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1
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Zhao SH, Zhang SM, Yang JW, Liu CJ, Zeng XQ, Zhang YL, Chen SQ, Zhao ZM, Xia YX, Li XR, Shang Y. Preliminary study on the active substances and cellular pathways of lactic acid bacteria for colorectal cancer treatment. J Cancer 2024; 15:4902-4921. [PMID: 39132155 PMCID: PMC11310875 DOI: 10.7150/jca.94530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 06/30/2024] [Indexed: 08/13/2024] Open
Abstract
Colorectal cancer (CRC) is a common malignant tumor and is one of the three most common cancers worldwide. Traditional surgical treatment, supplemented by chemotherapy and radiotherapy, has obvious side effects on patients. Immunotherapy may lead to some unpredictable complications. Low introduction rate and high cost are some of the problems of gene therapy, so finding a safe, reliable and least toxic treatment method became the main research direction for this study. Lactic acid bacteria and their metabolites are widely used in functional foods or as adjuvant therapies for various diseases because they are safe to eat and have no adverse reactions. Research has shown that lactic acid bacteria and their metabolites play an auxiliary therapeutic role in colorectal cancer mainly by improving the intestinal flora composition, inhibiting the growth of pathogenic bacteria and inhibiting the proliferation of cancer cells. It is now widely believed that the substances that probiotics such as lactic acid bacteria exert anti-cancer effects are mainly secondary metabolites such as butyric acid. Lb. plantarum AY01 isolated from fermented food has good anti-cancer ability, and its main anti-cancer substance is 2'-deoxyinosine. Through flow cytometry detection, it was found that Lb. plantarum AY01 can block cell proliferation in the S phase. In addition, Lb. plantarum AY01 culture reduces the sensitivity of mice to colitis-associated CRC induced by azoxymethane (AOM)/dextran sulfate sodium salt (DSS) and exhibits the occurrence and promotion of tumors. According to transcriptome analysis, Lb. plantarum AY01 may induce apoptosis of colorectal cancer cells by activating the p38 MAPK pathway. This experiment provided possibilities for the treatment of CRC.
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Affiliation(s)
- Si-Hui Zhao
- Second Department of General Surgery, First People' s Hospital of Yunnan Province, Kunming 650032, Yunnan, China
- Second Department of General Surgery, Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan, China
| | - Shu-Ming Zhang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan, China
| | - Jin-Wei Yang
- Second Department of General Surgery, First People' s Hospital of Yunnan Province, Kunming 650032, Yunnan, China
- Second Department of General Surgery, Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan, China
- Institute of Neuroscience, Kunming Medical University, Kunming 650500, Yunnan, China
| | - Chen-Jian Liu
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan, China
| | - Xue-Qin Zeng
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan, China
| | - Yuan-Lian Zhang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan, China
| | - Si-Qian Chen
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan, China
| | - Zhi-Min Zhao
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan, China
| | - Yun-Xin Xia
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan, China
| | - Xiao-Ran Li
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan, China
| | - Yun Shang
- Second Department of General Surgery, First People' s Hospital of Yunnan Province, Kunming 650032, Yunnan, China
- Second Department of General Surgery, Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan, China
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2
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Sadeghi M, Mestivier D, Sobhani I. Contribution of pks+ Escherichia coli ( E. coli) to Colon Carcinogenesis. Microorganisms 2024; 12:1111. [PMID: 38930493 PMCID: PMC11205849 DOI: 10.3390/microorganisms12061111] [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: 05/21/2024] [Revised: 05/24/2024] [Accepted: 05/29/2024] [Indexed: 06/28/2024] Open
Abstract
Colorectal cancer (CRC) stands as a significant global health concern, ranking second in mortality and third in frequency among cancers worldwide. While only a small fraction of CRC cases can be attributed to inherited genetic mutations, the majority arise sporadically due to somatic mutations. Emerging evidence reveals gut microbiota dysbiosis to be a contributing factor, wherein polyketide synthase-positive Escherichia coli (pks+ E. coli) plays a pivotal role in CRC pathogenesis. pks+ bacteria produce colibactin, a genotoxic protein that causes deleterious effects on DNA within host colonocytes. In this review, we examine the role of the gut microbiota in colon carcinogenesis, elucidating how colibactin-producer bacteria induce DNA damage, promote genomic instability, disrupt the gut epithelial barrier, induce mucosal inflammation, modulate host immune responses, and influence cell cycle dynamics. Collectively, these actions foster a microenvironment conducive to tumor initiation and progression. Understanding the mechanisms underlying pks+ bacteria-mediated CRC development may pave the way for mass screening, early detection of tumors, and therapeutic strategies such as microbiota modulation, bacteria-targeted therapy, checkpoint inhibition of colibactin production and immunomodulatory pathways.
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Affiliation(s)
- Mohammad Sadeghi
- EA7375–EC2M3: Early, Detection of Colonic Cancer by Using Microbial & Molecular Markers, Paris East Créteil University (UPEC), 94010 Créteil, France;
| | - Denis Mestivier
- EA7375–EC2M3: Early, Detection of Colonic Cancer by Using Microbial & Molecular Markers, Paris East Créteil University (UPEC), 94010 Créteil, France;
| | - Iradj Sobhani
- EA7375–EC2M3: Early, Detection of Colonic Cancer by Using Microbial & Molecular Markers, Paris East Créteil University (UPEC), 94010 Créteil, France;
- Department of Gastroenterology, Assistance Publique–Hôpitaux de Paris (APHP), Henri Mondor Hospital, 94010 Créteil, France
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3
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Pandey M, Bhattacharyya J. Gut microbiota and epigenetics in colorectal cancer: implications for carcinogenesis and therapeutic intervention. Epigenomics 2024; 16:403-418. [PMID: 38410915 DOI: 10.2217/epi-2023-0382] [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] [Indexed: 02/28/2024] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. The occurrence of CRC is associated with various genetic and epigenetic mutations in intestinal epithelial cells that transform them into adenocarcinomas. There is increasing evidence indicating the gut microbiota plays a crucial role in the regulation of host physiological processes. Alterations in gut microbiota composition are responsible for initiating carcinogenesis through diverse epigenetic modifications, including histone modifications, ncRNAs and DNA methylation. This work was designed to comprehensively review recent findings to provide insight into the associations between the gut microbiota and CRC at an epigenetic level. These scientific insights can be used in the future to develop effective strategies for early detection and treatment of CRC.
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Affiliation(s)
- Monu Pandey
- Centre for Biomedical Engineering, Indian Institute of Technology, Delhi, 110016, India
- Department of Biomedical Engineering, All India Institute of Medical Science, Delhi, 110608, India
| | - Jayanta Bhattacharyya
- Centre for Biomedical Engineering, Indian Institute of Technology, Delhi, 110016, India
- Department of Biomedical Engineering, All India Institute of Medical Science, Delhi, 110608, India
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4
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Addington E, Sandalli S, Roe AJ. Current understandings of colibactin regulation. MICROBIOLOGY (READING, ENGLAND) 2024; 170:001427. [PMID: 38314762 PMCID: PMC10924459 DOI: 10.1099/mic.0.001427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 01/12/2024] [Indexed: 02/07/2024]
Abstract
The biosynthetic machinery for the production of colibactin is encoded by 19 genes (clbA - S) within the pks pathogenicity island harboured by many E. coli of the B2-phylogroup. Colibactin is a potent genotoxic metabolite which causes DNA-damage and which has potential roles in microbial competition and fitness of pks+ bacteria. Colibactin has also been strongly implicated in the development of colorectal cancer. Given the genotoxicity of colibactin and the metabolic cost of its synthesis, the regulatory system governing the clb cluster is accordingly highly complex, and many of the mechanisms remain to be elucidated. In this review we summarise the current understanding of regulation of colibactin biosynthesis by internal molecular components and how these factors are modulated by signals from the external environment.
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Affiliation(s)
- Emily Addington
- School of Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland, UK
| | - Sofia Sandalli
- School of Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland, UK
| | - Andrew J. Roe
- School of Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland, UK
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5
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Sharma K, Sundling KE, Zhang R, Matkowskyj KA. Pathologic Features of Primary Colon, Rectal, and Anal Malignancies. Cancer Treat Res 2024; 192:233-263. [PMID: 39212924 DOI: 10.1007/978-3-031-61238-1_12] [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: 09/04/2024]
Abstract
In USA, colorectal cancer is the third most commonly diagnosed cancer in men, second in women, as well as the third leading cause of cancer deaths (Siegel et al. in Cancer J Clin 73:1-112, 2023 [109]). Worldwide, colorectal cancer is the second leading cause of death and causes almost 916,000 deaths each year (Ferlay in Global cancer observatory: cancer today. International Agency for Research on Cancer, Lyon, 2020 [28]). Fortunately, due to the colon's surgical and endoscopic accessibility and functional redundancy, colorectal cancer is very treatable. Colonoscopic surveillance has the potential for not only providing tissue for the diagnosis of precancerous polyps and invasive carcinoma, but also preventing development of invasive carcinoma by the removal of precancerous lesions. This chapter discusses the clinical and pathologic features of the spectrum of epithelial, hematolymphoid, and mesenchymal malignant tumors of the colon, rectum, appendix, and anus.
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Affiliation(s)
- Kusum Sharma
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Kaitlin E Sundling
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
- Wisconsin State Laboratory of Hygiene, Madison, WI, USA
| | - Ranran Zhang
- Alberta Precision Laboratories, Grande Prairie Regional Hospital, Grande Prairie, Canada
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6
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Hou Y, Li J, Ying S. Tryptophan Metabolism and Gut Microbiota: A Novel Regulatory Axis Integrating the Microbiome, Immunity, and Cancer. Metabolites 2023; 13:1166. [PMID: 37999261 PMCID: PMC10673612 DOI: 10.3390/metabo13111166] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 11/16/2023] [Accepted: 11/18/2023] [Indexed: 11/25/2023] Open
Abstract
Tryptophan metabolism and gut microbiota form an integrated regulatory axis that impacts immunity, metabolism, and cancer. This review consolidated current knowledge on the bidirectional interactions between microbial tryptophan processing and the host. We focused on how the gut microbiome controls tryptophan breakdown via the indole, kynurenine, and serotonin pathways. Dysbiosis of the gut microbiota induces disruptions in tryptophan catabolism which contribute to disorders like inflammatory conditions, neuropsychiatric diseases, metabolic syndromes, and cancer. These disruptions affect immune homeostasis, neurotransmission, and gut-brain communication. Elucidating the mechanisms of microbial tryptophan modulation could enable novel therapeutic approaches like psychobiotics and microbiome-targeted dietary interventions. Overall, further research on the microbiota-tryptophan axis has the potential to revolutionize personalized diagnostics and treatments for improving human health.
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Affiliation(s)
- Yingjian Hou
- Target Discovery Center, China Pharmaceutical University, Nanjing 211198, China;
| | - Jing Li
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha 410000, China
| | - Shuhuan Ying
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
- Shanghai Bocimed Pharmaceutical Research Co., Ltd., Shanghai 201203, China
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7
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Van Dingenen L, Segers C, Wouters S, Mysara M, Leys N, Kumar-Singh S, Malhotra-Kumar S, Van Houdt R. Dissecting the role of the gut microbiome and fecal microbiota transplantation in radio- and immunotherapy treatment of colorectal cancer. Front Cell Infect Microbiol 2023; 13:1298264. [PMID: 38035338 PMCID: PMC10687483 DOI: 10.3389/fcimb.2023.1298264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 10/31/2023] [Indexed: 12/02/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and poses a major burden on the human health worldwide. At the moment, treatment of CRC consists of surgery in combination with (neo)adjuvant chemotherapy and/or radiotherapy. More recently, immune checkpoint blockers (ICBs) have also been approved for CRC treatment. In addition, recent studies have shown that radiotherapy and ICBs act synergistically, with radiotherapy stimulating the immune system that is activated by ICBs. However, both treatments are also associated with severe toxicity and efficacy issues, which can lead to temporary or permanent discontinuation of these treatment programs. There's growing evidence pointing to the gut microbiome playing a role in these issues. Some microorganisms seem to contribute to radiotherapy-associated toxicity and hinder ICB efficacy, while others seem to reduce radiotherapy-associated toxicity or enhance ICB efficacy. Consequently, fecal microbiota transplantation (FMT) has been applied to reduce radio- and immunotherapy-related toxicity and enhance their efficacies. Here, we have reviewed the currently available preclinical and clinical data in CRC treatment, with a focus on how the gut microbiome influences radio- and immunotherapy toxicity and efficacy and if these treatments could benefit from FMT.
