virginia, Charlottesville, VA, United States
| | - Gaizun Hu
- Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, United States
| | - Xiangqing Sun
- Department of Family Medicine, University of Virginia, Charlottesville, VA, United States
| | - Ethan Jakum
- Department of Biology, University of Virginia, Charlottesville, VA, United States
| | - Samyukta Venkatesh
- Department of Family Medicine, University of Virginia, Charlottesville, VA, United States
| | - Steven M Powell
- Digestive Health Center, University of Virginia, Charlottesville, VA, United States
| | - Cynthia Yoshida
- Digestive Health Center, University of Virginia, Charlottesville, VA, United States
| | - Daniel J Weisenberger
- Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, United States
| | - Gregory S Cooper
- Department of Medicine, Case Western Reserve University/University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - Joseph Willis
- Department of Pathology, Case Western Reserve University/University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - Seham Ebrahim
- Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, United States
| | - Jamie Zoellner
- University of Virginia Comprehensive Cancer Center, University of Virginia, Charlottesville, VA, United States; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States; Department of Public Health Sciences, University of Virginia, Charlottesville, VA, United States
| | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, VA, United States; University of Virginia Comprehensive Cancer Center, University of Virginia, Charlottesville, VA, United States.
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Sun Y, Yao J, Gao R, Hao J, Liu Y, Liu S. Interactions of non-starch polysaccharides with the gut microbiota and the effect of non-starch polysaccharides with different structures on the metabolism of the gut microbiota: A review. Int J Biol Macromol 2025; 296:139664. [PMID: 39798752 DOI: 10.1016/j.ijbiomac.2025.139664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 12/19/2024] [Accepted: 01/07/2025] [Indexed: 01/15/2025]
Abstract
Humans consume large amounts of non-starch polysaccharides(NPs) daily. Some NPs, not absorbed by the body, proceed to the intestines. An increasing number of studies reveal a close relationship between NPs and gut microbiota(GM) that impact the human body. This review not only describes in detail the structures of several common NPs and their effects on GM, but also elucidates the degradation mechanisms of NPs in the intestine. The purpose of this review is to elucidate how NPs interact with GM in the intestine, which can provide valuable information for further studies of NPs.
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Affiliation(s)
- Yujiao Sun
- Natural Food Macromolecule Research Center, School of Food Science and Engineering, Shaanxi University of Science and Technology, Xi'an 710021, PR China; Shaanxi Research Institute of Agricultural Products Processing Technology, Xi'an 710021, PR China.
| | - Jiaxuan Yao
- Natural Food Macromolecule Research Center, School of Food Science and Engineering, Shaanxi University of Science and Technology, Xi'an 710021, PR China
| | - Running Gao
- Natural Food Macromolecule Research Center, School of Food Science and Engineering, Shaanxi University of Science and Technology, Xi'an 710021, PR China
| | - Junyu Hao
- Natural Food Macromolecule Research Center, School of Food Science and Engineering, Shaanxi University of Science and Technology, Xi'an 710021, PR China
| | - Yang Liu
- Shaanxi Academy of Traditional Chinese Medicine, Xi'an 710003, China
| | - Shuai Liu
- Shaanxi Academy of Traditional Chinese Medicine, Xi'an 710003, China.
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33
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Wang Z, Chen H, Xiong S, Chen X, Gao X, Huang P, Zou J, Cao H. Lactobacillus plantarum SMUM211204 Exopolysaccharides Have Tumor-Suppressive Effects on Colorectal Cancer by Regulating Autophagy via the mTOR Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025. [PMID: 40017402 DOI: 10.1021/acs.jafc.4c09818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/01/2025]
Abstract
Probiotics have demonstrated their ability to suppress tumors in cell lines and mouse models. However, the precise molecules responsible for these effects remain unidentified. We focused on isolating and analyzing the exopolysaccharides (EPSs) produced by Lactobacillus plantarum (L. plantarum) SMUM211204. Our findings confirm that EPSs impair the growth of HCT116 cells and induce autophagy and apoptosis. Moreover, further experimental evidence demonstrates that EPSs diminish the expression of phosphorylation levels of PI3K, AKT, and mTOR. In contrast, they boost the expression of AMPKa, elevate the ULK1 level, and increase the protein LC3-II/I ratio. Furthermore, when rapamycin is employed to impede EPS-induced autophagy, it results in an enhancement of apoptosis and cell death in HCT116 cells. To validate these findings in vivo, we conducted an animal study using a colorectal cancer xenograft model. The results showed a significant reduction in tumor volume and weight in the EPS-treated group compared with the control group. Immunohistochemical analysis of tumors indicated increased expressions of LC3 and caspase-3, along with decreased levels of phospho-PI3Kinase, phospho-AKT, and P62, consistent with in vitro findings. Our study proved that EPSs have an inhibitory effect on colorectal cancer and can be used as a preventive and therapeutic drug for cancer.
