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Thulasinathan B, Suvilesh KN, Maram S, Grossmann E, Ghouri Y, Teixeiro EP, Chan J, Kaif JT, Rachagani S. The impact of gut microbial short-chain fatty acids on colorectal cancer development and prevention. Gut Microbes 2025; 17:2483780. [PMID: 40189834 PMCID: PMC11980463 DOI: 10.1080/19490976.2025.2483780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 02/18/2025] [Accepted: 03/18/2025] [Indexed: 04/11/2025] Open
Abstract
Cancer is a long-term illness that involves an imbalance in cellular and immune functions. It can be caused by a range of factors, including exposure to environmental carcinogens, poor diet, infections, and genetic alterations. Maintaining a healthy gut microbiome is crucial for overall health, and short-chain fatty acids (SCFAs) produced by gut microbiota play a vital role in this process. Recent research has established that alterations in the gut microbiome led to decreased production of SCFA's in lumen of the colon, which associated with changes in the intestinal epithelial barrier function, and immunity, are closely linked to colorectal cancer (CRC) development and its progression. SCFAs influence cancer progression by modifying epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNA functions thereby affecting tumor initiation and metastasis. This suggests that restoring SCFA levels in colon through microbiota modulation could serve as an innovative strategy for CRC prevention and treatment. This review highlights the critical relationship between gut microbiota and CRC, emphasizing the potential of targeting SCFAs to enhance gut health and reduce CRC risk.
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Affiliation(s)
- Boobalan Thulasinathan
- Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO, USA
- Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO, USA
| | - Kanve N. Suvilesh
- Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO, USA
- Department of Surgery, Ellis Fischel Cancer Centre, University of Missouri, Columbia, MO, USA
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO, USA
| | - Sumanas Maram
- Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO, USA
| | - Erik Grossmann
- Department of Surgery, Ellis Fischel Cancer Centre, University of Missouri, Columbia, MO, USA
- Department of Medicine, Digestive Centre, Ellis Fischel Cancer Centre, University of Missouri, Columbia, MO, USA
| | - Yezaz Ghouri
- Department of Medicine, Digestive Centre, Ellis Fischel Cancer Centre, University of Missouri, Columbia, MO, USA
| | - Emma Pernas Teixeiro
- Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO, USA
- Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, USA
| | - Joshua Chan
- Chemical and Biological Engineering, Colorado State University, Fort Collins, CO, USA
| | - Jussuf T. Kaif
- Department of Surgery, Ellis Fischel Cancer Centre, University of Missouri, Columbia, MO, USA
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO, USA
- Siteman Cancer Centre, Washington University, St. Louis, MO, USA
| | - Satyanarayana Rachagani
- Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO, USA
- Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO, USA
- Department of Surgery, Ellis Fischel Cancer Centre, University of Missouri, Columbia, MO, USA
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO, USA
- Siteman Cancer Centre, Washington University, St. Louis, MO, USA
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Xiao Q, Liu Y, Li T, Wang C, He S, Zhai L, Yang Z, Zhang X, Wu Y, Liu Y. Viral oncogenesis in cancer: from mechanisms to therapeutics. Signal Transduct Target Ther 2025; 10:151. [PMID: 40350456 PMCID: PMC12066790 DOI: 10.1038/s41392-025-02197-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 01/22/2025] [Accepted: 03/03/2025] [Indexed: 05/14/2025] Open
Abstract
The year 2024 marks the 60th anniversary of the discovery of the Epstein-Barr virus (EBV), the first virus confirmed to cause human cancer. Viral infections significantly contribute to the global cancer burden, with seven known Group 1 oncogenic viruses, including hepatitis B virus (HBV), human papillomavirus (HPV), EBV, Kaposi sarcoma-associated herpesvirus (KSHV), hepatitis C virus (HCV), human T-cell leukemia virus type 1 (HTLV-1), and human immunodeficiency virus (HIV). These oncogenic viruses induce cellular transformation and cancer development by altering various biological processes within host cells, particularly under immunosuppression or co-carcinogenic exposures. These viruses are primarily associated with hepatocellular carcinoma, gastric cancer, cervical cancer, nasopharyngeal carcinoma, Kaposi sarcoma, lymphoma, and adult T-cell leukemia/lymphoma. Understanding the mechanisms of viral oncogenesis is crucial for identifying and characterizing the early biological processes of virus-related cancers, providing new targets and strategies for treatment or prevention. This review first outlines the global epidemiology of virus-related tumors, milestone events in research, and the process by which oncogenic viruses infect target cells. It then focuses on the molecular mechanisms by which these viruses induce tumors directly or indirectly, including the regulation of oncogenes or tumor suppressor genes, induction of genomic instability, disruption of regular life cycle of cells, immune suppression, chronic inflammation, and inducing angiogenesis. Finally, current therapeutic strategies for virus-related tumors and recent advances in preclinical and clinical research are discussed.
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Affiliation(s)
- Qing Xiao
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Yi Liu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Tingting Li
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Chaoyu Wang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Sanxiu He
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Liuyue Zhai
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Zailin Yang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Xiaomei Zhang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China.
| | - Yongzhong Wu
- Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing, China.
| | - Yao Liu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China.
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Xiao K, Li K, Xiao K, Yang J, Zhou L. Gut Microbiota and Hepatocellular Carcinoma: Metabolic Products and Immunotherapy Modulation. Cancer Med 2025; 14:e70914. [PMID: 40314129 PMCID: PMC12046294 DOI: 10.1002/cam4.70914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 03/31/2025] [Accepted: 04/16/2025] [Indexed: 05/03/2025] Open
Abstract
BACKGROUND The relationship between hepatocellular carcinoma (HCC) and gut microbiota has gained attention for its impact on HCC immunotherapy. METHODS Key gut microbial metabolites, including bile acids, toll-like receptor 4, short-chain fatty acids, and bacterial toxins, contribute to HCC progression and influence immune responses through the gut-liver axis. As immune checkpoint inhibitors (ICIs) become common in HCC treatment, modulating the gut microbiota offers new strategies to enhance ICIs efficacy. However, individual differences in microbial composition introduce challenges, with some HCC patients showing resistance to ICIs. RESULTS This review summarizes the latest findings on the role of gut microbiota in HCC and explores emerging therapeutic approaches, including fecal microbiota transplantation, probiotics, antibiotics, and natural compounds. CONCLUSIONS The focus is on translating these insights into personalized medicine to optimize ICIs responses and improve HCC treatment outcomes.
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Affiliation(s)
- Kunmin Xiao
- Department of OncologyLonghua Hospital, Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Kexin Li
- Department of Traditional Chinese MedicinePeking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical ScienceBeijingChina
| | - Kunlin Xiao
- Department of EmergencyZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Jinzu Yang
- Department of OncologyLonghua Hospital, Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Lei Zhou
- Department of OncologyLonghua Hospital, Shanghai University of Traditional Chinese MedicineShanghaiChina
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Zhang W, Wu Y, Cheng M, Wei H, Sun R, Peng H, Tian Z, Chen Y. Chronic hepatitis B virus infection imbalances short-chain fatty acids and amino acids in the liver and gut via microbiota modulation. Gut Pathog 2025; 17:18. [PMID: 40188120 PMCID: PMC11971750 DOI: 10.1186/s13099-025-00695-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 03/20/2025] [Indexed: 04/07/2025] Open
Abstract
The commensal microbiota is closely related to HBV infection and HBV-related liver diseases; however, how HBV and viral components dynamically affect the targeted organ liver microbiota is not well-known. In this study, an HBV-carrier mouse model established by HBsAg+ hepatocyte replacement in Fah-/- recipient mice, named HBs-HepR mice, was used to analyze the microbiota and metabolomics at the time of triggering the specific anti-HBV CD8+ T cell response in the liver. The composition and relative abundance of microbiota were both altered in the gut and liver of HBs-HepR mice. Particularly, increased Muribaculaceae and Alloprevotella, and decreased Lachnospiraceae-NK4A136 and Rikenella were observed in the gut; while increased Ralstonia and Geobacillus were observed in the liver of HBs-HepR mice. Furthermore, changes in microbial functions were revealed. There were no significant differences in the levels of SCFAs in fecal and serum; however, decreased propionic acid and acetic acid were detected in the livers of HBs-HepR mice, which was negatively related to the abundance of Geobacillus in the liver. Significantly decreased levels of 9 kinds of amino acids were detected in the feces of HBs-HepR mice, which was positively related to decreased Rikenella in the gut. A significant increase in L-glycine was observed in the liver and serum, positively related to the abundance of Geobaillus in the livers of HBs-HepR mice. In conclusion, chronic HBV infection imbalanced SCFA and amino acid metabolism by modulating microbiota in the liver, unlike in the gut, which was involved in the immune activation phase.
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Affiliation(s)
- Wendi Zhang
- Key Laboratory of Immune Response and Immunotherapy, the Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, #443 Huangshan Road, Hefei, 230027, Anhui, China
| | - Yuwei Wu
- Key Laboratory of Immune Response and Immunotherapy, the Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, #443 Huangshan Road, Hefei, 230027, Anhui, China
| | - Min Cheng
- Key Laboratory of Immune Response and Immunotherapy, the Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, #443 Huangshan Road, Hefei, 230027, Anhui, China
- Department of Geriatrics, Gerontology Institute of Anhui Province, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Haiming Wei
- Key Laboratory of Immune Response and Immunotherapy, the Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, #443 Huangshan Road, Hefei, 230027, Anhui, China
| | - Rui Sun
- Key Laboratory of Immune Response and Immunotherapy, the Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, #443 Huangshan Road, Hefei, 230027, Anhui, China
| | - Hui Peng
- Key Laboratory of Immune Response and Immunotherapy, the Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, #443 Huangshan Road, Hefei, 230027, Anhui, China
| | - Zhigang Tian
- Key Laboratory of Immune Response and Immunotherapy, the Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, #443 Huangshan Road, Hefei, 230027, Anhui, China
| | - Yongyan Chen
- Key Laboratory of Immune Response and Immunotherapy, the Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, #443 Huangshan Road, Hefei, 230027, Anhui, China.
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Wang Y, Li Y, Lin Y, Cao C, Chen D, Huang X, Li C, Xu H, Lai H, Chen H, Zhou Y. Roles of the gut microbiota in hepatocellular carcinoma: from the gut dysbiosis to the intratumoral microbiota. Cell Death Discov 2025; 11:140. [PMID: 40185720 PMCID: PMC11971373 DOI: 10.1038/s41420-025-02413-z] [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: 08/08/2024] [Revised: 02/23/2025] [Accepted: 03/18/2025] [Indexed: 04/07/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is closely linked to alterations in the gut microbiota. This dysbiosis is characterized by significant changes in the microbial population, which correlate with the progression of HCC. Gut dysbiosis ultimately promotes HCC development in several ways: it damages the integrity of the gut-vascular barrier (GVB), alters the tumor microenvironment (TME), and even affects the intratumoral microbiota. Subsequently, intratumoral microbiota present a characteristic profile and play an essential role in HCC progression mainly by causing DNA damage, mediating tumor-related signaling pathways, altering the TME, promoting HCC metastasis, or through other mechanisms. Both gut microbiota and intratumoral microbiota have dual effects on HCC progression; a comprehensive understanding of their complex biological roles will provide a theoretical foundation for potential clinical applications in HCC treatment.