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Affiliation(s)
- Lena Van Dingenen
- Nuclear Medical Applications, Belgian Nuclear Research Centre, SCK CEN, Mol, Belgium
- Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, Faculty of Medicine, University of Antwerp, Antwerp, Belgium
| | - Charlotte Segers
- Nuclear Medical Applications, Belgian Nuclear Research Centre, SCK CEN, Mol, Belgium
| | - Shari Wouters
- Nuclear Medical Applications, Belgian Nuclear Research Centre, SCK CEN, Mol, Belgium
- Molecular Pathology Group, Laboratory of Cell Biology and Histology, Faculty of Medicine, University of Antwerp, Antwerp, Belgium
| | - Mohamed Mysara
- Bioinformatics Group, Center for Informatics Science, School of Information Technology and Computer Science, Nile University, Giza, Egypt
| | - Natalie Leys
- Nuclear Medical Applications, Belgian Nuclear Research Centre, SCK CEN, Mol, Belgium
| | - Samir Kumar-Singh
- Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, Faculty of Medicine, University of Antwerp, Antwerp, Belgium
- Molecular Pathology Group, Laboratory of Cell Biology and Histology, Faculty of Medicine, University of Antwerp, Antwerp, Belgium
| | - Surbhi Malhotra-Kumar
- Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, Faculty of Medicine, University of Antwerp, Antwerp, Belgium
| | - Rob Van Houdt
- Nuclear Medical Applications, Belgian Nuclear Research Centre, SCK CEN, Mol, Belgium
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8
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Ghorbani Ranjbary A, Mehrzad J, Rahbar N, Dehghani H. Impacts of some clinicopathodemography and colorectal tissues key cell cycle and mucin stabilizing molecules on the metastasis trend in colorectal cancer patients. Mol Biol Rep 2023; 50:8589-8601. [PMID: 37644368 DOI: 10.1007/s11033-023-08766-x] [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: 07/06/2023] [Accepted: 08/16/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND We aimed to evaluate the various clinicopathodemographical, epidemiological, and molecular contributors to cumulatively worldwide metastatic colorectal cancer (CRC) in CRC patients from a highly populated area in northeastern Iran to pinpoint metastasis risk. METHODS A retrospective clinical material-based cohort including a total of 6260 registered CRC patients, of whom 3829 underwent surgery, from regional university hospitals, during 2006-2016, were analyzed for the clinicopathodemographical aspects of age, sex, stage of CRC, history of smoking, type 2 diabetes (T2D), hypertension, body mass index (BMI), familial/occupational status, post-surgery survival period and mRNA/protein expression of mucin stabilizer (B3GALNT2), mucin I (MUC1), key cell cycle molecules (i.e., P53 and Ki67), and MMR-related genes. Factors were set to estimate the risk of metastatic CRC and mortality. RESULTS Predominant adenocarcinomatous CRCs were found in colon. Post-surgery survival period of metastatic CRC patients was remarkably longer in patients aged > 50 compared to those aged < 50 years, and worse in females than males. B3GALNT2high, MUChigh, P53low, and Ki67high mRNA/protein expression in the metastatic stage III CRC along with T2D and hypertension were associated with increased metastasis/mortality, with more worsening in males, older, BMI > 25, urban residing, and employed individuals, indicative of non-genetic attributable factors. CONCLUSION B3GALNT2, MUC1, and "Ki67" can be used as promising biomarkers for prognosis and early diagnosis of increasingly/predominantly non-genetic/environmental originated metastatic CRCs.
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Affiliation(s)
- Ali Ghorbani Ranjbary
- Department of Pathobiology, Section Biotechnology, Faculty of Veterinary Medicine, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
- Department of Microbiology and Immunology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Jalil Mehrzad
- Department of Microbiology and Immunology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Nasrollah Rahbar
- Department of Microbiology and Immunology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Hesam Dehghani
- Department of Basic Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
- Stem Cells and Regenerative Medicine Research Group, Research Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
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9
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Stokowa-Sołtys K, Kierpiec K, Szczerba K, Wieczorek R. Can bacteria F. nucleatum be actively involved in colon cancer progression via a radical mediated mechanism? J Inorg Biochem 2023; 246:112307. [PMID: 37406386 DOI: 10.1016/j.jinorgbio.2023.112307] [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: 04/25/2023] [Revised: 06/23/2023] [Accepted: 06/27/2023] [Indexed: 07/07/2023]
Abstract
Outer membrane proteins of Fusobacterium nucleatum, a cancer‑leading bacteria, are considered as the factors responsible for its pathogenicity. Among them, homotrimeric autotransporter protein YadA (Yersinia adhesin A) is an important virulence factor also found in the outer membrane of pathogenic Yersinia species. In this paper, the structure and stability of certain Cu(II) complexes with YadA fragments were investigated using both, experimental and theoretical methods. Potentiometry, UV-Vis, CD, EPR, and calculations at the density functional theory (DFT) level were applied to determine the metal ion coordination sphere. Moreover, the complexes ability to DNA cleavage and reactive oxygen species (ROS) production was studied. We have shown that copper(II) complexes can cleave DNA by 1O2, O2•- and •OH, which are formed in the studied systems. However, the results of electrophoretic experiments revealed that complexes cleave DNA less effectively than free copper(II) ions. Therefore, the presence of studied peptides may prevent DNA from a Cu(II)-induced damage to some extent.
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Affiliation(s)
- Kamila Stokowa-Sołtys
- Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland.
| | - Karolina Kierpiec
- Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland
| | - Klaudia Szczerba
- Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland
| | - Robert Wieczorek
- Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland
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10
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Abbes S, Baldi S, Sellami H, Amedei A, Keskes L. Molecular methods for colorectal cancer screening: Progress with next-generation sequencing evolution. World J Gastrointest Oncol 2023; 15:425-442. [PMID: 37009313 PMCID: PMC10052664 DOI: 10.4251/wjgo.v15.i3.425] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/02/2023] [Accepted: 02/14/2023] [Indexed: 03/14/2023] Open
Abstract
Currently, colorectal cancer (CRC) represents the third most common malignancy and the second most deadly cancer worldwide, with a higher incidence in developed countries. Like other solid tumors, CRC is a heterogeneous genomic disease in which various alterations, such as point mutations, genomic rearrangements, gene fusions or chromosomal copy number alterations, can contribute to the disease development. However, because of its orderly natural history, easily accessible onset location and high lifetime incidence, CRC is ideally suited for preventive intervention, but the many screening efforts of the last decades have been compromised by performance limitations and low penetrance of the standard screening tools. The advent of next-generation sequencing (NGS) has both facilitated the identification of previously unrecognized CRC features such as its relationship with gut microbial pathogens and revolutionized the speed and throughput of cataloguing CRC-related genomic alterations. Hence, in this review, we summarized the several diagnostic tools used for CRC screening in the past and the present, focusing on recent NGS approaches and their revolutionary role in the identification of novel genomic CRC characteristics, the advancement of understanding the CRC carcinogenesis and the screening of clinically actionable targets for personalized medicine.
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Affiliation(s)
- Salma Abbes
- Laboratory of Parasitic and Fungal Molecular Biology, University of Sfax, Sfax 3029, Tunisia
| | - Simone Baldi
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Hayet Sellami
- Drosophila Research Unit-Parasitology and Mycologie Laboratory, University of Sfax, Sfax 3029, Tunisia
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
- SOD of Interdisciplinary Internal Medicine, Careggi University Hospital, Florence 50134, Italy
| | - Leila Keskes
- Laboratory of Human Molecular Genetic, University of Sfax, Sfax 3029, Tunisia
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11
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Kapsetaki SE, Marquez Alcaraz G, Maley CC, Whisner CM, Aktipis A. Diet, Microbes, and Cancer Across the Tree of Life: a Systematic Review. Curr Nutr Rep 2022; 11:508-525. [PMID: 35704266 PMCID: PMC9197725 DOI: 10.1007/s13668-022-00420-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2022] [Indexed: 11/09/2022]
Abstract
PURPOSE OF REVIEW Cancers are a leading cause of death in humans and for many other species. Diet has often been associated with cancers, and the microbiome is an essential mediator between diet and cancers. Here, we review the work on cancer and the microbiome across species to search for broad patterns of susceptibility associated with different microbial species. RECENT FINDINGS Some microbes, such as Helicobacter bacteria, papillomaviruses, and the carnivore-associated Fusobacteria, consistently induce tumorigenesis in humans and other species. Other microbes, such as the milk-associated Lactobacillus, consistently inhibit tumorigenesis in humans and other species. We systematically reviewed over a thousand published articles and identified links between diet, microbes, and cancers in several species of mammals, birds, and flies. Future work should examine a larger variety of host species to discover new model organisms for human preclinical trials, to better understand the observed variance in cancer prevalence across species, and to discover which microbes and diets are associated with cancers across species. Ultimately, this could help identify microbial and dietary interventions to diagnose, prevent, and treat cancers in humans as well as other animals.
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Affiliation(s)
- Stefania E Kapsetaki
- Arizona Cancer Evolution Center, Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, AZ, USA.
- Biodesign Center for Biocomputing, Security and Society, Arizona State University, Tempe, USA.
| | - Gissel Marquez Alcaraz
- Arizona Cancer Evolution Center, Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, AZ, USA
- Biodesign Center for Biocomputing, Security and Society, Arizona State University, Tempe, USA
| | - Carlo C Maley
- Arizona Cancer Evolution Center, Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, AZ, USA
- Biodesign Center for Biocomputing, Security and Society, Arizona State University, Tempe, USA
| | - Corrie M Whisner
- College of Health Solutions, Arizona State University, Phoenix, AZ, USA
- Biodesign Center for Health Through Microbiomes, Arizona State University, Tempe, AZ, USA
| | - Athena Aktipis
- Arizona Cancer Evolution Center, Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, AZ, USA
- Department of Psychology, Arizona State University, Tempe, AZ, USA
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12
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Alfaro Alfaro ÁE, Murillo Castillo B, Cordero García E, Tascón J, Morales AI. Colon Cancer Pharmacogenetics: A Narrative Review. PHARMACY 2022; 10:95. [PMID: 36005935 PMCID: PMC9413567 DOI: 10.3390/pharmacy10040095] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/22/2022] [Accepted: 07/27/2022] [Indexed: 12/16/2022] Open
Abstract
Currently, metastatic colon cancer is treated with monotherapeutic regimens such as folinic acid, fluorouracil, and oxaliplatin (FOLFOX), capecitabine and oxaliplatin (CapeOX), and leucovorin, fluorouracil, and irinotecan hydrochloride (FOLFIRI). Other treatments include biological therapies and immunotherapy with drugs such as bevacizumab, panitumumab, cetuximab, and pembrolizumab. After the research, it was found that some mutations make those treatments not as effective in all patients. In this bibliographic review, we investigated the pharmacogenetic explanations for how mutations in the genes coding for rat sarcoma virus (RAS) and rapidly accelerated fibrosarcoma (RAF) reduce the effectiveness of these treatments and allow the continued proliferation of tumors. Furthermore, we note that patients with mutations in the dihydropyrimidine dehydrogenase (DPDY) gene usually require lower doses of therapies such as 5-fluorouracyl (5-FU) and capecitabine to avoid severe adverse effects. Some other mutations in the thymidylate synthase gene (TSYM), methylenetetrahydrofolate reductase gene (MTHFR), and ATP binding cassette transporter B (ABCB1 and ABCB2) affect efficacy and security of the treatments. It is important to address the clinical implication of the oncologist in the study of gene mutations than can influence in the antitumoral response and safety of colon cancer treatments.
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Affiliation(s)
| | | | | | - Javier Tascón
- Toxicology Unit, Universidad de Salamanca, 37007 Salamanca, Spain
| | - Ana I. Morales
- Toxicology Unit, Universidad de Salamanca, 37007 Salamanca, Spain
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13
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Png CW, Chua YK, Law JH, Zhang Y, Tan KK. Alterations in co-abundant bacteriome in colorectal cancer and its persistence after surgery: a pilot study. Sci Rep 2022; 12:9829. [PMID: 35701595 PMCID: PMC9198081 DOI: 10.1038/s41598-022-14203-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 05/17/2022] [Indexed: 02/07/2023] Open
Abstract
There is growing interest in the role of gut microbiome in colorectal cancer (CRC), ranging from screening to disease recurrence. Our study aims to identify microbial markers characteristic of CRC and to examine if changes in bacteriome persist after surgery. Forty-nine fecal samples from 25 non-cancer (NC) individuals and 12 CRC patients, before and 6-months after surgery, were collected for analysis by bacterial 16S rRNA gene sequencing. Bacterial richness and diversity were reduced, while pro-carcinogenic bacteria such as Bacteroides fragilis and Odoribacter splanchnicus were increased in CRC patients compared to NC group. These differences were no longer observed after surgery. Comparison between pre-op and post-op CRC showed increased abundance of probiotic bacteria after surgery. Concomitantly, bacteria associated with CRC progression were observed to have increased after surgery, implying persistent dysbiosis. In addition, functional pathway predictions based on the bacterial 16S rRNA gene data showed that various pathways were differentially enriched in CRC compared to NC. Microbiome signatures characteristic of CRC comprise altered bacterial composition. Elements of these dysbiotic signatures persists even after surgery, suggesting possible field-change in remnant non-diseased colon. Future studies should involve a larger sample size with microbiome data collected at multiple time points after surgery to examine if these dysbiotic patterns truly persist and also correlate with disease outcomes.
