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Huang M, Ji Q, Huang H, Wang X, Wang L. Gut microbiota in hepatocellular carcinoma immunotherapy: immune microenvironment remodeling and gut microbiota modification. Gut Microbes 2025; 17:2486519. [PMID: 40166981 PMCID: PMC11970798 DOI: 10.1080/19490976.2025.2486519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 03/05/2025] [Accepted: 03/25/2025] [Indexed: 04/02/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with limited treatment options at advanced stages. The gut microbiota, a diverse community of microorganisms residing in the gastrointestinal tract, plays a pivotal role in regulating immune responses through the gut-liver axis. Emerging evidence underscores its impact on HCC progression and the efficacy of immunotherapy. This review explores the intricate interactions between gut microbiota and the immune system in HCC, with a focus on key immune cells and pathways involved in tumor immunity. Additionally, it highlights strategies for modulating the gut microbiota - such as fecal microbiota transplantation, dietary interventions, and probiotics - as potential approaches to enhancing immunotherapy outcomes. A deeper understanding of these mechanisms could pave the way for novel therapeutic strategies aimed at improving patient prognosis.
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Affiliation(s)
- Mingyao Huang
- School of Basic Medicine, Putian University, Putian, Fujian, China
- Department of Breast Surgery, Clinical Oncology School of Fujian Medical University, Fuzhou, Fujian, China
| | - Quansong Ji
- Department of Urology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Huiyan Huang
- Ward 3, De’an Hospital, Xianyou County, Putian, Fujian, China
| | - Xiaoqian Wang
- Department of Rehabilitation Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Lin Wang
- Department of Orthopedics, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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Xiao K, Li K, Xiao K, Yang J, Zhou L. Gut Microbiota and Hepatocellular Carcinoma: Metabolic Products and Immunotherapy Modulation. Cancer Med 2025; 14:e70914. [PMID: 40314129 PMCID: PMC12046294 DOI: 10.1002/cam4.70914] [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: 01/16/2025] [Revised: 03/31/2025] [Accepted: 04/16/2025] [Indexed: 05/03/2025] Open
Abstract
BACKGROUND The relationship between hepatocellular carcinoma (HCC) and gut microbiota has gained attention for its impact on HCC immunotherapy. METHODS Key gut microbial metabolites, including bile acids, toll-like receptor 4, short-chain fatty acids, and bacterial toxins, contribute to HCC progression and influence immune responses through the gut-liver axis. As immune checkpoint inhibitors (ICIs) become common in HCC treatment, modulating the gut microbiota offers new strategies to enhance ICIs efficacy. However, individual differences in microbial composition introduce challenges, with some HCC patients showing resistance to ICIs. RESULTS This review summarizes the latest findings on the role of gut microbiota in HCC and explores emerging therapeutic approaches, including fecal microbiota transplantation, probiotics, antibiotics, and natural compounds. CONCLUSIONS The focus is on translating these insights into personalized medicine to optimize ICIs responses and improve HCC treatment outcomes.
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Affiliation(s)
- Kunmin Xiao
- Department of OncologyLonghua Hospital, Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Kexin Li
- Department of Traditional Chinese MedicinePeking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical ScienceBeijingChina
| | - Kunlin Xiao
- Department of EmergencyZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Jinzu Yang
- Department of OncologyLonghua Hospital, Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Lei Zhou
- Department of OncologyLonghua Hospital, Shanghai University of Traditional Chinese MedicineShanghaiChina
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3
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Du J, Guan Y, Zhang E. Regulatory role of gut microbiota in immunotherapy of hepatocellular carcinoma. Hepatol Int 2025:10.1007/s12072-025-10822-6. [PMID: 40229514 DOI: 10.1007/s12072-025-10822-6] [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: 11/20/2024] [Accepted: 03/07/2025] [Indexed: 04/16/2025]
Abstract
BACKGROUND The gut microbiota plays a role in triggering innate immunity and regulating the immune microenvironment (IME) of hepatocellular carcinoma (HCC) by acting on various signaling receptors and transcription factors through its metabolites and related molecules. Furthermore, there is an increasing recognition of the gut microbiota as a potential therapeutic target for HCC, given its ability to modulate the efficacy of immune checkpoint inhibitors (ICIs). OBJECTIVE This review will discuss the mechanisms of gut microbiota in modulating immunotherapy of HCC, the predictive value of efficacy, and the therapeutic strategies for modulating the gut microbiota in detail. METHODS We conducted a systematic literature search in PubMed, Embase, Scopus, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Chinese databases for articles involving the influence of gut microbiota on HCC immunotherapy. RESULTS The mechanisms underlying the effect of gut microbiota on HCC immunotherapy include gut-liver axis, tumor immune microenvironment (TIME), and antibodies. Patients who benefit from ICIs exhibit a higher abundance of gut microbiota. Antibiotics, fecal microbiota transplantation (FMT), probiotics, and prebiotics are effective methods to regulate gut microbiota. CONCLUSION The strong connection between the liver and gut will provide numerous opportunities for the development of microbiome-based diagnostics, treatments, or prevention strategies for HCC patients.
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Affiliation(s)
- Jiajia Du
- Hepatic Surgery Center, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
| | - Yan Guan
- Hepatic Surgery Center, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
| | - Erlei Zhang
- Hepatic Surgery Center, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China.
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Guo X, Zhao Z, Zhu L, Liu S, Zhou L, Wu F, Fang S, Chen M, Zheng L, Ji J. The evolving landscape of biomarkers for systemic therapy in advanced hepatocellular carcinoma. Biomark Res 2025; 13:60. [PMID: 40221793 PMCID: PMC11993949 DOI: 10.1186/s40364-025-00774-2] [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: 01/26/2025] [Accepted: 03/29/2025] [Indexed: 04/14/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the most prevalent and deadliest cancers. With the approval of multiple first- and second-line agents, especially the combination therapies based on immune checkpoint inhibitor (ICI) regimens, the landscape of systemic therapy for advanced HCC (aHCC) is more diverse than ever before. The efficacy of current systemic therapies shows great heterogeneity in patients with aHCC, thereby identifying biomarkers for response prediction and patient stratification has become an urgent need. The main biomarkers for systemic therapy in hepatocellular carcinoma are derived from peripheral blood, tissues, and imaging. Currently, the understanding of the clinical response to systemic therapy indicates unequivocally that a single biomarker cannot be used to identify patients who are likely to benefit from these treatments. In this review, we provide an integrated landscape of the recent development in molecular targeted therapies and ICIs-based therapies, especially focusing on the role of clinically applicable predictive biomarkers. Additionally, we further highlight the latest advancements in biomarker-driven therapies, including targeted treatments, adoptive cell therapies, and bispecific antibodies.
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Affiliation(s)
- Xinyu Guo
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Zhongwei Zhao
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Lingyi Zhu
- The 2nd Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, China
| | - Shuang Liu
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Lingling Zhou
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Fazong Wu
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Shiji Fang
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Minjiang Chen
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Liyun Zheng
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China.
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China.
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China.
| | - Jiansong Ji
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China.
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China.
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China.
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Li C, Cai C, Wang C, Chen X, Zhang B, Huang Z. Gut microbiota-mediated gut-liver axis: a breakthrough point for understanding and treating liver cancer. Clin Mol Hepatol 2025; 31:350-381. [PMID: 39659059 PMCID: PMC12016628 DOI: 10.3350/cmh.2024.0857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/22/2024] [Accepted: 12/06/2024] [Indexed: 12/12/2024] Open
Abstract
The trillions of commensal microorganisms living in the gut lumen profoundly influence the physiology and pathophysiology of the liver through a unique gut-liver axis. Disruptions in the gut microbial communities, arising from environmental and genetic factors, can lead to altered microbial metabolism, impaired intestinal barrier and translocation of microbial components to the liver. These alterations collaboratively contribute to the pathogenesis of liver disease, and their continuous impact throughout the disease course plays a critical role in hepatocarcinogenesis. Persistent inflammatory responses, metabolic rearrangements and suppressed immunosurveillance induced by microbial products underlie the pro-carcinogenic mechanisms of gut microbiota. Meanwhile, intrahepatic microbiota derived from the gut also emerges as a novel player in the development and progression of liver cancer. In this review, we first discuss the causes of gut dysbiosis in liver disease, and then specify the pivotal role of gut microbiota in the malignant progression from chronic liver diseases to hepatobiliary cancers. We also delve into the cellular and molecular interactions between microbes and liver cancer microenvironment, aiming to decipher the underlying mechanism for the malignant transition processes. At last, we summarize the current progress in the clinical implications of gut microbiota for liver cancer, shedding light on microbiota-based strategies for liver cancer prevention, diagnosis and therapy.
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Affiliation(s)
- Chenyang Li
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chujun Cai
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chendong Wang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences; NHC Key Laboratory of Organ Transplantation, Wuhan, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences; NHC Key Laboratory of Organ Transplantation, Wuhan, China
| | - Zhao Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Sun J, Song S, Liu J, Chen F, Li X, Wu G. Gut microbiota as a new target for anticancer therapy: from mechanism to means of regulation. NPJ Biofilms Microbiomes 2025; 11:43. [PMID: 40069181 PMCID: PMC11897378 DOI: 10.1038/s41522-025-00678-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 03/04/2025] [Indexed: 03/15/2025] Open
Abstract
In order to decipher the relationship between gut microbiota imbalance and cancer, this paper reviewed the role of intestinal microbiota in anticancer therapy and related mechanisms, discussed the current research status of gut microbiota as a biomarker of cancer, and finally summarized the reasonable means of regulating gut microbiota to assist cancer therapy. Overall, our study reveals that the gut microbiota can serve as a potential target for improving cancer management.
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Affiliation(s)
- Jiaao Sun
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shiyan Song
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jiahua Liu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Feng Chen
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
| | - Xiaorui Li
- Department of oncology, Cancer Hospital of Dalian University of Technology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China.
| | - Guangzhen Wu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
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Fongmanee J, Wanitsuwan W, Wanna W, Surachat K, Saechan C, Srinoun K, Buncherd H, Thanapongpichat S, Kanjanapradit K, Tansila N. Characterization of Mucosa-Associated Microbiota in Formalin-Fixed, Paraffin-Embedded Tissues From Southern Thai Patients With Familial Adenomatous Polyposis. Genes Cells 2025; 30:e70008. [PMID: 40007099 DOI: 10.1111/gtc.70008] [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: 05/28/2024] [Revised: 02/18/2025] [Accepted: 02/18/2025] [Indexed: 02/27/2025]
Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome associated with germline mutations in the adenomatous polyposis coli (APC) gene. Patients eventually may develop colorectal cancer (CRC) if they are not diagnosed in the early stages. Dysbiosis is an important contributing factor to the complex events in carcinogenesis, which are poorly understood. First, 25 tissue samples from 13 patients with FAP at Songklanagarind Hospital were classified as nontumor (n = 18) or tumor tissues (n = 7). Following isolation, 5 DNA samples of insufficient quantity and quality were excluded. The 16S rRNA gene targeting the V3-V4 region was sequenced, and the sequencing data were analyzed using bioinformatics tools. The abundance of Romboutsia and Clostridium genera and Lachnospiraceae NK4A136 was significantly higher in tumor tissues than that in nonneoplastic samples. Furthermore, several bacterial genera, including Acinetobacter, Paracoccus, Brevundimonas, and Brevibacillus, were predominant or key taxa in nontumor mucosae. We found an alteration in the mucosa-associated microbiota composition of southern Thai patients that may have contributed to the tumorigenesis of FAP. These findings may improve the knowledge of the potential roles of microbes in FAP and aid the development of preventive measures for cancer development and progression through modulation of the gut microbiota.