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Affiliation(s)
- Yiqin Wang
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Yongqiang Li
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Yong Lin
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Chuangyu Cao
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Dongcheng Chen
- Department of Gastroenterology and Hepatology, Baiyun Hospital of Guangzhou First People's Hospital (The Second People's Hospital of Baiyun District), Guangzhou, China
| | - Xianguang Huang
- Department of Gastroenterology and Hepatology, Baiyun Hospital of Guangzhou First People's Hospital (The Second People's Hospital of Baiyun District), Guangzhou, China
| | - Canhua Li
- Department of Gastroenterology and Hepatology, Baiyun Hospital of Guangzhou First People's Hospital (The Second People's Hospital of Baiyun District), Guangzhou, China
| | - Haoming Xu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Huasheng Lai
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Huiting Chen
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
| | - Yongjian Zhou
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
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Romeo M, Dallio M, Di Nardo F, Napolitano C, Vaia P, Martinelli G, Federico P, Olivieri S, Iodice P, Federico A. The Role of the Gut-Biliary-Liver Axis in Primary Hepatobiliary Liver Cancers: From Molecular Insights to Clinical Applications. J Pers Med 2025; 15:124. [PMID: 40278303 PMCID: PMC12028696 DOI: 10.3390/jpm15040124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 03/14/2025] [Accepted: 03/20/2025] [Indexed: 04/26/2025] Open
Abstract
Background: Hepatobiliary liver cancers (HBLCs) represent the sixth most common neoplasm in the world. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) constitute the main HBLC types, with alarming epidemiological projections. Methods: In recent decades, alterations in gut microbiota, with mutual implications on the gut-liver axis and gut-biliary axis permeability status, have been massively investigated and proposed as HBLC pathogenetic deus ex machina. Results: In the HCC setting, elevated intestinal levels of Escherichia coli and other Gram-negative bacteria have been demonstrated, resulting in a close association with increased lipopolysaccharide (LPS) serum levels and, consequently, chronic systemic inflammation. In contrast, the intestinal microbiota of HCC individuals feature reduced levels of Lactobacillus spp., Bifidobacterium spp., and Enterococcus spp. In the CC setting, evidence has revealed an increased expression of Lactobacillus spp., with enhanced levels of Actynomices spp. and Alloscardovia spp. Besides impaired strains/species representation, gut-derived metabolites, including bile acids (BAs), short-chain fatty acids (SCFAs), and oxidative-stress-derived products, configure a network severely impacting the progression of HBLC. Conclusions: In the era of Precision Medicine, the clarification of microbiota composition and functioning in HCC and CC settings can contribute to the identification of individual signatures, potentially providing novel diagnostic markers, therapeutic approaches, and prognostic/predictive tools.
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Affiliation(s)
- Mario Romeo
- Department of Precision Medicine, Hepatogastroenterology Division, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.R.); (F.D.N.); (C.N.); (P.V.); (G.M.); (S.O.); (A.F.)
| | - Marcello Dallio
- Department of Precision Medicine, Hepatogastroenterology Division, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.R.); (F.D.N.); (C.N.); (P.V.); (G.M.); (S.O.); (A.F.)
| | - Fiammetta Di Nardo
- Department of Precision Medicine, Hepatogastroenterology Division, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.R.); (F.D.N.); (C.N.); (P.V.); (G.M.); (S.O.); (A.F.)
| | - Carmine Napolitano
- Department of Precision Medicine, Hepatogastroenterology Division, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.R.); (F.D.N.); (C.N.); (P.V.); (G.M.); (S.O.); (A.F.)
| | - Paolo Vaia
- Department of Precision Medicine, Hepatogastroenterology Division, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.R.); (F.D.N.); (C.N.); (P.V.); (G.M.); (S.O.); (A.F.)
| | - Giuseppina Martinelli
- Department of Precision Medicine, Hepatogastroenterology Division, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.R.); (F.D.N.); (C.N.); (P.V.); (G.M.); (S.O.); (A.F.)
| | - Pierluigi Federico
- Pharmaceutical Department, ASL NA3 Sud, Torre del Greco, 80059 Naples, Italy;
| | - Simone Olivieri
- Department of Precision Medicine, Hepatogastroenterology Division, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.R.); (F.D.N.); (C.N.); (P.V.); (G.M.); (S.O.); (A.F.)
| | | | - Alessandro Federico
- Department of Precision Medicine, Hepatogastroenterology Division, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.R.); (F.D.N.); (C.N.); (P.V.); (G.M.); (S.O.); (A.F.)
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Li C, Yao J, Yang C, Yu S, Yang Z, Wang L, Li S, He N. Gut microbiota-derived short chain fatty acids act as mediators of the gut-liver-brain axis. Metab Brain Dis 2025; 40:122. [PMID: 39921774 DOI: 10.1007/s11011-025-01554-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 02/03/2025] [Indexed: 02/10/2025]
Abstract
The gut microbiota plays a crucial role in the communication between the gut, liver, and brain through the production of short chain fatty acids (SCFAs). SCFAs serve as key mediators in the Gut-Liver-Brain Axis, influencing various physiological processes and contributing to overall health. SCFAs are produced by bacterial fermentation of dietary fiber in the gut, and they exert systemic effects by signaling through various pathways. In the Gut-Liver axis, SCFAs regulate liver metabolism through peroxisome proliferator-activated receptor-γ (PPAR-γ), AMP-activated protein kinase (AMPK) and other pathways, promotes fat oxidation, modulate inflammation through mTOR pathway, and impact metabolic health. In the Gut-Brain axis, SCFAs influence brain function, behavior, and may have implications for neurological disorders, in which G-protein coupled receptors (GPCRs) play an essential role, along with other pathways such as hypothalamic-pituitary-adrenal (HPA) pathway. Understanding the mechanisms by which SCFAs mediate communication between the gut, liver, and brain is crucial for elucidating the complex interplay of the Gut-Liver-Brain Axis. This review aims to provide insight into the role of gut microbiota-derived SCFAs as mediators of the Gut-Liver-Brain Axis and their potential therapeutic implications. Further research in this area will be instrumental in developing novel strategies to target the Gut-Liver-Brain Axis for the prevention and treatment of various health conditions.
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Affiliation(s)
- Cunyin Li
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266071, China
- Department of Obstetrics and Gynecology, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, 266000, China
| | - Jingtong Yao
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266071, China
| | - Chang Yang
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266071, China
| | - Shengnan Yu
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266071, China
- Affiliated Hospital of Inner Mongolia University for Nationalities, TongLiao, 028005, China
| | - Zizhen Yang
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266071, China
| | - Lijing Wang
- Department of Obstetrics and Gynecology, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, 266000, China.
- Department of Obstetrics, Qingdao Municipal Hospital, Qingdao, 266000, China.
| | - Shangyong Li
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266071, China.
- Department of Ultrasound, the Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
| | - Ningning He
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266071, China.
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Merali C, Quinn C, Huffman KM, Pieper CF, Bogan JS, Barrero CA, Merali S. Sustained caloric restriction potentiates insulin action by activating prostacyclin synthase. Obesity (Silver Spring) 2024; 32:2286-2298. [PMID: 39420421 PMCID: PMC12034231 DOI: 10.1002/oby.24150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 08/08/2024] [Accepted: 08/12/2024] [Indexed: 10/19/2024]
Abstract
OBJECTIVE Caloric restriction (CR) is known to enhance insulin sensitivity and reduce the risk of metabolic disorders; however, its molecular mechanisms are not fully understood. This study aims to elucidate specific proteins and pathways responsible for these benefits. METHODS We examined adipose tissue from participants in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE 2) study, comparing proteomic profiles from individuals after 12 and 24 months of CR with baseline and an ad libitum group. Biochemical and cell-specific physiological approaches complemented these analyses. RESULTS Our data revealed that CR upregulates prostacyclin synthase (PTGIS) in adipose tissue, an enzyme crucial for producing prostacyclin (PGI2). PGI2 improves the ability of insulin to stimulate the tether-containing UBX domain for GLUT4 (TUG) cleavage pathway, which is essential for glucose uptake regulation. Additionally, iloprost, a PGI2 analog, was shown to increase insulin receptor density on cell membranes, increasing glucose uptake in human adipocytes. CR also reduces carbonylation of GLUT4, a modification that is detrimental to GLUT4 function. CONCLUSIONS CR enhances insulin sensitivity by promoting PTGIS expression and stimulating the TUG cleavage pathway, leading to increased GLUT4 translocation to the cell surface and decreased GLUT4 carbonylation. These findings shed light on the complex molecular mechanisms through which CR favorably impacts insulin sensitivity and metabolic health.
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Affiliation(s)
- Carmen Merali
- Temple University School of Pharmacy, Philadelphia, Pennsylvania, USA
| | - Connor Quinn
- Temple University School of Pharmacy, Philadelphia, Pennsylvania, USA
| | - Kim M. Huffman
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA
| | - Carl F. Pieper
- Duke Center for Aging and Human Development, Duke University School of Medicine, Durham, North Carolina, USA
| | - Jonathan S. Bogan
- Section of Endocrinology and Metabolism, Department of Medicine, Yale School of Medicine, New Haven, Connecticut, USA
- Department of Cell Biology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Carlos A. Barrero
- Temple University School of Pharmacy, Philadelphia, Pennsylvania, USA
| | - Salim Merali
- Temple University School of Pharmacy, Philadelphia, Pennsylvania, USA
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Ma Q, Li W, Wu W, Sun M. Exploring the active ingredients and mechanisms of Liujunzi decoction in treating hepatitis B: a study based on network pharmacology, molecular docking, and molecular dynamics simulations. Comput Methods Biomech Biomed Engin 2024:1-25. [PMID: 39534925 DOI: 10.1080/10255842.2024.2427117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 09/24/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024]
Abstract
Liujunzi decoction (LJZD) is commonly used to treat hepatitis B virus (HBV), though its active ingredients and mechanisms are not fully known. This study identified core targets and active components of LJZD for treating hepatitis B (HB) through network pharmacology, molecular docking, and molecular dynamics simulation. Screening from databases yielded 533 active components, 2619 targets for LJZD, and 2910 for HB, with 891 intersecting targets. STRING and CytoHubba analyses identified AR and VDR as core targets, with key pathways including PI3K-Akt and MAPK. The findings clarify LJZD's multicomponent, multitarget mechanisms, supporting its clinical application for HB treatment.
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Affiliation(s)
- Qing Ma
- Department of Pharmacy, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, China
| | - Wenjun Li
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenying Wu
- Department of Pharmacy, The Ninth People's Hospital of Chongqing, Chongqing, China
| | - Mei Sun
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
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10
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Liu H, Lu H, Wang Y, Yu C, He Z, Dong H. Unlocking the power of short-chain fatty acids in ameliorating intestinal mucosal immunity: a new porcine nutritional approach. Front Cell Infect Microbiol 2024; 14:1449030. [PMID: 39286812 PMCID: PMC11402818 DOI: 10.3389/fcimb.2024.1449030] [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: 06/14/2024] [Accepted: 08/12/2024] [Indexed: 09/19/2024] Open
Abstract
Short-chain fatty acids (SCFAs), a subset of organic fatty acids with carbon chains ranging from one to six atoms in length, encompass acetate, propionate, and butyrate. These compounds are the endproducts of dietary fiber fermentation, primarily catalyzed by the glycolysis and pentose phosphate pathways within the gut microbiota. SCFAs act as pivotal energy substrates and signaling molecules in the realm of animal nutrition, exerting a profound influence on the intestinal, immune system, and intestinal barrier functions. Specifically, they contibute to 60-70% of the total energy requirements in ruminants and 10-25% in monogastric animals. SCFAs have demonstrated the capability to effectively modulate intestinal pH, optimize the absorption of mineral elements, and impede pathogen invasion. Moreover, they enhance the expression of proteins associated with intestinal tight junctions and stimulate mucus production, thereby refining intestinal tissue morphology and preserving the integrity of the intestinal structure. Notably, SCFAs also exert anti-inflammatory properties, mitigating inflammation within the intestinal epithelium and strengthening the intestinal barrier's defensive capabilities. The present review endeavors to synthesize recent findings regarding the role of SCFAs as crucial signaling intermediaries between the metabolic activities of gut microbiota and the status of porcine cells. It also provides a comprehensive overview of the current literature on SCFAs' impact on immune responses within the porcine intestinal mucosa.