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Affiliation(s)
- Zixuan Wang
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Hengqiu Chen
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Shasha Xiong
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Xiaoliang Chen
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Xuefeng Gao
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Pengwei Huang
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Jinhu Zou
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Hong Cao
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
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Wang X, He S, Gong X, Lei S, Zhang Q, Xiong J, Liu Y. Neutrophils in colorectal cancer: mechanisms, prognostic value, and therapeutic implications. Front Immunol 2025; 16:1538635. [PMID: 40092983 PMCID: PMC11906667 DOI: 10.3389/fimmu.2025.1538635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 02/04/2025] [Indexed: 03/19/2025] Open
Abstract
Neutrophils, the most abundant myeloid cells in human peripheral blood, serve as the first defense line against infection and are also significantly involved in the initiation and progression of cancer. In colorectal cancer (CRC), neutrophils exhibit a dual function by promoting tumor events and exerting antitumor activity, which is related to the heterogeneity of neutrophils. The neutrophil extracellular traps (NETs), gut microbiota, and various cells within the tumor microenvironment (TME) are involved in shaping the heterogeneous function of neutrophils. This article provides an updated overview of the complex functions and underlying mechanisms of neutrophils in CRC and their pivotal role in guiding prognosis assessment and therapeutic strategies, aiming to offer novel insights into neutrophil-associated treatment approaches for CRC.
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Affiliation(s)
- Xingyue Wang
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shukang He
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangmei Gong
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shijun Lei
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qianwen Zhang
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junqi Xiong
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Liu
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Zalila-Kolsi I, Dhieb D, Osman HA, Mekideche H. The Gut Microbiota and Colorectal Cancer: Understanding the Link and Exploring Therapeutic Interventions. BIOLOGY 2025; 14:251. [PMID: 40136508 PMCID: PMC11939563 DOI: 10.3390/biology14030251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 02/23/2025] [Accepted: 02/26/2025] [Indexed: 03/27/2025]
Abstract
CRC remains a significant public health challenge due to its high prevalence and mortality rates. Emerging evidence highlights the critical role of the gut microbiota in both the pathogenesis of CRC and the efficacy of treatment strategies, including chemotherapy and immunotherapy. Dysbiosis, characterized by imbalances in microbial communities, has been implicated in CRC progression and therapeutic outcomes. This review examines the intricate relationship between gut microbiota composition and CRC, emphasizing the potential for microbial profiles to serve as biomarkers for early detection and prognosis. Various interventions, such as prebiotics, probiotics, postbiotics, fecal microbiota transplantation, and dietary modifications, aim to restore microbiota balance and shift dysbiosis toward eubiosis, thereby improving health outcomes. Additionally, the integration of microbial profiling into clinical practice could enhance diagnostic capabilities and personalize treatment strategies, advancing the field of oncology. The study of intratumoral microbiota offers new diagnostic and prognostic tools that, combined with artificial intelligence algorithms, could predict treatment responses and assess the risk of adverse effects. Given the growing understanding of the gut microbiome-cancer axis, developing microbiota-oriented strategies for CRC prevention and treatment holds promise for improving patient care and clinical outcomes.
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Affiliation(s)
- Imen Zalila-Kolsi
- Faculty of Medical and Health Sciences, Liwa College, Abu Dhabi P.O. Box 41009, United Arab Emirates; (H.A.O.); (H.M.)
| | - Dhoha Dhieb
- College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar;
| | - Hussam A. Osman
- Faculty of Medical and Health Sciences, Liwa College, Abu Dhabi P.O. Box 41009, United Arab Emirates; (H.A.O.); (H.M.)
| | - Hadjer Mekideche
- Faculty of Medical and Health Sciences, Liwa College, Abu Dhabi P.O. Box 41009, United Arab Emirates; (H.A.O.); (H.M.)
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Hu M, Xu Y, Wang Y, Huang Z, Wang L, Zeng F, Qiu B, Liu Z, Yuan P, Wan Y, Ge S, Zhong D, Xiao S, Luo R, He J, Sun M, Zhuang X, Guo N, Cui C, Gao J, Zhou H, He X. Gut microbial-derived N-acetylmuramic acid alleviates colorectal cancer via the AKT1 pathway. Gut 2025:gutjnl-2024-332891. [PMID: 40015949 DOI: 10.1136/gutjnl-2024-332891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 02/15/2025] [Indexed: 03/01/2025]
Abstract
BACKGROUND Gut microbial metabolites are recognised as critical effector molecules that influence the development of colorectal cancer (CRC). Peptidoglycan fragments (PGFs) produced by microbiota play a crucial role in maintaining intestinal homeostasis, but their role in CRC remains unclear. OBJECTIVE Here, we aimed to explore the potential contribution of PGFs in intestinal tumourigenesis. DESIGN The relative abundance of peptidoglycan synthase and hydrolase genes was assessed by metagenomic analysis. Specific PGFs in the faeces and serum of CRC patients were quantified using targeted mass spectrometry. The effects of PGF on intestinal tumourigenesis were systematically evaluated using various murine models of CRC and organoids derived from CRC patients. Downstream molecular targets were screened and evaluated using proteome microarray, transcriptome sequencing and rescue assays. RESULTS Metagenomic analysis across seven independent cohorts (n=1121) revealed a comprehensive reduction in peptidoglycan synthase gene relative abundance in CRC patients. Targeted mass spectrometry identified significant depletion of a specific PGF, N-acetylmuramic acid (NAM) in CRC patients, which decreased as tumours progressed (p<0.001). NAM significantly inhibits intestinal tumourigenesis in various models, including Apc Min/+, AOM/DSS-treated and MC38 tumour-bearing mice. Additionally, NAM inhibits the growth of patient-derived CRC organoids in a concentration-dependent manner. Mechanistically, NAM inhibits the activation of AKT1 by directly binding to it and blocking its phosphorylation, which is a partial mediator of NAM's anticancer effects. CONCLUSION The PGF NAM protects against intestinal tumourigenesis by targeting the AKT1 signalling pathway. NAM may serve as a novel potential preventive and therapeutic biomarker against CRC.