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Grants
- Faculty of Medical Technology Research Fund, Prince of Songkla University
- MED6505193b National Science, Research, and Innovation Fund (NSRF), Thailand
- MED6505193c National Science, Research, and Innovation Fund (NSRF), Thailand
- MET6601065S National Science, Research, and Innovation Fund (NSRF), Thailand
- MET6701197S National Science, Research, and Innovation Fund (NSRF), Thailand
- MET6402032S Prince of Songkla University
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Affiliation(s)
- Jukrayupat Fongmanee
- Program in Molecular Biotechnology and Bioinformatics, Division of Biological Sciences, Faculty of Science, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
| | - Worrawit Wanitsuwan
- Medical Science Research and Innovation Institute, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
- Department of Surgery, Faculty of Medicine, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
| | - Warapond Wanna
- Program in Molecular Biotechnology and Bioinformatics, Division of Biological Sciences, Faculty of Science, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
- Center for Genomics and Bioinformatics Research, Faculty of Science, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
| | - Komwit Surachat
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
- Translational Medicine Research Center, Faculty of Medicine, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
| | - Charinrat Saechan
- Faculty of Medical Technology, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
| | - Kanitta Srinoun
- Faculty of Medical Technology, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
| | - Hansuk Buncherd
- Faculty of Medical Technology, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
| | | | - Kanet Kanjanapradit
- Division of Pathology, Faculty of Medicine, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
| | - Natta Tansila
- Faculty of Medical Technology, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
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Ren S, Zhang Y, Wang X, Su J, Wang X, Yuan Z, He X, Guo S, Chen Y, Deng S, Wu X, Li M, Du F, Zhao Y, Shen J, Hu W, Li X, Xiao Z. Emerging insights into the gut microbiota as a key regulator of immunity and response to immunotherapy in hepatocellular carcinoma. Front Immunol 2025; 16:1526967. [PMID: 40070843 PMCID: PMC11893557 DOI: 10.3389/fimmu.2025.1526967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 02/10/2025] [Indexed: 03/14/2025] Open
Abstract
The gut microbiota, a complex microbial ecosystem closely connected to the liver via the portal vein, has emerged as a critical regulator of liver health and disease. Numerous studies have underscored its role in the onset and progression of liver disorders, including alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). This review provides a comprehensive overview of current insights into the influence of the gut microbiota on HCC progression, particularly its effects on immune cells within the HCC tumor microenvironment (TME). Furthermore, we explore the potential of gut microbiota-targeted interventions, such as antibiotics, probiotics, prebiotics, and fecal microbiota transplantation (FMT), to modulate the immune response and improve outcomes of immunotherapy in HCC. By synthesizing insights from recent studies, this review aims to highlight microbiota-based strategies that may enhance immunotherapy outcomes, advancing personalized approaches in HCC treatment.
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Affiliation(s)
- Siqi Ren
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yinping Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xingyue Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Jiahong Su
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xiang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zijun Yuan
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xinyu He
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Sipeng Guo
- Research and Experiment Center, Sichuan College of Traditional Chinese Medicine, Mianyang, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Shuai Deng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Wei Hu
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China
| | - Xiaobing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Research and Experiment Center, Sichuan College of Traditional Chinese Medicine, Mianyang, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
- Gulin Traditional Chinese Medicine Hospital, Luzhou, China
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9
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Gazzaniga FS, Kasper DL. The gut microbiome and cancer response to immune checkpoint inhibitors. J Clin Invest 2025; 135:e184321. [PMID: 39895632 PMCID: PMC11785914 DOI: 10.1172/jci184321] [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: 02/04/2025] Open
Abstract
Immune checkpoint inhibitors (ICIs) are widely used for cancer immunotherapy, yet only a fraction of patients respond. Remarkably, gut bacteria impact the efficacy of ICIs in fighting tumors outside of the gut. Certain strains of commensal gut bacteria promote antitumor responses to ICIs in a variety of preclinical mouse tumor models. Patients with cancer who respond to ICIs have a different microbiome compared with that of patients who don't respond. Fecal microbiota transplants (FMTs) from patients into mice phenocopy the patient tumor responses: FMTs from responders promote response to ICIs, whereas FMTs from nonresponders do not promote a response. In patients, FMTs from patients who have had a complete response to ICIs can overcome resistance in patients who progress on treatment. However, the responses to FMTs are variable. Though emerging studies indicate that gut bacteria can promote antitumor immunity in the absence of ICIs, this Review will focus on studies that demonstrate relationships between the gut microbiome and response to ICIs. We will explore studies investigating which bacteria promote response to ICIs in preclinical models, which bacteria are associated with response in patients with cancer receiving ICIs, the mechanisms by which gut bacteria promote antitumor immunity, and how microbiome-based therapies can be translated to the clinic.
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Affiliation(s)
- Francesca S. Gazzaniga
- Department of Pathology and Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Dennis L. Kasper
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA
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Al-Matouq J, Al-Ghafli H, Alibrahim NN, Alsaffar N, Radwan Z, Ali MD. Unveiling the Interplay Between the Human Microbiome and Gastric Cancer: A Review of the Complex Relationships and Therapeutic Avenues. Cancers (Basel) 2025; 17:226. [PMID: 39858007 PMCID: PMC11763844 DOI: 10.3390/cancers17020226] [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: 11/25/2024] [Revised: 12/23/2024] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
The human microbiota plays a crucial role in maintaining overall health and well-being. The gut microbiota has been implicated in developing and progressing various diseases, including cancer. This review highlights the related mechanisms and the compositions that influence cancer pathogenesis with a highlight on gastric cancer. We provide a comprehensive overview of the mechanisms by which the microbiome influences cancer development, progression, and response to treatment, with a focus on identifying potential biomarkers for early detection, prevention strategies, and novel therapeutic interventions that leverage microbiome modulation. This comprehensive review can guide future research and clinical practices in understanding and harnessing the microbiome to optimize gastric cancer therapies.
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Affiliation(s)
- Jenan Al-Matouq
- Department of Medical Laboratory Sciences, Mohammed Al-Mana College for Medical Sciences, Al Safa, Dammam 34222, Saudi Arabia; (H.A.-G.); (N.N.A.); (N.A.); (Z.R.)
| | - Hawra Al-Ghafli
- Department of Medical Laboratory Sciences, Mohammed Al-Mana College for Medical Sciences, Al Safa, Dammam 34222, Saudi Arabia; (H.A.-G.); (N.N.A.); (N.A.); (Z.R.)
| | - Noura N. Alibrahim
- Department of Medical Laboratory Sciences, Mohammed Al-Mana College for Medical Sciences, Al Safa, Dammam 34222, Saudi Arabia; (H.A.-G.); (N.N.A.); (N.A.); (Z.R.)
| | - Nida Alsaffar
- Department of Medical Laboratory Sciences, Mohammed Al-Mana College for Medical Sciences, Al Safa, Dammam 34222, Saudi Arabia; (H.A.-G.); (N.N.A.); (N.A.); (Z.R.)
| | - Zaheda Radwan
- Department of Medical Laboratory Sciences, Mohammed Al-Mana College for Medical Sciences, Al Safa, Dammam 34222, Saudi Arabia; (H.A.-G.); (N.N.A.); (N.A.); (Z.R.)
| | - Mohammad Daud Ali
- Department of Pharmacy, Mohammed Al-Mana College for Medical Sciences, Al Safa, Dammam 34222, Saudi Arabia;
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11
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Yu J, Chen X, Yang X, Zhang B. Understanding gut dysbiosis for hepatocellular carcinoma diagnosis and treatment. Trends Endocrinol Metab 2024; 35:1006-1020. [PMID: 38969601 DOI: 10.1016/j.tem.2024.06.003] [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: 04/09/2024] [Revised: 06/02/2024] [Accepted: 06/04/2024] [Indexed: 07/07/2024]
Abstract
The gut microbiome can play a crucial role in hepatocellular carcinoma (HCC) progression through the enterohepatic circulation, primarily acting via metabolic reprogramming and alterations in the hepatic immune microenvironment triggered by microbe-associated molecular patterns (MAMPs), metabolites, and fungi. In addition, the gut microbiome shows potential as a biomarker for early HCC diagnosis and for assessing the efficacy of immunotherapy in unresectable HCC. This review examines how gut microbiota dysbiosis, with varied functional profiles, contributes to HCCs of different etiologies. We discuss therapeutic strategies to modulate the gut microbiome including diets, antibiotics, probiotics, fecal microbiota transplantation, and nano-delivery systems, and underscore their potential as an adjunctive treatment modality for HCC.
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Affiliation(s)
- Jingjing Yu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China; Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiangliang Yang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China; Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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12
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Hrubesz G, Leigh J, Ng TL. Understanding the relationship between breast cancer, immune checkpoint inhibitors, and gut microbiota: a narrative review. TRANSLATIONAL BREAST CANCER RESEARCH : A JOURNAL FOCUSING ON TRANSLATIONAL RESEARCH IN BREAST CANCER 2024; 5:31. [PMID: 39534584 PMCID: PMC11557166 DOI: 10.21037/tbcr-24-14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 08/27/2024] [Indexed: 11/16/2024]
Abstract
Background and Objective The composition of gut microbiota plays an important role in predicting and influencing outcomes of cancer treated with immunotherapy. Our objective is to summarize the role of gut microbiota and immunotherapy in breast cancer. Methods A systematic search from inception until July 2024 of key search terms including immunity, breast neoplasm, gastrointestinal microbiome/microbiota, fecal microbiota transplantation, pro- and prebiotics, antibiotics and immunotherapy using EMBASE, MEDLINE and CENTRAL was conducted. The results were screened by two reviewers independently and synthesized and presented descriptively. Key Content and Findings Thirteen studies (5 clinical, 8 pre-clinical) met the eligibility criteria and were published from 2020-2024. Clinical studies showed that the composition and diversity of gut microbiota was associated with patient response to immunotherapy. In pre-clinical studies, dysbiotic states induced by obesity, antibiotics, and diet were associated with immunosuppression and influenced response to programmed cell death-ligand 1 (PD-L1) inhibitors. Microbiota-modulating treatments such as probiotics showed the ability to enhance response to immunotherapy, indicating their potential use as adjunct therapies in breast cancer treatment. Conclusions The composition of gut microbiota could help predict the chance of response to immunotherapy, and modulating gut microbiota has the potential to enhance the efficacy of chemo-immunotherapy in breast cancer. However, the available data relating to breast cancer are limited. Larger prospective studies are required to further elucidate their role as a biomarker and treatment.
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Affiliation(s)
- Gabriella Hrubesz
- Division of Medical Oncology, The Ottawa Hospital Cancer Center, Ottawa, Ontario, Canada
| | - Jennifer Leigh
- Division of Medical Oncology, The Ottawa Hospital Cancer Center, Ottawa, Ontario, Canada
| | - Terry L Ng
- Division of Medical Oncology, The Ottawa Hospital Cancer Center, Ottawa, Ontario, Canada
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13
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Ryan T, Ling S, Trinh A, Segal JP. The role of the microbiome in immune checkpoint inhibitor colitis and hepatitis. Best Pract Res Clin Gastroenterol 2024; 72:101945. [PMID: 39645281 DOI: 10.1016/j.bpg.2024.101945] [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: 05/20/2024] [Accepted: 08/05/2024] [Indexed: 12/09/2024]
Abstract
Immune checkpoint inhibitors have revolutionised management for a variety of different types of malignancies. However, gastrointestinal adverse effects, in particular colitis and hepatitis, are relatively common with up to 30 % of patients being affected. The gut microbiome has emerged as a potential contributor to both the effectiveness of immune checkpoint inhibitors and their side effects. This review will attempt to examine the impact the microbiome has on adverse effects as a result of immune checkpoint inhibitors as well as the potential for manipulation of the microbiome as a form of management for immune mediated colitis.