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Affiliation(s)
- Haoyang Liu
- Beijing Key Laboratory of Traditional Chinese Veterinary Medicine, Beijing University of Agriculture, Beijing, China
- Beijing Engineering Research Center of Chinese Veterinary Medicine, Beijing University of Agriculture, Beijing, China
| | - Hongde Lu
- Beijing Key Laboratory of Traditional Chinese Veterinary Medicine, Beijing University of Agriculture, Beijing, China
- Beijing Engineering Research Center of Chinese Veterinary Medicine, Beijing University of Agriculture, Beijing, China
| | - Yuxuan Wang
- Beijing Key Laboratory of Traditional Chinese Veterinary Medicine, Beijing University of Agriculture, Beijing, China
- Beijing Engineering Research Center of Chinese Veterinary Medicine, Beijing University of Agriculture, Beijing, China
| | - Chenyun Yu
- Beijing Key Laboratory of Traditional Chinese Veterinary Medicine, Beijing University of Agriculture, Beijing, China
- Beijing Engineering Research Center of Chinese Veterinary Medicine, Beijing University of Agriculture, Beijing, China
| | - Zhiyuan He
- Beijing Key Laboratory of Traditional Chinese Veterinary Medicine, Beijing University of Agriculture, Beijing, China
| | - Hong Dong
- Beijing Key Laboratory of Traditional Chinese Veterinary Medicine, Beijing University of Agriculture, Beijing, China
- Beijing Engineering Research Center of Chinese Veterinary Medicine, Beijing University of Agriculture, Beijing, China
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11
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Watling CZ, Wojt A, Florio AA, Butera G, Albanes D, Weinstein SJ, Huang WY, Parisi D, Zhang X, Graubard BI, Petrick JL, McGlynn KA. Fiber and whole grain intakes in relation to liver cancer risk: An analysis in 2 prospective cohorts and systematic review and meta-analysis of prospective studies. Hepatology 2024; 80:552-565. [PMID: 38441973 PMCID: PMC11803500 DOI: 10.1097/hep.0000000000000819] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 02/07/2024] [Indexed: 03/07/2024]
Abstract
BACKGROUND AND AIMS The association between fiber or whole grain intakes and the risk of liver cancer remains unclear. We assessed the associations between fiber or whole grain intakes and liver cancer risk among 2 prospective studies, and systematically reviewed and meta-analyzed these results with published prospective studies. APPROACH AND RESULTS A total of 111,396 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and 26,085 men from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study were included. Intakes of total fiber and whole grains were estimated from validated food frequency questionnaires. Study-specific HRs and 95% CI with liver cancer risk were estimated using multivariable-adjusted Cox regression. We systematically reviewed existing literature, and studies were combined in a dose-response meta-analysis. A total of 277 (median follow-up = 15.6 y) and 165 (median follow-up = 16.0 y) cases of liver cancer were observed in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, respectively. Dietary fiber was inversely associated with liver cancer risk in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (HR 10g/day : 0.69; 95% CI: 0.55-0.86). No significant associations were observed between whole grain intakes and liver cancer risk in either study. Our meta-analysis included 2383 incident liver cancer cases (7 prospective cohorts) for fiber intake and 1523 cases (5 prospective cohorts) for whole grain intake; combined HRs for liver cancer risk were 0.83 (0.76-0.91) per 10 g/day of fiber and 0.92 (0.85-0.99) per 16 g/day (1 serving) of whole grains. CONCLUSIONS Dietary fiber and whole grains were inversely associated with liver cancer risk. Further research exploring potential mechanisms and different fiber types is needed.
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Affiliation(s)
- Cody Z Watling
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Aika Wojt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Andrea A Florio
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
| | - Gisela Butera
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Stephanie J Weinstein
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Wen-Yi Huang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Dominick Parisi
- Information Management Services Inc., Calverton, Maryland, USA
| | - Xuehong Zhang
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
| | - Barry I Graubard
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Jessica L Petrick
- Slone Epidemiology Center at Boston University, Boston, Massachusetts, USA
| | - Katherine A McGlynn
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
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12
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Gou H, Zeng R, Lau HCH, Yu J. Gut microbial metabolites: Shaping future diagnosis and treatment against gastrointestinal cancer. Pharmacol Res 2024; 208:107373. [PMID: 39197712 DOI: 10.1016/j.phrs.2024.107373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 08/01/2024] [Accepted: 08/22/2024] [Indexed: 09/01/2024]
Abstract
Gastrointestinal cancer is a worldwide health challenge due to its dramatically increasing prevalence and as a leading cause of cancer-related mortality. Increasing evidence has illustrated the vital role of gut microbes-derived metabolites in gastrointestinal cancer progression and treatment. Microbial metabolites are produced by the gut microbiota that utilizes both extrinsic dietary components and intrinsic host-generated compounds. Meanwhile, certain categories of metabolites such as short-chain fatty acids, bile acids, tryptophan, and indole derivatives, are linked to gastrointestinal malignancy. In this review, the major classes of microbial metabolites and their impacts on various gastrointestinal cancers including colorectal cancer, gastric cancer, and hepatocellular carcinoma, have been introduced. The application of microbial metabolites as predictive biomarkers for early diagnosis and prognosis of gastrointestinal cancer has also been explored. In addition, therapeutic potential of strategies that target microbial metabolites against gastrointestinal cancer is further evaluated.
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Affiliation(s)
- Hongyan Gou
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR
| | - Ruijie Zeng
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR
| | - Harry Cheuk Hay Lau
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR.
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13
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Pallozzi M, De Gaetano V, Di Tommaso N, Cerrito L, Santopaolo F, Stella L, Gasbarrini A, Ponziani FR. Role of Gut Microbial Metabolites in the Pathogenesis of Primary Liver Cancers. Nutrients 2024; 16:2372. [PMID: 39064815 PMCID: PMC11280141 DOI: 10.3390/nu16142372] [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: 05/29/2024] [Revised: 07/08/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
Hepatobiliary malignancies, which include hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are the sixth most common cancers and the third leading cause of cancer-related death worldwide. Hepatic carcinogenesis is highly stimulated by chronic inflammation, defined as fibrosis deposition, and an aberrant imbalance between liver necrosis and nodular regeneration. In this context, the gut-liver axis and gut microbiota have demonstrated a critical role in the pathogenesis of HCC, as dysbiosis and altered intestinal permeability promote bacterial translocation, leading to chronic liver inflammation and tumorigenesis through several pathways. A few data exist on the role of the gut microbiota or bacteria resident in the biliary tract in the pathogenesis of CCA, and some microbial metabolites, such as choline and bile acids, seem to show an association. In this review, we analyze the impact of the gut microbiota and its metabolites on HCC and CCA development and the role of gut dysbiosis as a biomarker of hepatobiliary cancer risk and of response during anti-tumor therapy. We also discuss the future application of gut microbiota in hepatobiliary cancer management.
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Affiliation(s)
- Maria Pallozzi
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (M.P.); (V.D.G.); (N.D.T.); (L.C.); (F.S.); (L.S.); (A.G.)
| | - Valeria De Gaetano
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (M.P.); (V.D.G.); (N.D.T.); (L.C.); (F.S.); (L.S.); (A.G.)
| | - Natalia Di Tommaso
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (M.P.); (V.D.G.); (N.D.T.); (L.C.); (F.S.); (L.S.); (A.G.)
| | - Lucia Cerrito
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (M.P.); (V.D.G.); (N.D.T.); (L.C.); (F.S.); (L.S.); (A.G.)
| | - Francesco Santopaolo
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (M.P.); (V.D.G.); (N.D.T.); (L.C.); (F.S.); (L.S.); (A.G.)
| | - Leonardo Stella
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (M.P.); (V.D.G.); (N.D.T.); (L.C.); (F.S.); (L.S.); (A.G.)
| | - Antonio Gasbarrini
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (M.P.); (V.D.G.); (N.D.T.); (L.C.); (F.S.); (L.S.); (A.G.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (M.P.); (V.D.G.); (N.D.T.); (L.C.); (F.S.); (L.S.); (A.G.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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14
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Matsui T, Morozumi T, Yamamoto Y, Kobayashi T, Takuma R, Yoneda M, Nogami A, Kessoku T, Tamura M, Nomura Y, Takahashi T, Kamata Y, Sugihara S, Arai K, Minabe M, Aoyama N, Mitsudo K, Nakajima A, Komaki M. Relationship of Metabolic Dysfunction-Associated Steatohepatitis-Related Hepatocellular Carcinoma with Oral and Intestinal Microbiota: A Cross-Sectional Pilot Study. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1150. [PMID: 39064580 PMCID: PMC11279156 DOI: 10.3390/medicina60071150] [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: 06/05/2024] [Revised: 07/06/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024]
Abstract
Background and Objectives: The incidence of metabolic dysfunction-associated steatohepatitis (MASH)-related hepatocellular carcinoma (HCC) is increasing worldwide, alongside the epidemic of obesity and metabolic syndrome. Based on preliminary reports regarding the potential association of HCC and periodontitis, this study aimed to analyze the involvement of periodontal bacteria as well as the oral and intestinal bacterial flora in MASH-related HCC (MASH-HCC). Materials and Methods: Forty-one patients with MASH and nineteen with MASH-HCC participated in the study, completing survey questionnaires, undergoing periodontal examinations, and providing samples of saliva, mouth-rinsed water, feces, and peripheral blood. The oral and fecal microbiome profiles were analyzed by 16S ribosomal RNA sequencing. Bayesian network analysis was used to analyze the causation between various factors, including MASH-HCC, examinations, and bacteria. Results: The genus Fusobacterium had a significantly higher occupancy rate (p = 0.002) in the intestinal microflora of the MASH-HCC group compared to the MASH group. However, Butyricicoccus (p = 0.022) and Roseburia (p < 0.05) had significantly lower occupancy rates. The Bayesian network analysis revealed the absence of periodontal pathogenic bacteria and enteric bacteria affecting HCC. However, HCC directly affected the periodontal bacterial species Porphyromonas gingivalis, Tannerella forsythia, Fusobacterium nucleatum, and Prevotella intermedia in the saliva, as well as the genera Lactobacillus, Roseburia, Fusobacterium, Prevotella, Clostridium, Ruminococcus, Trabulsiella, and SMB53 in the intestine. Furthermore, P. gingivalis in the oral cavity directly affected the genera Lactobacillus and Streptococcus in the intestine. Conclusions: MASH-HCC directly affects periodontal pathogenic and intestinal bacteria, and P. gingivalis may affect the intestinal bacteria associated with gastrointestinal cancer.