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Affiliation(s)
- Chin-Wen Png
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yong-Kang Chua
- Division of Colorectal Surgery, Department of Surgery, National University Hospital, Singapore, Singapore
| | - Jia-Hao Law
- Division of Colorectal Surgery, Department of Surgery, National University Hospital, Singapore, Singapore
| | - Yongliang Zhang
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ker-Kan Tan
- Division of Colorectal Surgery, Department of Surgery, National University Hospital, Singapore, Singapore.
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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14
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Zhao L, Cho WC, Luo JL. Exploring the patient-microbiome interaction patterns for pan-cancer. Comput Struct Biotechnol J 2022; 20:3068-3079. [PMID: 35782745 PMCID: PMC9233187 DOI: 10.1016/j.csbj.2022.06.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 06/06/2022] [Accepted: 06/06/2022] [Indexed: 11/03/2022] Open
Abstract
Microbes play important roles in human health and disease. Immunocompromised cancer patients are more vulnerable to getting microbial infections. Regions of hypoxia and acidic tumor microenvironment shape the microbial community diversity and abundance. Each cancer has its own microbiome, making cancer-specific sets of microbiomes. High-throughput profiling technologies provide a culture-free approach for microbial profiling in tumor samples. Microbial compositional data was extracted and examined from the TCGA unmapped transcriptome data. Biclustering, correlation, and statistical analyses were performed to determine the seven patient-microbe interaction patterns. These two-dimensional patterns consist of a group of microbial species that show significant over-representation over the 7 pan-cancer subtypes (S1-S7), respectively. Approximately 60% of the untreated cancer patients have experienced tissue microbial composition and functional changes between subtypes and normal controls. Among these changes, subtype S5 had loss of microbial diversity as well as impaired immune functions. S1, S2, and S3 had been enriched with microbial signatures derived from the Gammaproteobacteria, Actinobacteria and Betaproteobacteria, respectively. Colorectal cancer (CRC) was largely composed of two subtypes, namely S4 and S6, driven by different microbial profiles. S4 patients had increased microbial load, and were enriched with CRC-related oncogenic pathways. S6 CRC together with other cancer patients, making up almost 40% of all cases were classified into the S6 subtype, which not only resembled the normal control's microbiota but also retained their original "normal-like" functions. Lastly, the S7 was a rare and understudied subtype. Our study investigated the pan-cancer heterogeneity at the microbial level. The identified seven pan-cancer subtypes with 424 subtype-specific microbial signatures will help us find new therapeutic targets and better treatment strategies for cancer patients.
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Affiliation(s)
- Lan Zhao
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - William C.S. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China
| | - Jun-Li Luo
- The Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
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15
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Cellular Carcinogenesis: Role of Polarized Macrophages in Cancer Initiation. Cancers (Basel) 2022; 14:cancers14112811. [PMID: 35681791 PMCID: PMC9179569 DOI: 10.3390/cancers14112811] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/26/2022] [Accepted: 06/02/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Inflammation is a hallmark of many cancers. Macrophages are key participants in innate immunity and important drivers of inflammation. When chronically polarized beyond normal homeostatic responses to infection, injury, or aging, macrophages can express several pro-carcinogenic phenotypes. In this review, evidence supporting polarized macrophages as endogenous sources of carcinogenesis is discussed. In addition, the depletion or modulation of macrophages by small molecule inhibitors and probiotics are reviewed as emerging strategies in cancer prevention. Abstract Inflammation is an essential hallmark of cancer. Macrophages are key innate immune effector cells in chronic inflammation, parainflammation, and inflammaging. Parainflammation is a form of subclinical inflammation associated with a persistent DNA damage response. Inflammaging represents low-grade inflammation due to the dysregulation of innate and adaptive immune responses that occur with aging. Whether induced by infection, injury, or aging, immune dysregulation and chronic macrophage polarization contributes to cancer initiation through the production of proinflammatory chemokines/cytokines and genotoxins and by modulating immune surveillance. This review presents pre-clinical and clinical evidence for polarized macrophages as endogenous cellular carcinogens in the context of chronic inflammation, parainflammation, and inflammaging. Emerging strategies for cancer prevention, including small molecule inhibitors and probiotic approaches, that target macrophage function and phenotype are also discussed.
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16
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Artemev A, Naik S, Pougno A, Honnavar P, Shanbhag NM. The Association of Microbiome Dysbiosis With Colorectal Cancer. Cureus 2022; 14:e22156. [PMID: 35174040 PMCID: PMC8840808 DOI: 10.7759/cureus.22156] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2022] [Indexed: 02/06/2023] Open
Abstract
Many studies have been conducted to identify the causative organisms in colorectal cancer (CRC) and compare the microbiota of healthy individuals and those with CRC. The pathways by which the microbiota promotes CRC development are not yet fully understood. The hypothesized mechanisms include damage to the DNA, production of carcinogenic metabolites, and promotion of chronic inflammation. In a state of dysbiosis, the gut loses protective bacteria and is enriched with pathogenic and cancer-promoting bacteria, which promotes functions associated with cancer such as angiogenesis, loss of apoptosis, and cell proliferation. We have established a strong link between microbiota dysbiosis and certain species of bacteria and even viruses involved in tumorigenesis. In this review, we look at some of the major identified species and how they are related to CRC. Future research should include and even focus on mycobiome and virome on CRC development. Due to the diversity of the gut microbiome, there is a high possibility that the gain and loss of bacteria and their metabolic functions lead to CRC.
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Affiliation(s)
- Artem Artemev
- Medicine, Xavier University School of Medicine, Oranjestad, ABW
| | - Sheetal Naik
- Physiology, American University of Antigua, St. Johns, ATG
| | | | - Prasanna Honnavar
- Microbiology and Immunology, American University of Antigua, St. Johns, ATG
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17
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Novel Diagnostic Biomarkers in Colorectal Cancer. Int J Mol Sci 2022; 23:ijms23020852. [PMID: 35055034 PMCID: PMC8776048 DOI: 10.3390/ijms23020852] [Citation(s) in RCA: 124] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 12/27/2021] [Accepted: 01/03/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is still a leading cause of cancer death worldwide. Less than half of cases are diagnosed when the cancer is locally advanced. CRC is a heterogenous disease associated with a number of genetic or somatic mutations. Diagnostic markers are used for risk stratification and early detection, which might prolong overall survival. Nowadays, the widespread use of semi-invasive endoscopic methods and feacal blood tests characterised by suboptimal accuracy of diagnostic results has led to the detection of cases at later stages. New molecular noninvasive tests based on the detection of CRC alterations seem to be more sensitive and specific then the current methods. Therefore, research aiming at identifying molecular markers, such as DNA, RNA and proteins, would improve survival rates and contribute to the development of personalized medicine. The identification of “ideal” diagnostic biomarkers, having high sensitivity and specificity, being safe, cheap and easy to measure, remains a challenge. The purpose of this review is to discuss recent advances in novel diagnostic biomarkers for tumor tissue, blood and stool samples in CRC patients.
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18
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Berbert L, Santos A, Magro D, Guadagnini D, Assalin H, Lourenço L, Martinez C, Saad M, Coy C. Metagenomics analysis reveals universal signatures of the intestinal microbiota in colorectal cancer, regardless of regional differences. Braz J Med Biol Res 2022; 55:e11832. [PMID: 35293551 PMCID: PMC8922548 DOI: 10.1590/1414-431x2022e11832] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 01/10/2022] [Indexed: 12/14/2022] Open
Affiliation(s)
- L. Berbert
- Universidade Estadual de Campinas, Brasil
| | - A. Santos
- Universidade Estadual de Campinas, Brasil
| | - D.O. Magro
- Universidade Estadual de Campinas, Brasil
| | | | | | | | | | | | - C.S.R. Coy
- Universidade Estadual de Campinas, Brasil
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19
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Gao R, Zhu Y, Kong C, Xia K, Li H, Zhu Y, Zhang X, Liu Y, Zhong H, Yang R, Chen C, Qin N, Qin H. Alterations, Interactions, and Diagnostic Potential of Gut Bacteria and Viruses in Colorectal Cancer. Front Cell Infect Microbiol 2021; 11:657867. [PMID: 34307189 PMCID: PMC8294192 DOI: 10.3389/fcimb.2021.657867] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 05/18/2021] [Indexed: 12/11/2022] Open
Abstract
Gut microbiome alteration was closely associated with colorectal cancer (CRC). Previous studies had demonstrated the bacteria composition changes but lacked virome profiles, trans-kindom interactions, and reliable diagnostic model explorations in CRC. Hence, we performed metagenomic sequencing to investigate the gut microbiome and microbial interactions in adenoma and CRC patients. We found the decreased microbial diversity in CRC and revealed the taxonomic alterations of bacteria and viruses were highly associated with CRC at the species level. The relative abundance of oral-derived species, such as Fusobacterium nucleatum, Fusobacterium hwasookii, Porphyromonas gingivalis, and Bacteroides fragilis, increased. At the same time, butyrate-producing and anti-inflammatory microbes decreased in adenoma and CRC by non-parametric Kruskal-Wallis test. Despite that, the relative abundance of Escherichia viruses and Salmonella viruses increased, whereas some phages, including Enterobacteria phages and Uncultured crAssphage, decreased along with CRC development. Gut bacteria was negatively associated with viruses in CRC and healthy control by correlation analysis (P=0.017 and 0.002, respectively). Viruses were much more dynamic than the bacteria as the disease progressed, and the altered microbial interactions were distinctively stage-dependent. The degree centrality of microbial interactions decreased while closeness centrality increased along with the adenoma to cancer development. Uncultured crAssphage was the key bacteriophage that enriched in healthy controls and positively associated with butyrate-producing bacteria. Diagnostic tests based on bacteria by random forest confirmed in independent cohorts showed better performance than viruses for CRC. In conclusion, our study revealed the novel CRC-associated bacteria and viruses that exhibited specific differences and intensive microbial correlations, which provided a reliable diagnostic panel for CRC.
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Affiliation(s)
- Renyuan Gao
- Diagnostic and Treatment Center for Refractory Diseases of Abdomen Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.,Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China
| | - Yefei Zhu
- Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China.,Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Cheng Kong
- Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China.,Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Kai Xia
- Diagnostic and Treatment Center for Refractory Diseases of Abdomen Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.,Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China
| | - Hao Li
- Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China.,Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yin Zhu
- Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China.,Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaohui Zhang
- Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China.,Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yongqiang Liu
- Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China.,Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hui Zhong
- Department of Pediatrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Rong Yang
- Department of Pediatrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Chunqiu Chen
- Diagnostic and Treatment Center for Refractory Diseases of Abdomen Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.,Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China
| | - Nan Qin
- Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China.,Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Huanlong Qin
- Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China.,Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
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20
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Biondi A, Basile F, Vacante M. Familial adenomatous polyposis and changes in the gut microbiota: New insights into colorectal cancer carcinogenesis. World J Gastrointest Oncol 2021; 13:495-508. [PMID: 34163569 PMCID: PMC8204352 DOI: 10.4251/wjgo.v13.i6.495] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/15/2021] [Accepted: 05/08/2021] [Indexed: 02/06/2023] Open
Abstract
Patients with familial adenomatous polyposis (FAP), an autosomal dominant hereditary colorectal cancer syndrome, have a lifetime risk of developing cancer of nearly 100%. Recent studies have pointed out that the gut microbiota could play a crucial role in the development of colorectal adenomas and the consequent progression to colorectal cancer. Some gut bacteria, such as Fusobacterium nucleatum, Escherichia coli, Clostridium difficile, Peptostreptococcus, and enterotoxigenic Bacteroides fragilis, could be implicated in colorectal carcinogenesis through different mechanisms, including the maintenance of a chronic inflammatory state, production of bioactive tumorigenic metabolites, and DNA damage. Studies using the adenomatous polyposis coliMin/+ mouse model, which resembles FAP in most respects, have shown that specific changes in the intestinal microbial community could influence a multistep progression, the intestinal "adenoma-carcinoma sequence", which involves mucosal barrier injury, low-grade inflammation, activation of the Wnt pathway. Therefore, modulation of gut microbiota might represent a novel therapeutic target for patients with FAP. Administration of probiotics, prebiotics, antibiotics, and nonsteroidal anti-inflammatory drugs could potentially prevent the progression of the adenoma-carcinoma sequence in FAP. The aim of this review was to summarize the best available knowledge on the role of gut microbiota in colorectal carcinogenesis in patients with FAP.