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Affiliation(s)
- Mengyao Hu
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yi Xu
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yuqing Wang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhenhe Huang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Lei Wang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Fanan Zeng
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Bowen Qiu
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zefeng Liu
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Peibo Yuan
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yu Wan
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Shuang Ge
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Dian Zhong
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Siyu Xiao
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Rongrong Luo
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jiaqi He
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Meiling Sun
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaoduan Zhuang
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Nannan Guo
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Chunhui Cui
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jie Gao
- Department of Gastroenterology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
- The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Hongwei Zhou
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaolong He
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Single-cell and Extracellular Vesicles, Southern Medical University, Guangzhou, Guangdong, China
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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Zhang L, Liu ZX, Liu YH, Chen Y, Chen J, Lu CH. Auricularia auriculaPolysaccharides Exert Anti-inflammatory Effects in Hepatic Fibrosis by the Gut-Liver Axis and Enhancing SCFA Metabolism. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:4617-4629. [PMID: 39945558 PMCID: PMC11869285 DOI: 10.1021/acs.jafc.4c07952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 01/29/2025] [Accepted: 02/04/2025] [Indexed: 02/27/2025]
Abstract
Auricularia auricula, esteemed in Chinese culture for their culinary and medicinal properties, exhibits notable metabolic and immunomodulatory effects. The principal active constituents are indigestible fermentable polysaccharides, which not only exhibit anti-inflammatory activities but also facilitate the proliferation of beneficial gut microbiota. However, the influence of gut-derived components on liver-regulated metabolic products remains insufficiently understood. This item offers insights into the therapeutic potential of wood ear mushrooms for treating hepatic fibrosis and the associated mechanisms. Following 8 weeks of treatment, a substantial reduction in ECM deposition was recorded, linked to modulation of the NLRP3 inflammasome activation. This study aims to reveal the potential microbiome-mediated mechanisms behind its therapeutic effects. Insights from antibiotic combination treatments indicate that the protective effects against ECM deposition rely on the presence of specific gut microbiota. This fecal microbiota intervention enhances key physiological mechanisms, underscoring the contributions of Lactobacillales, Rikenellaceae, and Bacteroidaceae in potentially mitigating fibrosis. Collectively, these findings suggest that interventions utilizing wood ear mushrooms may reduce inflammation and ECM deposition, mediated by the TLR4/NF-κB pathway.
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Affiliation(s)
- Lu Zhang
- Department
Gastroenterology, Medical School of Nantong University, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Zhao-Xiu Liu
- Department
Gastroenterology, Medical School of Nantong University, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Yi-Heng Liu
- Department
Gastroenterology, Medical School of Nantong University, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Yuyan Chen
- Division
of Hepatobiliary and Transplantation Surgery, Department of General
Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical
School, Nanjing University, Nanjing 210008, China
| | - Jing Chen
- Department
Gastroenterology, Medical School of Nantong University, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Cui-Hua Lu
- Department
Gastroenterology, Medical School of Nantong University, Affiliated Hospital of Nantong University, Nantong 226001, China
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Khizar H, Ali K, Wang J. From silent partners to potential therapeutic targets: macrophages in colorectal cancer. Cancer Immunol Immunother 2025; 74:121. [PMID: 39998578 PMCID: PMC11861851 DOI: 10.1007/s00262-025-03965-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 01/30/2025] [Indexed: 02/27/2025]
Abstract
Cancer cells grow and survive in the tumor microenvironment, which is a complicated process. As a key part of how colorectal cancer (CRC) progresses, tumor-associated macrophages (TAMs) exhibit a double role. Through angiogenesis, this TAM can promote the growth of cancers. Although being able to modify and adjust immune cells is a great advantage, these cells can also exhibit anti-cancer properties including direct killing of cancer cells, presenting antigens, and aiding T cell-mediated responses. The delicate regulatory mechanisms between the immune system and tumors are composed of a complex network of pathways regulated by several factors including hypoxia, metabolic reprogramming, cytokine/chemokine signaling, and cell interactions. Decoding and figuring out these complex systems become significant in building targeted treatment programs. Targeting TAMs in CRC involves disrupting chemokine signaling or adhesion molecules, reprogramming them to an anti-tumor phenotype using TLR agonists, CD40 agonists, or metabolic modulation, and selectively removing TAM subsets that promote tumor growth. Multi-drug resistance, the absence of an accurate biomarker, and drug non-specificity are also major problems. Combining macrophage-targeted therapies with chemotherapy and immunotherapy may revolutionize treatment. Macrophage studies will advance with new technology and multi-omics methodologies to help us understand CRC and build specific and efficient treatments.
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Affiliation(s)
- Hayat Khizar
- Department of Surgery, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Kamran Ali
- Department of Surgery, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Jianwei Wang
- Department of Surgery, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China.
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, 2nd Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88th, Hangzhou, 310009, China.