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Affiliation(s)
- Thomas Ryan
- Faculty of Medicine, University of Melbourne, Melbourne, Australia.
| | - Sophia Ling
- Department of Gastroenterology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Andrew Trinh
- Department of Gastroenterology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Jonathan P Segal
- Faculty of Medicine, University of Melbourne, Melbourne, Australia; Department of Gastroenterology, Peter MacCallum Cancer Centre, Melbourne, Australia
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14
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Won EJ, Lee YJ, Kim MJ, Kim TJ, Shin HJ, Kim TO, Kwon YS. Lower respiratory tract microbiota in patients with clinically suspected nontuberculous mycobacterial pulmonary disease according to the presence of gastroesophageal reflux. PLoS One 2024; 19:e0309446. [PMID: 39196906 PMCID: PMC11355550 DOI: 10.1371/journal.pone.0309446] [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: 02/16/2024] [Accepted: 08/12/2024] [Indexed: 08/30/2024] Open
Abstract
Although gastroesophageal reflux has been recognized as one of the risk factors of nontuberculous mycobacterial pulmonary disease (NTM-PD) progression, the effect of reflux on the lower respiratory tract microbiota has not been studied in detail. We investigated the composition of the lower respiratory tract microbiota in patients with clinically suspected NTM-PD, comparing them based on the presence of reflux. Forty-seven patients suspected of having NTM-PD were enrolled and assigned according to presence of reflux (n = 22) and non- reflux (n = 25). We performed a pepsin ELISA assay to identify the presence of reflux and 16S ribosomal RNA gene amplicon sequencing to evaluate the microbiota in bronchoalveolar lavage fluid. There were no significant differences in the diversity or composition of the lower respiratory microbiota between the NTM-PD and non-NTM-PD groups. Bacterial richness was observed in the non-reflux group than in the reflux group [P = 0.03] and a cluster in the reflux group was observed. The reflux group showed a predominance for Pseudomonas aeruginosa or Staphylococcus aureus among the NTM-PD group and for P. aeruginosa, Haemophilus influenzae, Klebsiella pneumoniae, or Eikenella species among the non-NTM-PD group. The non-reflux groups presented diverse patterns. A linear discriminant analysis and volcano plot demonstrated that P. aeruginosa, H. haemolyticus, Selenomonas artemidis, and Dolosigranulum pigrum were specifically associated with the NTM-PD reflux group, while P. aeruginosa was specifically associated with the non-NTM-PD reflux group. These observations confirm that the lower respiratory microbiota is consistently altered by reflux but not in NTM-PD.
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Affiliation(s)
- Eun Jeong Won
- Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yu Jeong Lee
- Department of Biomedical Sciences, Graduate School of Chonnam National University, Gwangju, Republic of Korea
- Department of Rheumatology, Chonnam National University Hospital, Gwangju, Republic of Korea
| | - Moon-Ju Kim
- Department of Rheumatology, Chonnam National University Hospital, Gwangju, Republic of Korea
| | - Tae-Jong Kim
- Department of Rheumatology, Chonnam National University Hospital, Gwangju, Republic of Korea
| | - Hong-Joon Shin
- Department of Internal Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Tae-Ok Kim
- Department of Internal Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Yong-Soo Kwon
- Department of Internal Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea
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15
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Ajab SM, Zoughbor SH, Labania LA, Östlundh LM, Orsud HS, Olanda MA, Alkaabi O, Alkuwaiti SH, Alnuaimi SM, Al Rasbi Z. Microbiota composition effect on immunotherapy outcomes in colorectal cancer patients: A systematic review. PLoS One 2024; 19:e0307639. [PMID: 39047017 PMCID: PMC11268651 DOI: 10.1371/journal.pone.0307639] [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: 03/12/2024] [Accepted: 07/09/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have emerged as an effective treatment for colorectal cancer (CRC). Studies indicate that the composition of gut microbiota could potentially serve as a biomarker for predicting the clinical effectiveness of immune checkpoint inhibitors. METHODS Following PRISMA guidelines, the review was conducted after registering the protocol with PROSPERO. A comprehensive literature search was carried out across five databases: PubMed, Scopus, Web of Science, Embase, and Cochrane Library. Assessment tools from the National Institutes of Health (NIH) were used to gauge the quality of the studies. RESULTS A total of 5,132 papers were identified, and three studies and one conference abstract published between 2017-2022 met the inclusion criteria and were summarized in a descriptive synthesis table. These four studies were in accord with the following findings, four main phyla, Firmicutes, Bacteroidata, Actinobacteria, and Verrucomicrobiota were associated with CRC patients' clinical response toward ICIs treatment. Ruminococcaceae was predominantly related to CRC patients responding to therapy, while the Micrococcaceae family was more common among the non-responders. Bacterial taxa such as Faecalibacterium and Prevotellaceae were associated with better responses to ICIs and could be predictive biomarkers. The signature of fecal microbiota with Akkermansia muciniphila and Eubacterium rectale enrichment, and Rothia mucilaginosa depletion could independently predict better response to ICIs in patients with CRC. CONCLUSION The findings have brought attention to the notable differences in terms of richness and composition of microbiota between patients who responded positively to the treatment and those who did not. Bacterial species and families, such as Faecalibacterium, Bifidobacterium, Lachnospiraceae, Akkermansia sp., Ruminococcaceae, and Prevotellaceae, have consistently surfaced as potential indicators of immunotherapeutic responses. Furthermore, this review also emphasizes the need for additional comprehensive, multi-center studies with larger sample sizes to validate reported microbiota and expand our understanding of the role of gut microbiota in CRC ICIs therapy. PROSPERO ID: CRD42021277691.
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Affiliation(s)
- Suad Mohamed Ajab
- Institute of Public Health, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Sumaya Hasan Zoughbor
- Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Lena Abdulbaset Labania
- Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
| | | | - Hiba Salaheldin Orsud
- Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Marie Antonette Olanda
- Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Obaid Alkaabi
- Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Shamma Hamad Alkuwaiti
- Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Shaikha Mohammed Alnuaimi
- Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Zakeya Al Rasbi
- Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
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16
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Marroncini G, Naldi L, Martinelli S, Amedei A. Gut-Liver-Pancreas Axis Crosstalk in Health and Disease: From the Role of Microbial Metabolites to Innovative Microbiota Manipulating Strategies. Biomedicines 2024; 12:1398. [PMID: 39061972 PMCID: PMC11273695 DOI: 10.3390/biomedicines12071398] [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: 05/27/2024] [Revised: 06/16/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
The functions of the gut are closely related to those of many other organs in the human body. Indeed, the gut microbiota (GM) metabolize several nutrients and compounds that, once released in the bloodstream, can reach distant organs, thus influencing the metabolic and inflammatory tone of the host. The main microbiota-derived metabolites responsible for the modulation of endocrine responses are short-chain fatty acids (SCFAs), bile acids and glucagon-like peptide 1 (GLP-1). These molecules can (i) regulate the pancreatic hormones (insulin and glucagon), (ii) increase glycogen synthesis in the liver, and (iii) boost energy expenditure, especially in skeletal muscles and brown adipose tissue. In other words, they are critical in maintaining glucose and lipid homeostasis. In GM dysbiosis, the imbalance of microbiota-related products can affect the proper endocrine and metabolic functions, including those related to the gut-liver-pancreas axis (GLPA). In addition, the dysbiosis can contribute to the onset of some diseases such as non-alcoholic steatohepatitis (NASH)/non-alcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC), and type 2 diabetes (T2D). In this review, we explored the roles of the gut microbiota-derived metabolites and their involvement in onset and progression of these diseases. In addition, we detailed the main microbiota-modulating strategies that could improve the diseases' development by restoring the healthy balance of the GLPA.
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Affiliation(s)
- Giada Marroncini
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (G.M.); (L.N.)
| | - Laura Naldi
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (G.M.); (L.N.)
| | - Serena Martinelli
- Department of Clinical and Experimental Medicine, University of Florence, 50139 Florence, Italy
| | - Amedeo Amedei
- Department of Clinical and Experimental Medicine, University of Florence, 50139 Florence, Italy
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), 50139 Florence, Italy
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17
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Davoutis E, Gkiafi Z, Lykoudis PM. Bringing gut microbiota into the spotlight of clinical research and medical practice. World J Clin Cases 2024; 12:2293-2300. [PMID: 38765739 PMCID: PMC11099419 DOI: 10.12998/wjcc.v12.i14.2293] [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: 12/27/2023] [Revised: 01/30/2024] [Accepted: 04/07/2024] [Indexed: 04/29/2024] Open
Abstract
Despite the increasing scientific interest and expanding role of gut microbiota (GM) in human health, it is rarely reported in case reports and deployed in clinical practice. Proteins and metabolites produced by microbiota contribute to immune system development, energy homeostasis and digestion. Exo- and endogenous factors can alter its composition. Disturbance of microbiota, also known as dysbiosis, is associated with various pathological conditions. Specific bacterial taxa and related metabolites are involved in disease pathogenesis and therefore can serve as a diagnostic tool. GM could also be a useful prognostic factor by predicting future disease onset and preventing hospital-associated infections. Additionally, it can influence response to treatments, including those for cancers, by altering drug bioavailability. A thorough understanding of its function has permitted significant development in therapeutics, such as probiotics and fecal transplantation. Hence, GM should be considered as a ground-breaking biological parameter, and it is advisable to be investigated and reported in literature in a more consistent and systematic way.
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Affiliation(s)
- Efstathia Davoutis
- School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Zoi Gkiafi
- School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Panagis M Lykoudis
- School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
- Division of Surgery and Interventional Science, University College London, London WC1E 6BT, United Kingdom
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18
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Li Z, Xiong W, Liang Z, Wang J, Zeng Z, Kołat D, Li X, Zhou D, Xu X, Zhao L. Critical role of the gut microbiota in immune responses and cancer immunotherapy. J Hematol Oncol 2024; 17:33. [PMID: 38745196 PMCID: PMC11094969 DOI: 10.1186/s13045-024-01541-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: 10/25/2023] [Accepted: 04/03/2024] [Indexed: 05/16/2024] Open
Abstract
The gut microbiota plays a critical role in the progression of human diseases, especially cancer. In recent decades, there has been accumulating evidence of the connections between the gut microbiota and cancer immunotherapy. Therefore, understanding the functional role of the gut microbiota in regulating immune responses to cancer immunotherapy is crucial for developing precision medicine. In this review, we extract insights from state-of-the-art research to decipher the complicated crosstalk among the gut microbiota, the systemic immune system, and immunotherapy in the context of cancer. Additionally, as the gut microbiota can account for immune-related adverse events, we discuss potential interventions to minimize these adverse effects and discuss the clinical application of five microbiota-targeted strategies that precisely increase the efficacy of cancer immunotherapy. Finally, as the gut microbiota holds promising potential as a target for precision cancer immunotherapeutics, we summarize current challenges and provide a general outlook on future directions in this field.
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Affiliation(s)
- Zehua Li
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China
- Chinese Academy of Medical Sciences (CAMS), CAMS Oxford Institute (COI), Nuffield Department of Medicine, University of Oxford, Oxford, England
| | - Weixi Xiong
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
- Institute of Brain Science and Brain-Inspired Technology of West China Hospital, Sichuan University, Chengdu, China
| | - Zhu Liang
- Chinese Academy of Medical Sciences (CAMS), CAMS Oxford Institute (COI), Nuffield Department of Medicine, University of Oxford, Oxford, England
- Target Discovery Institute, Center for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, England
| | - Jinyu Wang
- Departments of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China
| | - Ziyi Zeng
- Department of Neonatology, West China Second University Hospital of Sichuan University, Chengdu, China
| | - Damian Kołat
- Department of Functional Genomics, Medical University of Lodz, Lodz, Poland
- Department of Biomedicine and Experimental Surgery, Medical University of Lodz, Lodz, Poland
| | - Xi Li
- Department of Urology, Churchill Hospital, Oxford University Hospitals NHS Foundation, Oxford, UK
| | - Dong Zhou
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
- Institute of Brain Science and Brain-Inspired Technology of West China Hospital, Sichuan University, Chengdu, China
| | - Xuewen Xu
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Linyong Zhao
- Department of General Surgery and Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
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19
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Kang X, Lau HCH, Yu J. Modulating gut microbiome in cancer immunotherapy: Harnessing microbes to enhance treatment efficacy. Cell Rep Med 2024; 5:101478. [PMID: 38631285 PMCID: PMC11031381 DOI: 10.1016/j.xcrm.2024.101478] [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: 11/18/2023] [Revised: 01/15/2024] [Accepted: 02/22/2024] [Indexed: 04/19/2024]
Abstract
Immunotherapy has emerged as a robust approach against cancer, yet its efficacy has varied among individuals, accompanied by the occurrence of immune-related adverse events. As a result, the efficacy of immunotherapy is far from satisfactory, and enormous efforts have been invested to develop strategies to improve patient outcomes. The gut microbiome is now well acknowledged for its critical role in immunotherapy, with better understanding on host-microbes interaction in the context of cancer treatment. Also, an increasing number of trials have been conducted to evaluate the potential and feasibility of microbiome-targeting approaches to enhance efficacy of cancer treatment in patients. Here, the role of the gut microbiome and metabolites (e.g., short-chain fatty acids, tryptophan metabolites) in immunotherapy and the underlying mechanisms are explored. The application of microbiome-targeting approaches that aim to improve immunotherapy efficacy (e.g., fecal microbiota transplantation, probiotics, dietary intervention) is also elaborated, with further discussion on current challenges and suggestions for future research.