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Affiliation(s)
- Takaaki Matsui
- Department of Periodontology, Faculty of Dentistry, Kanagawa Dental University, Yokosuka 238-8580, Japan
| | - Toshiya Morozumi
- Department of Periodontology, Faculty of Dentistry, Kanagawa Dental University, Yokosuka 238-8580, Japan
- Department of Endodontics, The Nippon Dental University School of Life Dentistry at Niigata, Niigata 951-8580, Japan
| | - Yuko Yamamoto
- Department of Dental Hygiene, Kanagawa Dental University, Junior College, Yokosuka 238-8580, Japan
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Ryo Takuma
- Department of Periodontology, Faculty of Dentistry, Kanagawa Dental University, Yokosuka 238-8580, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Takaomi Kessoku
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
- Department of Palliative Medicine and Gastroenterology, International University of Health and Welfare, Narita Hospital, Narita 286-8520, Japan
| | - Muneaki Tamura
- Department of Microbiology and Immunology, Nihon University School of Dentistry, Tokyo 101-8310, Japan
| | - Yoshiaki Nomura
- Institute of Photochemistry and Photofunctional Materials, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Toru Takahashi
- Faculty of Pharmaceutical Sciences, Nihon Pharmaceutical University, Saitama 362-0806, Japan
| | - Yohei Kamata
- Department of Advanced Periodontology, Faculty of Dentistry, Kanagawa Dental University, Yokohama 221-0835, Japan
| | - Shuntaro Sugihara
- Department of Periodontology, Faculty of Dentistry, Kanagawa Dental University, Yokosuka 238-8580, Japan
| | - Kyoko Arai
- Department of Endodontics, The Nippon Dental University School of Life Dentistry at Niigata, Niigata 951-8580, Japan
| | | | - Norio Aoyama
- Department of Education Planning, Kanagawa Dental University, Yokosuka 238-8580, Japan
| | - Kenji Mitsudo
- Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Motohiro Komaki
- Department of Periodontology, Faculty of Dentistry, Kanagawa Dental University, Yokosuka 238-8580, Japan
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15
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Ai Z, Liu S, Zhang J, Hu Y, Tang P, Cui L, Wang X, Zou H, Li X, Liu J, Nan B, Wang Y. Ginseng Glucosyl Oleanolate from Ginsenoside Ro, Exhibited Anti-Liver Cancer Activities via MAPKs and Gut Microbiota In Vitro/Vivo. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:7845-7860. [PMID: 38501913 DOI: 10.1021/acs.jafc.3c08150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/20/2024]
Abstract
Ginseng is widely recognized for its diverse health benefits and serves as a functional food ingredient with global popularity. Ginsenosides with a broad range of pharmacological effects are the most crucial active ingredients in ginseng. This study aimed to derive ginseng glucosyl oleanolate (GGO) from ginsenoside Ro through enzymatic conversion and evaluate its impact on liver cancer in vitro and in vivo. GGO exhibited concentration-dependent HepG2 cell death and markedly inhibited cell proliferation via the MAPK signaling pathway. It also attenuated tumor growth in immunocompromised mice undergoing heterograft transplantation. Furthermore, GGO intervention caused a modulation of gut microbiota composition by specific bacterial populations, including Lactobacillus, Bacteroides, Clostridium, Enterococcus, etc., and ameliorated SCFA metabolism and colonic inflammation. These findings offer promising evidence for the potential use of GGO as a natural functional food ingredient in the prevention and treatment of cancer.
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Affiliation(s)
- Zhiyi Ai
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
| | - Sitong Liu
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
| | - Junshun Zhang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
| | - Yue Hu
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
| | - Ping Tang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
| | - Linlin Cui
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
| | - Xinzhu Wang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
| | - Hongyang Zou
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
| | - Xia Li
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
| | - Jingsheng Liu
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
| | - Bo Nan
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
| | - Yuhua Wang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun 130118, China
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16
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Wang Y, Qu Z, Chu J, Han S. Aging Gut Microbiome in Healthy and Unhealthy Aging. Aging Dis 2024; 16:980-1002. [PMID: 38607737 PMCID: PMC11964416 DOI: 10.14336/ad.2024.0331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 03/31/2024] [Indexed: 04/14/2024] Open
Abstract
The characteristics of human aging manifest in tissue and organ function decline, heightening susceptibility to age-related ailments, thereby presenting novel challenges to fostering and sustaining healthy longevity. In recent years, an abundance of research on human aging has surfaced. Intriguingly, evidence suggests a pervasive correlation among gut microbiota, bodily functions, and chronic diseases. From infancy to later stages of adulthood, healthy individuals witness dynamic shifts in gut microbiota composition. This microbial community is associated with tissue and organ function deterioration (e.g., brain, bones, muscles, immune system, vascular system) and heightened risk of age-related diseases. Thus, we present a narrative review of the aging gut microbiome in both healthy and unhealthy aging contexts. Additionally, we explore the potential for adjustments to physical health based on gut microbiome analysis and how targeting the gut microbiome can potentially slow down the aging process.
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Affiliation(s)
- Yangyanqiu Wang
- Huzhou Central Hospital, Affiliated Central Hospital Zhejiang University, Huzhou, Zhejiang, China.
- State Key Laboratory of Complex Severe and Rare Diseases, Medical ICU, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China.
- Key Laboratory of Multiomics Research and Clinical Transformation of Digestive Cancer, Huzhou, Zhejiang, China.
| | - Zhanbo Qu
- Huzhou Central Hospital, Affiliated Central Hospital Zhejiang University, Huzhou, Zhejiang, China.
- Key Laboratory of Multiomics Research and Clinical Transformation of Digestive Cancer, Huzhou, Zhejiang, China.
- Fifth School of Clinical Medicine of Zhejiang Chinese Medical University (Huzhou Central Hospital), Zhejiang, China.
| | - Jian Chu
- Huzhou Central Hospital, Affiliated Central Hospital Zhejiang University, Huzhou, Zhejiang, China.
- Key Laboratory of Multiomics Research and Clinical Transformation of Digestive Cancer, Huzhou, Zhejiang, China.
- Fifth School of Clinical Medicine of Zhejiang Chinese Medical University (Huzhou Central Hospital), Zhejiang, China.
| | - Shuwen Han
- Huzhou Central Hospital, Affiliated Central Hospital Zhejiang University, Huzhou, Zhejiang, China.
- Key Laboratory of Multiomics Research and Clinical Transformation of Digestive Cancer, Huzhou, Zhejiang, China.
- Fifth School of Clinical Medicine of Zhejiang Chinese Medical University (Huzhou Central Hospital), Zhejiang, China.
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17
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Yang J, Gao H, Zhang T, Fan Y, Wu Y, Zhao X, Li Y, Wu L, Zhao H, Yang L, Zhong H, Li L, Xie X, Wu Q. In Vitro Lactic Acid Bacteria Anti-Hepatitis B Virus (HBV) Effect and Modulation of the Intestinal Microbiota in Fecal Cultures from HBV-Associated Hepatocellular Carcinoma Patients. Nutrients 2024; 16:600. [PMID: 38474727 DOI: 10.3390/nu16050600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/18/2024] [Accepted: 02/19/2024] [Indexed: 03/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC), being ranked as the top fifth most prevalent cancer globally, poses a significant health challenge, with a considerable mortality rate. Hepatitis B virus (HBV) infection stands as the primary factor contributing to HCC, presenting substantial challenges in its treatment. This study aimed to identify lactic acid bacteria (LAB) with anti-HBV properties and evaluate their impact on the intestinal flora in HBV-associated HCC. Initially, two LAB strains, Levilactobacillus brevis SR52-2 (L. brevis SR52-2) and LeviLactobacillus delbrueckii subsp. bulgaicus Q80 (L. delbrueckii Q80), exhibiting anti-HBV effects, were screened in vitro from a pool of 498 LAB strains through cell experiments, with extracellular expression levels of 0.58 ± 0.05 and 0.65 ± 0.03, respectively. These strains exhibited the capability of inhibiting the expression of HBeAg and HBsAg. Subsequent in vitro fermentation, conducted under simulated anaerobic conditions mimicking the colon environment, revealed a decrease in pH levels in both the health control (HC) and HCC groups influenced by LAB, with a more pronounced effect observed in the HC group. Additionally, the density of total short-chain fatty acids (SCFAs) significantly increased (p < 0.05) in the HCC group. Analysis of 16S rRNA highlighted differences in the gut microbiota (GM) community structure in cultures treated with L. brevis SR52-2 and L. delbrueckii Q80. Fecal microflora in normal samples exhibited greater diversity compared to HBV-HCC samples. The HCC group treated with LAB showed a significant increase in the abundance of the phyla Firmicutes, Bacteroidetes and Actinobacteria, while Proteobacteria significantly decreased compared to the untreated HCC group after 48 h. In conclusion, the findings indicate that LAB, specifically L. brevis SR52-2 and L. delbrueckii Q80, possessing antiviral properties, contribute to an improvement in gastrointestinal health.
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Affiliation(s)
- Juan Yang
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China
- National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
| | - He Gao
- National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
| | - Tiantian Zhang
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China
- National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
| | - Yong Fan
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China
- National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
| | - Yuwei Wu
- Guangdong Huankai Microbial Co., Ltd., Zhaoqing 526238, China
| | - Xinyu Zhao
- Guangdong Huankai Microbial Co., Ltd., Zhaoqing 526238, China
| | - Ying Li
- National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
| | - Lei Wu
- National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
| | - Hui Zhao
- National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
| | - Lingshuang Yang
- National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
| | - Haojie Zhong
- National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
| | - Longyan Li
- National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
| | - Xinqiang Xie
- National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
| | - Qingping Wu
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China
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18
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Lau HCH, Zhang X, Ji F, Lin Y, Liang W, Li Q, Chen D, Fong W, Kang X, Liu W, Chu ESH, Ng QWY, Yu J. Lactobacillus acidophilus suppresses non-alcoholic fatty liver disease-associated hepatocellular carcinoma through producing valeric acid. EBioMedicine 2024; 100:104952. [PMID: 38176203 PMCID: PMC10801313 DOI: 10.1016/j.ebiom.2023.104952] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 12/05/2023] [Accepted: 12/19/2023] [Indexed: 01/06/2024] Open
Abstract
BACKGROUND Gut probiotic depletion is associated with non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC). Here, we investigated the prophylactic potential of Lactobacillus acidophilus against NAFLD-HCC. METHODS NAFLD-HCC conventional and germ-free mice were established by diethylnitrosamine (DEN) injection with feeding of high-fat high-cholesterol (HFHC) or choline-deficient high-fat (CDHF) diet. Orthotopic NAFLD-HCC allografts were established by intrahepatic injection of murine HCC cells with HFHC feeding. Metabolomic profiling was performed using liquid chromatography-mass spectrometry. Biological functions of L. acidophilus conditional medium (L.a CM) and metabolites were determined in NAFLD-HCC human cells and mouse organoids. FINDINGS L. acidophilus supplementation suppressed NAFLD-HCC formation in HFHC-fed DEN-treated mice. This was confirmed in orthotopic allografts and germ-free tumourigenesis mice. L.a CM inhibited the growth of NAFLD-HCC human cells and mouse organoids. The protective function of L. acidophilus was attributed to its non-protein small molecules. By metabolomic profiling, valeric acid was the top enriched metabolite in L.a CM and its upregulation was verified in liver and portal vein of L. acidophilus-treated mice. The protective function of valeric acid was demonstrated in NAFLD-HCC human cells and mouse organoids. Valeric acid significantly suppressed NAFLD-HCC formation in HFHC-fed DEN-treated mice, accompanied by improved intestinal barrier integrity. This was confirmed in another NAFLD-HCC mouse model induced by CDHF diet and DEN. Mechanistically, valeric acid bound to hepatocytic surface receptor GPR41/43 to inhibit Rho-GTPase pathway, thereby ablating NAFLD-HCC. INTERPRETATION L. acidophilus exhibits anti-tumourigenic effect in mice by secreting valeric acid. Probiotic supplementation is a potential prophylactic of NAFLD-HCC. FUNDING Shown in Acknowledgments.
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Affiliation(s)
- Harry Cheuk-Hay Lau
- State Key Laboratory of Digestive Disease, Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiang Zhang
- State Key Laboratory of Digestive Disease, Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Fenfen Ji
- State Key Laboratory of Digestive Disease, Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Yufeng Lin
- State Key Laboratory of Digestive Disease, Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Wei Liang
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qing Li
- State Key Laboratory of Digestive Disease, Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Danyu Chen
- State Key Laboratory of Digestive Disease, Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Winnie Fong
- State Key Laboratory of Digestive Disease, Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Xing Kang
- State Key Laboratory of Digestive Disease, Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Weixin Liu
- State Key Laboratory of Digestive Disease, Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Eagle Siu-Hong Chu
- State Key Laboratory of Digestive Disease, Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Queena Wing-Yin Ng
- State Key Laboratory of Digestive Disease, Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- State Key Laboratory of Digestive Disease, Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
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19
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Ichikawa M, Okada H, Nakamoto N, Taniki N, Chu PS, Kanai T. The gut-liver axis in hepatobiliary diseases. Inflamm Regen 2024; 44:2. [PMID: 38191517 PMCID: PMC10773109 DOI: 10.1186/s41232-023-00315-0] [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: 11/01/2023] [Accepted: 12/17/2023] [Indexed: 01/10/2024] Open
Abstract
Recent advances in the analysis of intestinal bacteria have led to reports of variations in intestinal bacterial levels among hepatobiliary diseases. The mechanisms behind the changes in intestinal bacteria in various hepatobiliary diseases include the abnormal composition of intestinal bacteria, weakening of the intestinal barrier, and bacterial translocation outside the intestinal tract, along with their metabolites, but many aspects remain unresolved. Further research employing clinical studies and animal models is expected to clarify the direct relationship between intestinal bacteria and hepatobiliary diseases and to validate the utility of intestinal bacteria as a diagnostic biomarker and potential therapeutic target. This review summarizes the involvement of the microbiota in the pathogenesis of hepatobiliary diseases via the gut-liver axis.