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Tsenkova M, Brauer M, Pozdeev VI, Kasakin M, Busi SB, Schmoetten M, Cheung D, Meyers M, Rodriguez F, Gaigneaux A, Koncina E, Gilson C, Schlicker L, Herebian D, Schmitz M, de Nies L, Mayatepek E, Haan S, de Beaufort C, Cramer T, Meiser J, Linster CL, Wilmes P, Letellier E. Ketogenic diet suppresses colorectal cancer through the gut microbiome long chain fatty acid stearate. Nat Commun 2025; 16:1792. [PMID: 39979287 PMCID: PMC11842570 DOI: 10.1038/s41467-025-56678-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 01/28/2025] [Indexed: 02/22/2025] Open
Abstract
Colorectal cancer (CRC) patients have been shown to possess an altered gut microbiome. Diet is a well-established modulator of the microbiome, and thus, dietary interventions might have a beneficial effect on CRC. An attenuating effect of the ketogenic diet (KD) on CRC cell growth has been previously observed, however the role of the gut microbiome in driving this effect remains unknown. Here, we describe a reduced colonic tumor burden upon KD consumption in a CRC mouse model with a humanized microbiome. Importantly, we demonstrate a causal relationship through microbiome transplantation into germ-free mice, whereby alterations in the gut microbiota were maintained in the absence of continued selective pressure from the KD. Specifically, we identify a shift toward bacterial species that produce stearic acid in ketogenic conditions, whereas consumers were depleted, resulting in elevated levels of free stearate in the gut lumen. This microbial product demonstrates tumor-suppressing properties by inducing apoptosis in cancer cells and decreasing colonic Th17 immune cell populations. Taken together, the beneficial effects of the KD are mediated through alterations in the gut microbiome, including, among others, increased stearic acid production, which in turn significantly reduces intestinal tumor growth.
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Grants
- OT2 OD030544 NIH HHS
- U2C DK119886 NIDDK NIH HHS
- This work was supported by the Luxembourg National Research Fund (FNR) (grant nos. CORE/C16/BM/11282028 (E.L.), PoC/18/12554295 (E.L.), AFR 17103240 (C.G.), PRIDE17/11823097 (M.T., M.K., L.d.N.) and CORE/15/BM/10404093 (P.W.)), by the Luxembourg National Research Fund and the Fondation Cancer Luxembourg (grant no. CORE/C20/BM/14591557 (E.L.)), AFR 17103240 as well as by the Fondation du Pélican de Mie and Pierre Hippert-Faber under the aegis of the Fondation de Luxembourg (‘Pelican Grant’; M.T. and M.M.), a FNRS-Télévie grant to M.M., no. 7.4565.21-40007364), an Internal Research Project at the University of Luxembourg (MiDiCa—integrated analysis of the effects of microbiome-diet interactions on human colorectal adenocarcinoma enterocytes; E.L., P.W. and S.H.), the Fondation Cancer and the Fondation Kriibskrank Kanner Luxembourg (V.I.P), the Action LIONS Vaincre le Cancer Luxembourg and a European Research Council grant under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 863664 to P.W.). This project was also supported by the Doctoral School in Science and Engineering (M.T., M.K., M.M. and L.d.N.) and the Department of Life Sciences and Medicine at the University of Luxembourg. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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Affiliation(s)
- Mina Tsenkova
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Madita Brauer
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
- Institute for Advanced Studies, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Vitaly Igorevich Pozdeev
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Marat Kasakin
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Susheel Bhanu Busi
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
- UK Centre for Ecology and Hydrology, Wallingford, United Kingdom
| | - Maryse Schmoetten
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Dean Cheung
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Marianne Meyers
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Fabien Rodriguez
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Anthoula Gaigneaux
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Eric Koncina
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Cedric Gilson
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Lisa Schlicker
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Diran Herebian
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Martine Schmitz
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Laura de Nies
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Ertan Mayatepek
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Serge Haan
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Carine de Beaufort
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
- Pediatric Clinic, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg
| | - Thorsten Cramer
- Department of General, Visceral, Children and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany
| | - Johannes Meiser
- Department of Cancer Research (DOCR), Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Carole L Linster
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Paul Wilmes
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Elisabeth Letellier
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
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François RMM, Massicard JM, Weissman KJ. The chemical ecology and physiological functions of type I polyketide natural products: the emerging picture. Nat Prod Rep 2025; 42:324-358. [PMID: 39555733 DOI: 10.1039/d4np00046c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Covering: up to 2024.For many years, the value of complex polyketides lay in their medical properties, including their antibiotic and antifungal activities, with little consideration paid to their native functions. However, more recent evidence gathered from the study of inter-organismal interactions has revealed the influence of these metabolites upon the ecological adaptation and distribution of their hosts, as well as their modes of communication. The increasing number of sequenced genomes and associated transcriptomes has also unveiled the widespread occurrence of the underlying biosynthetic enzymes across all kingdoms of life, and the important contributions they make to physiological events specific to each organism. This review depicts the diversity of roles fulfilled by type I polyketides, particularly in light of studies carried out during the last decade, providing an initial overall picture of their diverse functions.
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He J, Chen Y, Zhao H, Li Y. The interplay between gut bacteria and targeted therapies: implications for future cancer treatments. Mol Med 2025; 31:58. [PMID: 39948481 PMCID: PMC11827328 DOI: 10.1186/s10020-025-01108-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
Targeted therapy represents a form of cancer treatment that specifically focuses on molecular markers regulating the growth, division, and dissemination of cancer cells. It serves as the cornerstone of precision medicine and is associated with fewer adverse effects compared to conventional chemotherapy, thus enhancing the quality of patient survival. These make targeted therapy as a vital component of contemporary anti-cancer strategies. Although targeted therapy has achieved excellent anti-cancer results, there are still many factors affecting its efficacy. Among the numerous factors affecting anti-cancer treatment, the role of intestinal bacteria and its metabolites are becoming increasingly prominent, particularly in immunotherapy. However, their effects on anticancer targeted therapy have not been systematically reviewed. Herein, we discuss the crosstalk between gut bacteria and anticancer targeted therapies, while also highlighting potential therapeutic strategies and future research directions.