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Affiliation(s)
- Xing Kang
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, Hong Kong; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Harry Cheuk-Hay Lau
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Jun Yu
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, Hong Kong.
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20
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Ladd AD, Duarte S, Sahin I, Zarrinpar A. Mechanisms of drug resistance in HCC. Hepatology 2024; 79:926-940. [PMID: 36680397 DOI: 10.1097/hep.0000000000000237] [Citation(s) in RCA: 79] [Impact Index Per Article: 79.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 11/21/2022] [Indexed: 01/22/2023]
Abstract
HCC comprises ∼80% of primary liver cancer. HCC is the only major cancer for which death rates have not improved over the last 10 years. Most patients are diagnosed with advanced disease when surgical and locoregional treatments are not feasible or effective. Sorafenib, a multikinase inhibitor targeting cell growth and angiogenesis, was approved for advanced unresectable HCC in 2007. Since then, other multikinase inhibitors have been approved. Lenvatinib was found to be noninferior to sorafenib as a first-line agent. Regorafenib, cabozantinib, and ramucirumab were shown to prolong survival as second-line agents. Advances in immunotherapy for HCC have also added hope for patients, but their efficacy remains limited. A large proportion of patients with advanced HCC gain no long-term benefit from systemic therapy due to primary and acquired drug resistance, which, combined with its rising incidence, keeps HCC a highly fatal disease. This review summarizes mechanisms of primary and acquired resistance to therapy and includes methods for bypassing resistance. It addresses recent advancements in immunotherapy, provides new perspectives on the linkage between drug resistance and molecular etiology of HCC, and evaluates the role of the microbiome in drug resistance. It also discusses alterations in signaling pathways, dysregulation of apoptosis, modulations in the tumor microenvironment, involvement of cancer stem cells, changes in drug metabolism/transport, tumor hypoxia, DNA repair, and the role of microRNAs in drug resistance. Understanding the interplay among these factors will provide guidance on the development of new therapeutic strategies capable of improving patient outcomes.
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Affiliation(s)
- Alexandra D Ladd
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Sergio Duarte
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Ilyas Sahin
- Division of Hematology/Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Ali Zarrinpar
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, USA
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21
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Pinto E, Meneghel P, Farinati F, Russo FP, Pelizzaro F, Gambato M. Efficacy of immunotherapy in hepatocellular carcinoma: Does liver disease etiology have a role? Dig Liver Dis 2024; 56:579-588. [PMID: 37758610 DOI: 10.1016/j.dld.2023.08.062] [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: 07/02/2023] [Revised: 08/18/2023] [Accepted: 08/30/2023] [Indexed: 09/29/2023]
Abstract
The systemic treatment of hepatocellular carcinoma (HCC) is changing rapidly. After a decade of tyrosine kinase inhibitors (TKIs), as the only therapeutic option for the treatment of advanced HCC, in the last few years several phase III trials demonstrated the efficacy of immune checkpoint inhibitors (ICIs). The combination of the anti-PD-L1 atezolizumab and the anti-vascular endothelial growth factor (VEGF) bevacizumab demonstrated the superiority over sorafenib and currently represents the standard of care treatment for advanced HCC. In addition, the combination of durvalumab (an anti-PD-L1) and tremelimumab (an anti-CTLA4) proved to be superior to sorafenib, and in the same trial durvalumab monotherapy showed non-inferiority compared to sorafenib. However, early reports suggest an influence of HCC etiology in modulating the response to these drugs. In particular, a lower effectiveness of ICIs has been suggested in patients with non-viral HCC (in particular non-alcoholic fatty liver disease). Nevertheless, randomized controlled trials available to date have not been stratified for etiology and data suggesting a possible impact of etiology in the outcome of patients managed with ICIs derive from subgroup not pre-specified analyses. In this review, we aim to examine the potential impact of HCC etiology on the response to immunotherapy regimens for HCC.
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Affiliation(s)
- Elisa Pinto
- Gastroenterology and Multivisceral Transplant Unit, Padua University Hospital, Padua, Italy
| | - Paola Meneghel
- Gastroenterology and Multivisceral Transplant Unit, Padua University Hospital, Padua, Italy
| | - Fabio Farinati
- Gastroenterology and Multivisceral Transplant Unit, Padua University Hospital, Padua, Italy
| | - Francesco Paolo Russo
- Gastroenterology and Multivisceral Transplant Unit, Padua University Hospital, Padua, Italy.
| | - Filippo Pelizzaro
- Gastroenterology and Multivisceral Transplant Unit, Padua University Hospital, Padua, Italy
| | - Martina Gambato
- Gastroenterology and Multivisceral Transplant Unit, Padua University Hospital, Padua, Italy.
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22
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Li R, Wang J, Li X, Liang Y, Jiang Y, Zhang Y, Xu P, Deng L, Wang Z, Sun T, Wu J, Xie H, Wang Y. T-cell receptor sequencing reveals hepatocellular carcinoma immune characteristics according to Barcelona Clinic liver cancer stages within liver tissue and peripheral blood. Cancer Sci 2024; 115:94-108. [PMID: 37962061 PMCID: PMC10823291 DOI: 10.1111/cas.16013] [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: 07/02/2023] [Revised: 10/19/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023] Open
Abstract
Analysis of T-cell receptor (TCR) repertoires in different stages of hepatocellular carcinoma (HCC) might help to elucidate its pathogenesis and progression. This study aimed to investigate TCR profiles in liver biopsies and peripheral blood mononuclear cells (PBMCs) in different Barcelona Clinic liver cancer (BCLC) stages of HCC. Ten patients in early stage (BCLC_A), 10 patients in middle stage (BCLC_B), and 10 patients in late stage (BCLC_C) cancer were prospectively enrolled. The liver tumor tissues, adjacent tissues, and PBMCs of each patient were collected and examined by TCR β sequencing. Based on the ImMunoGeneTics (IMGT) database, we aligned the V, D, J, and C gene segments and identified the frequency of CDR3 sequences and amino acids sequence. Diversity of TCR in PBMCs was higher than in both tumor tissues and adjacent tissues, regardless of BCLC stage and postoperative recurrence. TCR clonality was increased in T cells from peripheral blood in advanced HCC, compared with the early and middle stages. No statistical differences were observed between different BCLC stages, either in tumors or adjacent tissues. TCR clonality revealed no significant difference between recurrent tumor and non-recurrent tumor, therefore PBMCs was better to be representative of TCR characteristics in different stages of HCC compared to tumor tissues. Clonal expansion of T cells was associated with low risk of recurrence in HCC patients.
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Affiliation(s)
- Rui Li
- School of MedicineSouthern University of Science and TechnologyShenzhenChina
| | - Junxiao Wang
- Interventional Radiology, The Fifth Medical CenterChinese PLA General HospitalBeijingChina
- Aerospace Medical Center, Aerospace Center HospitalPeking University Aerospace Clinical CollegeBeijingChina
| | - Xiubin Li
- Department of Urology, The Third Medical CenterChinese PLA General HospitalBeijingChina
| | - Yining Liang
- School of MedicineSouthern University of Science and TechnologyShenzhenChina
| | - Yiyun Jiang
- Department of Pathology and Hepatology, The Fifth Medical CenterChinese PLA General HospitalBeijingChina
| | - Yuwei Zhang
- School of MedicineSouthern University of Science and TechnologyShenzhenChina
| | - Pengfei Xu
- Hangzhou ImmuQuad BiotechnologiesHangzhouChina
| | - Ling Deng
- Hangzhou ImmuQuad BiotechnologiesHangzhouChina
| | - Zhe Wang
- School of MedicineSouthern University of Science and TechnologyShenzhenChina
| | - Tao Sun
- Hangzhou ImmuQuad BiotechnologiesHangzhouChina
- Institute of Wenzhou, Zhejiang UniversityWenzhouChina
| | - Jian Wu
- Department of Laboratory MedicineThe Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical UniversitySuzhouChina
| | - Hui Xie
- Interventional Radiology, The Fifth Medical CenterChinese PLA General HospitalBeijingChina
| | - Yijin Wang
- School of MedicineSouthern University of Science and TechnologyShenzhenChina
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23
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Sparfel L, Ratodiarivony S, Boutet-Robinet E, Ellero-Simatos S, Jolivet-Gougeon A. Akkermansia muciniphila and Alcohol-Related Liver Diseases. A Systematic Review. Mol Nutr Food Res 2024; 68:e2300510. [PMID: 38059838 DOI: 10.1002/mnfr.202300510] [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: 07/18/2023] [Revised: 10/03/2023] [Indexed: 12/08/2023]
Abstract
SCOPE Akkermansia muciniphila (A. muciniphila) are Gram negative commensal bacteria, degrading mucin in the intestinal mucosa, modulating intestinal permeability and inflammation in the digestive tract, liver, and blood. Some components can promote the relative abundance of A. muciniphila in the gut microbiota, but lower levels of A. muciniphila are more commonly found in people with obesity, diabetes, metabolic syndromes, or inflammatory digestive diseases. Over-intake of ethanol can also induce a decrease of A. muciniphila, associated with dysregulation of microbial metabolite production, impaired intestinal permeability, induction of chronic inflammation, and production of cytokines. METHODS AND RESULTS Using a PRISMA search strategy, a review is performed on the bacteriological characteristics of A. muciniphila, the factors capable of modulating its relative abundance in the digestive tract and its probiotic use in alcohol-related liver diseases (alcoholic hepatitis, cirrhosis, hepatocellular carcinoma, hepatic transplantation, partial hepatectomy). CONCLUSION Several studies have shown that supplementation with A. muciniphila can improve ethanol-related hepatic pathologies, and highlight the interest in using this bacterial species as a probiotic.
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Affiliation(s)
- Lydie Sparfel
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, F-35000, France
| | - Sandy Ratodiarivony
- Univ Rennes, Bacterial Regulatory RNAs and Medicine (BRM), UMR_S 1230, Rennes, F-35000, France
| | - Elisa Boutet-Robinet
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300, Toulouse, France
| | - Sandrine Ellero-Simatos
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300, Toulouse, France
| | - Anne Jolivet-Gougeon
- Univ Rennes, Bacterial Regulatory RNAs and Medicine (BRM), UMR_S 1230, Rennes, F-35000, France
- Teaching Hospital, CHU Rennes, 2 rue Henri Le Guilloux 35033, Rennes, F-35000, France
- INSERM, INRAE, Institut NUMECAN (Nutrition Metabolisms and Cancer), U1241, INSERM 1241, Rennes, F-35000, France
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24
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Chua HH, Chen YH, Wu LL, Yang HC, Lin CR, Chen HL, Wu JF, Chang MH, Chen PJ, Ni YH. Antagonism Between Gut Ruminococcus gnavus and Akkermansia muciniphila Modulates the Progression of Chronic Hepatitis B. Cell Mol Gastroenterol Hepatol 2023; 17:361-381. [PMID: 38092311 PMCID: PMC10821531 DOI: 10.1016/j.jcmgh.2023.12.003] [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: 06/03/2023] [Revised: 11/14/2023] [Accepted: 12/04/2023] [Indexed: 01/01/2024]
Abstract
BACKGROUND & AIMS A long immune-tolerant (IT) phase lasting for decades and delayed HBeAg seroconversion (HBe-SC) in patients with chronic hepatitis B (CHB) increase the risk of liver diseases. Early entry into the immune-active (IA) phase and HBe-SC confers a favorable clinical outcome with an unknown mechanism. We aimed to identify factor(s) triggering IA entry and HBe-SC in the natural history of CHB. METHODS To study the relevance of gut microbiota evolution in the risk of CHB activity, fecal samples were collected from CHB patients (n = 102) in different disease phases. A hepatitis B virus (HBV)-hydrodynamic injection (HDI) mouse model was therefore established in several mouse strains and germ-free mice, and multiplatform metabolomic and bacteriologic assays were performed. RESULTS Ruminococcus gnavus was the most abundant species in CHB patients in the IT phase, whereas Akkermansia muciniphila was predominantly enriched in IA patients and associated with alanine aminotransferase flares, HBeAg loss, and early HBe-SC. HBV-HDI mouse models recapitulated this human finding. Increased cholesterol-to-bile acids (BAs) metabolism was found in IT patients because R gnavus encodes bile salt hydrolase to deconjugate primary BAs and augment BAs total pool for facilitating HBV persistence and prolonging the IT course. A muciniphila counteracted this activity through the direct removal of cholesterol. The secretome metabolites of A muciniphila, which contained small molecules structurally similar to apigenin, lovastatin, ribavirin, etc., inhibited the growth and the function of R gnavus to allow HBV elimination. CONCLUSIONS R gnavus and A muciniphila play opposite roles in HBV infection. A muciniphila metabolites, which benefit the elimination of HBV, may contribute to future anti-HBV strategies.