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Affiliation(s)
- Antonio Biondi
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
- Multidisciplinary Research Center for Rare Diseases, University of Catania, Catania 95123, Italy
| | - Francesco Basile
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
- Multidisciplinary Research Center for Rare Diseases, University of Catania, Catania 95123, Italy
| | - Marco Vacante
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
- Multidisciplinary Research Center for Rare Diseases, University of Catania, Catania 95123, Italy
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21
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Kumar R, Harilal S, Carradori S, Mathew B. A Comprehensive Overview of Colon Cancer- A Grim Reaper of the 21st Century. Curr Med Chem 2021; 28:2657-2696. [PMID: 33106132 DOI: 10.2174/0929867327666201026143757] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 09/18/2020] [Accepted: 09/18/2020] [Indexed: 12/09/2022]
Abstract
A few decades ago, the incidence of colorectal cancer (CRC) was low and is now the fourth in the list of deadly cancers producing nearly a million deaths annually. A population that is aging along with risk factors such as smoking, obesity, sedentary lifestyle with little or no physical activity, and non-healthy food habits of developed countries can increase the risk of colorectal cancer. The balance in gut microbiota and the metabolites produced during bacterial fermentation within the host plays a significant role in regulating intestinal diseases as well as colorectal cancer development. Recent progress in the understanding of illness resulted in multiple treatment options such as surgery, radiation, and chemotherapy, including targeted therapy and multitherapies. The treatment plan for CRC depends on the location, stage and grade of cancer as well as genomic biomarker tests. Despite all the advancements made in the genetic and molecular aspects of the disease, the knowledge seems inadequate as the drug action as well as the wide variation in drug response did not appear strongly correlated with the individual molecular and genetic characteristics, which suggests the requirement of comprehensive molecular understanding of this complex heterogeneous disease. Furthermore, multitherapies or a broad spectrum approach, which is an amalgamation of the various promising as well as effective therapeutic strategies that can tackle heterogeneity and act on several targets of the disease, need to be validated in clinical studies. The latest treatment options have significantly increased the survival of up to three years in the case of advanced disease. The fact that colorectal cancer is developed from a polypoid precursor, as well as the symptoms of the disease that occur at an advanced stage, underlines how screening programs can help early detection and decrease mortality as well as morbidity from CRC.
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Affiliation(s)
- Rajesh Kumar
- Department of Pharmacy, Kerala University of Health Sciences, Thrissur, Kerala, India
| | - Seetha Harilal
- Department of Pharmacy, Kerala University of Health Sciences, Thrissur, Kerala, India
| | - Simone Carradori
- Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, via dei Vestini 31, 66100 Chieti, Italy
| | - Bijo Mathew
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi-682 041, India
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22
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Mughal MJ, Kwok HF. Multidimensional role of bacteria in cancer: Mechanisms insight, diagnostic, preventive and therapeutic potential. Semin Cancer Biol 2021; 86:1026-1044. [PMID: 34119644 DOI: 10.1016/j.semcancer.2021.06.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/28/2021] [Accepted: 06/08/2021] [Indexed: 02/08/2023]
Abstract
The active role of bacteria in oncogenesis has long been a topic of debate. Although, it was speculated to be a transmissible cause of cancer as early as the 16th-century, yet the idea about the direct involvement of bacteria in cancer development has only been explored in recent decades. More recently, several studies have uncovered the mechanisms behind the carcinogenic potential of bacteria which are inflammation, immune evasion, pro-carcinogenic metabolite production, DNA damage and genomic instability. On the other side, the recent development on the understanding of tumor microenvironment and technological advancements has turned this enemy into an ally. Studies using bacteria for cancer treatment and detection have shown noticeable effects. Therapeutic abilities of bioengineered live bacteria such as high specificity, selective cytotoxicity to cancer cells, responsiveness to external signals and control after ingestion have helped to overcome the challenges faced by conventional cancer therapies and highlighted the bacterial based therapy as an ideal approach for cancer treatment. In this review, we have made an effort to compile substantial evidence to support the multidimensional role of bacteria in cancer. We have discussed the multifaceted role of bacteria in cancer by highlighting the wide impact of bacteria on different cancer types, their mechanisms of actions in inducing carcinogenicity, followed by the diagnostic and therapeutic potential of bacteria in cancers. Moreover, we have also highlighted the existing gaps in the knowledge of the association between bacteria and cancer as well as the limitation and advantage of bacteria-based therapies in cancer. A better understanding of these multidimensional roles of bacteria in cancer can open up the new doorways to develop early detection strategies, prevent cancer, and develop therapeutic tactics to cure this devastating disease.
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Affiliation(s)
- Muhammad Jameel Mughal
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau
| | - Hang Fai Kwok
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau; MOE Frontiers Science Center for Precision Oncology, University of Macau, Avenida de Universidade, Taipa, Macau.
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23
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Shirazi MSR, Al-Alo KZK, Al-Yasiri MH, Lateef ZM, Ghasemian A. Microbiome Dysbiosis and Predominant Bacterial Species as Human Cancer Biomarkers. J Gastrointest Cancer 2021; 51:725-728. [PMID: 31605288 DOI: 10.1007/s12029-019-00311-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE To evaluate bacterial agents as cancer biomarkers. METHODS AND RESULTS Various bacterial species have been demonstrated to involve in human cancers. However, the data is not enough for better understanding of predominant specific species. Application of a rapid and early-diagnostic, cost-effective, non-invasive, and inclusive method is a crucial approach for obtaining valid results. The role of Helicobacter pylori (H. pylori) in gastric and duodenal cancer has been confirmed. From investigation among previous publications, we attempted to make it clear which bacterial species significantly and specifically increase in various cancer types. It was unraveled that there is significant change in Granulicatella adiacens (G. adiacens) in lung cancer (LC), Fusobacterium nucleatum (F. nucleatum) in colorectal cancer (CRC), H. pylori and Porphyromonas gingivalis (P. gingivalis) in pancreatic cancer, and Streptococcus spp. in oral cancer. CONCLUSION Alteration in the cell cycle by means of different mechanisms such as inflammation, alteration in cell signaling, invasion and immune evasion, specific niche colonization, induction of DNA damage and mutation, expression of some microRNAs, and enhancing epigenetic effects are the most common mechanisms employed by bacterial species.
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Affiliation(s)
| | - K Z K Al-Alo
- Department of Veterinary Clinical Sciences, Faculty of Veterinary Medicine, University of Kufa, Kufa, Iraq
| | | | | | - Abdolmajid Ghasemian
- Department of Biology, Central Tehran Branch, Islamic Azad University, Tehran, Iran.
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24
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Loke YL, Chew MT, Ngeow YF, Lim WWD, Peh SC. Colon Carcinogenesis: The Interplay Between Diet and Gut Microbiota. Front Cell Infect Microbiol 2020; 10:603086. [PMID: 33364203 PMCID: PMC7753026 DOI: 10.3389/fcimb.2020.603086] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 10/28/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) incidence increases yearly, and is three to four times higher in developed countries compared to developing countries. The well-known risk factors have been attributed to low physical activity, overweight, obesity, dietary consumption including excessive consumption of red processed meats, alcohol, and low dietary fiber content. There is growing evidence of the interplay between diet and gut microbiota in CRC carcinogenesis. Although there appears to be a direct causal role for gut microbes in the development of CRC in some animal models, the link between diet, gut microbes, and colonic carcinogenesis has been established largely as an association rather than as a cause-and-effect relationship. This is especially true for human studies. As essential dietary factors influence CRC risk, the role of proteins, carbohydrates, fat, and their end products are considered as part of the interplay between diet and gut microbiota. The underlying molecular mechanisms of colon carcinogenesis mediated by gut microbiota are also discussed. Human biological responses such as inflammation, oxidative stress, deoxyribonucleic acid (DNA) damage can all influence dysbiosis and consequently CRC carcinogenesis. Dysbiosis could add to CRC risk by shifting the effect of dietary components toward promoting a colonic neoplasm together with interacting with gut microbiota. It follows that dietary intervention and gut microbiota modulation may play a vital role in reducing CRC risk.
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Affiliation(s)
- Yean Leng Loke
- Centre for Biomedical Physics, School of Healthcare and Medical Sciences, Sunway University, Petaling Jaya, Malaysia
| | - Ming Tsuey Chew
- Centre for Biomedical Physics, School of Healthcare and Medical Sciences, Sunway University, Petaling Jaya, Malaysia
| | - Yun Fong Ngeow
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Kajang, Malaysia.,Centre for Research on Communicable Diseases, Universiti Tunku Abdul Rahman, Kajang, Malaysia
| | - Wendy Wan Dee Lim
- Department of Gastroenterology, Sunway Medical Centre, Petaling Jaya, Malaysia
| | - Suat Cheng Peh
- Ageing Health and Well-Being Research Centre, Sunway University, Petaling Jaya, Malaysia.,Department of Medical Sciences, School of Healthcare and Medical Sciences, Sunway University, Petaling Jaya, Malaysia
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25
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Sobhani I, Rotkopf H, Khazaie K. Bacteria-related changes in host DNA methylation and the risk for CRC. Gut Microbes 2020; 12:1800898. [PMID: 32931352 PMCID: PMC7575230 DOI: 10.1080/19490976.2020.1800898] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 07/17/2020] [Indexed: 02/03/2023] Open
Abstract
Colorectal cancer (CRC) is the second most common cause of cancer deaths in men and women combined. Colon-tumor growth is multistage and the result of the accumulation of spontaneous mutations and epigenetic events that silence tumor-suppressor genes and activate oncogenes. Environmental factors are primary contributors to these somatic gene alterations, which account for the increase in incidence of CRC in western countries. In recent decades, gut microbiota and their metabolites have been recognized as essential contributing factors to CRC, and now serve as biomarkers for the diagnosis and prognosis of CRC. In the present review, we highlight holistic approaches to understanding how gut microbiota contributes to CRC. We particularly focus herein on bacteria-related changes in host DNA methylation and the risk for CRC.
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Affiliation(s)
- Iradj Sobhani
- Head of the Department of Gastroenterology, Consultant in GI Oncology, Hopital Henri Mondor, APHP. Créteil-France; Head of the Research Team EC2M3, Université Paris-Est Créteil (UPEC), Créteil, France
| | - Hugo Rotkopf
- Department of Gastroenterology Hospital Henri Mondor, APHP. Créteil-France; Member of Research Team EC2M3, Université Paris-Est Créteil (UPEC). Créteil, France
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Cruz BCS, Sarandy MM, Messias AC, Gonçalves RV, Ferreira CLLF, Peluzio MCG. Preclinical and clinical relevance of probiotics and synbiotics in colorectal carcinogenesis: a systematic review. Nutr Rev 2020; 78:667-687. [PMID: 31917829 DOI: 10.1093/nutrit/nuz087] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
CONTEXT Recent evidence suggests that modulation of the gut microbiota may help prevent colorectal cancer. OBJECTIVE The aim of this systematic review was to investigate the role of probiotics and synbiotics in the prevention of colorectal cancer and to clarify potential mechanisms involved. DATA SOURCES The PubMed, ScienceDirect, and LILACS databases were searched for studies conducted in humans or animal models and published up to August 15, 2018. STUDY SELECTION Clinical trials and placebo-controlled experimental studies that evaluated the effects of probiotics and synbiotics in colorectal cancer and cancer associated with inflammatory bowel disease were included. Of 247 articles identified, 31 remained after exclusion criteria were applied. A search of reference lists identified 5 additional studies, for a total of 36 included studies. DATA EXTRACTION Two authors independently assessed risk of bias of included studies and extracted data. Data were pooled by type of study, ie, preclinical or clinical. RESULTS The results showed positive effects of probiotics and synbiotics in preventing colorectal cancer. The main mechanisms identified were alterations in the composition and metabolic activity of the intestinal microbiota; reduction of inflammation; induction of apoptosis and inhibition of tumor growth; modulation of immune responses and cell proliferation; enhanced function of the intestinal barrier; production of compounds with anticarcinogenic activity; and modulation of oxidative stress. CONCLUSIONS Probiotics or synbiotics may help prevent colorectal cancer, but additional studies in humans are required to better inform clinical practice.