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Affiliation(s)
- Juan He
- Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Yu Chen
- Department of Medical Oncology, Chongqing University Cancer Hospital, 181 Hanyu Road, Shapingba District, Chongqing, 400030, China
| | - Huakan Zhao
- Department of Medical Oncology, Chongqing University Cancer Hospital, 181 Hanyu Road, Shapingba District, Chongqing, 400030, China
| | - Yongsheng Li
- Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China.
- Department of Medical Oncology, Chongqing University Cancer Hospital, 181 Hanyu Road, Shapingba District, Chongqing, 400030, China.
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Nai S, Song J, Su W, Liu X. Bidirectional Interplay Among Non-Coding RNAs, the Microbiome, and the Host During Development and Diseases. Genes (Basel) 2025; 16:208. [PMID: 40004537 PMCID: PMC11855195 DOI: 10.3390/genes16020208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/24/2025] [Accepted: 01/29/2025] [Indexed: 02/27/2025] Open
Abstract
It is widely known that the dysregulation of non-coding RNAs (ncRNAs) and dysbiosis of the gut microbiome play significant roles in host development and the progression of various diseases. Emerging evidence has highlighted the bidirectional interplay between ncRNAs and the gut microbiome. This article aims to review the current understanding of the molecular mechanisms underlying the crosstalk between ncRNAs, especially microRNA (miRNA), and the gut microbiome in the context of development and diseases, such as colorectal cancer, inflammatory bowel diseases, neurological disorders, obesity, and cardiovascular disease. Ultimately, this review seeks to provide a foundation for exploring the potential roles of ncRNAs and gut microbiome interactions as biomarkers and therapeutic targets for clinical diagnosis and treatment, such as ncRNA mimics, antisense oligonucleotides, and small-molecule compounds, as well as probiotics, prebiotics, and diets.
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Affiliation(s)
| | | | | | - Xiaoqian Liu
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China; (S.N.); (J.S.); (W.S.)
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Luo D, Zhou J, Ruan S, Zhang B, Zhu H, Que Y, Ying S, Li X, Hu Y, Song Z. Overcoming immunotherapy resistance in gastric cancer: insights into mechanisms and emerging strategies. Cell Death Dis 2025; 16:75. [PMID: 39915459 PMCID: PMC11803115 DOI: 10.1038/s41419-025-07385-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 01/07/2025] [Accepted: 01/22/2025] [Indexed: 02/09/2025]
Abstract
Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with limited treatment options in advanced stages. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting PD1/PD-L1, has emerged as a promising therapeutic approach. However, a significant proportion of patients exhibit primary or acquired resistance, limiting the overall efficacy of immunotherapy. This review provides a comprehensive analysis of the mechanisms underlying immunotherapy resistance in GC, including the role of the tumor immune microenvironment, dynamic PD-L1 expression, compensatory activation of other immune checkpoints, and tumor genomic instability. Furthermore, the review explores GC-specific factors such as molecular subtypes, unique immune evasion mechanisms, and the impact of Helicobacter pylori infection. We also discuss emerging strategies to overcome resistance, including combination therapies, novel immunotherapeutic approaches, and personalized treatment strategies based on tumor genomics and the immune microenvironment. By highlighting these key areas, this review aims to inform future research directions and clinical practice, ultimately improving outcomes for GC patients undergoing immunotherapy.
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Affiliation(s)
- Dingtian Luo
- Gastroenterology Department, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Jing Zhou
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Shuiliang Ruan
- Gastroenterology Department, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Binzhong Zhang
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Huali Zhu
- Gastroenterology Department, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Yangming Que
- Gastroenterology Department, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Shijie Ying
- Gastroenterology Department, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Xiaowen Li
- Pathology Department, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Yuanmin Hu
- Intensive Care Unit, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China.
| | - Zhengwei Song
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China.
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He X, Xie T, Shi L, Kuang X, Li L, Shang X, Fu B. Research hotspots and frontiers in the tumor microenvironment of colorectal cancer: a bibliometric study from 2014 to 2024. Front Oncol 2025; 15:1525280. [PMID: 39975599 PMCID: PMC11835677 DOI: 10.3389/fonc.2025.1525280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 01/20/2025] [Indexed: 02/21/2025] Open
Abstract
Background Colorectal cancer (CRC) is the second leading cause of cancer deaths globally, which poses a heavy burden on our healthcare and economy. In recent years, increasing researches suggest that the tumor microenvironment (TME) influences cancer onset, progression, metastasis, and treatment. This has become a popular direction for researching and attacking cancer. However, to date, there is no bibliometric analysis of colorectal cancer and tumor microenvironment from 2014 to 2024. This study aims to provide a comprehensive picture of the current research status, hotspots, and future trends in this field from a bibliometric perspective. Methods In this study, the publications about colorectal cancer and tumor microenvironment from 2014 to 2024 were searched based on the Web of Science Core Collection database. Then we analyzed and visualized the data using CiteSpace, VOSviewer, bibliometrix package, and Microsoft Excel 2019. Results A total of 748 publications were included in our study, and the number of publications entered a period of rapid growth after 2019. China and the United States are the major research and collaboration centers in this field. Elkord, Eyad is the most prolific author, and Frontiers in Immunology is the journal that published the most papers on the TME of CRC. In addition, keyword and cluster analysis showed that immune checkpoint inhibitors, cancer-associated fibroblasts, macrophage polarization, intestinal microbiota, colorectal cancer liver metastasis, drug resistance, scRNA-seq, etc. may be the research hotspots and trends in this field. Conclusions Colorectal cancer and tumor microenvironment research is in the developmental stage, and strengthening international cooperation can help to drive this field forward. The main components and signaling in TME, CRC immunotherapy, colorectal cancer liver metastasis, and new research techniques are the hot research directions in this domain. Our findings will provide scholars with an up-to-date perspective on the current state of research, hotspots, and future trends in this field.