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Affiliation(s)
- Masataka Ichikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, 1608582, Japan
| | - Haruka Okada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, 1608582, Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, 1608582, Japan.
| | - Nobuhito Taniki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, 1608582, Japan
| | - Po-Sung Chu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, 1608582, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, 1608582, Japan.
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20
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Jiang S, Ma W, Ma C, Zhang Z, Zhang W, Zhang J. An emerging strategy: probiotics enhance the effectiveness of tumor immunotherapy via mediating the gut microbiome. Gut Microbes 2024; 16:2341717. [PMID: 38717360 PMCID: PMC11085971 DOI: 10.1080/19490976.2024.2341717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/31/2024] [Accepted: 04/08/2024] [Indexed: 05/12/2024] Open
Abstract
The occurrence and progression of tumors are often accompanied by disruptions in the gut microbiota. Inversely, the impact of the gut microbiota on the initiation and progression of cancer is becoming increasingly evident, influencing the tumor microenvironment (TME) for both local and distant tumors. Moreover, it is even suggested to play a significant role in the process of tumor immunotherapy, contributing to high specificity in therapeutic outcomes and long-term effectiveness across various cancer types. Probiotics, with their generally positive influence on the gut microbiota, may serve as effective agents in synergizing cancer immunotherapy. They play a crucial role in activating the immune system to inhibit tumor growth. In summary, this comprehensive review aims to provide valuable insights into the dynamic interactions between probiotics, gut microbiota, and cancer. Furthermore, we highlight recent advances and mechanisms in using probiotics to improve the effectiveness of cancer immunotherapy. By understanding these complex relationships, we may unlock innovative approaches for cancer diagnosis and treatment while optimizing the effects of immunotherapy.
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Affiliation(s)
- Shuaiming Jiang
- School of Food Science and Engineering, Hainan University, Haikou, PR China
| | - Wenyao Ma
- School of Food Science and Engineering, Hainan University, Haikou, PR China
| | - Chenchen Ma
- Department of Human Cell Biology and Genetics, Southern University of Science and Technology, Shenzhen, PR China
| | - Zeng Zhang
- School of Food Science and Engineering, Hainan University, Haikou, PR China
| | - Wanli Zhang
- School of Food Science and Engineering, Hainan University, Haikou, PR China
| | - Jiachao Zhang
- School of Food Science and Engineering, Hainan University, Haikou, PR China
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21
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Li SQ, Shen Y, Zhang J, Weng CZ, Wu SD, Jiang W. Immune modulation of gut microbiota and its metabolites in chronic hepatitis B. Front Microbiol 2023; 14:1285556. [PMID: 38094621 PMCID: PMC10716252 DOI: 10.3389/fmicb.2023.1285556] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 11/14/2023] [Indexed: 02/05/2025] Open
Abstract
The gut microbiota is a diverse ecosystem consisting of 100 trillion microbiomes. The interaction between the host's gut and distal organs profoundly impacts various functions such as metabolism, immunity, neurology, and nutrition within the human body. The liver, as the primary immune organ, plays a crucial role in maintaining immune homeostasis by receiving a significant influx of gut-derived components and toxins. Perturbations in gut microbiota homeostasis have been linked to a range of liver diseases. The advancements in sequencing technologies, such as 16S rRNA and metagenomics, have opened up new avenues for comprehending the intricate physiological interplay between the liver and the intestine. Metabolites produced by the gut microbiota function as signaling molecules and substrates, influencing both pathological and physiological processes. Establishing a comprehensive host-bacterium-metabolism axis holds tremendous potential for investigating the mechanisms underlying liver diseases. In this review, we have provided a summary of the detrimental effects of the gut-liver axis in chronic liver diseases, primarily focusing on hepatitis B virus-related chronic liver diseases. Moreover, we have explored the potential mechanisms through which the gut microbiota and its derivatives interact with liver immunity, with implications for future clinical therapies.
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Affiliation(s)
- Shi-Qin Li
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yue Shen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, China
| | - Jun Zhang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Cheng-Zhao Weng
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Sheng-Di Wu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, China
| | - Wei Jiang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, China
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22
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Xiang Z, Wu J, Li J, Zheng S, Wei X, Xu X. Gut Microbiota Modulation: A Viable Strategy to Address Medical Needs in Hepatocellular Carcinoma and Liver Transplantation. ENGINEERING 2023; 29:59-72. [DOI: 10.1016/j.eng.2022.12.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/05/2024]
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23
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Quinn C, Rico MC, Merali C, Barrero CA, Perez-Leal O, Mischley V, Karanicolas J, Friedman SL, Merali S. Secreted folate receptor γ drives fibrogenesis in metabolic dysfunction-associated steatohepatitis by amplifying TGFβ signaling in hepatic stellate cells. Sci Transl Med 2023; 15:eade2966. [PMID: 37756380 PMCID: PMC11816833 DOI: 10.1126/scitranslmed.ade2966] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 08/16/2023] [Indexed: 09/29/2023]
Abstract
Hepatic fibrosis is the primary determinant of mortality in patients with metabolic dysfunction-associated steatohepatitis (MASH). Transforming growth factor-β (TGFβ), a master profibrogenic cytokine, is a promising therapeutic target that has not yet been translated into an effective therapy in part because of liabilities associated with systemic TGFβ antagonism. We have identified that soluble folate receptor γ (FOLR3), which is expressed in humans but not in rodents, is a secreted protein that is elevated in the livers of patients with MASH but not in those with metabolic dysfunction-associated steatotic liver disease, those with type II diabetes, or healthy individuals. Global proteomics showed that FOLR3 was the most highly significant MASH-specific protein and was positively correlated with increasing fibrosis stage, consistent with stimulation of activated hepatic stellate cells (HSCs), which are the key fibrogenic cells in the liver. Exposure of HSCs to exogenous FOLR3 led to elevated extracellular matrix (ECM) protein production, an effect synergistically potentiated by TGFβ1. We found that FOLR3 interacts with the serine protease HTRA1, a known regulator of TGFBR, and activates TGFβ signaling. Administration of human FOLR3 to mice induced severe bridging fibrosis and an ECM pattern resembling human MASH. Our study thus uncovers a role of FOLR3 in enhancing fibrosis.
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Affiliation(s)
- Connor Quinn
- Temple University School of Pharmacy, Philadelphia, PA 19140 USA
| | - Mario C. Rico
- Temple University School of Pharmacy, Philadelphia, PA 19140 USA
| | - Carmen Merali
- Temple University School of Pharmacy, Philadelphia, PA 19140 USA
| | | | - Oscar Perez-Leal
- Temple University School of Pharmacy, Philadelphia, PA 19140 USA
| | - Victoria Mischley
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
- Drexel University College of Medicine, Philadelphia, PA 19102, USA
| | - John Karanicolas
- Temple University School of Pharmacy, Philadelphia, PA 19140 USA
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Scott L. Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Salim Merali
- Temple University School of Pharmacy, Philadelphia, PA 19140 USA
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24
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Liu Y, Zhou Q, Ye F, Yang C, Jiang H. Gut microbiota-derived short-chain fatty acids promote prostate cancer progression via inducing cancer cell autophagy and M2 macrophage polarization. Neoplasia 2023; 43:100928. [PMID: 37579688 PMCID: PMC10429288 DOI: 10.1016/j.neo.2023.100928] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 07/24/2023] [Accepted: 08/08/2023] [Indexed: 08/16/2023]
Abstract
We have previously demonstrated abnormal gut microbial composition in castration-resistant prostate cancer (CRPC) patients, here we revealed the mechanism of gut microbiota-derived short-chain fatty acids (SCFAs) as a mediator linking CRPC microbiota dysbiosis and prostate cancer (PCa) progression. By using transgenic TRAMP mouse model, PCa patient samples, in vitro PCa cell transwell and macrophage recruitment assays, we examined the effects of CRPC fecal microbiota transplantation (FMT) and SCFAs on PCa progression. Our results showed that FMT with CRPC patients' fecal suspension increased SCFAs-producing gut microbiotas such as Ruminococcus, Alistipes, Phascolarctobaterium in TRAMP mice, and correspondingly raised their gut SCFAs (acetate and butyrate) levels. CRPC FMT or SCFAs supplementation significantly accelerated mice's PCa progression. In vitro, SCFAs enhanced PCa cells migration and invasion by inducing TLR3-triggered autophagy that further activated NF-κB and MAPK signalings. Meanwhile, autophagy of PCa cells released higher level of chemokine CCL20 that could reprogramme the tumor microenvironment by recruiting more macrophage infiltration and simultaneously polarizing them into M2 type, which in turn further strengthened PCa cells invasiveness. Finally in a cohort of 362 PCa patients, we demonstrated that CCL20 expression in prostate tissue was positively correlated with Gleason grade, pre-operative PSA, neural/seminal vesical invasion, and was negatively correlated with post-operative biochemical recurrence-free survival. Collectively, CRPC gut microbiota-derived SCFAs promoted PCa progression via inducing cancer cell autophagy and M2 macrophage polarization. CCL20 could become a biomarker for prediction of prognosis in PCa patients. Intervention of SCFAs-producing microbiotas may be a useful strategy in manipulation of CRPC.
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Affiliation(s)
- Yufei Liu
- Department of Urology, Huashan Hospital Fudan University, No. 12 Middle Wulumuqi Road, Shanghai 200040, China.
| | - Quan Zhou
- Department of Urology, Huashan Hospital Fudan University, No. 12 Middle Wulumuqi Road, Shanghai 200040, China
| | - Fangdie Ye
- Department of Urology, Huashan Hospital Fudan University, No. 12 Middle Wulumuqi Road, Shanghai 200040, China
| | - Chen Yang
- Department of Urology, Huashan Hospital Fudan University, No. 12 Middle Wulumuqi Road, Shanghai 200040, China
| | - Haowen Jiang
- Department of Urology, Huashan Hospital Fudan University, No. 12 Middle Wulumuqi Road, Shanghai 200040, China.
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25
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Feitelson MA, Arzumanyan A, Medhat A, Spector I. Short-chain fatty acids in cancer pathogenesis. Cancer Metastasis Rev 2023; 42:677-698. [PMID: 37432606 PMCID: PMC10584782 DOI: 10.1007/s10555-023-10117-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 06/05/2023] [Indexed: 07/12/2023]
Abstract
Cancer is a multi-step process that can be viewed as a cellular and immunological shift away from homeostasis in response to selected infectious agents, mutations, diet, and environmental carcinogens. Homeostasis, which contributes importantly to the definition of "health," is maintained, in part by the production of short-chain fatty acids (SCFAs), which are metabolites of specific gut bacteria. Alteration in the composition of gut bacteria, or dysbiosis, is often a major risk factor for some two dozen tumor types. Dysbiosis is often characterized by diminished levels of SCFAs in the stool, and the presence of a "leaky gut," permitting the penetration of microbes and microbial derived molecules (e.g., lipopolysaccharides) through the gut wall, thereby triggering chronic inflammation. SCFAs attenuate inflammation by inhibiting the activation of nuclear factor kappa B, by decreasing the expression of pro-inflammatory cytokines such as tumor necrosis factor alpha, by stimulating the expression of anti-inflammatory cytokines such as interleukin-10 and transforming growth factor beta, and by promoting the differentiation of naïve T cells into T regulatory cells, which down-regulate immune responses by immunomodulation. SCFA function epigenetically by inhibiting selected histone acetyltransferases that alter the expression of multiple genes and the activity of many signaling pathways (e.g., Wnt, Hedgehog, Hippo, and Notch) that contribute to the pathogenesis of cancer. SCFAs block cancer stem cell proliferation, thereby potentially delaying or inhibiting cancer development or relapse by targeting genes and pathways that are mutated in tumors (e.g., epidermal growth factor receptor, hepatocyte growth factor, and MET) and by promoting the expression of tumor suppressors (e.g., by up-regulating PTEN and p53). When administered properly, SCFAs have many advantages compared to probiotic bacteria and fecal transplants. In carcinogenesis, SCFAs are toxic against tumor cells but not to surrounding tissue due to differences in their metabolic fate. Multiple hallmarks of cancer are also targets of SCFAs. These data suggest that SCFAs may re-establish homeostasis without overt toxicity and either delay or prevent the development of various tumor types.