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Affiliation(s)
- Bruna C S Cruz
- Department of Nutrition and Health, Nutritional Biochemistry Laboratory, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
| | - Mariáurea M Sarandy
- Department of Animal Biology, Experimental Pathology Laboratory, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
| | - Anny C Messias
- Department of Nutrition and Health, Nutritional Biochemistry Laboratory, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
| | - Reggiani V Gonçalves
- Department of Animal Biology, Experimental Pathology Laboratory, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
| | - Célia L L F Ferreira
- Institute of Biotechnology Applied to Agriculture (BIOAGRO), Laboratory of Dairy Cultures, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
| | - Maria C G Peluzio
- Department of Nutrition and Health, Nutritional Biochemistry Laboratory, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
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27
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Assessment of oncogenic role of intestinal microbiota in colorectal cancer patients. J Gastrointest Cancer 2020; 52:1016-1021. [DOI: 10.1007/s12029-020-00531-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/2020] [Indexed: 02/07/2023]
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Gomes SD, Oliveira CS, Azevedo-Silva J, Casanova MR, Barreto J, Pereira H, Chaves SR, Rodrigues LR, Casal M, Côrte-Real M, Baltazar F, Preto A. The Role of Diet Related Short-Chain Fatty Acids in Colorectal Cancer Metabolism and Survival: Prevention and Therapeutic Implications. Curr Med Chem 2020; 27:4087-4108. [PMID: 29848266 DOI: 10.2174/0929867325666180530102050] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 12/22/2017] [Accepted: 05/15/2018] [Indexed: 12/16/2022]
Abstract
Colorectal Cancer (CRC) is a major cause of cancer-related death worldwide. CRC increased risk has been associated with alterations in the intestinal microbiota, with decreased production of Short Chain Fatty Acids (SCFAs). SCFAs produced in the human colon are the major products of bacterial fermentation of undigested dietary fiber and starch. While colonocytes use the three major SCFAs, namely acetate, propionate and butyrate, as energy sources, transformed CRC cells primarily undergo aerobic glycolysis. Compared to normal colonocytes, CRC cells exhibit increased sensitivity to SCFAs, thus indicating they play an important role in cell homeostasis. Manipulation of SCFA levels in the intestine, through changes in microbiota, has therefore emerged as a potential preventive/therapeutic strategy for CRC. Interest in understanding SCFAs mechanism of action in CRC cells has increased in the last years. Several SCFA transporters like SMCT-1, MCT-1 and aquaporins have been identified as the main transmembrane transporters in intestinal cells. Recently, it was shown that acetate promotes plasma membrane re-localization of MCT-1 and triggers changes in the glucose metabolism. SCFAs induce apoptotic cell death in CRC cells, and further mechanisms have been discovered, including the involvement of lysosomal membrane permeabilization, associated with mitochondria dysfunction and degradation. In this review, we will discuss the current knowledge on the transport of SCFAs by CRC cells and their effects on CRC metabolism and survival. The impact of increasing SCFA production by manipulation of colon microbiota on the prevention/therapy of CRC will also be addressed.
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Affiliation(s)
- Sara Daniela Gomes
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal,ICVS - Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal
| | - Cláudia Suellen Oliveira
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal,ICBAS - Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal
| | - João Azevedo-Silva
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
| | - Marta R Casanova
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal,CEB - Centre of Biological Engineering, University of Minho, Braga, Portugal
| | - Judite Barreto
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
| | - Helena Pereira
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
| | - Susana R Chaves
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
| | - Lígia R Rodrigues
- CEB - Centre of Biological Engineering, University of Minho, Braga, Portugal
| | - Margarida Casal
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
| | - Manuela Côrte-Real
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
| | - Fátima Baltazar
- ICVS - Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal,ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Ana Preto
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
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29
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Al-Hilu SA, Al-Shujairi WH. Dual Role of Bacteria in Carcinoma: Stimulation and Inhibition. Int J Microbiol 2020; 2020:4639761. [PMID: 32908523 PMCID: PMC7463420 DOI: 10.1155/2020/4639761] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 07/10/2020] [Accepted: 07/30/2020] [Indexed: 12/11/2022] Open
Abstract
Although what unifies the carcinogenic microorganisms has not been determined by multiple studies, the role of bacteria in the development of neoplasms has not been properly elucidated. In this review, we discuss links between the bacterial species and cancer, with focus on immune responses for the stimulation of tumor cells such as induction of inflammation. Finally, we will describe the potential therapeutic strategies of bacteria on target tumors to improve treatment while mitigating adverse reactions. Cancer is a series of genetic changes that transform normal cells into tumor cells. These changes come from several reasons, including smoking, drinking alcohol, sunlight, exposure to chemical or physical factors, and finally chronic infection with microorganisms, including bacteria. In fact, bacterial infections are not carcinogenic, but recently it was discovered that the association between bacteria and cancer is through two mechanisms, the first stimulating chronic inflammation and the second producing carcinogenic metabolites. While bacteria are carcinogenic agents also, they have a dual role eliminating and removing tumor cells. However, the traditional cancer treatments that include chemotherapy, radiotherapy, surgery, and immunotherapy increase the chances of survival, and there are many side effects of these therapies, including the high toxicity of tissues and normal cells, could not penetrate the tumor cells, and resistance of these therapies by tumor cells. Therefore, the world has turned to an alternative solution, which is the use of genetically engineered microorganisms; thus, the use of living bacteria targeting cancerous cells is the unique option to overcome these challenges. Bacterial therapies, whether used alone or combination with chemotherapy, give a positive effect to treat multiple conditions of cancer. Also, bacteria can be used as vectors for drug, gene, or therapy, and this is a great step to treat cancer. Thus, we review the mechanisms underlying the interaction of the microbiota residents with cancer. Cancer-associated bacteria differ from those in healthy human and are linked with gene-expression profile. We also discuss how live bacteria interact with tumor microenvironments to induce tumor regression through colonization and spread. Finally, we provide past and ongoing clinical trials that include bacteria targeting tumors.
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Affiliation(s)
- Suad A Al-Hilu
- Department of Biology/Faculty of Sciences, University of Kufa, 54001 Najaf, Iraq
| | - Wisam H Al-Shujairi
- Department of Clinical Laboratory Sciences/College of Pharmacy, University of Babylon, 51001 Hilla, Iraq
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30
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Xia X, Wu WKK, Wong SH, Liu D, Kwong TNY, Nakatsu G, Yan PS, Chuang YM, Chan MWY, Coker OO, Chen Z, Yeoh YK, Zhao L, Wang X, Cheng WY, Chan MTV, Chan PKS, Sung JJY, Wang MH, Yu J. Bacteria pathogens drive host colonic epithelial cell promoter hypermethylation of tumor suppressor genes in colorectal cancer. MICROBIOME 2020; 8:108. [PMID: 32678024 PMCID: PMC7367367 DOI: 10.1186/s40168-020-00847-4] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 04/26/2020] [Indexed: 05/09/2023]
Abstract
BACKGROUND Altered microbiome composition and aberrant promoter hypermethylation of tumor suppressor genes (TSGs) are two important hallmarks of colorectal cancer (CRC). Here we performed concurrent 16S rRNA gene sequencing and methyl-CpG binding domain-based capture sequencing in 33 tissue biopsies (5 normal colonic mucosa tissues, 4 pairs of adenoma and adenoma-adjacent tissues, and 10 pairs of CRC and CRC-adjacent tissues) to identify significant associations between TSG promoter hypermethylation and CRC-associated bacteria, followed by functional validation of the methylation-associated bacteria. RESULTS Fusobacterium nucleatum and Hungatella hathewayi were identified as the top two methylation-regulating bacteria. Targeted analysis on bona fide TSGs revealed that H. hathewayi and Streptococcus spp. significantly correlated with CDX2 and MLH1 promoter hypermethylation, respectively. Mechanistic validation with cell-line and animal models revealed that F. nucleatum and H. hathewayi upregulated DNA methyltransferase. H. hathewayi inoculation also promoted colonic epithelial cell proliferation in germ-free and conventional mice. CONCLUSION Our integrative analysis revealed previously unknown epigenetic regulation of TSGs in host cells through inducing DNA methyltransferase by F. nucleatum and H. hathewayi, and established the latter as CRC-promoting bacteria. Video abstract.
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Affiliation(s)
- Xiaoxuan Xia
- Division of Biostatistics, Centre for Clinical Research and Biostatistics, JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - William Ka Kei Wu
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Sunny Hei Wong
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Dabin Liu
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Thomas Ngai Yeung Kwong
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Geicho Nakatsu
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Pearlly S Yan
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - Yu-Ming Chuang
- Department of Biomedical Sciences, National Chung Cheng University, Chia-Yi, Taiwan, Republic of China
| | - Michael Wing-Yan Chan
- Department of Biomedical Sciences, National Chung Cheng University, Chia-Yi, Taiwan, Republic of China
| | - Olabisi Oluwabukola Coker
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Zigui Chen
- Department of Microbiology, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Yun Kit Yeoh
- Department of Microbiology, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Liuyang Zhao
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Xiansong Wang
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Wing Yin Cheng
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Matthew Tak Vai Chan
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Paul Kay Sheung Chan
- Department of Microbiology, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Joseph Jao Yiu Sung
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China
| | - Maggie Haitian Wang
- Division of Biostatistics, Centre for Clinical Research and Biostatistics, JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China.
| | - Jun Yu
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China.
- State Key Laboratory of Digestive Diseases, Institute of Digestive Diseases, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China.
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Special Administrative Region of China.
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31
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Wang Q, Yu C, Yue C, Liu X. Fusobacterium nucleatum produces cancer stem cell characteristics via EMT-resembling variations. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2020; 13:1819-1828. [PMID: 32782710 PMCID: PMC7414483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 04/28/2020] [Indexed: 06/11/2023]
Abstract
OBJECTIVE To explore the involvement of epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) characteristics induced by Fusobacterium nucleatum (Fn) in colorectal cancer (CRC) in vitro. METHODS SW480 and HCT116 cells were co-cultivated with Fn. Western blot (WB) and real-time PCR were used for detecting EMT markers' expression. CSC-resembling phenotypes were observed through migration, intrusion, and spherical colony formation assays. Flow cytometry was employed for sorting, based on the expression of CD44. RESULTS It was displayed that Fn infection was responsible for an EMT phenotype associated with an increase in mesenchymal markers (Snail1, Vimentin, and ZEB1) as well as CD44 expression. Fn treatment induced stronger expressions of such markers when MOI increased. Furthermore, infection resulted in augmented migration, intrusion, and tumorsphere formation capacities. Cell classification implicated that mere CD44high cells exhibited CSC characteristics and mesenchymal phenotype (MP) in vitro, accompanied with augmented tumor-causing capacity over CD44low cells. Finally, we demonstrated IL-6/STAT3 pathway was involved in EMT-CSC-resembling behavior of CRC cells. CONCLUSION All of these data suggest that Fn reveals CSC-resembling characteristics through activating IL-6/STAT3 and eliciting EMT-resembling variations in colorectal epithelial cells (CECs).
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Affiliation(s)
- Qin Wang
- Department of Clinical Medicine, Jiangsu Health Vocational CollegeNanjing, China
| | - Chen Yu
- Department of Integrated Traditional Chinese and Western Medicine, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical UniversityNanjing, China
| | - Chao Yue
- Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical UniversityNanjing, China
| | - Xin Liu
- Department of Prevention and Control for Occupational Disease, Jiangsu Provincial Center for Disease Prevention and ControlNanjing, China
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Niccolai E, Boem F, Emmi G, Amedei A. The link "Cancer and autoimmune diseases" in the light of microbiota: Evidence of a potential culprit. Immunol Lett 2020; 222:12-28. [PMID: 32145242 DOI: 10.1016/j.imlet.2020.03.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 02/20/2020] [Accepted: 03/03/2020] [Indexed: 12/15/2022]
Abstract
Evidence establishes that chronic inflammation and autoimmunity are associated with cancer development and patients with a primary malignancy may develop autoimmune-like diseases. Despite immune dysregulation is a common feature of both cancer and autoimmune diseases, precise mechanisms underlying this susceptibility are not clarified and different hypotheses have been proposed, starting from genetic and environmental common features, to intrinsic properties of immune system. Moreover, as the development and use of immunomodulatory therapies for cancer and autoimmune diseases are increasing, the elucidation of this relationship must be investigated in order to offer the best and most secure therapeutic options. The microbiota could represent a potential link between autoimmune diseases and cancer. The immunomodulation role of microbiota is widely recognized and under eubiosis, it orchestrates both the innate and adaptive response of immunity, in order to discriminate and modulate the immune response itself in the most appropriate way. Therefore, a dysbiotic status can alter the immune tonus rendering the host prone to exogenous or endogenous infections, breaking the tolerance against self-components and activating the immune responses in an excessive (i.e. chronic inflammation) or deficient way, favoring the onset of neoplastic and autoimmune diseases.