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Affiliation(s)
- Xinran He
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Tingyi Xie
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Li Shi
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Xuyi Kuang
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Lei Li
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Xingyu Shang
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Bo Fu
- Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
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Xu X, Zhang L, An Y, Han H, Chen R, Zhang M, Li Y, Zhang S. The association between ambient air pollution and colorectal cancer: a Mendelian randomization study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL HEALTH RESEARCH 2025; 35:495-505. [PMID: 38819028 DOI: 10.1080/09603123.2024.2361453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 05/25/2024] [Indexed: 06/01/2024]
Abstract
Mounting epidemiology studies have reported the potential associations between ambient air pollution exposure and colorectal cancer (CRC). However, the genetic association between ambient air pollution and CRC remains unclear. Using the Genome-wide association study (GWAS) data from UK biobank, we explored the genetic association of CRC (5,657 cases and 372,016 controls) with four ambient air pollutants (PM2.5, PM10, NO2, NOx; n = 423,796 to 456,380) under the framework of Mendelian randomization (MR). Our results revealed a significant association between long-term NO2 exposure (per 10 µg/m3) and increased CRC risk, with an odds ratio (OR) of 1.02 (95% confidence interval [CI]: 1.00-1.03), while no statistical association was found between CRC risk and the other air pollutants. Sensitivity analysis confirmed the robustness of the results. It is imperative to consider the impact of air pollution, particularly NO2, in mitigating the risk of CRC.
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Affiliation(s)
- Xinshu Xu
- Department of Anorectal, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, PR China
- First Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, Henan, PR China
| | - Linhan Zhang
- Department of Anorectal, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, PR China
| | - Yongkang An
- Department of Anorectal, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, PR China
| | - Haitao Han
- Department of Anorectal, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, PR China
| | - Ruobing Chen
- Department of Anorectal, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, PR China
- First Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, Henan, PR China
| | - Mengmeng Zhang
- Department of Anorectal, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, PR China
- First Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, Henan, PR China
| | - Yan Li
- Department of Operating Room, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, PR China
| | - Shuangxi Zhang
- Department of Anorectal, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, PR China
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Bilal H, Khan MN, Khan S, Shafiq M, Fang W, Zeng Y, Guo Y, Li X, Zhao B, Lv QL, Xu B. Fungal Influences on Cancer Initiation, Progression, and Response to Treatment. Cancer Res 2025; 85:413-423. [PMID: 39589783 DOI: 10.1158/0008-5472.can-24-1609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 09/13/2024] [Accepted: 11/12/2024] [Indexed: 11/27/2024]
Abstract
Fungal dysbiosis is increasingly recognized as a key factor in cancer, influencing tumor initiation, progression, and treatment outcomes. This review explores the role of fungi in carcinogenesis, with a focus on mechanisms such as immunomodulation, inflammation induction, tumor microenvironment remodeling, and interkingdom interactions. Fungal metabolites are involved in oncogenesis, and antifungals can interact with anticancer drugs, including eliciting potential adverse effects and influencing immune responses. Furthermore, mycobiota profiles have potential as diagnostic and prognostic biomarkers, emphasizing their clinical relevance. The interplay between fungi and cancer therapies can affect drug resistance, therapeutic efficacy, and risk of invasive fungal infections associated with targeted therapies. Finally, emerging strategies for modulating mycobiota in cancer care are promising approaches to improve patient outcomes.
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Affiliation(s)
- Hazrat Bilal
- Jiangxi Key Laboratory of Oncology, JXHC Key Laboratory of Tumor Metastasis, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Institute, Nanchang, China
| | - Muhammad Nadeen Khan
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, China
| | - Sabir Khan
- Department of Dermatology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Muhammad Shafiq
- Department of Pharmacology, Research Institute of Clinical Pharmacy, Shantou University Medical College, Shantou, China
| | - Wenjie Fang
- Department of Dermatology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Yuebin Zeng
- Department of Dermatology, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yangzhong Guo
- Jiangxi Key Laboratory of Oncology, JXHC Key Laboratory of Tumor Metastasis, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Institute, Nanchang, China
| | - Xiaohui Li
- Jiangxi Key Laboratory of Oncology, JXHC Key Laboratory of Tumor Metastasis, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Institute, Nanchang, China
| | - Bing Zhao
- Jiangxi Key Laboratory of Oncology, JXHC Key Laboratory of Tumor Metastasis, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Institute, Nanchang, China
| | - Qiao-Li Lv
- Jiangxi Key Laboratory of Oncology, JXHC Key Laboratory of Tumor Metastasis, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Institute, Nanchang, China
| | - Bin Xu
- Jiangxi Key Laboratory of Oncology, JXHC Key Laboratory of Tumor Metastasis, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Institute, Nanchang, China
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Wu Z, Yu M, Zeng Y, Huang Y, Zheng W. LRP11-AS1 mediates enterotoxigenic Bacteroides fragilis-related carcinogenesis in colorectal Cancer via the miR-149-3p/CDK4 pathway. Cancer Gene Ther 2025; 32:184-197. [PMID: 39672916 PMCID: PMC11839468 DOI: 10.1038/s41417-024-00862-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 11/19/2024] [Accepted: 11/29/2024] [Indexed: 12/15/2024]
Abstract
Long noncoding RNAs (lncRNAs) are critical in tumorigenesis and show potential for tumor diagnosis and therapy. Enterotoxigenic Bacteroides fragilis (ETBF), known for producing enterotoxins, is implicated in human gut tumorigenesis, yet the underlying mechanisms are not fully elucidated. This study aims to clarify the molecular mechanisms by which lncRNAs contribute to ETBF-induced tumorigenesis, with a focus on LRP11-AS1's role in modulating ETBF's colorectal carcinogenesis. We found a marked increase in LRP11-AS1 expression in colorectal cancer (CRC) tissues compared to adjacent non-tumorous tissues. In vitro, CRC cells exposed to ETBF showed elevated LRP11-AS1 levels. Mechanistically, LRP11-AS1 was shown to enhance CDK4 expression by competitively binding to miR-149-3p. These results indicate that LRP11-AS1 may facilitate ETBF-related carcinogenesis in CRC and could serve as a therapeutic target and diagnostic biomarker for ETBF-associated CRC.