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Affiliation(s)
- Mark A Feitelson
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, 19122, USA.
| | - Alla Arzumanyan
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, 19122, USA
| | - Arvin Medhat
- Department of Molecular Cell Biology, Islamic Azad University Tehran North Branch, Tehran, 1975933411, Iran
| | - Ira Spector
- SFA Therapeutics, Jenkintown, PA, 19046, USA
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26
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Yang X, Mai H, Zhou J, Li Z, Wang Q, Lan L, Lu F, Yang X, Guo B, Ye L, Cui P, Liang H, Huang J. Alterations of the gut microbiota associated with the occurrence and progression of viral hepatitis. Front Cell Infect Microbiol 2023; 13:1119875. [PMID: 37342245 PMCID: PMC10277638 DOI: 10.3389/fcimb.2023.1119875] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 05/22/2023] [Indexed: 06/22/2023] Open
Abstract
Background Gut microbiota is the largest population of microorganisms and is closely related to health. Many studies have explored changes in gut microbiota in viral hepatitis. However, the correlation between gut microbiota and the occurrence and progression of viral hepatitis has not been fully clarified. Methods PubMed and BioProject databases were searched for studies about viral hepatitis disease and 16S rRNA gene sequencing of gut microbiota up to January 2023. With bioinformatics analyses, we explored changes in microbial diversity of viral hepatitis, screened out crucial bacteria and microbial functions related to viral hepatitis, and identified the potential microbial markers for predicting risks for the occurrence and progression of viral hepatitis based on ROC analysis. Results Of the 1389 records identified, 13 studies met the inclusion criteria, with 950 individuals including 656 patient samples (HBV, n = 546; HCV, n = 86; HEV, n = 24) and 294 healthy controls. Gut microbial diversity is significantly decreased as the infection and progression of viral hepatitis. Alpha diversity and microbiota including Butyricimonas, Escherichia-Shigella, Lactobacillus, and Veillonella were identified as the potential microbial markers for predicting the risk of development of viral hepatitis (AUC>0.7). Microbial functions including tryptophan metabolism, fatty acid biosynthesis, lipopolysaccharide biosynthesis, and lipid metabolism related to the microbial community increased significantly as the development of viral hepatitis. Conclusions This study demonstrated comprehensively the gut microbiota characteristics in viral hepatitis, screened out crucial microbial functions related to viral hepatitis, and identified the potential microbial markers for predicting the risk of viral hepatitis.
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Affiliation(s)
- Xing Yang
- School of Public Health, Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, Guangxi Medical University, Nanning, China
| | - Huanzhuo Mai
- School of Public Health, Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, Guangxi Medical University, Nanning, China
| | - Jie Zhou
- School of Public Health, Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, Guangxi Medical University, Nanning, China
| | - Zhuoxin Li
- School of Public Health, Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, Guangxi Medical University, Nanning, China
| | - Qing Wang
- School of Public Health, Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, Guangxi Medical University, Nanning, China
| | - Liuyan Lan
- School of Public Health, Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, Guangxi Medical University, Nanning, China
| | - Fang Lu
- School of Public Health, Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, Guangxi Medical University, Nanning, China
| | - Xiping Yang
- School of Public Health, Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, Guangxi Medical University, Nanning, China
| | - Baodong Guo
- School of Public Health, Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, Guangxi Medical University, Nanning, China
| | - Li Ye
- School of Public Health, Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, Guangxi Medical University, Nanning, China
| | - Ping Cui
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, Guangxi Medical University, Nanning, China
- Life Science Institute, Guangxi Medical University, Nanning, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning, China
| | - Hao Liang
- School of Public Health, Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, Guangxi Medical University, Nanning, China
- Life Science Institute, Guangxi Medical University, Nanning, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning, China
| | - Jiegang Huang
- School of Public Health, Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, Guangxi Medical University, Nanning, China
- Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, China
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Ney LM, Wipplinger M, Grossmann M, Engert N, Wegner VD, Mosig AS. Short chain fatty acids: key regulators of the local and systemic immune response in inflammatory diseases and infections. Open Biol 2023; 13:230014. [PMID: 36977462 PMCID: PMC10049789 DOI: 10.1098/rsob.230014] [Citation(s) in RCA: 62] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2023] Open
Abstract
The human intestinal microbiome substantially affects human health and resistance to infections in its dynamic composition and varying release of microbial-derived metabolites. Short-chain fatty acids (SCFA) produced by commensal bacteria through fermentation of indigestible fibres are considered key regulators in orchestrating the host immune response to microbial colonization by regulating phagocytosis, chemokine and central signalling pathways of cell growth and apoptosis, thereby shaping the composition and functionality of the intestinal epithelial barrier. Although research of the last decades provided valuable insight into the pleiotropic functions of SCFAs and their capability to maintain human health, mechanistic details on how SCFAs act across different cell types and other organs are not fully understood. In this review, we provide an overview of the various functions of SCFAs in regulating cellular metabolism, emphasizing the orchestration of the immune response along the gut-brain, the gut-lung and the gut-liver axes. We discuss their potential pharmacological use in inflammatory diseases and infections and highlight new options of relevant human three-dimensional organ models to investigate and validate their biological functions in more detail.
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Affiliation(s)
- Lisa-Marie Ney
- Institute of Biochemistry II, Jena University Hospital, Kastanienallee 1, 07747 Jena, Germany
| | - Maximilian Wipplinger
- Institute of Biochemistry II, Jena University Hospital, Kastanienallee 1, 07747 Jena, Germany
| | - Martha Grossmann
- Institute of Biochemistry II, Jena University Hospital, Kastanienallee 1, 07747 Jena, Germany
| | - Nicole Engert
- Institute of Biochemistry II, Jena University Hospital, Kastanienallee 1, 07747 Jena, Germany
| | - Valentin D Wegner
- Institute of Biochemistry II, Jena University Hospital, Kastanienallee 1, 07747 Jena, Germany
| | - Alexander S Mosig
- Institute of Biochemistry II, Jena University Hospital, Kastanienallee 1, 07747 Jena, Germany
- Center for Sepsis Control and Care, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany
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28
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Huang X, Yang Y, Li X, Zhu X, Lin D, Ma Y, Zhou M, Cui X, Zhang B, Dang D, Lü Y, Yue C. The gut microbiota: A new perspective for tertiary prevention of hepatobiliary and gallbladder diseases. Front Nutr 2023; 10:1089909. [PMID: 36814514 PMCID: PMC9940272 DOI: 10.3389/fnut.2023.1089909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 01/11/2023] [Indexed: 02/10/2023] Open
Abstract
The gut microbiota is a complex ecosystem that has coevolved with the human body for hundreds of millions of years. In the past 30 years, with the progress of gene sequencing and omics technology, the research related to gut microbiota has developed rapidly especially in the field of digestive system diseases and systemic metabolic diseases. Mechanical, biological, immune, and other factors make the intestinal flora form a close bidirectional connection with the liver and gallbladder, which can be called the "gut-liver-biliary axis." Liver and gallbladder, as internal organs of the peritoneum, suffer from insidious onset, which are not easy to detect. The diagnosis is often made through laboratory chemical tests and imaging methods, and intervention measures are usually taken only when organic lesions have occurred. At this time, some people may have entered the irreversible stage of disease development. We reviewed the literature describing the role of intestinal flora in the pathogenesis and biotherapy of hepatobiliary diseases in the past 3-5 years, including the dynamic changes of intestinal flora at different stages of the disease, as well as the signaling pathways involved in intestinal flora and its metabolites, etc. After summarizing the above contents, we hope to highlight the potential of intestinal flora as a new clinical target for early prevention, early diagnosis, timely treatment and prognosis of hepatobiliary diseases. GRAPHICAL ABSTRACT.
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Affiliation(s)
- Xiaoyu Huang
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Yi Yang
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Xueli Li
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
- Shaanxi Key Laboratory of Chemical Reaction Engineering, College of Chemistry and Chemical Engineering, Yan’an University, Yan’an, Shaanxi, China
| | - Xiaoya Zhu
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Dan Lin
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Yueran Ma
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Min Zhou
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Xiangyi Cui
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Bingyu Zhang
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Dongmei Dang
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Yuhong Lü
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Changwu Yue
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
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Zhou Y, Zhang F, Mao L, Feng T, Wang K, Xu M, Lv B, Wang X. Bifico relieves irritable bowel syndrome by regulating gut microbiota dysbiosis and inflammatory cytokines. Eur J Nutr 2023; 62:139-155. [PMID: 35918555 PMCID: PMC9899748 DOI: 10.1007/s00394-022-02958-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 07/08/2022] [Indexed: 02/07/2023]
Abstract
PURPOSE Gut microbiota dysbiosis, a core pathophysiology of irritable bowel syndrome (IBS), is closely related to immunological and metabolic functions. Gut microbiota-based therapeutics have been recently explored in several studies. Bifico is a probiotic cocktail widely used in gastrointestinal disorders which relate to the imbalance of gut microbiota. However, the efficacy and potential mechanisms of Bifico treatment in IBS remains incompletely understood. METHODS Adopting a wrap restraint stress (WRS) -induced IBS mice model. Protective effect of Bifico in IBS mice was examined through abdominal withdrawal reflex (AWR) scores. 16S rDNA, 1H nuclear magnetic resonance (1H-NMR) and western blot assays were performed to analyze alterations of gut microbiota, microbiome metabolites and inflammatory cytokines, respectively. RESULTS Bifico could decrease intestinal visceral hypersensitivity. Although gut microbiota diversity did not increase, composition of gut microbiota was changed after treatment of Bifico, which were characterized by an increase of Proteobacteria phylum and Actinobacteria phylum, Muribaculum genus, Bifidobacterium genus and a decrease of Parabacteroides genus, Sutterella genus and Lactobacillus genus. Moreover, Bifico elevated the concentration of short-chain fatty acids (SCFAs) and reduced protein levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). From further Spearman's correlation analysis, Bifidobacterium genus were positively correlated with SCFAs including propionate, butyrate, valerate and negatively correlated with IL-6 and TNF-α. CONCLUSION Bifico could alleviate symptoms of IBS mice through regulation of the gut microbiota, elevating production of SCFAs and reducing the colonic inflammatory response.