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Affiliation(s)
- Huey-Huey Chua
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan
| | - Ya-Hui Chen
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan
| | - Li-Ling Wu
- Department and Institute of Physiology, National Yang-Ming Chiao-Tung University College of Medicine, Taipei, Taiwan
| | - Hung-Chih Yang
- Department of Internal Medicine, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chia-Ray Lin
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan; Graduate Institute of Medical Education and Bioethics, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jia-Feng Wu
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Department of Internal Medicine, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Center of Genomic and Precision Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan; Center of Genomic and Precision Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Medical Microbiota Center, National Taiwan University College of Medicine, Taipei, Taiwan.
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25
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Cheng M, Zheng X, Wei J, Liu M. Current state and challenges of emerging biomarkers for immunotherapy in hepatocellular carcinoma (Review). Exp Ther Med 2023; 26:586. [PMID: 38023367 PMCID: PMC10665984 DOI: 10.3892/etm.2023.12285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 08/29/2023] [Indexed: 12/01/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer. According to the American Cancer Society, among patients diagnosed with advanced liver cancer, HCC has the sixth-highest incident rate, resulting in a poor prognosis. Surgery, radiofrequency ablation, transcatheter arterial chemoembolization, radiation, chemotherapy, targeted therapy and immunotherapy are the current treatment options available. Immunotherapy, which has emerged as an innovative treatment strategy over the past decade, is serving a vital role in the treatment of advanced liver cancer. Since only a small number of individuals can benefit from immunotherapy, biomarkers are required to help clinicians identify the target populations for this precision medicine. These biomarkers, such as PD-1/PD-L1, tumor mutational burden and circulating tumor DNA, can be used to investigate interactions between immune checkpoint inhibitors and tumors. The present review summarizes information on the currently available biomarkers used for immunotherapy and the challenges that are present.
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Affiliation(s)
- Mo Cheng
- Department of Medical Oncology, Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xiufeng Zheng
- Department of Medical Oncology, Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Jing Wei
- Department of Medical Oncology, Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Ming Liu
- Department of Medical Oncology, Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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26
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Guo C, Kong L, Xiao L, Liu K, Cui H, Xin Q, Gu X, Jiang C, Wu J. The impact of the gut microbiome on tumor immunotherapy: from mechanism to application strategies. Cell Biosci 2023; 13:188. [PMID: 37828613 PMCID: PMC10571290 DOI: 10.1186/s13578-023-01135-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 09/15/2023] [Indexed: 10/14/2023] Open
Abstract
Immunotherapy is one of the fastest developing areas in the field of oncology. Many immunological treatment strategies for refractory tumors have been approved and marketed. Nevertheless, much clinical and preclinical experimental evidence has shown that the efficacy of immunotherapy in tumor treatment varies markedly among individuals. The commensal microbiome mainly colonizes the intestinal lumen in humans, is affected by a variety of factors and exhibits individual variation. Moreover, the gut is considered the largest immune organ of the body due to its influence on the immune system. In the last few decades, with the development of next-generation sequencing (NGS) techniques and in-depth research, the view that the gut microbiota intervenes in antitumor immunotherapy through the immune system has been gradually confirmed. Here, we review important studies published in recent years focusing on the influences of microbiota on immune system and the progression of malignancy. Furthermore, we discuss the mechanism by which microbiota affect tumor immunotherapy, including immune checkpoint blockade (ICB) and adoptive T-cell therapy (ACT), and strategies for modulating the microbial composition to facilitate the antitumor immune response. Finally, opportunity and some challenges are mentioned to enable a more systematic understanding of tumor treatment in the future and promote basic research and clinical application in related fields.
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Affiliation(s)
- Ciliang Guo
- State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, National Institute of Healthcare Data Science at Nanjing University, Nanjing University, 22 Hankou Road, Nanjing, 210093, Jiangsu, China
| | - Lingkai Kong
- State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, National Institute of Healthcare Data Science at Nanjing University, Nanjing University, 22 Hankou Road, Nanjing, 210093, Jiangsu, China
| | - Lingjun Xiao
- State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, National Institute of Healthcare Data Science at Nanjing University, Nanjing University, 22 Hankou Road, Nanjing, 210093, Jiangsu, China
| | - Kua Liu
- State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, National Institute of Healthcare Data Science at Nanjing University, Nanjing University, 22 Hankou Road, Nanjing, 210093, Jiangsu, China
| | - Huawei Cui
- State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, National Institute of Healthcare Data Science at Nanjing University, Nanjing University, 22 Hankou Road, Nanjing, 210093, Jiangsu, China
| | - Qilei Xin
- Jinan Microecological Biomedicine Shandong Laboratory, Shounuo City Light West Block, Qingdao Road 3716#, Huaiyin District, Jinan, Shandong, China
| | - Xiaosong Gu
- State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, National Institute of Healthcare Data Science at Nanjing University, Nanjing University, 22 Hankou Road, Nanjing, 210093, Jiangsu, China
- Jinan Microecological Biomedicine Shandong Laboratory, Shounuo City Light West Block, Qingdao Road 3716#, Huaiyin District, Jinan, Shandong, China
| | - Chunping Jiang
- State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, National Institute of Healthcare Data Science at Nanjing University, Nanjing University, 22 Hankou Road, Nanjing, 210093, Jiangsu, China.
- Jinan Microecological Biomedicine Shandong Laboratory, Shounuo City Light West Block, Qingdao Road 3716#, Huaiyin District, Jinan, Shandong, China.
| | - Junhua Wu
- State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, National Institute of Healthcare Data Science at Nanjing University, Nanjing University, 22 Hankou Road, Nanjing, 210093, Jiangsu, China.
- Jinan Microecological Biomedicine Shandong Laboratory, Shounuo City Light West Block, Qingdao Road 3716#, Huaiyin District, Jinan, Shandong, China.
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27
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Gok Yavuz B, Datar S, Chamseddine S, Mohamed YI, LaPelusa M, Lee SS, Hu ZI, Koay EJ, Tran Cao HS, Jalal PK, Daniel-MacDougall C, Hassan M, Duda DG, Amin HM, Kaseb AO. The Gut Microbiome as a Biomarker and Therapeutic Target in Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:4875. [PMID: 37835569 PMCID: PMC10571776 DOI: 10.3390/cancers15194875] [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: 09/10/2023] [Revised: 10/03/2023] [Accepted: 10/05/2023] [Indexed: 10/15/2023] Open
Abstract
The microbiome is pivotal in maintaining health and influencing disease by modulating essential inflammatory and immune responses. Hepatocellular carcinoma (HCC), ranking as the third most common cause of cancer-related fatalities globally, is influenced by the gut microbiome through bidirectional interactions between the gut and liver, as evidenced in both mouse models and human studies. Consequently, biomarkers based on gut microbiota represent promising non-invasive tools for the early detection of HCC. There is a growing body of evidence suggesting that the composition of the gut microbiota may play a role in the efficacy of immunotherapy in different types of cancer; thus, it could be used as a predictive biomarker. In this review, we will dissect the gut microbiome's role as a potential predictive and diagnostic marker in HCC and evaluate the latest progress in leveraging the gut microbiome as a novel therapeutic avenue for HCC patients, with a special emphasis on immunotherapy.
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Affiliation(s)
- Betul Gok Yavuz
- Department of Medicine, University of Missouri, St. Louis, MO 63121, USA;
| | - Saumil Datar
- Department of Medicine, University of Texas at Houston, Houston, TX 77030, USA;
| | - Shadi Chamseddine
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (Y.I.M.); (S.S.L.); (Z.I.H.)
| | - Yehia I. Mohamed
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (Y.I.M.); (S.S.L.); (Z.I.H.)
| | - Michael LaPelusa
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Sunyoung S. Lee
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (Y.I.M.); (S.S.L.); (Z.I.H.)
| | - Zishuo Ian Hu
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (Y.I.M.); (S.S.L.); (Z.I.H.)
| | - Eugene J. Koay
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Hop S. Tran Cao
- Hepato-Pancreato-Biliary Section, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Prasun Kumar Jalal
- Division of Gastroenterology, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Carrie Daniel-MacDougall
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (C.D.-M.); (M.H.)
| | - Manal Hassan
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (C.D.-M.); (M.H.)
| | - Dan G. Duda
- Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA;
| | - Hesham M. Amin
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Ahmed O. Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (Y.I.M.); (S.S.L.); (Z.I.H.)
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28
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Sun J, Chen F, Wu G. Potential effects of gut microbiota on host cancers: focus on immunity, DNA damage, cellular pathways, and anticancer therapy. THE ISME JOURNAL 2023; 17:1535-1551. [PMID: 37553473 PMCID: PMC10504269 DOI: 10.1038/s41396-023-01483-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 07/14/2023] [Accepted: 07/20/2023] [Indexed: 08/10/2023]
Abstract
The symbiotic bacteria that live in the human gut and the metabolites they produce have long influenced local and systemic physiological and pathological processes of the host. The gut microbiota are increasingly being recognized for its impact on a range of human diseases, including cancer, it may play a key role in the occurrence, progression, treatment, and prognosis of many types of cancer. Understanding the functional role of the gut microbiota in cancer is crucial for the development of the era of personalized medicine. Here, we review recent advances in research and summarize the important associations and clear experimental evidence for the role of the gut microbiota in a variety of human cancers, focus on the application and possible challenges associated with the gut microbiota in antitumor therapy. In conclusion, our research demonstrated the multifaceted mechanisms of gut microbiota affecting human cancer and provides directions and ideas for future clinical research.
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Affiliation(s)
- Jiaao Sun
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Feng Chen
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
| | - Guangzhen Wu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
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29
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Zhang M, Liu J, Xia Q. Role of gut microbiome in cancer immunotherapy: from predictive biomarker to therapeutic target. Exp Hematol Oncol 2023; 12:84. [PMID: 37770953 PMCID: PMC10537950 DOI: 10.1186/s40164-023-00442-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 09/04/2023] [Indexed: 09/30/2023] Open
Abstract
Immunotherapy has emerged as an effective treatment for various types of cancers. Recent studies have highlighted a significant correlation between the gut microbiome and patients' response to immunotherapy. Several characteristics of the gut microbiome, such as community structures, taxonomic compositions, and molecular functions, have been identified as crucial biomarkers for predicting immunotherapy response and immune-related adverse events (irAEs). Unlike other -omics, the gut microbiome can serve as not only biomarkers but also potential targets for enhancing the efficacy of immunotherapy. Approaches for modulating the gut microbiome include probiotics/prebiotics supplementation, dietary interventions, fecal microbiota transplantation (FMT), and antibiotic administration. This review primarily focuses on elucidating the potential role of the gut microbiome in predicting the response to cancer immunotherapy and improving its efficacy. Notably, we explore reasons behind inconsistent findings observed in different studies, and highlight the underlying benefits of antibiotics in liver cancer immunotherapy.