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Affiliation(s)
- Zhongguang Wu
- Department of Laboratory Medicine, Shenzhen University General Hospital, Shenzhen, China
| | - Mengqiu Yu
- Department of Laboratory Medicine, Shenzhen University General Hospital, Shenzhen, China
| | - Yu Zeng
- Department of Laboratory Medicine, Shenzhen University General Hospital, Shenzhen, China
| | - Yingfeng Huang
- Department of Laboratory Medicine, Shenzhen University General Hospital, Shenzhen, China
| | - Weidong Zheng
- Department of Laboratory Medicine, Shenzhen University General Hospital, Shenzhen, China.
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Health Science Center, Shenzhen University, Shenzhen, China.
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Zhang L, Liu S, Ding K, Zeng B, Li B, Zhou J, Li J, Wang J, Su X, Sun R. Yanghe decoction inhibits inflammation-induced lung metastasis of colorectal cancer. JOURNAL OF ETHNOPHARMACOLOGY 2025; 340:119257. [PMID: 39694428 DOI: 10.1016/j.jep.2024.119257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 12/07/2024] [Accepted: 12/15/2024] [Indexed: 12/20/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Positive deficiency and cancer toxicity are the main pathogenesis of colorectal cancer (CRC) lung metastasis. Yanghe decoction (YHD), a traditional Chinese medicine, has the effects of warming yang, tonifying blood, dispersing cold and clearing stagnation, adopting a treatment method that combines supporting the right and dispelling the wrong, which has remarkable efficacy in anti-tumor.Although, its precise mechanism of inhibiting the metastasis of colorectal cancer to the lung is still poorly understood. AIM OF THE STUDY This study aimed to elucidate the antitumor properties of YHD within the context of colorectal cancer lung metastasis. MATERIALS AND METHODS Ultrahigh-performance liquid chromatography coupled with mass spectrometry (UHPLC-MS) was utilized to analyze the chemical composition of YHD. The anticancer activity of YHD was evaluated in a CRC lung metastasis mouse model by quantifying pulmonary metastatic nodules. The effects of YHD on CRC cell proliferation, apoptosis, cell cycle progression, and invasion were assessed using CCK-8 assays, flow cytometry, and Transwell assays. YHD-mediated immune modulation in tumor-bearing mice was evaluated by analyzing antitumor immunity, immunosuppressive cells, and cytokines in peripheral blood and tumor tissue. Gut microbiota analysis was conducted to determine the impact of YHD on the gut microbiota in mice. RESULTS Our analysis identified 1801 chemical markers in YHD. CFA exacerbated lung metastasis in CRC, whereas oral administration of YHD significantly mitigated this effect, as evidenced by the reduced number of metastatic lung nodules in CRC tumor-bearing mice. In vitro experiments demonstrated that YHD inhibits CRC cell proliferation, induces apoptosis, and suppresses invasion. In the lung tissues of mice with CRC metastasis treated with CFA, there was a significant reduction in NK cells and IL-21, along with an increase in M2 macrophages and IL-6. Following YHD treatment, there was a notable increase in NK cells and IL-21, accompanied by a decrease in M2 macrophages and IL-6 in lung tissues. YHD administration was also associated with an increase in beneficial bacterial species such as Bacillus and a decrease in deleterious bacterial species such as Oscillibacter. CONCLUSION Our findings demonstrate that YHD inhibits lung metastasis in CRC by suppressing CRC cell proliferation and invasion, in addition to modulating the tumor microenvironment to favor antitumor immunity. These results provide a scientific basis for the clinical application of YHD in the treatment of CRC patients.
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Affiliation(s)
- Lu Zhang
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Songyu Liu
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Kai Ding
- Department of Anesthesiology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Bin Zeng
- Department of Anesthesiology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Bo Li
- Department of Neurosurgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, China
| | - Jinyi Zhou
- Department of Neurosurgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, China
| | - Jv Li
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Junliang Wang
- Scientific Research and Experimental Center, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Xiaosan Su
- Scientific Research and Experimental Center, Yunnan University of Chinese Medicine, Kunming, 650500, China.
| | - Ruifen Sun
- School of Nursing, Yunnan University of Chinese Medicine, Kunming, 650500, China.