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Affiliation(s)
- Elena Niccolai
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134, Florence, Italy
| | - Federico Boem
- Department of Oncology and Hemato-Oncology, University of Milan, Via Festa del Perdono 7, 20122, Milan, Italy; Department of Philosophy and Educational Sciences. University of Turin, Via Verdi 8, 10124, Turin, Italy
| | - Giacomo Emmi
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134, Florence, Italy; Neuromusculoskeletal Department (Interdisciplinary Internal Medicine), Azienda Ospedaliera Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134, Florence, Italy; Neuromusculoskeletal Department (Interdisciplinary Internal Medicine), Azienda Ospedaliera Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy.
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Clos-Garcia M, Garcia K, Alonso C, Iruarrizaga-Lejarreta M, D’Amato M, Crespo A, Iglesias A, Cubiella J, Bujanda L, Falcón-Pérez JM. Integrative Analysis of Fecal Metagenomics and Metabolomics in Colorectal Cancer. Cancers (Basel) 2020; 12:1142. [PMID: 32370168 PMCID: PMC7281174 DOI: 10.3390/cancers12051142] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 04/28/2020] [Accepted: 04/30/2020] [Indexed: 12/24/2022] Open
Abstract
Although colorectal cancer (CRC) is the second leading cause of death in developed countries, current diagnostic tests for early disease stages are suboptimal. We have performed a combination of UHPLC-MS metabolomics and 16S microbiome analyses on 224 feces samples in order to identify early biomarkers for both advanced adenomas (AD) and CRC. We report differences in fecal levels of cholesteryl esters and sphingolipids in CRC. We identified Fusobacterium, Parvimonas and Staphylococcus to be increased in CRC patients and Lachnospiraceae family to be reduced. We finally described Adlercreutzia to be more abundant in AD patients' feces. Integration of metabolomics and microbiome data revealed tight interactions between bacteria and host and performed better than FOB test for CRC diagnosis. This study identifies potential early biomarkers that outperform current diagnostic tools and frame them into the stablished gut microbiota role in CRC pathogenesis.
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Affiliation(s)
- Marc Clos-Garcia
- Exosomes Laboratory, CIC bioGUNE, 48160 Derio, Spain;
- Biodonostia, Grupo de Enfermedades Gastrointestinales, 20014 San Sebastian, Spain;
| | - Koldo Garcia
- Biodonostia, Grupo de Genética Gastrointestinal, 20014 San Sebastian, Spain; (K.G.); (M.D.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain;
| | - Cristina Alonso
- OWL Metabolomics, Bizkaia Technology Park, Derio, 48160 Bizkaia, Spain; (C.A.); (M.I.-L.)
| | | | - Mauro D’Amato
- Biodonostia, Grupo de Genética Gastrointestinal, 20014 San Sebastian, Spain; (K.G.); (M.D.)
- IKERBASQUE, Basque Foundation for Sciences, 48013 Bilbao, Spain
- School of Biological Sciences, Monash University, Clayton VIC 3800, Australia
| | - Anais Crespo
- Department of Gastroenterology, Complexo Hospitalario Universitario de Ourense, Instituto de Investigación Sanitario Galicia Sur, 32005 Ourense, Spain; (A.C.); (A.I.)
| | - Agueda Iglesias
- Department of Gastroenterology, Complexo Hospitalario Universitario de Ourense, Instituto de Investigación Sanitario Galicia Sur, 32005 Ourense, Spain; (A.C.); (A.I.)
| | - Joaquín Cubiella
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain;
- Department of Gastroenterology, Complexo Hospitalario Universitario de Ourense, Instituto de Investigación Sanitario Galicia Sur, 32005 Ourense, Spain; (A.C.); (A.I.)
| | - Luis Bujanda
- Biodonostia, Grupo de Enfermedades Gastrointestinales, 20014 San Sebastian, Spain;
| | - Juan Manuel Falcón-Pérez
- Exosomes Laboratory, CIC bioGUNE, 48160 Derio, Spain;
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain;
- IKERBASQUE, Basque Foundation for Sciences, 48013 Bilbao, Spain
- Metabolomics Platform, CIC bioGUNE, 48160 Derio, Spain
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Wu Y, He Q, Yu L, Pham Q, Cheung L, Kim YS, Wang TTY, Smith AD. Indole-3-Carbinol Inhibits Citrobacter rodentium Infection through Multiple Pathways Including Reduction of Bacterial Adhesion and Enhancement of Cytotoxic T Cell Activity. Nutrients 2020; 12:E917. [PMID: 32230738 PMCID: PMC7230886 DOI: 10.3390/nu12040917] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 03/13/2020] [Accepted: 03/19/2020] [Indexed: 12/24/2022] Open
Abstract
Intestinal inflammation is associated with an increased risk of developing colorectal cancer and may result from dysregulated responses to commensal bacteria or exposure to bacterial pathogens. Dietary modulation of intestinal inflammation may protect against development of colon cancer. However, the precise diet-derived components and underlying mechanisms remain elusive. Citrobacter rodentium (Cr) induces acute intestinal inflammation and has been used to study the role of inflammation in the susceptibility to colon cancer. Here we examine the effects of indole-3-carbinol (I3C), a dietary compound with anticarcinogenic properties, on intestinal immune and inflammatory responses to Cr infection and adhesion to colonic cells in vitro. C57BL/6J mice were fed a diet with/without 1 μmol/g I3C and infected with Cr. Compared to infected mice fed with a control diet, consumption of a 1 μmol I3C/g diet significantly reduced fecal excretion of Cr, Cr colonization of the colon, and reduced colon crypt hyperplasia. Furthermore, expression of Cr-induced inflammatory markers such as IL-17A, IL-6, and IL1β were attenuated in infected mice fed with the I3C diet, compared to mice fed a control diet. The expression of cytotoxic T cell markers CD8 and FasL mRNA were increased in I3C-fed infected mice. In-vitro, I3C inhibited Cr growth and adhesion to Caco-2 cells. I3C alleviates Cr-induced murine colitis through multiple mechanisms including inhibition of Cr growth and adhesion to colonic cells in vitro and enhancement of cytotoxic T cell activity.
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Affiliation(s)
- Yanbei Wu
- China-Canada Joint Lab of Food Nutrition and Health (Beijing), Beijing Technology & Business University, Beijing 100048, China;
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Technology & Business University, Beijing 100048, China
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, USDA-ARS, Beltsville, MD 20705, USA; (Q.P.); (L.C.)
| | - Qiang He
- College of Biomass Science and Engineering, Sichuan University, Chengdu 610065, China;
| | - Liangli Yu
- Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742, USA;
| | - Quynhchi Pham
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, USDA-ARS, Beltsville, MD 20705, USA; (Q.P.); (L.C.)
| | - Lumei Cheung
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, USDA-ARS, Beltsville, MD 20705, USA; (Q.P.); (L.C.)
| | - Young S. Kim
- Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Thomas T. Y. Wang
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, USDA-ARS, Beltsville, MD 20705, USA; (Q.P.); (L.C.)
| | - Allen D. Smith
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, USDA-ARS, Beltsville, MD 20705, USA; (Q.P.); (L.C.)
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Metaproteomics characterizes human gut microbiome function in colorectal cancer. NPJ Biofilms Microbiomes 2020; 6:14. [PMID: 32210237 PMCID: PMC7093434 DOI: 10.1038/s41522-020-0123-4] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 02/26/2020] [Indexed: 02/08/2023] Open
Abstract
Pathogenesis of colorectal cancer (CRC) is associated with alterations in gut microbiome. Previous studies have focused on the changes of taxonomic abundances by metagenomics. Variations of the function of intestinal bacteria in CRC patients compared to healthy crowds remain largely unknown. Here we collected fecal samples from CRC patients and healthy volunteers and characterized their microbiome using quantitative metaproteomic method. We have identified and quantified 91,902 peptides, 30,062 gut microbial protein groups, and 195 genera of microbes. Among the proteins, 341 were found significantly different in abundance between the CRC patients and the healthy volunteers. Microbial proteins related to iron intake/transport; oxidative stress; and DNA replication, recombination, and repair were significantly alternated in abundance as a result of high local concentration of iron and high oxidative stress in the large intestine of CRC patients. Our study shows that metaproteomics can provide functional information on intestinal microflora that is of great value for pathogenesis research, and can help guide clinical diagnosis in the future.
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Hradicka P, Beal J, Kassayova M, Foey A, Demeckova V. A Novel Lactic Acid Bacteria Mixture: Macrophage-Targeted Prophylactic Intervention in Colorectal Cancer Management. Microorganisms 2020; 8:microorganisms8030387. [PMID: 32168834 PMCID: PMC7142725 DOI: 10.3390/microorganisms8030387] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 02/25/2020] [Accepted: 03/10/2020] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common forms of cancer. Its onset from chronic inflammation is widely accepted. Moreover, dysbiosis plays an undeniable role, thus the use of probiotics in CRC has been suggested. They exhibit both anti- and pro-inflammatory properties and restore balance in the microbiota. The aim of this study was to investigate the immunomodulatory properties of six lactobacilli with probiotic features in an in vitro model of macrophage-like cells and to test these pooled probiotics for their anti-tumour properties in a chemically induced CRC model using Wistar male rats. Upon co-culture of M1- and M2-like macrophages with lactobacilli, cytokine release (TNF-α, IL-1β, IL-18, IL-23) and phagocytic activity using fluorescent-labelled bacteria were tested. The effects of orally administered probiotics on basic cancer and immune parameters and cytokine concentration (TNF-α, IL-1β, IL-18) in colon tumours were studied. Tested lactobacilli exhibited both pro- and anti-inflammatory properties in in vitro conditions. In vivo study showed that the administration of probiotics was able to decrease multiplicity, volume and total tumour numbers, restore colon length (p < 0.05) and increase IL-18 production (p < 0.05) in tumour tissue. These data indicate both an immunomodulatory effect of probiotics on distinct macrophage subsets and a protective effect against chemically-induced CRC.
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Affiliation(s)
- Petra Hradicka
- Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Safarik University in Kosice, Srobarova 2, 041 54 Kosice, Slovak; (P.H.); (M.K.)
| | - Jane Beal
- School of Biological and Marine Sciences, University of Plymouth, Drake Circus, Plymouth PL4 8AA, UK;
| | - Monika Kassayova
- Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Safarik University in Kosice, Srobarova 2, 041 54 Kosice, Slovak; (P.H.); (M.K.)
| | - Andrew Foey
- School of Biomedical Sciences, University of Plymouth, Drake Circus, Plymouth PL4 8AA, UK;
| | - Vlasta Demeckova
- Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Safarik University in Kosice, Srobarova 2, 041 54 Kosice, Slovak; (P.H.); (M.K.)
- Correspondence:
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Aslam MN, Bassis CM, Bergin IL, Knuver K, Zick SM, Sen A, Turgeon DK, Varani J. A Calcium-Rich Multimineral Intervention to Modulate Colonic Microbial Communities and Metabolomic Profiles in Humans: Results from a 90-Day Trial. Cancer Prev Res (Phila) 2020; 13:101-116. [PMID: 31771942 PMCID: PMC7528938 DOI: 10.1158/1940-6207.capr-19-0325] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 08/02/2019] [Accepted: 11/22/2019] [Indexed: 12/27/2022]
Abstract
Aquamin is a calcium-, magnesium-, and multiple trace element-rich natural product with colon polyp prevention efficacy based on preclinical studies. The goal of this study was to determine the effects of Aquamin on colonic microbial community and attendant metabolomic profile. Thirty healthy human participants were enrolled in a 90-day trial in which Aquamin (delivering 800 mg of calcium per day) was compared with calcium alone or placebo. Before and after the intervention, colonic biopsies and stool specimens were obtained. All 30 participants completed the study without serious adverse event or change in liver and renal function markers. Compared with pretreatment values, intervention with Aquamin led to a reduction in total bacterial DNA (P = 0.0001) and a shift in the microbial community measured by thetaYC (θYC; P = 0.0087). Treatment with calcium also produced a decline in total bacteria, but smaller than seen with Aquamin, whereas no reduction was observed with placebo in the colon. In parallel with microbial changes, a reduction in total bile acid levels (P = 0.0375) and a slight increase in the level of the short-chain fatty acid (SCFA) acetate in stool specimens (P < 0.0001) from Aquamin-treated participants were noted. No change in bile acids or SCFAs was observed with calcium or placebo. We conclude that Aquamin is safe and tolerable in healthy human participants and may produce beneficial alterations in the colonic microbial community and the attendant metabolomic profile. Because the number of participants was small, the findings should be considered preliminary.