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Affiliation(s)
- Mengwei Zhang
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China
- Shanghai Institute of Transplantation, Shanghai, China
| | - Jinkai Liu
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China
- Shanghai Institute of Transplantation, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China
- Shanghai Institute of Transplantation, Shanghai, China
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30
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Patel R, Chong DST, Guy AJ, Kennedy M. Dialister pneumosintes and aortic graft infection - a case report. BMC Infect Dis 2023; 23:617. [PMID: 37726696 PMCID: PMC10507818 DOI: 10.1186/s12879-023-08584-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 09/05/2023] [Indexed: 09/21/2023] Open
Abstract
BACKGROUND Dialister pneumosintes is an anaerobic, Gram negative bacillus, found in the human oral cavity and associated with periodontitis. It has also been isolated from gastric mucosa and stool samples. Recent case reports implicate D. pneumosintes in local infection such as dental root canals, sinusitis, Lemierres syndrome and brain abscesses, as well as distal infections of the liver and lung through haematogenous spread. CASE PRESENTATION We present a novel case of aortic graft infection and aortoenteric fistula (AEF) in a 75 year old Caucasian male, associated with D. pneumosintes bacteraemia. Microbiological evaluation of septic emboli in the lower limbs revealed other gastrointestinal flora. This suggests either AEF leading to graft infection and subsequent distal emboli and bacteraemia, or a dental origin of infection which seeded to the graft, resulting in AEF and systemic infection. To our knowledge this is the first report of D. pneumosintes associated aortic graft infection. The patient underwent surgical explantation, oversew of the aorta and placement of extra-anatomical bypass graft in conjunction with antimicrobial therapy, making a good recovery with discharge home after a 35-day hospital admission. CONCLUSION We report a case of Dialister pneumosintes bacteraemia associated with aortic graft infection. To our knowledge, vascular graft-associated infection with D. pneumosintes has not been reported before.
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Affiliation(s)
- Rachel Patel
- Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
- University of Exeter, Exeter, UK.
| | - Debra S T Chong
- Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
| | - Alison J Guy
- Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
| | - Matthew Kennedy
- Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
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31
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Xiong W, Yang C, Xia J, Wang W, Li N. G. lucidum triterpenes restores intestinal flora balance in non-hepatitis B virus-related hepatocellular carcinoma: evidence of 16S rRNA sequencing and network pharmacology analysis. Front Pharmacol 2023; 14:1197418. [PMID: 37790812 PMCID: PMC10544910 DOI: 10.3389/fphar.2023.1197418] [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: 03/31/2023] [Accepted: 08/28/2023] [Indexed: 10/05/2023] Open
Abstract
Background: Ganoderma lucidum (G. lucidum) is a popular traditional remedy medicine used in Asia to promote health and longevity, which has also been highlighted for anti-cancer effects. This study investigated the molecular pharmacological mechanism of G. lucidum triterpenes in influencing intestinal flora imbalance in non-hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) based on 16S rRNA sequencing technology and network pharmacology analysis. Methods: 16S rRNA sequencing data of fecal samples from normal controls and HCC patients were obtained from the SRA database. G. lucidum triterpenes and HCC-related targets were screened by BATMAN-TCM, ETCM, and GeneCards databases. The TCGA-LIHC dataset was downloaded through the TCGA database to analyze the differential expression of key genes. NHBV-related HCC-related transcriptome RNA sequencing dataset was downloaded via the GEO database. Results: Abundance of intestinal flora in the HBV-related HCC and NHBV-related samples was higher than that of control samples. The intestinal flora of NHBV samples was mainly enriched in apoptosis and p53 pathways. Totally, 465 G. lucidum triterpenes-related targets were intersected with 4186 HCC-related targets, yielding 176 intersected targets. Among them, apoptosis and p53 pathway factors were located at the core of the protein-protein interactions network. Ganosporelactone B, the active component of G. lucidum triterpenes, had the lowest binding free energy to CASP3. CASP3 expression were upregulated in HCC tissue samples, and had higher predictive value in NHBV-related HCC patients. Conclusion: Therefore, Ganosporelactone B, the active ingredient of G. lucidum triterpenes, improves the imbalance of intestinal flora and ultimately curtails development of NHBV-related HCC.
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Affiliation(s)
| | | | | | - Wenxiang Wang
- Chongqing Three Gorges Medical College, Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing, China
| | - Ning Li
- Chongqing Three Gorges Medical College, Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing, China
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Schaft N, Dörrie J, Schuler G, Schuler-Thurner B, Sallam H, Klein S, Eisenberg G, Frankenburg S, Lotem M, Khatib A. The future of affordable cancer immunotherapy. Front Immunol 2023; 14:1248867. [PMID: 37736099 PMCID: PMC10509759 DOI: 10.3389/fimmu.2023.1248867] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 08/11/2023] [Indexed: 09/23/2023] Open
Abstract
The treatment of cancer was revolutionized within the last two decades by utilizing the mechanism of the immune system against malignant tissue in so-called cancer immunotherapy. Two main developments boosted cancer immunotherapy: 1) the use of checkpoint inhibitors, which are characterized by a relatively high response rate mainly in solid tumors; however, at the cost of serious side effects, and 2) the use of chimeric antigen receptor (CAR)-T cells, which were shown to be very efficient in the treatment of hematologic malignancies, but failed to show high clinical effectiveness in solid tumors until now. In addition, active immunization against individual tumors is emerging, and the first products have reached clinical approval. These new treatment options are very cost-intensive and are not financially compensated by health insurance in many countries. Hence, strategies must be developed to make cancer immunotherapy affordable and to improve the cost-benefit ratio. In this review, we discuss the following strategies: 1) to leverage the antigenicity of "cold tumors" with affordable reagents, 2) to use microbiome-based products as markers or therapeutics, 3) to apply measures that make adoptive cell therapy (ACT) cheaper, e.g., the use of off-the-shelf products, 4) to use immunotherapies that offer cheaper platforms, such as RNA- or peptide-based vaccines and vaccines that use shared or common antigens instead of highly personal antigens, 5) to use a small set of predictive biomarkers instead of the "sequence everything" approach, and 6) to explore affordable immunohistochemistry markers that may direct individual therapies.
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Affiliation(s)
- Niels Schaft
- Department of Dermatology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), Erlangen, Germany
| | - Jan Dörrie
- Department of Dermatology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), Erlangen, Germany
| | - Gerold Schuler
- Department of Dermatology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Beatrice Schuler-Thurner
- Department of Dermatology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Husam Sallam
- Molecular Genetics and Genetic Toxicology, Health Science Department, American Arab University, Ramallah, Palestine
| | - Shiri Klein
- Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Galit Eisenberg
- Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Shoshana Frankenburg
- Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Michal Lotem
- Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel
- Hadassah Cancer Research Institute, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Areej Khatib
- Women's Health Research Unit, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
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Muscolino P, Granata B, Omero F, De Pasquale C, Campana S, Calabrò A, D’Anna F, Drommi F, Pezzino G, Cavaliere R, Ferlazzo G, Silvestris N, Speranza D. Potential predictive role of gut microbiota to immunotherapy in HCC patients: a brief review. Front Oncol 2023; 13:1247614. [PMID: 37692859 PMCID: PMC10486017 DOI: 10.3389/fonc.2023.1247614] [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: 06/26/2023] [Accepted: 08/07/2023] [Indexed: 09/12/2023] Open
Abstract
The recent evolution of immunotherapy has revolutionised the treatment of hepatocellular carcinoma (HCC) and has led to new therapeutic standards. The advances in immunotherapy have been accompanied by the recognition of the role of the gut-liver axis in the progression of HCC but also of the clinical relevance of the gut microbiota, which influences host homeostasis but also cancer development and the response to treatment. Dysbiosis, by altering the tumour microenvironment, favours the activation of intracellular signalling pathways and promotes carcinogenesis. The gut microbiota, through their composition and immunomodulatory role, are thus strong predictors of the response to immune checkpoint inhibitor (ICI) treatment as well as an available target to improve ICI efficacy and reduce drug toxicities. In this review we examine the novel role of the gut microbiota as biomarkers in both the diagnosis of HCC and the clinical response to immunotherapy as well as its potential impact on clinical practice in the future.
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Affiliation(s)
- Paola Muscolino
- Medical Oncology Unit, Department of Human Pathology “G.Barresi”, University of Messina, Messina, Italy
| | - Barbara Granata
- Medical Oncology Unit, Department of Human Pathology “G.Barresi”, University of Messina, Messina, Italy
| | - Fausto Omero
- Medical Oncology Unit, Department of Human Pathology “G.Barresi”, University of Messina, Messina, Italy
| | - Claudia De Pasquale
- Laboratory of Immunology and Biotherapy, Department of Human Pathology “G.Barresi”, University of Messina, Messina, Italy
| | - Stefania Campana
- Laboratory of Immunology and Biotherapy, Department of Human Pathology “G.Barresi”, University of Messina, Messina, Italy
| | - Alessia Calabrò
- Laboratory of Immunology and Biotherapy, Department of Human Pathology “G.Barresi”, University of Messina, Messina, Italy
| | - Federica D’Anna
- Medical Oncology Unit, Department of Human Pathology “G.Barresi”, University of Messina, Messina, Italy
| | - Fabiana Drommi
- Laboratory of Immunology and Biotherapy, Department of Human Pathology “G.Barresi”, University of Messina, Messina, Italy
| | - Gaetana Pezzino
- Laboratory of Immunology and Biotherapy, Department of Human Pathology “G.Barresi”, University of Messina, Messina, Italy
| | - Riccardo Cavaliere
- Laboratory of Immunology and Biotherapy, Department of Human Pathology “G.Barresi”, University of Messina, Messina, Italy
- Division of Clinical Pathology, University Hospital Policlinico G.Martino, Messina, Italy
| | - Guido Ferlazzo
- Department of Experimental Medicine (DIMES), University of Genoa, Genova, Italy
- Unit of Experimental Pathology and Immunology, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Nicola Silvestris
- Medical Oncology Unit, Department of Human Pathology “G.Barresi”, University of Messina, Messina, Italy
| | - Desirèe Speranza
- Medical Oncology Unit, Department of Human Pathology “G.Barresi”, University of Messina, Messina, Italy
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Dai M, Lui RN, Lau LH. The role of gut microbiome and fecal microbiota transplantation in liver cancer and related complications: mechanisms and therapeutic potentials. HEPATOMA RESEARCH 2023. [DOI: 10.20517/2394-5079.2023.33] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Liver cancer is the sixth commonest cancer and the third leading cause of cancer mortality worldwide. Accumulating evidence suggests a pivotal role of the gut microbiome in the progression of chronic liver disease and the subsequent development of liver cancer. Additionally, gut microbiome has been shown to contribute to the hosts’ antitumor responses following immunotherapy and chemotherapy for liver cancers, highlighting the therapeutic potential of gut microbiome modulation in enhancing treatment efficacy and reducing drug resistance. Fecal microbiota transplantation (FMT), a novel therapeutic modality to deliver a healthy donor's stool by endoscopy or capsule, has demonstrated potential in managing liver diseases and cancers by restoring and modulating the recipient’s gut microbiome composition. However, existing data on the clinical application of FMT in liver cancers are still limited. This review summarizes the underlying roles and mechanisms of gut microbiome in liver cancer and discusses the therapeutic potential of FMT in liver cancer treatment and the management of its related complications (e.g., hepatic encephalopathy).
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Abenavoli L, Montori M, Svegliati Baroni G, Argenziano ME, Giorgi F, Scarlata GGM, Ponziani F, Scarpellini E. Perspective on the Role of Gut Microbiome in the Treatment of Hepatocellular Carcinoma with Immune Checkpoint Inhibitors. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1427. [PMID: 37629716 PMCID: PMC10456509 DOI: 10.3390/medicina59081427] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 08/02/2023] [Accepted: 08/04/2023] [Indexed: 08/27/2023]
Abstract
Background and Objectives: Hepatocellular carcinoma (HCC) is the leading cause of liver cancer worldwide and has a high mortality rate. Its incidence has increased due to metabolic-associated liver disease (MAFLD) epidemics. Liver transplantation and surgery remain the most resolute measures. Despite the optimistic use of multi-kinase inhibitors, namely sorafenib, the co-existence of chronic liver disease made the response rate low in these patients. Immune checkpoint inhibitors (ICIs) have become a promising hope for certain advanced solid tumors and, also, for advanced HCC. Unfortunately, a large cohort of patients with HCC fail to respond to immunotherapy. Materials and Methods: We conducted a narrative search on the main medical databases for original articles, reviews, meta-analyses, randomized clinical trials, and case series using the following keywords and acronyms and their associations: hepatocellular carcinoma, immunotherapy, checkpoint inhibitors, gut microbiota, and fecal microbiota transplantation. Results: ICIs are a promising and sufficiently safe treatment option for HCC. In detail, they have significantly improved survival and prognosis in these patients vs. sorafenib. Although there are several highlighted mechanisms of resistance, the gut microbiota signature can be used both as a response biomarker and as an effect enhancer. Practically, probiotic dose-finding and fecal microbiota transplantation are the weapons that can be used to increase ICI's treatment-response-reducing resistance mechanisms. Conclusion: Immunotherapy has been a significant step-up in HCC treatment, and gut microbiota modulation is an effective liaison to increase its efficacy.