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Zhong Y, Chen G, Chen M, Cui J, Tan Q, Xiao Z. Gene prediction of immune cells association between gut microbiota and colorectal cancer: a Mendelian randomization study. Front Immunol 2025; 16:1460936. [PMID: 39958359 PMCID: PMC11825486 DOI: 10.3389/fimmu.2025.1460936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Accepted: 01/06/2025] [Indexed: 02/18/2025] Open
Abstract
Background An increasing number of studies have revealed that gut microbiota influences the development and progression of Colorectal cancer (CRC). However, whether a causal relationship exists between the two remains unclear, and the role of immune cells in this context is not well understood. Objective To elucidate the causal relationship between gut microbiota and CRC and to explore the potential mediating role of circulating immune cells. Materials and methods To analyze the causal relationship between gut microbiota and CRC, we employed a univariable Mendelian randomization (UVMR) approach. Subsequently, a two-step multivariable Mendelian randomization (MVMR) to assess the potential mediating role of circulating immune cells. Primarily, applied the Inverse-Variance Weighted method to evaluate the causal relationship between exposure and outcome. To ensure the robustness of the results linking gut microbiota and CRC, we validated the findings using Robust Inverse-Variance Weighted, Penalized Inverse-Variance Weighted, and Penalized Robust Inverse-Variance Weighted methods. Additionally, we employed MR-Egger Intercept to mitigate the influence of horizontal pleiotropy. MR-PRESSO was used to detect and correct outliers by excluding anomalous instrumental variables. Finally, we supplemented our analysis with methods such as Bayesian Weighted Mendelian Randomization (BWMR), Maximum-Likelihood, Lasso, Debiased Inverse Variance Weighted, and Contamination Mixture to establish a robust and compelling causal relationship. Results After accounting for reverse causality, horizontal pleiotropy, and various methodological corrections, Bifidobacterium kashiwanohense, GCA-900066755 sp900066755, Geminocystis, and Saccharofermentanaceae exhibited strong and robust causal effects on CRC. Specifically, CD40 on monocytes (2.82%) and CD45 on CD33+HLA-DR+CD14- cells (12.87%) mediated the causal relationship between Bifidobacterium kashiwanohense and CRC risk. Furthermore, CD45 on CD33-HLA-DR+ (3.94%) mediated the causal relationship between GCA-900066755 sp900066755 and CRC risk. Additionally, terminally differentiated CD4+T cells (11.55%) mediated the causal relationship between Geminocystis and CRC risk. Lastly, CD40 on monocytes (2.35%), central memory CD4+T cells (5.76%), and CD28 on CD28+CD45RA+CD8+T cells (5.00%) mediated the causal relationship between Saccharofermentanaceae and CRC risk. Conclusion Our mediation MR analysis provides genetic evidence suggesting that circulating immune cells may mediate the causal relationship between gut microbiota and CRC. The identified associations and mediation effects offer new insights into potential therapeutic avenues for CRC.
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Affiliation(s)
- Yan Zhong
- Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| | - Guanglei Chen
- Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| | - Menglu Chen
- Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| | - Junsong Cui
- The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| | - Qianren Tan
- The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| | - Zhenghua Xiao
- The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
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50
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Li B, Liu M, Du W, Wang S, Xu Z, Zhang X, Zhang Y, Hua S. Cecropin AD ameliorates pneumonia and intestinal injury in mice with mycoplasma pneumoniae by mediating gut microbiota. BMC Vet Res 2025; 21:39. [PMID: 39881281 PMCID: PMC11776147 DOI: 10.1186/s12917-025-04500-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 01/15/2025] [Indexed: 01/31/2025] Open
Abstract
Animals infected with mycoplasma pneumoniae not only develop respiratory diseases, but also cause digestive diseases through the lung-gut axis mediated by the intestinal flora, and vice versa. Antimicrobial peptides are characterized by their bactericidal, anti-inflammatory, and intestinal flora-regulating properties. However, the effect of cecropin AD (CAD) against mycoplasma pneumonia remains unclear. To investigate the anti-inflammatory effect of CAD on mycoplasma pneumonia and the associated mechanism, mice were infected with Mycoplasma capricolum subsp. Capripneumoniae(Mccp) to elicit lung inflammation, followed by oral administration of CAD via gavage. The findings showed that mice receiving twice injections of 2.08 × 108 copies of Mccp suffered significant pathological damage to their lungs and colons. Additionally, there was a notable upsurge in inflammatory factors within the affected tissues. 16 S rDNA sequencing revealed alterations in the colonic microbiota, including a decrease in the abundance of beneficial bacteria such as Corynebacterium_glutamicum and Candidatus_Saccharimonas, and an increase in the abundance of potential pathogens like Lachnospiraceae_NK4A136_group and Escherichia-Shigella. As a result, there were abnormal rises in lipopolysaccharide (LPS) levels in both colonic content and blood. Moreover, CAD treatment reversed the microbial dysbiosis and decreased the LPS levels induced by Mccp, thereby suppressing the activation of the TLR-4/NF-κB pathway and the Fas/FasL-caspase-8/-3 pathway. Consequently, this significantly mitigated the morphological and functional damage to the lungs and colons caused by Mccp. The findings offer novel insights and approaches for the clinical management of Mccp infections.
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Affiliation(s)
- Bowen Li
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Mingming Liu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Wenjing Du
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Shuaidong Wang
- Mianyang Habio Bioengineering Co., Ltd., Mianyang, Sichuan, China
| | - Zekang Xu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Xiaoqian Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Yang Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China
- Mianyang Habio Bioengineering Co., Ltd., Mianyang, Sichuan, China
| | - Song Hua
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China.
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