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Affiliation(s)
- Yanlin Zhou
- grid.417400.60000 0004 1799 0055Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310003 Zhejiang China ,grid.268505.c0000 0000 8744 8924The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, 310053 Zhejiang China ,Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hubin Campus, Hangzhou, 310006 China
| | - Fan Zhang
- grid.268505.c0000 0000 8744 8924The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, 310053 Zhejiang China ,Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hubin Campus, Hangzhou, 310006 China ,grid.417400.60000 0004 1799 0055Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310003 Zhejiang China
| | - Liqi Mao
- grid.411440.40000 0001 0238 8414Department of Gastroenterology, The First People’s Hospital of Huzhou, The First Affiliated Hospital of Huzhou Teachers College, Huzhou, 313000 Zhejiang China
| | - Tongfei Feng
- grid.417400.60000 0004 1799 0055Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310003 Zhejiang China ,Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hubin Campus, Hangzhou, 310006 China
| | - Kaijie Wang
- grid.417400.60000 0004 1799 0055Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310003 Zhejiang China ,Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hubin Campus, Hangzhou, 310006 China
| | - Maosheng Xu
- grid.417400.60000 0004 1799 0055Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310003 Zhejiang China
| | - Bin Lv
- grid.417400.60000 0004 1799 0055Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310003 Zhejiang China ,Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hubin Campus, Hangzhou, 310006 China
| | - Xi Wang
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hubin Campus, Hangzhou, 310006 China
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30
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Dong Y, Zhang K, Wei J, Ding Y, Wang X, Hou H, Wu J, Liu T, Wang B, Cao H. Gut microbiota-derived short-chain fatty acids regulate gastrointestinal tumor immunity: a novel therapeutic strategy? Front Immunol 2023; 14:1158200. [PMID: 37122756 PMCID: PMC10140337 DOI: 10.3389/fimmu.2023.1158200] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 03/17/2023] [Indexed: 05/02/2023] Open
Abstract
Tumor immune microenvironment (TIME), a tumor-derived immune component, is proven to be closely related to the development, metastasis, and recurrence of tumors. Gut microbiota and its fermented-metabolites short-chain fatty acids (SCFAs) play a critical role in maintaining the immune homeostasis of gastrointestinal tumors. Consisting mainly of acetate, propionate, and butyrate, SCFAs can interact with G protein-coupled receptors 43 of T helper 1 cell or restrain histone deacetylases (HDACs) of cytotoxic T lymphocytes to exert immunotherapy effects. Studies have shed light on SCFAs can mediate the differentiation and function of regulatory T cells, as well as cytokine production in TIME. Additionally, SCFAs can alter epigenetic modification of CD8+ T cells by inhibiting HDACs to participate in the immune response process. In gastrointestinal tumors, the abundance of SCFAs and their producing bacteria is significantly reduced. Direct supplementation of dietary fiber and probiotics, or fecal microbiota transplantation to change the structure of gut microbiota can both increase the level of SCFAs and inhibit tumor development. The mechanism by which SCFAs modulate the progression of gastrointestinal tumors has been elucidated in this review, aiming to provide prospects for the development of novel immunotherapeutic strategies.
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Mei S, Deng Z, Chen Y, Ning D, Guo Y, Fan X, Wang R, Meng Y, Zhou Q, Tian X. Dysbiosis: The first hit for digestive system cancer. Front Physiol 2022; 13:1040991. [PMID: 36483296 PMCID: PMC9723259 DOI: 10.3389/fphys.2022.1040991] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 11/01/2022] [Indexed: 03/01/2025] Open
Abstract
Gastrointestinal cancer may be associated with dysbiosis, which is characterized by an alteration of the gut microbiota. Understanding the role of gut microbiota in the development of gastrointestinal cancer is useful for cancer prevention and gut microbiota-based therapy. However, the potential role of dysbiosis in the onset of tumorigenesis is not fully understood. While accumulating evidence has demonstrated the presence of dysbiosis in the intestinal microbiota of both healthy individuals and patients with various digestive system diseases, severe dysbiosis is often present in patients with digestive system cancer. Importantly, specific bacteria have been isolated from the fecal samples of these patients. Thus, the association between dysbiosis and the development of digestive system cancer cannot be ignored. A new model describing this relationship must be established. In this review, we postulate that dysbiosis serves as the first hit for the development of digestive system cancer. Dysbiosis-induced alterations, including inflammation, aberrant immune response, bacteria-produced genotoxins, and cellular stress response associated with genetic, epigenetic, and/or neoplastic changes, are second hits that speed carcinogenesis. This review explains the mechanisms for these four pathways and discusses gut microbiota-based therapies. The content included in this review will shed light on gut microbiota-based strategies for cancer prevention and therapy.
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Affiliation(s)
- Si Mei
- Department of Physiology, Faculty of Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Zhe Deng
- Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Department of Internal Medicine, College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Yating Chen
- Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Department of Internal Medicine, College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Dimin Ning
- Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Department of Internal Medicine, College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Yinmei Guo
- Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Xingxing Fan
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, Macau SAR, China
| | - Ruoyu Wang
- Department of Internal Medicine, College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Department of Liver Diseases, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Yuelin Meng
- Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Department of Internal Medicine, College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Qing Zhou
- Department of Andrology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Xuefei Tian
- Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Department of Internal Medicine, College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
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Tilg H, Adolph TE, Trauner M. Gut-liver axis: Pathophysiological concepts and clinical implications. Cell Metab 2022; 34:1700-1718. [PMID: 36208625 DOI: 10.1016/j.cmet.2022.09.017] [Citation(s) in RCA: 307] [Impact Index Per Article: 102.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 08/17/2022] [Accepted: 09/16/2022] [Indexed: 02/07/2023]
Abstract
Bidirectional crosstalk along the gut-liver axis controls gastrointestinal health and disease and exploits environmental and host mediators. Nutrients, microbial antigens, metabolites, and bile acids regulate metabolism and immune responses in the gut and liver, which reciprocally shape microbial community structure and function. Perturbation of such host-microbe interactions is observed in a variety of experimental liver diseases and is facilitated by an impaired intestinal barrier, which is fueling hepatic inflammation and disease progression. Clinical evidence describes perturbation of the gut-liver crosstalk in non-alcoholic fatty liver disease, alcoholic liver disease, and primary sclerosing cholangitis. In liver cirrhosis, a common sequela of these diseases, the intestinal microbiota and microbial pathogen-associated molecular patterns constitute liver inflammation and clinical complications, such as hepatic encephalopathy. Understanding the intricate metabolic interplay between the gut and liver in health and disease opens an avenue for targeted therapies in the future, which is probed in controlled clinical trials.
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Affiliation(s)
- Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University, Innsbruck, Austria.
| | - Timon E Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University, Innsbruck, Austria
| | - Michael Trauner
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University, Vienna, Austria
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Feitelson MA, Arzumanyan A, Spector I, Medhat A. Hepatitis B x (HBx) as a Component of a Functional Cure for Chronic Hepatitis B. Biomedicines 2022; 10:biomedicines10092210. [PMID: 36140311 PMCID: PMC9496119 DOI: 10.3390/biomedicines10092210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/22/2022] [Accepted: 09/02/2022] [Indexed: 11/20/2022] Open
Abstract
Patients who are carriers of the hepatitis B virus (HBV) are at high risk of chronic liver disease (CLD) which proceeds from hepatitis, to fibrosis, cirrhosis and to hepatocellular carcinoma (HCC). The hepatitis B-encoded X antigen, HBx, promotes virus gene expression and replication, protects infected hepatocytes from immunological destruction, and promotes the development of CLD and HCC. For virus replication, HBx regulates covalently closed circular (ccc) HBV DNA transcription, while for CLD, HBx triggers cellular oxidative stress, in part, by triggering mitochondrial damage that stimulates innate immunity. Constitutive activation of NF-κB by HBx transcriptionally activates pro-inflammatory genes, resulting in hepatocellular destruction, regeneration, and increased integration of the HBx gene into the host genome. NF-κB is also hepatoprotective, which sustains the survival of infected cells. Multiple therapeutic approaches include direct-acting anti-viral compounds and immune-stimulating drugs, but functional cures were not achieved, in part, because none were yet devised to target HBx. In addition, many patients with cirrhosis or HCC have little or no virus replication, but continue to express HBx from integrated templates, suggesting that HBx contributes to the pathogenesis of CLD. Blocking HBx activity will, therefore, impact multiple aspects of the host–virus relationship that are relevant to achieving a functional cure.
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Affiliation(s)
- Mark A. Feitelson
- Room 409 Biolife Building, Department of Biology, College of Science and Technology, Temple University, 1900 N. 12th Street, Philadelphia, PA 19122, USA
- Correspondence: ; Tel.: +1-215-204-8434
| | - Alla Arzumanyan
- Room 409 Biolife Building, Department of Biology, College of Science and Technology, Temple University, 1900 N. 12th Street, Philadelphia, PA 19122, USA
| | | | - Arvin Medhat
- Department of Molecular Cell Biology, Islamic Azad University Tehran North Branch, Tehran 1975933411, Iran
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Xiang Z, Li J, Lu D, Wei X, Xu X. Advances in multi-omics research on viral hepatitis. Front Microbiol 2022; 13:987324. [PMID: 36118247 PMCID: PMC9478034 DOI: 10.3389/fmicb.2022.987324] [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] [Received: 07/06/2022] [Accepted: 08/11/2022] [Indexed: 11/13/2022] Open
Abstract
Viral hepatitis is a major global public health problem that affects hundreds of millions of people and is associated with significant morbidity and mortality. Five biologically unrelated hepatotropic viruses account for the majority of the global burden of viral hepatitis, including hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV). Omics is defined as the comprehensive study of the functions, relationships and roles of various types of molecules in biological cells. The multi-omics analysis has been proposed and considered key to advancing clinical precision medicine, mainly including genomics, transcriptomics and proteomics, metabolomics. Overall, the applications of multi-omics can show the origin of hepatitis viruses, explore the diagnostic and prognostics biomarkers and screen out the therapeutic targets for viral hepatitis and related diseases. To better understand the pathogenesis of viral hepatitis and related diseases, comprehensive multi-omics analysis has been widely carried out. This review mainly summarizes the applications of multi-omics in different types of viral hepatitis and related diseases, aiming to provide new insight into these diseases.
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Affiliation(s)
- Ze Xiang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiayuan Li
- Zhejiang University School of Medicine, Hangzhou, China
| | - Di Lu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, China
| | - Xuyong Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, China
| | - Xiao Xu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, China
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35
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Qin H, Yuan B, Huang W, Wang Y. Utilizing Gut Microbiota to Improve Hepatobiliary Tumor Treatments: Recent Advances. Front Oncol 2022; 12:924696. [PMID: 35924173 PMCID: PMC9339707 DOI: 10.3389/fonc.2022.924696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/20/2022] [Indexed: 11/13/2022] Open
Abstract
Hepatobiliary tumors, which include cholangiocarcinoma, hepatocellular carcinoma (HCC), and gallbladder cancer, are common cancers that have high morbidity and mortality rates and poor survival outcomes. In humans, the microbiota is comprised of symbiotic microbial cells (10-100 trillion) that belong to the bacterial ecosystem mainly residing in the gut. The gut microbiota is a complicated group that can largely be found in the intestine and has a dual role in cancer occurrence and progression. Previous research has focused on the crucial functions of the intestinal microflora as the main pathophysiological mechanism in HCC development. Intestinal bacteria produce a broad range of metabolites that exhibit a variety of pro- and anticarcinogenic effects on HCC. Therefore, probiotic alteration of the gut microflora could promote gut flora balance and help prevent the occurrence of HCC. Recent evidence from clinical and translational studies suggests that fecal microbiota transplant is one of the most successful therapies to correct intestinal bacterial imbalance. We review the literature describing the effects and mechanisms of the microbiome in the gut in the context of HCC, including gut bacterial metabolites, probiotics, antibiotics, and the transplantation of fecal microbiota, and discuss the potential influence of the microbiome environment on cholangiocarcinoma and gallbladder cancer. Our findings are expected to reveal therapeutic targets for the prevention of hepatobiliary tumors, and the development of clinical treatment strategies, by emphasizing the function of the gut microbiota.