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Affiliation(s)
- Ludovico Abenavoli
- Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy;
| | - Michele Montori
- Clinic of Gastroenterology and Hepatology, Emergency Digestive Endoscopy, Polytechnics University of Marche, 60126 Ancona, Italy; (M.M.); (M.E.A.)
| | | | - Maria Eva Argenziano
- Clinic of Gastroenterology and Hepatology, Emergency Digestive Endoscopy, Polytechnics University of Marche, 60126 Ancona, Italy; (M.M.); (M.E.A.)
| | - Francesca Giorgi
- Oncology Unit, “Madonna del Soccorso” General Hospital, 63074 San Benedetto del Tronto, Italy;
| | | | - Francesca Ponziani
- Digestive Disease Center (C.E.M.A.D.), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy;
- Translational Medicine and Surgery Department, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Emidio Scarpellini
- Translational Research in GastroIntestinal Disorders (T.A.R.G.I.D.), KU Leuven, Herestraat 49, 3000 Leuven, Belgium;
- Hepatology Outpatient Clinic, “Madonna del Soccorso” General Hospital, 63074 San Benedetto del Tronto, Italy
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Luo L, Lin C, Wang P, Cao D, Lin Y, Wang W, Zhao Y, Shi Y, Gao Z, Kang X, Zhang Y, Wang S, Wang J, Xu M, Liu H, Liu SL. Combined Use of Immune Checkpoint Inhibitors and Phytochemicals as a Novel Therapeutic Strategy against Cancer. J Cancer 2023; 14:2315-2328. [PMID: 37576404 PMCID: PMC10414047 DOI: 10.7150/jca.85966] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 07/03/2023] [Indexed: 08/15/2023] Open
Abstract
Immune checkpoint inhibitor (ICI) therapy has dramatically changed cancer treatment, opening novel opportunities to cure malignant diseases. To date, most prevalently targeted immune checkpoints are programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), with many others being under extensive investigations. However, according to available data, only a fraction of patients may respond to ICI therapy. Additionally, this therapy may cause severe adverse immune-related side effects, such as diarrhea, headache, muscle weakness, rash, hepatitis and leucopenia, although most of them are not fatal, they can affect the patient's treatment outcome and quality of life. On the other hand, growing evidence has shown that phytochemicals with anticancer effects may combine ICI therapy to augment the safety and effectiveness of the treatment against cancer while reducing the adverse side effects. In this review, we summarize the state of art in the various experiments and clinical application of ICIs plus phytochemicals, with a focus on their combined use as a novel therapeutic strategy to cure cancer.
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Affiliation(s)
- LingJie Luo
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Caiji Lin
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Pengfei Wang
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
- Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Danli Cao
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Yiru Lin
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Wenxue Wang
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Yufan Zhao
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Yongwei Shi
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Zixiang Gao
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Xin Kang
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Yuanyuan Zhang
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Shuang Wang
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Jiaxing Wang
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Mengzhi Xu
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Huidi Liu
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, T2N 4N1, Canada
| | - Shu-Lin Liu
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, State-Province Key Laboratory of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD) College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Harbin Medical University-University of Calgary Cumming School of Medicine Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, T2N 4N1, Canada
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Lai HC, Lin HJ, Shih YH, Chou JW, Lin KW, Jeng LB, Huang ST. LipoCol Forte capsules reduce the risk of liver cancer: A propensity score-matched, nationwide, population-based cohort study. World J Gastrointest Oncol 2023; 15:828-842. [PMID: 37275448 PMCID: PMC10237025 DOI: 10.4251/wjgo.v15.i5.828] [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: 01/25/2023] [Revised: 03/03/2023] [Accepted: 04/19/2023] [Indexed: 05/12/2023] Open
Abstract
BACKGROUND Liver cancer is among the top five most common cancers globally. Lipid-lowering drugs such as statins can lower the risk of liver cancer, but may also cause liver damage. LipoCol Forte capsules (LFC), a red yeast rice product, have demonstrated significant antihypercholesterolemic effects and a good safety profile in clinical studies.
AIM To evaluate whether LFC lowers the risk of liver cancer in adults in this propensity score-matched, nationwide, population-based cohort study.
METHODS We used data from Taiwan’s National Health Insurance Research Database, which includes electronic medical records for up to 99.99% of Taiwan’s population. LFC users and LFC non-users were matched 1:1 by propensity scores between January 2010 and December 2017. All had follow-up data for at least 1 year. Statistical analyses compared demographic distributions including sex, age, comorbidities, and prescribed medications. Cox regression analyses estimated adjusted hazard ratios (aHRs) after adjusting for potential confounders.
RESULTS We enrolled 33231 LFC users and 33231 non-LFC users (controls). No significant differences between the study cohorts were identified regarding comorbidities and medications [standardized mean difference (SMD) < 0.05]. At follow-up, the overall incidence of liver cancer was significantly lower in the LFC cohort compared with controls [aHR 0.91; 95% confidence interval (CI): 0.86-0.95; P < 0.001]. The risk of liver cancer was significantly reduced in both females (aHR 0.87; 95%CI: 0.8-0.94; P < 0.001) and males (aHR 0.93; 95%CI: 0.87-0.98; P < 0.01) in the LFC cohort compared with their counterparts in the non-LFC cohort. The antitumor protective effects applied to patients with comorbidities (including hypertension, ischemic stroke, diabetes mellitus, hyperlipidemia, hepatitis B infection and hepatitis C infection). Those using LFC for more than 84 drug days had a 0.64-fold lower risk of liver cancer compared with controls (P < 0.001). Compared with controls, the risk of developing liver cancer in the LFC cohort progressively decreased over time; the lowest incidence of liver cancer occurred in LFC users followed-up for more than 6 years (27.44 vs 31.49 per 1,000 person-years; aHR 0.75; 95%CI: 0.68-0.82; P < 0.001).
CONCLUSION This retrospective cohort study indicates that LFC has a significantly protective effect on lowering the risk of liver cancer, in a dose-dependent and time-dependent manner.
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Affiliation(s)
- Hsiang-Chun Lai
- Graduate Institute of Chinese Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40447, Taiwan
| | - Hung-Jen Lin
- School of Post-Baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan
| | - Ying-Hsiu Shih
- Management Office for Health Data, China Medical University Hospital, Taichung 40447, Taiwan
| | - Jen-Wei Chou
- Department of Internal Medicine, China Medical University Hospital, Taichung 40447, Taiwan
| | - Kuan-Wen Lin
- Department of Surgery, China Medical University Hospital, Taichung 40447, Taiwan
| | - Long-Bin Jeng
- Organ Transplantation Center, China Medical University Hospital, Taichung 40447, Taiwan
| | - Sheng-Teng Huang
- Department of Chinese Medicine, China Medical University Hospital, Taichung 40447, Taiwan
- Cancer Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung 40447, Taiwan
- An-Nan Hospital, China Medical University, Tainan 709204, Taiwan
- School of Chinese Medicine, China Medical University, Taichung 40447, Taiwan
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Najafi S, Majidpoor J, Mortezaee K. The impact of microbiota on PD-1/PD-L1 inhibitor therapy outcomes: A focus on solid tumors. Life Sci 2022; 310:121138. [DOI: 10.1016/j.lfs.2022.121138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 10/02/2022] [Accepted: 10/25/2022] [Indexed: 11/06/2022]
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Pallozzi M, Di Tommaso N, Maccauro V, Santopaolo F, Gasbarrini A, Ponziani FR, Pompili M. Non-Invasive Biomarkers for Immunotherapy in Patients with Hepatocellular Carcinoma: Current Knowledge and Future Perspectives. Cancers (Basel) 2022; 14:cancers14194631. [PMID: 36230554 PMCID: PMC9559710 DOI: 10.3390/cancers14194631] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/18/2022] [Accepted: 09/20/2022] [Indexed: 12/16/2022] Open
Abstract
Simple Summary The search for non-invasive biomarkers is a hot topic in modern oncology, since a tissue biopsy has significant limitations in terms of cost and invasiveness. The treatment perspectives have been significantly improved after the approval of immunotherapy for patients with hepatocellular carcinoma; therefore, the quick identification of responders is crucial to define the best therapeutic strategy. In this review, the current knowledge on the available non-invasive biomarkers of the response to immunotherapy is described. Abstract The treatment perspectives of advanced hepatocellular carcinoma (HCC) have deeply changed after the introduction of immunotherapy. The results in responders show improved survival compared with Sorafenib, but only one-third of patients achieve a significant benefit from treatment. As the tumor microenvironment exerts a central role in shaping the response to immunotherapy, the future goal of HCC treatment should be to identify a proxy of the hepatic tissue condition that is easy to use in clinical practice. Therefore, the search for biomarkers that are accurate in predicting prognosis will be the hot topic in the therapeutic management of HCC in the near future. Understanding the mechanisms of resistance to immunotherapy may expand the patient population that will benefit from it, and help researchers to find new combination regimens to improve patients’ outcomes. In this review, we describe the current knowledge on the prognostic non-invasive biomarkers related to treatment with immune checkpoint inhibitors, focusing on serological markers and gut microbiota.
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Affiliation(s)
- Maria Pallozzi
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Natalia Di Tommaso
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Valeria Maccauro
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Correspondence: (F.R.P.); (M.P.)
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Correspondence: (F.R.P.); (M.P.)
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Finnicum CT, Rahal Z, Hassane M, Treekitkarnmongkol W, Sinjab A, Morris R, Liu Y, Tang EL, Viet S, Petersen JL, Lorenzi PL, Tan L, Petrosino J, Hoffman KL, Fujimoto J, Moghaddam SJ, Kadara H. Pathogenesis of Tobacco-Associated Lung Adenocarcinoma Is Closely Coupled with Changes in the Gut and Lung Microbiomes. Int J Mol Sci 2022; 23:10930. [PMID: 36142843 PMCID: PMC9502774 DOI: 10.3390/ijms231810930] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 09/12/2022] [Accepted: 09/15/2022] [Indexed: 11/23/2022] Open
Abstract
Microbial dysbiosis has emerged as a modulator of oncogenesis and response to therapy, particularly in lung cancer. Here, we investigate the evolution of the gut and lung microbiomes following exposure to a tobacco carcinogen. We performed 16S rRNA-Seq of fecal and lung samples collected prior to and at several timepoints following (nicotine-specific nitrosamine ketone/NNK) exposure in Gprc5a-/- mice that were previously shown to exhibit accelerated lung adenocarcinoma (LUAD) development following NNK exposure. We found significant progressive changes in human-relevant gut and lung microbiome members (e.g., Odoribacter, Alistipes, Akkermansia, and Ruminococus) that are closely associated with the phenotypic development of LUAD and immunotherapeutic response in human lung cancer patients. These changes were associated with decreased short-chain fatty acids (propionic acid and butyric acid) following exposure to NNK. We next sought to study the impact of Lcn2 expression, a bacterial growth inhibitor, given our previous findings on its protective role in LUAD development. Indeed, we found that the loss of Lcn2 was associated with widespread gut and lung microbiome changes at all timepoints, distinct from those observed in our Gprc5a-/- mouse model, including a decrease in abundance and diversity. Our overall findings apprise novel cues implicating microbial phenotypes in the development of tobacco-associated LUAD.