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Affiliation(s)
- Muhammad N Aslam
- Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan.
| | - Christine M Bassis
- Division of Infectious Diseases, Department of Internal Medicine, The University of Michigan Medical School, Ann Arbor, Michigan
| | - Ingrid L Bergin
- The Unit for Laboratory Animal Medicine, The University of Michigan Medical School, Ann Arbor, Michigan
| | - Karsten Knuver
- Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan
| | - Suzanna M Zick
- Department of Family Medicine, The University of Michigan Medical School, Ann Arbor, Michigan
- Department of Nutritional Science, The University of Michigan School of Public Health, Ann Arbor, Michigan
| | - Ananda Sen
- Department of Family Medicine, The University of Michigan Medical School, Ann Arbor, Michigan
- Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, Michigan
| | - D Kim Turgeon
- Division of Gastroenterology, Department of Internal Medicine, The University of Michigan Medical School, Ann Arbor, Michigan
| | - James Varani
- Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan
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Dong L, Xie J, Wang Y, Zuo D. Gut Microbiota and Immune Responses. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1238:165-193. [PMID: 32323185 DOI: 10.1007/978-981-15-2385-4_10] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The gut microbiota consists of a dynamic multispecies community living within a particular niche in a mutual synergy with the host organism. Recent findings have revealed roles for the gut microbiota in the modulation of host immunity and the development and progression of immune-mediated diseases. Besides, growing evidence supports the concept that some metabolites mainly originated from gut microbiota are linked to the immune regulation implicated in systemic inflammatory and autoimmune disorders. In this chapter, we describe the recent advances in our understanding of how host-microbiota interactions shape the immune system, how they affect the pathogenesis of immune-associated diseases and the impact of these mechanisms in the efficacy of disease therapy.
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Affiliation(s)
- Lijun Dong
- The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, 510900, China
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Jingwen Xie
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Youyi Wang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
- School of Laboratory Medicine and Biotechnology, Institute of Molecular Immunology, Southern Medical University, Guangzhou, 510515, China
| | - Daming Zuo
- School of Laboratory Medicine and Biotechnology, Institute of Molecular Immunology, Southern Medical University, Guangzhou, 510515, China.
- Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
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Zhuo Q, Yu B, Zhou J, Zhang J, Zhang R, Xie J, Wang Q, Zhao S. Lysates of Lactobacillus acidophilus combined with CTLA-4-blocking antibodies enhance antitumor immunity in a mouse colon cancer model. Sci Rep 2019; 9:20128. [PMID: 31882868 PMCID: PMC6934597 DOI: 10.1038/s41598-019-56661-y] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 12/13/2019] [Indexed: 02/07/2023] Open
Abstract
Previous reports have suggested that many gut microbiomes were associated with the development of colorectal cancer (CRC), and could modulate response to numerous forms of cancer therapy, including checkpoint blockade immunotherapy. Here we evaluated the protective efficacy of Lactobacillus acidophilus (L. acidophilus) cell lysates combined with an anti-CTL antigen-4 blocking antibody (CTLA-4 mAb) in syngeneic BALB/c mice CRC models induce by a single intraperitoneal injection of 10 mg/kg azoxymethane (AOM), followed by three cycles of 2% dextran sulfate sodium (DSS) in drinking water. In contrast to CTLA-4 mAb monotherapy, L. acidophilus lysates could attenuate the loss of body weight and the combined administration significantly protected mice against CRC development, which suggested that the lysates enhanced antitumor activity of CTLA-4 mAb in model mice. The enhanced efficacy was associated with the increased CD8 + T cell, increased effector memory T cells (CD44 + CD8 + CD62L+), decreased Treg (CD4 + CD25 + Foxp3+) and M2 macrophages (F4/80 + CD206+) in the tumor microenvironment. In addition, our results revealed that L. acidophilus lysates had an immunomodulatory effect through inhibition the M2 polarization and the IL-10 expressed levels of LPS-activated Raw264.7 macrophages. Finally, the 16S rRNA gene sequencing of fecal microbiota demonstrated that the combined administration significantly inhibited the abnormal increase in the relative abundance of proteobacteria and partly counterbalance CRC-induced dysbiosis in model mice. Overall, these data support promising clinical possibilities of L. acidophilus lysates with CTLA-4 mAb in cancer patients and the hypothesis that probiotics help shape the anticancer immune response.
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Affiliation(s)
- Qian Zhuo
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China.,Department of Pathology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Bohai Yu
- Medical Laboratory Department, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, 518034, China
| | - Jing Zhou
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
| | - Jingyun Zhang
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
| | - Runling Zhang
- University of Chinese Academy of Sciences Shenzhen Hospital, Shenzhen, Guangdong, 518106, China
| | - Jingyan Xie
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
| | - Qingling Wang
- Department of Pathology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
| | - Shuli Zhao
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China.
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Esteban-Gil A, Pérez-Sanz F, García-Solano J, Alburquerque-González B, Parreño-González MA, Legaz-García MDC, Fernández-Breis JT, Rodriguez-Braun E, Pimentel P, Tuomisto A, Mäkinen M, Slaby O, Conesa-Zamora P. ColPortal, an integrative multiomic platform for analysing epigenetic interactions in colorectal cancer. Sci Data 2019; 6:255. [PMID: 31672979 PMCID: PMC6823353 DOI: 10.1038/s41597-019-0198-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 09/06/2019] [Indexed: 12/21/2022] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer mortality worldwide. Different pathological pathways and molecular drivers have been described and some of the associated markers are used to select effective anti-neoplastic therapy. More recent evidence points to a causal role of microbiota and altered microRNA expression in CRC carcinogenesis, but their relationship with pathological drivers or molecular phenotypes is not clearly established. Joint analysis of clinical and omics data can help clarify such relations. We present ColPortal, a platform that integrates transcriptomic, microtranscriptomic, methylomic and microbiota data of patients with colorectal cancer. ColPortal also includes detailed information of histological features and digital histological slides from the study cases, since histology is a morphological manifestation of a complex molecular change. The current cohort consists of Caucasian patients from Europe. For each patient, demographic information, location, histology, tumor staging, tissue prognostic factors, molecular biomarker status and clinical outcomes are integrated with omics data. ColPortal allows one to perform multiomics analyses for groups of patients selected by their clinical data.
| Measurement(s) | miRNA • methylation • clinical history • histology • transcription profiling assay • microbiome | | Technology Type(s) | DNA sequencing • clinical monitoring • RNA sequencing • amplicon sequencing • ex vivo photography with digital image analysis • methylation profiling by array | | Factor Type(s) | tumor status | | Sample Characteristic - Organism | Homo sapiens |
Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.9785795
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Affiliation(s)
- Angel Esteban-Gil
- Biomedical Informatics & Bioinformatics Platform, Institute for Biomedical Research of Murcia (IMIB)/Foundation for Healthcare Training & Research of the Region of Murcia (FFIS), Calle Luis Fontes Pagán 9, 30003, Murcia, Spain.
| | - Fernando Pérez-Sanz
- Biomedical Informatics & Bioinformatics Platform, Institute for Biomedical Research of Murcia (IMIB)/Foundation for Healthcare Training & Research of the Region of Murcia (FFIS), Calle Luis Fontes Pagán 9, 30003, Murcia, Spain
| | - José García-Solano
- Department of Pathology, Santa Lucía General University Hospital (HGUSL), Calle Mezquita sn, 30202, Cartagena, Spain.,Department of Histology and Pathology, Faculty of Life Sciences, Catholic University of Murcia (UCAM), Murcia, Spain.,Research Group on Molecular Pathology and Pharmacogenetics, Institute for Biomedical Research of Murcia (IMIB), Calle Mezquita sn, 30202, Cartagena, Spain
| | - Begoña Alburquerque-González
- Department of Histology and Pathology, Faculty of Life Sciences, Catholic University of Murcia (UCAM), Murcia, Spain
| | - María Antonia Parreño-González
- Biomedical Informatics & Bioinformatics Platform, Institute for Biomedical Research of Murcia (IMIB)/Foundation for Healthcare Training & Research of the Region of Murcia (FFIS), Calle Luis Fontes Pagán 9, 30003, Murcia, Spain
| | - María Del Carmen Legaz-García
- Biomedical Informatics & Bioinformatics Platform, Institute for Biomedical Research of Murcia (IMIB)/Foundation for Healthcare Training & Research of the Region of Murcia (FFIS), Calle Luis Fontes Pagán 9, 30003, Murcia, Spain
| | | | | | - Paola Pimentel
- Department of Oncology, HGUSL, Calle Mezquita sn, 30202, Cartagena, Spain
| | - Anne Tuomisto
- Department of Pathology, University of Oulu, Aapistie, 9, 90014, Oulu, Finland
| | - Markus Mäkinen
- Department of Pathology, University of Oulu, Aapistie, 9, 90014, Oulu, Finland
| | - Ondrej Slaby
- Central European Institute of Technology, Masaryk University/Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic
| | - Pablo Conesa-Zamora
- Department of Histology and Pathology, Faculty of Life Sciences, Catholic University of Murcia (UCAM), Murcia, Spain. .,Research Group on Molecular Pathology and Pharmacogenetics, Institute for Biomedical Research of Murcia (IMIB), Calle Mezquita sn, 30202, Cartagena, Spain. .,Department of Laboratory Medicine, HGUSL, Cartagena, Spain.
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Albayrak L, Khanipov K, Golovko G, Fofanov Y. Detection of multi-dimensional co-exclusion patterns in microbial communities. Bioinformatics 2019; 34:3695-3701. [PMID: 29878050 DOI: 10.1093/bioinformatics/bty414] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Accepted: 06/01/2018] [Indexed: 01/08/2023] Open
Abstract
Motivation Identification of complex relationships among members of microbial communities is key to understand and control the microbiota. Co-exclusion is arguably one of the most important patterns reflecting micro-organisms' intolerance to each other's presence. Knowing these relations opens an opportunity to manipulate microbiotas, personalize anti-microbial and probiotic treatments as well as guide microbiota transplantation. The co-exclusion pattern however, cannot be appropriately described by a linear function nor its strength be estimated using covariance or (negative) Pearson and Spearman correlation coefficients. This manuscript proposes a way to quantify the strength and evaluate the statistical significance of co-exclusion patterns between two, three or more variables describing a microbiota and allows one to extend analysis beyond micro-organism abundance by including other microbiome associated measurements such as, pH, temperature etc., as well as estimate the expected numbers of false positive co-exclusion patterns in a co-exclusion network. Results The implemented computational pipeline (CoEx) tested against 2380 microbial profiles (samples) from The Human Microbiome Project resulted in body-site specific pairwise co-exclusion patterns. Availability and implementation C++ source code for calculation of the score and P-value for two, three and four dimensional co-exclusion patterns as well as source code and executable files for the CoEx pipeline are available at https://scsb.utmb.edu/labgroups/fofanov/co-exclusion_in_microbial_communities.asp. Supplementary information Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Levent Albayrak
- Department of Pharmacology and Toxicology, University of Texas Medical Branch-Galveston, Galveston, USA.,Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch-Galveston, Galveston, USA
| | - Kamil Khanipov
- Department of Pharmacology and Toxicology, University of Texas Medical Branch-Galveston, Galveston, USA.,Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch-Galveston, Galveston, USA.,Department of Computer Science, University of Houston, Houston, USA
| | - George Golovko
- Department of Pharmacology and Toxicology, University of Texas Medical Branch-Galveston, Galveston, USA.,Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch-Galveston, Galveston, USA
| | - Yuriy Fofanov
- Department of Pharmacology and Toxicology, University of Texas Medical Branch-Galveston, Galveston, USA.,Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch-Galveston, Galveston, USA
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Borroni EM, Qehajaj D, Farina FM, Yiu D, Bresalier RS, Chiriva-Internati M, Mirandola L, Štifter S, Laghi L, Grizzi F. Fusobacterium nucleatum and the Immune System in Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2019; 15:149-156. [DOI: 10.1007/s11888-019-00442-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Lin Y, Ma C, Bezabeh T, Wang Z, Liang J, Huang Y, Zhao J, Liu X, Ye W, Tang W, Ouyang T, Wu R. 1 H NMR-based metabolomics reveal overlapping discriminatory metabolites and metabolic pathway disturbances between colorectal tumor tissues and fecal samples. Int J Cancer 2019; 145:1679-1689. [PMID: 30720869 DOI: 10.1002/ijc.32190] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 01/29/2019] [Indexed: 02/05/2023]
Abstract
Previous studies have compared fecal metabolites from healthy and colorectal cancer (CRC) patients to predict the pro-CRC signatures. However, the systemic mechanistic link between feces and colonic tissues of CRC patients is still limited. The current study was a paralleled investigation of colonic tumor tissues and their normal adjacent tissues alongside patient-matched feces by using 1 H nuclear magnetic resonance spectroscopy combined with pattern recognition to investigate how fecal metabolic phenotypes are linked to the changes in colorectal tumor profiles. A set of overlapping discriminatory metabolites across feces and tumor tissues of CRC were identified, including elevated levels of lactate, glutamate, alanine, succinate and reduced amounts of butyrate. These changes could indicate the networks for metabolic pathway perturbations in CRC potentially involved in the disruptions of glucose and glycolytic metabolism, TCA cycle, glutaminolysis, and short chain fatty acids metabolism. Furthermore, changes in fecal acetate were positively correlated with alterations of glucose and myo-inositol in colorectal tumor tissues, implying enhanced energy production for rapid cell proliferation. Compared to other fecal metabolites, acetate demonstrated the highest diagnostic performance for diagnosing CRC, with an AUC of 0.843 in the training set, and a good predictive ability in the validation set. Overall, these associations provide evidence of distinct metabolic signatures and metabolic pathway disturbances between the colonic tissues and feces within the same individual, and changes of fecal metabolic signature could reflect the CRC tissue microenvironment, highlighting the significance of the distinct fecal metabolic profiles as potential novel and noninvasive relevant indicators for CRC detection.