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Affiliation(s)
- Hao Qin
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Baowen Yuan
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Huang
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
- *Correspondence: Wei Huang, ; Yan Wang,
| | - Yan Wang
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
- *Correspondence: Wei Huang, ; Yan Wang,
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Wang T, Rong X, Zhao C. Circadian Rhythms Coordinated With Gut Microbiota Partially Account for Individual Differences in Hepatitis B-Related Cirrhosis. Front Cell Infect Microbiol 2022; 12:936815. [PMID: 35846774 PMCID: PMC9283756 DOI: 10.3389/fcimb.2022.936815] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 06/09/2022] [Indexed: 12/12/2022] Open
Abstract
Cirrhosis is the end stage of chronic liver diseases like chronic hepatitis B. In China, hepatitis B accounts for around 60% of cases of cirrhosis. So far, clinical and laboratory indexes for the early diagnosis of cirrhosis are far from satisfactory. Nevertheless, there haven't been specific drugs for cirrhosis. Thus, it is quite necessary to uncover more specific factors which play their roles in cirrhosis and figure out the possible therapeutic targets. Among emerging factors taking part in the initiation and progression of cirrhosis, gut microbiota might be a pivot of systemic factors like metabolism and immune and different organs like gut and liver. Discovery of detailed molecular mechanism in gut microbiota and gut liver axis leads to a more promising prospect of developing new drugs intervening in these pathways. Time-based medication regimen has been proofed to be helpful in hormonotherapy, especially in the use of glucocorticoid. Thus, circadian rhythms, though haven't been strongly linked to hepatitis B and its complications, are still pivotal to various pathophysiological progresses. Gut microbiota as a potential effective factor of circadian rhythms has also received increasing attentions. Here, our work, restricting cirrhosis to the post-hepatitis B one, is aimed to summarize how circadian rhythms and hepatitis B-related cirrhosis can intersect via gut microbiota, and to throw new insights on the development of new and time-based therapies for hepatitis B-related cirrhosis and other cirrhosis.
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Affiliation(s)
- Tongyao Wang
- Ministry of Education (MOE)/National Health Commission (NHC)/Chinese Academy of Medical Science (CAMS) Key Lab of Medical Molecular Virology, School of Basic Medical Sciences & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xingyu Rong
- Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Chao Zhao
- Ministry of Education (MOE)/National Health Commission (NHC)/Chinese Academy of Medical Science (CAMS) Key Lab of Medical Molecular Virology, School of Basic Medical Sciences & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai, China
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Shrestha J, Santerre M, Allen CNS, Arjona SP, Merali C, Mukerjee R, Chitrala KN, Park J, Bagashev A, Bui V, Eugenin EA, Merali S, Kaul M, Chin J, Sawaya BE. HIV-1 gp120 Impairs Spatial Memory Through Cyclic AMP Response Element-Binding Protein. Front Aging Neurosci 2022; 14:811481. [PMID: 35615594 PMCID: PMC9124804 DOI: 10.3389/fnagi.2022.811481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 03/31/2022] [Indexed: 11/13/2022] Open
Abstract
HIV-associated neurocognitive disorders (HAND) remain an unsolved problem that persists despite using antiretroviral therapy. We have obtained data showing that HIV-gp120 protein contributes to neurodegeneration through metabolic reprogramming. This led to decreased ATP levels, lower mitochondrial DNA copy numbers, and loss of mitochondria cristae, all-important for mitochondrial biogenesis. gp120 protein also disrupted mitochondrial movement and synaptic plasticity. Searching for the mechanisms involved, we found that gp120 alters the cyclic AMP response element-binding protein (CREB) phosphorylation on serine residue 133 necessary for its function as a transcription factor. Since CREB regulates the promoters of PGC1α and BDNF genes, we found that CREB dephosphorylation causes PGC1α and BDNF loss of functions. The data was validated in vitro and in vivo. The negative effect of gp120 was alleviated in cells and animals in the presence of rolipram, an inhibitor of phosphodiesterase protein 4 (PDE4), restoring CREB phosphorylation. We concluded that HIV-gp120 protein contributes to HAND via inhibition of CREB protein function.
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Affiliation(s)
- Jenny Shrestha
- Molecular Studies of Neurodegenerative Diseases Lab, Philadelphia, PA, United States
- Fels Cancer Institute for Personalized Medicine Institute, Philadelphia, PA, United States
| | - Maryline Santerre
- Molecular Studies of Neurodegenerative Diseases Lab, Philadelphia, PA, United States
- Fels Cancer Institute for Personalized Medicine Institute, Philadelphia, PA, United States
| | - Charles N. S. Allen
- Molecular Studies of Neurodegenerative Diseases Lab, Philadelphia, PA, United States
- Fels Cancer Institute for Personalized Medicine Institute, Philadelphia, PA, United States
| | - Sterling P. Arjona
- Molecular Studies of Neurodegenerative Diseases Lab, Philadelphia, PA, United States
- Fels Cancer Institute for Personalized Medicine Institute, Philadelphia, PA, United States
| | - Carmen Merali
- Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, PA, United States
| | - Ruma Mukerjee
- Molecular Studies of Neurodegenerative Diseases Lab, Philadelphia, PA, United States
- Fels Cancer Institute for Personalized Medicine Institute, Philadelphia, PA, United States
| | | | - Jin Park
- Memory and Brain Research Center, Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
| | - Asen Bagashev
- Molecular Studies of Neurodegenerative Diseases Lab, Philadelphia, PA, United States
| | - Viet Bui
- Molecular Studies of Neurodegenerative Diseases Lab, Philadelphia, PA, United States
- Fels Cancer Institute for Personalized Medicine Institute, Philadelphia, PA, United States
| | - Eliseo A. Eugenin
- Department of Neuroscience, Cell Biology, and Anatomy, The University of Texas Medical Branch, Galveston, TX, United States
| | - Salim Merali
- Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, PA, United States
| | - Marcus Kaul
- Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
- Department of Psychiatry, University of California, San Diego, San Diego, CA, United States
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Jeannie Chin
- Memory and Brain Research Center, Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
| | - Bassel E. Sawaya
- Molecular Studies of Neurodegenerative Diseases Lab, Philadelphia, PA, United States
- Fels Cancer Institute for Personalized Medicine Institute, Philadelphia, PA, United States
- Department of Neurology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
- Department of Cancer and Cell Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
- Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
- *Correspondence: Bassel E. Sawaya,
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38
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Luo W, Guo S, Zhou Y, Zhao J, Wang M, Sang L, Chang B, Wang B. Hepatocellular Carcinoma: How the Gut Microbiota Contributes to Pathogenesis, Diagnosis, and Therapy. Front Microbiol 2022; 13:873160. [PMID: 35572649 PMCID: PMC9092458 DOI: 10.3389/fmicb.2022.873160] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 04/05/2022] [Indexed: 12/12/2022] Open
Abstract
The gut microbiota is gaining increasing attention, and the concept of the "gut-liver axis" is gradually being recognized. Leaky gut resulting from injury and/or inflammation can cause the translocation of flora to the liver. Microbiota-associated metabolites and components mediate the activation of a series of signalling pathways, thereby playing an important role in the development of hepatocellular carcinoma (HCC). For this reason, targeting the gut microbiota in the diagnosis, prevention, and treatment of HCC holds great promise. In this review, we summarize the gut microbiota and the mechanisms by which it mediates HCC development, and the characteristic alterations in the gut microbiota during HCC pathogenesis. Furthermore, we propose several strategies to target the gut microbiota for the prevention and treatment of HCC, including antibiotics, probiotics, faecal microbiota transplantation, and immunotherapy.
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Affiliation(s)
- Wenyu Luo
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, China
- The Second Clinical College, China Medical University, Shenyang, China
| | - Shiqi Guo
- The Second Clinical College, China Medical University, Shenyang, China
| | - Yang Zhou
- The Second Clinical College, China Medical University, Shenyang, China
| | - Jingwen Zhao
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Mengyao Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Lixuan Sang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Bing Chang
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Bingyuan Wang
- Department of Geriatric Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China
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Multiomics Analysis of Endocytosis upon HBV Infection and Identification of SCAMP1 as a Novel Host Restriction Factor against HBV Replication. Int J Mol Sci 2022; 23:ijms23042211. [PMID: 35216324 PMCID: PMC8874515 DOI: 10.3390/ijms23042211] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/08/2022] [Accepted: 02/11/2022] [Indexed: 02/04/2023] Open
Abstract
Hepatitis B virus (HBV) infection remains a major global health problem and the primary cause of cirrhosis and hepatocellular carcinoma (HCC). HBV intrusion into host cells is prompted by virus–receptor interactions in clathrin-mediated endocytosis. Here, we report a comprehensive view of the cellular endocytosis-associated transcriptome, proteome and ubiquitylome upon HBV infection. In this study, we quantified 273 genes in the transcriptome and 190 endocytosis-associated proteins in the proteome by performing multi-omics analysis. We further identified 221 Lys sites in 77 endocytosis-associated ubiquitinated proteins. A weak negative correlation was observed among endocytosis-associated transcriptome, proteome and ubiquitylome. We found 33 common differentially expressed genes (DEGs), differentially expressed proteins (DEPs), and Kub-sites. Notably, we reported the HBV-induced ubiquitination change of secretory carrier membrane protein (SCAMP1) for the first time, differentially expressed across all three omics data sets. Overexpression of SCAMP1 efficiently inhibited HBV RNAs/pgRNA and secreted viral proteins, whereas knockdown of SCAMP1 significantly increased viral production. Mechanistically, the EnhI/XP, SP1, and SP2 promoters were inhibited by SCAMP1, which accounts for HBV X and S mRNA inhibition. Overall, our study unveils the previously unknown role of SCAMP1 in viral replication and HBV pathogenesis and provides cumulative and novel information for a better understanding of endocytosis in response to HBV infection.
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Dysregulation of S-adenosylmethionine Metabolism in Nonalcoholic Steatohepatitis Leads to Polyamine Flux and Oxidative Stress. Int J Mol Sci 2022; 23:ijms23041986. [PMID: 35216100 PMCID: PMC8878801 DOI: 10.3390/ijms23041986] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 01/28/2022] [Accepted: 02/08/2022] [Indexed: 02/01/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease worldwide, with 25% of these patients developing nonalcoholic steatohepatitis (NASH). NASH significantly increases the risk of cirrhosis and decompensated liver failure. Past studies in rodent models have shown that glycine-N-methyltransferase (GNMT) knockout results in rapid steatosis, fibrosis, and hepatocellular carcinoma progression. However, the attenuation of GNMT in subjects with NASH and the molecular basis for its impact on the disease process is still unclear. To address this knowledge gap, we show the reduction of GNMT protein levels in the liver of NASH subjects compared to healthy controls. To gain insight into the impact of decreased GNMT in the disease process, we performed global label-free proteome studies on the livers from a murine modified amylin diet-based model of NASH. Histological and molecular characterization of the animal model demonstrate a high resemblance to human disease. We found that a reduction of GNMT leads to a significant increase in S-adenosylmethionine (AdoMet), an essential metabolite for transmethylation reactions and a substrate for polyamine synthesis. Further targeted proteomic and metabolomic studies demonstrated a decrease in GNMT transmethylation, increased flux through the polyamine pathway, and increased oxidative stress production contributing to NASH pathogenesis.
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Medhat A, Arzumanyan A, Feitelson MA. Hepatitis B x antigen (HBx) is an important therapeutic target in the pathogenesis of hepatocellular carcinoma. Oncotarget 2021; 12:2421-2433. [PMID: 34853663 PMCID: PMC8629409 DOI: 10.18632/oncotarget.28077] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/04/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) is a human pathogen that has infected an estimated two billion people worldwide. Despite the availability of highly efficacious vaccines, universal screening of the blood supply for virus, and potent direct acting anti-viral drugs, there are more than 250 million carriers of HBV who are at risk for the sequential development of hepatitis, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). More than 800,000 deaths per year are attributed to chronic hepatitis B. Many different therapeutic approaches have been developed to block virus replication, and although effective, none are curative. These treatments have little or no impact upon the portions of integrated HBV DNA, which often encode the virus regulatory protein, HBx. Although given little attention, HBx is an important therapeutic target because it contributes importantly to (a) HBV replication, (b) in protecting infected cells from immune mediated destruction during chronic infection, and (c) in the development of HCC. Thus, the development of therapies targeting HBx, combined with other established therapies, will provide a functional cure that will target virus replication and further reduce or eliminate both the morbidity and mortality associated with chronic liver disease and HCC. Simultaneous targeting of all these characteristics underscores the importance of developing therapies against HBx.
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Affiliation(s)
- Arvin Medhat
- Department of Molecular Cell Biology, Azad University, North Unit, Tehran, Iran
| | - Alla Arzumanyan
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, USA
| | - Mark A Feitelson
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, USA
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