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Affiliation(s)
| | - Zahraa Rahal
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Maya Hassane
- Faculty of Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon
| | - Warapen Treekitkarnmongkol
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ansam Sinjab
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Rhiannon Morris
- College of Natural Sciences, University of Texas at Austin, Austin, TX 78705, USA
| | - Yuejiang Liu
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Elizabeth L. Tang
- Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Sarah Viet
- Avera Institute for Human Genetics, Sioux Falls, SD 57108, USA
| | | | - Philip L. Lorenzi
- Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Lin Tan
- Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Joseph Petrosino
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Kristi L. Hoffman
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Junya Fujimoto
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Seyed Javad Moghaddam
- UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Humam Kadara
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Trivedi R, Upadhyay TK, Kausar MA, Saeed A, Sharangi AB, Almatroudi A, Alabdallah NM, Saeed M, Aqil F. Nanotechnological interventions of the microbiome as a next-generation antimicrobial therapy. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 833:155085. [PMID: 35398124 DOI: 10.1016/j.scitotenv.2022.155085] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 03/22/2022] [Accepted: 04/03/2022] [Indexed: 06/14/2023]
Abstract
The rise of antimicrobial resistance (AMR) impacts public health due to the diminished potency of existing antibiotics. The microbiome plays an important role in the host's immune system activity and shows the history of exposure to antimicrobials and its manipulation in combating antimicrobial resistance. Advancements in gene technologies, DNA sequencing, and computational biology have emerged as powerful platforms to better understand the relationship between animals and microorganisms (MOs). The past few years have witnessed an increase in the use of nanotechnology, both in industry and in academia, as tools to tackle antimicrobial resistance. New strategies of microbiome manipulation have been developed, such as the use of prebiotics, probiotics, peptides, antibodies, an appropriate diet, phage therapy, and the use of various nanotechnological techniques. Owing to the research outcomes, targeted delivery of antimicrobials with some modifications with nanoparticles can lead to the destruction of resistant microbial cells. In addition, nanoparticles have been studied for their potential antimicrobial effects both in vitro and in vivo. In this review, we highlight key opportunistic areas for applying nanotechnologies with the aim of manipulating the microbiome for the treatment of antimicrobial resistance. Besides providing a detailed review on various nanomaterials, technologies, opportunities, technical needs, and potential approaches for the manipulation of the microbiome to address these challenges, we discuss future challenges and our perspective.
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Affiliation(s)
- Rashmi Trivedi
- Department of Biotechnology, Parul Institute of Applied Sciences and Animal Cell Culture and Immunobiochemistry Lab, Centre of Research for Development, Parul University, Vadodara 391760, India
| | - Tarun Kumar Upadhyay
- Department of Biotechnology, Parul Institute of Applied Sciences and Animal Cell Culture and Immunobiochemistry Lab, Centre of Research for Development, Parul University, Vadodara 391760, India.
| | - Mohd Adnan Kausar
- Department of Biochemistry, College of Medicine, University of Hail, PO Box 2240, Hail, Saudi Arabia
| | - Amir Saeed
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Hail, PO Box 2240, Hail, Saudi Arabia
| | - Amit Baran Sharangi
- Department of Plantation Spices Medicinal and Aromatic Crops, Bidhan Chandra Krishi Viswavidyalaya, Mohanpur 741252, India
| | - Ahmad Almatroudi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Qassim 51431, Saudi Arabia
| | - Nadiyah M Alabdallah
- Department of Biology, College of Science, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, 31441 Dammam, Saudi Arabia
| | - Mohd Saeed
- Department of Biology, College of Sciences, University of Hail, PO Box 2240, Hail, Saudi Arabia.
| | - Farrukh Aqil
- UofL Health - Brown Cancer Center and Department of Medicine, University of Louisville, Louisville, KY 40202, USA.
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Spanu D, Pretta A, Lai E, Persano M, Donisi C, Mariani S, Dubois M, Migliari M, Saba G, Ziranu P, Pusceddu V, Puzzoni M, Astara G, Scartozzi M. Hepatocellular carcinoma and microbiota: Implications for clinical management and treatment. World J Hepatol 2022; 14:1319-1332. [PMID: 36158925 PMCID: PMC9376771 DOI: 10.4254/wjh.v14.i7.1319] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 04/11/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
Gut microbiota plays an essential role in host homeostasis. It is involved in several physiological processes such as nutrients digestion and absorption, maintenance of intestinal epithelial barrier integrity and immune system self-tolerance. Especially the gut microbiota is assumed to play a crucial role in many gastrointestinal, pancreatic and liver disorders. Its role in hepatic carcinogenesis is also gaining increasing interest, especially regarding the development of therapeutic strategies. Different studies are highlighting a link between some bacterial strains and liver disease, including hepatocellular carcinoma (HCC). Indeed, HCC represents an interesting field of research in this perspective, due to the gut-liver axis, to the implication of microbiota in the immune system and to the increasing number of immunotherapy agents investigated in this tumour. Thus, the assessment of the role of microbiota in influencing clinical outcome for patients treated with these drugs is becoming of increasing importance. Our review aims to give an overview on the relationship between microbiota and HCC development/progression and treatment. We focus on potential implications on the available treatment strategies and those under study in the various stages of disease. We highlight the pathogenic mechanisms and investigate the underlying molecular pathways involved. Moreover, we investigate the potential prognostic and/or predictive role of microbiota for target therapies, immune checkpoint inhibitors and loco-regional treatment. Finally, given the limitation of current treatments, we analyze the gut microbiota-mediated therapies and its potential options for HCC treatment focusing on fecal microbiota transplantation.
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Affiliation(s)
- Dario Spanu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Giorgio Astara
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
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Gunjur A, Manrique‐Rincón AJ, Klein O, Behren A, Lawley TD, Welsh SJ, Adams DJ. 'Know thyself' - host factors influencing cancer response to immune checkpoint inhibitors. J Pathol 2022; 257:513-525. [PMID: 35394069 PMCID: PMC9320825 DOI: 10.1002/path.5907] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/01/2022] [Accepted: 04/05/2022] [Indexed: 11/30/2022]
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionised oncology and are now standard-of-care for the treatment of a wide variety of solid neoplasms. However, tumour responses remain unpredictable, experienced by only a minority of ICI recipients across malignancy types. Therefore, there is an urgent need for better predictive biomarkers to identify a priori the patients most likely to benefit from these therapies. Despite considerable efforts, only three such biomarkers are FDA-approved for clinical use, and all rely on the availability of tumour tissue for immunohistochemical staining or genomic assays. There is emerging evidence that host factors - for example, genetic, metabolic, and immune factors, as well as the composition of one's gut microbiota - influence the response of a patient's cancer to ICIs. Tantalisingly, some of these factors are modifiable, paving the way for co-therapies that may enhance the therapeutic index of these treatments. Herein, we review key host factors that are of potential biomarker value for response to ICI therapy, with a particular focus on the proposed mechanisms for these influences. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Ashray Gunjur
- Experimental Cancer Genetics, Wellcome Sanger InstituteHinxtonUK,Olivia Newton‐John Cancer Research InstituteLa Trobe University School of Cancer MedicineHeidelbergAustralia
| | - Andrea J Manrique‐Rincón
- Experimental Cancer Genetics, Wellcome Sanger InstituteHinxtonUK,Cambridge Institute of Therapeutic Immunology & Infectious Disease, Department of MedicineUniversity of CambridgeCambridgeUK
| | - Oliver Klein
- Olivia Newton‐John Cancer Research InstituteLa Trobe University School of Cancer MedicineHeidelbergAustralia,Department of Medical OncologyAustin HealthHeidelbergAustralia
| | - Andreas Behren
- Olivia Newton‐John Cancer Research InstituteLa Trobe University School of Cancer MedicineHeidelbergAustralia,Department of MedicineUniversity of MelbourneParkvilleAustralia
| | | | - Sarah J Welsh
- Department of SurgeryUniversity of CambridgeCambridgeUK,Cambridge University Hospitals NHS Foundation TrustCambridgeUK
| | - David J Adams
- Experimental Cancer Genetics, Wellcome Sanger InstituteHinxtonUK
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Kang YB, Cai Y. Future prospect of "Gut microbiome composition can predict the response to nivolumab in advanced hepatocellular carcinoma patients". World J Gastroenterol 2022; 28:2248-2250. [PMID: 35721889 PMCID: PMC9157621 DOI: 10.3748/wjg.v28.i20.2248] [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: 12/10/2021] [Revised: 01/14/2021] [Accepted: 04/24/2022] [Indexed: 02/06/2023] Open
Abstract
Recently, we read the article "Gut microbiome composition can predict the response to nivolumab in advanced hepatocellular carcinoma patients" with interest, and it is preliminary suggested that gut microbiota is closely related to therapeutic effect of nivolumab. Based on the meaningful results of this article, several valuable research directions are proposed to enhance the therapeutic effect of immune checkpoint inhibitors on advanced hepatocellular carcinoma.
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Affiliation(s)
- Yong-Bo Kang
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Shanxi Medical University, Jinzhong 030600, Shanxi Province, China
| | - Yue Cai
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Shanxi Medical University, Jinzhong 030600, Shanxi Province, China
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Tomita Y, Goto Y, Sakata S, Imamura K, Minemura A, Oka K, Hayashi A, Jodai T, Akaike K, Anai M, Hamada S, Iyama S, Saruwatari K, Saeki S, Takahashi M, Ikeda T, Sakagami T. Clostridium butyricum therapy restores the decreased efficacy of immune checkpoint blockade in lung cancer patients receiving proton pump inhibitors. Oncoimmunology 2022; 11:2081010. [PMID: 35655708 PMCID: PMC9154751 DOI: 10.1080/2162402x.2022.2081010] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Yusuke Tomita
- Department of Respiratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yoshihiko Goto
- Department of Respiratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Shinya Sakata
- Department of Respiratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Kosuke Imamura
- Department of Respiratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Ayaka Minemura
- R&D Division, Miyarisan Pharmaceutical Co., Ltd., Saitama, Japan
| | - Kentaro Oka
- R&D Division, Miyarisan Pharmaceutical Co., Ltd., Saitama, Japan
| | - Atsushi Hayashi
- R&D Division, Miyarisan Pharmaceutical Co., Ltd., Saitama, Japan
| | - Takayuki Jodai
- Department of Respiratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Kimitaka Akaike
- Department of Respiratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Moriyasu Anai
- Department of Respiratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Shohei Hamada
- Department of Respiratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Shinji Iyama
- Department of Respiratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Koichi Saruwatari
- Department of Respiratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Sho Saeki
- Department of Respiratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | | | - Tokunori Ikeda
- Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan
| | - Takuro Sakagami
- Department of Respiratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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Rizzo A, Ricci AD. Predictors of response for hepatocellular carcinoma immunotherapy: is there anything on the horizon? EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2022. [DOI: 10.1080/23808993.2022.2075724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Alessandro Rizzo
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico “Don Tonino Bello,” I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”, Bari, Italy
| | - Angela Dalia Ricci
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
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Rizzo A, Cusmai A, Gadaleta-Caldarola G, Palmiotti G. Which role for predictors of response to immune checkpoint inhibitors in hepatocellular carcinoma? Expert Rev Gastroenterol Hepatol 2022; 16:333-339. [PMID: 35403533 DOI: 10.1080/17474124.2022.2064273] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) remains a frequently diagnosed malignancy worldwide, still representing an important cause of cancer-related death. Recent years have seen the emergence of novel systemic treatments for HCC patients, including immune checkpoint inhibitors (ICIs). Nonetheless, several questions regarding HCC immunotherapy remain unanswered, especially in terms of biochemical predictors of response. AREAS COVERED In the current paper, we will discuss available evidence regarding predictive biomarkers of response to HCC immunotherapy. A literature search was conducted in January 2022 of Pubmed/Medline, Cochrane library, and Scopus databases. EXPERT OPINION The identification of predictive biomarkers represents an unmet need in HCC patients receiving ICIs. The HCC medical community is called to further efforts aimed to elucidate the effective role of PD-L1 expression, TMB, MSI, gut microbiota, and other emerging biomarkers.
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Affiliation(s)
- Alessandro Rizzo
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico "Don Tonino Bello," I.R.C.C.S. Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Antonio Cusmai
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico "Don Tonino Bello," I.R.C.C.S. Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Gennaro Gadaleta-Caldarola
- Medical Oncology Unit, 'Mons. R. Dimiccoli' Hospital, Barletta (BT), Azienda Sanitaria Locale Barletta, 76121, Italy
| | - Gennaro Palmiotti
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico "Don Tonino Bello," I.R.C.C.S. Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco 65, 70124 Bari, Italy
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