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Affiliation(s)
- Yan Lin
- Department of Radiology, Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Changchun Ma
- Radiation Oncology, Cancer Hospital, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Tedros Bezabeh
- College of Natural & Applied Sciences, University of Guam, UOG Station, Mangilao, Guam
| | - Zhening Wang
- Department of Radiology, Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Jiahao Liang
- Department of Radiology, Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Yao Huang
- Department of Radiology, Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Jiayun Zhao
- Department of Radiology, Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Xinmu Liu
- Department of Surgery, Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Wei Ye
- Department of Radiology, Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Wan Tang
- Department of Radiology, Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Ting Ouyang
- Department of Radiology, Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Renhua Wu
- Department of Radiology, Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, China
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Leng J, Peruluswami P, Bari S, Gaur S, Radparvar F, Parvez F, Chen Y, Flores C, Gany F. South Asian Health: Inflammation, Infection, Exposure, and the Human Microbiome. J Immigr Minor Health 2019; 21:26-36. [PMID: 28952002 PMCID: PMC5871532 DOI: 10.1007/s10903-017-0652-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
This paper presents the results of the literature review conducted for the working group topic on inflammation, infection, exposure, and the human microbiome. Infection and chronic inflammation can elevate risk for cardiovascular disease and cancer. Environmental exposures common among South Asian (SA) subgroups, such as arsenic exposure among Bangladeshis and particulate matter air pollution among taxi drivers, also pose risks. This review explores the effects of exposure to arsenic and particulate matter, as well as other infections common among SAs, including human papillomavirus (HPV) and hepatitis B/C infection. Emerging research on the human microbiome, and the effect of microbiome changes on obesity and diabetes risk among SAs are also explored.
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Affiliation(s)
- Jennifer Leng
- Department of Psychiatry and Behavioral Sciences, Immigrant Health and Cancer Disparities Service, Memorial Sloan Kettering Cancer Center, 485 Lexington Avenue, 2nd Floor, New York, NY, 10017, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA
- Department of Healthcare Policy and Research, Weill Cornell Medical College, 1300 York Avenue, New York, NY, USA
| | - Ponni Peruluswami
- Department of Medicine, Icahn School of Medicine at the Mount Sinai Medical Center, 1468 Madison Avenue, New York, NY, USA
| | - Sehrish Bari
- The Earth Institute, Columbia University, 2910 Broadway, New York, NY, USA
| | - Sunanda Gaur
- Robert Wood Johnson Medical School, South Asian Total Health Initiative, Rutgers School of Public Health, Rutgers, The State University of New Jersey, 1 Robert Wood Johnson Place, New Brunswick, NJ, USA
| | - Farshid Radparvar
- Cardiology Department, Queens Hospital Center, 82-68 164th Street, Jamaica, New York, NY, USA
| | - Faruque Parvez
- Department of Environmental Health Sciences, Columbia University, 722 W 168th Street, New York, NY, USA
| | - Yu Chen
- Department of Population Health, Department of Environmental Medicine, New York University School of Medicine, 550 1st Avenue, New York, NY, USA
| | - Cristina Flores
- The Warren Alpert Medical School, The Brown Human Rights Asylum Clinic (BHRAC), Brown University, 222 Richmond Street, Providence, RI, USA
| | - Francesca Gany
- Department of Psychiatry and Behavioral Sciences, Immigrant Health and Cancer Disparities Service, Memorial Sloan Kettering Cancer Center, 485 Lexington Avenue, 2nd Floor, New York, NY, 10017, USA.
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA.
- Department of Healthcare Policy and Research, Weill Cornell Medical College, 1300 York Avenue, New York, NY, USA.
- Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY, USA.
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Abstract
Discoveries made in the past 5 years indicate that the composition of the intestinal microbiota has a major influence on the effectiveness of anticancer immunosurveillance and thereby contributes to the therapeutic activity of immune-checkpoint inhibitors that target cytotoxic T lymphocyte protein 4 (CTLA-4) or the programmed cell death protein 1 (PD-1)-programmed cell death 1 ligand 1 (PD-L1) axis, as well as the activity of immunogenic chemotherapies. Herein, we highlight some of the bacteria, such as Akkermansia muciniphila, Bacteroides fragilis, Bifidobacterium spp. and Faecalibacterium spp., that have been associated with favourable anticancer immune responses in both preclinical tumour models and patients with cancer. Importantly, these bacteria also seem to have a positive influence on general health, thus reducing the incidence of metabolic disorders and a wide range of chronic inflammatory pathologies. We surmise that a diverse and propitious microbial ecosystem favours organismal homeostasis, particularly at the level of the cancer-immune dialogue.
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Hari Krishnan R. A review on squat-assist devices to aid elderly with lower limb difficulties in toileting to tackle constipation. Proc Inst Mech Eng H 2019; 233:464-475. [PMID: 30898031 DOI: 10.1177/0954411919838644] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Constipation is an important issue that has impact on quality of life and health expenses of the elderly. It may lead to many other gastrointestinal disorders like colon cancer, haemorrhoids, anal fissures and so on. Squatting is considered to be the natural, traditional and most widely followed posture for defecation and hence, it is one of the practical solutions for avoiding constipation. Musculoskeletal issues due to ageing and changes in lifestyle make it difficult for the elder population to follow squatting or semi-squatting posture for defecation. Developing assistive devices to overcome older people's difficulty to attain squatting or semi-squatting posture is one of the research areas which need to be explored further. This review covers various designs of such devices which will enable a user to attain 'semi-squatting' posture to defecate and also addresses various challenges and limitations to overcome.
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Affiliation(s)
- R Hari Krishnan
- School of Mechanical Engineering, SASTRA Deemed to be University, Thanjavur, India
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Wang G, Yu Y, Wang YZ, Wang JJ, Guan R, Sun Y, Shi F, Gao J, Fu XL. Role of SCFAs in gut microbiome and glycolysis for colorectal cancer therapy. J Cell Physiol 2019; 234:17023-17049. [PMID: 30888065 DOI: 10.1002/jcp.28436] [Citation(s) in RCA: 123] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Revised: 02/02/2019] [Accepted: 02/14/2019] [Indexed: 12/19/2022]
Abstract
Increased risk of colorectal cancer (CRC) is associated with altered intestinal microbiota as well as short-chain fatty acids (SCFAs) reduction of output The energy source of colon cells relies mainly on three SCFAs, namely butyrate (BT), propionate, and acetate, while CRC transformed cells rely mainly on aerobic glycolysis to provide energy. This review summarizes recent research results for dysregulated glucose metabolism of SCFAs, which could be initiated by gut microbiome of CRC. Moreover, the relationship between SCFA transporters and glycolysis, which may correlate with the initiation and progression of CRC, are also discussed. Additionally, this review explores the linkage of BT to transport of SCFAs expressions between normal and cancerous colonocyte cell growth for tumorigenesis inhibition in CRC. Furthermore, the link between gut microbiota and SCFAs in the metabolism of CRC, in addition, the proteins and genes related to SCFAs-mediated signaling pathways, coupled with their correlation with the initiation and progression of CRC are also discussed. Therefore, targeting the SCFA transporters to regulate lactate generation and export of BT, as well as applying SCFAs or gut microbiota and natural compounds for chemoprevention may be clinically useful for CRCs treatment. Future research should focus on the combination these therapeutic agents with metabolic inhibitors to effectively target the tumor SCFAs and regulate the bacterial ecology for activation of potent anticancer effect, which may provide more effective application prospect for CRC therapy.
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Affiliation(s)
- Gang Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai, China
| | - Yang Yu
- Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yu-Zhu Wang
- Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jun-Jie Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai, China
| | - Rui Guan
- Information Resources Department, Hubei University of Medicine, Shiyan, Hubei, China
| | - Yan Sun
- Information Resources Department, Hubei University of Medicine, Shiyan, Hubei, China
| | - Feng Shi
- Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jing Gao
- Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xing-Li Fu
- Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
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Abstract
Apart from the classic knowledge that ethanol mediates its hepatotoxicity through its metabolism to acetaldehyde, a well-known hepatotoxic molecule, recent research has elucidated several key mechanisms that potentiate ethanol's damage to the liver parenchyma, such as generation of free radicals, activation of Kupffer cells, and alterations to the human bacterial and fungal microbiome. Genetic studies have suggested the role of PNPLA3 and TM6SF2 gene mutations in the progression of alcoholic liver disease.
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Affiliation(s)
- Themistoklis Kourkoumpetis
- Department of Gastroenterology, Baylor College of Medicine, 6620 Main Street, Suite 1450, Houston, TX 77030, USA
| | - Gagan Sood
- Department of Surgery, Division of Abdominal Transplantation, Baylor College of Medicine, 6620 Main Street, Suite 1450, Houston, TX 77030, USA.
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Megat Mohd Azlan PIH, Chin SF, Low TY, Neoh HM, Jamal R. Analyzing the Secretome of Gut Microbiota as the Next Strategy For Early Detection of Colorectal Cancer. Proteomics 2019; 19:e1800176. [PMID: 30557447 DOI: 10.1002/pmic.201800176] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 12/02/2018] [Indexed: 12/20/2022]
Abstract
Dysbiosis of gut microbiome can contribute to inflammation, and subsequently initiation and progression of colorectal cancer (CRC). Throughout these stages, various proteins and metabolites are secreted to the external environment by microorganisms or the hosts themselves. Studying these proteins may help enhance our understanding of the host-microorganism relationship or they may even serve as useful biomarkers for CRC. However, secretomic studies of gut microbiome of CRC patients, until now, are scarcely performed. In this review article, the focus is on the roles of gut microbiome in CRC, the current findings on CRC secretome are highlighted, and the emerging challenges and strategies to drive forward this area of research are addressed.
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Affiliation(s)
| | - Siok-Fong Chin
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, 56000 Cheras, Kuala Lumpur, Malaysia
| | - Teck Yew Low
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, 56000 Cheras, Kuala Lumpur, Malaysia
| | - Hui-Min Neoh
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, 56000 Cheras, Kuala Lumpur, Malaysia
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, 56000 Cheras, Kuala Lumpur, Malaysia
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Sasso A, Latella G. Role of Heme Iron in the Association Between Red Meat Consumption and Colorectal Cancer. Nutr Cancer 2019; 70:1173-1183. [DOI: 10.1080/01635581.2018.1521441] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Arianna Sasso
- Division of Gastroenterology, Hepatology and Nutrition, Department of Life, Health, and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
| | - Giovanni Latella
- Division of Gastroenterology, Hepatology and Nutrition, Department of Life, Health, and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
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