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Sadri M, Shafaghat Z, Roozbehani M, Hoseinzadeh A, Mohammadi F, Arab FL, Minaeian S, Fard SR, Faraji F. Effects of Probiotics on Liver Diseases: Current In Vitro and In Vivo Studies. Probiotics Antimicrob Proteins 2025; 17:1688-1710. [PMID: 39739162 DOI: 10.1007/s12602-024-10431-z] [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] [Accepted: 12/06/2024] [Indexed: 01/02/2025]
Abstract
Various types of liver or hepatic diseases cause the death of about 2 million people worldwide every year, of which 1 million die from the complications of cirrhosis and another million from hepatocellular carcinoma and viral hepatitis. Currently, the second most common solid organ transplant is the liver, and the current rate represents less than 10% of global transplant requests. Hence, finding new approaches to treat and prevent liver diseases is essential. In liver diseases, the interaction between the liver, gut, and immune system is crucial, and probiotics positively affect the human microbiota. Probiotics are a non-toxic and biosafe alternative to synthetic chemical compounds. Health promotion by lowering cholesterol levels, stimulating host immunity, the natural gut microbiota, and other functions are some of the activities of probiotics, and their metabolites, including bacteriocins, can exert antimicrobial effects against a broad range of pathogenic bacteria. The present review discusses the available data on the results of preclinical and clinical studies on the effects of probiotic administration on different types of liver diseases.
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Affiliation(s)
- Maryam Sadri
- Department of Immunology, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Shafaghat
- Department of Immunology, Iran University of Medical Sciences, Tehran, Iran
| | - Mona Roozbehani
- Vaccine Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Akram Hoseinzadeh
- Cancer Research Center, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Mohammadi
- Department of Immunology, School of Medicine, Mashhad University of Medicine Sciences, Mashhad, Iran
| | - Fahimeh Lavi Arab
- Department of Immunology, School of Medicine, Mashhad University of Medicine Sciences, Mashhad, Iran
| | - Sara Minaeian
- Antimicrobial Resistance Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medicine Sciences, Tehran, Iran
| | - Soheil Rahmani Fard
- Antimicrobial Resistance Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medicine Sciences, Tehran, Iran
| | - Fatemeh Faraji
- Antimicrobial Resistance Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medicine Sciences, Tehran, Iran.
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Li RP, Wu GZ, Fang XD, Yang WW, Zhang HY, Yue HX, Zheng Y, Wang YP, Zhou YN. Single-Cell Transcriptional Analysis Reveals the Mechanism of AZD6738 in HCC Immunotherapy via EZH2 Targeting. Drug Des Devel Ther 2025; 19:2897-2920. [PMID: 40255471 PMCID: PMC12007511 DOI: 10.2147/dddt.s508709] [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: 01/05/2025] [Accepted: 04/05/2025] [Indexed: 04/22/2025] Open
Abstract
Objective This study aims to identify specific molecular targets sensitive to AZD6738 through the integration of network pharmacology and transcriptomic methods, and to assess their potential role in the treatment of hepatocellular carcinoma (HCC). Additionally, we explore the specific effects of AZD6738 on the tumor microenvironment and its ability to regulate immune responses. Methods We employed a combination of network pharmacology and transcriptomic analysis to identify specific molecules associated with HCC, including EZH2, CCNB1, PRKDC, CTSL, PSEN1, SLC6A3, and FKBP1A. Using these molecules and clinical features, we constructed a robust prognostic model for HCC. We further used single-cell transcriptomic technology to screen for core targets and performed spatial transcriptomic analysis to determine their spatial distribution. To validate the efficacy of AZD6738 in vivo, we established a subcutaneous tumor model, with the experimental group receiving oral administration of AZD6738 (75 mg/kg). Finally, we assessed the changes in the immune cell expression profile in tumor tissues post-AZD6738 treatment using flow cytometry. Results Our study indicates that the high expression of genes such as EZH2, CCNB1, PRKDC, and PSEN1 is associated with poor prognosis in HCC patients. Molecular docking and RT-PCR validation demonstrated that AZD6738 exhibits high affinity for these targets and significantly reduces the mRNA levels of EZH2, PRKDC, and CCNB1 in HCC cell lines, with EZH2 showing the most pronounced decrease. Animal experiments revealed that AZD6738 can enhance the immune microenvironment in liver cancer; specifically, AZD6738 not only promotes the proliferation of CD8+ T cells but also enhances their differentiation into effector memory T cells, indicating that the drug can potentiate anti-tumor immune responses. Conclusion This study reveals that AZD6738 demonstrates significant therapeutic efficacy by targeting the key molecule EZH2, thereby modulating the tumor microenvironment and enhancing anti-tumor immunity.
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Affiliation(s)
- Ren-peng Li
- The First Clinical Medical College, Lanzhou University, Lanzhou, People’s Republic of China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
| | - Guo-zhi Wu
- The First Clinical Medical College, Lanzhou University, Lanzhou, People’s Republic of China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
| | - Xi-dong Fang
- The First Clinical Medical College, Lanzhou University, Lanzhou, People’s Republic of China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
| | - Wen-wen Yang
- The First Clinical Medical College, Lanzhou University, Lanzhou, People’s Republic of China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
| | - Hui-yun Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou, People’s Republic of China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
| | - Han-xun Yue
- The First Clinical Medical College, Lanzhou University, Lanzhou, People’s Republic of China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
| | - Ya Zheng
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
| | - Yu-ping Wang
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
| | - Yong-ning Zhou
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
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Ren S, Zhang Y, Wang X, Su J, Wang X, Yuan Z, He X, Guo S, Chen Y, Deng S, Wu X, Li M, Du F, Zhao Y, Shen J, Hu W, Li X, Xiao Z. Emerging insights into the gut microbiota as a key regulator of immunity and response to immunotherapy in hepatocellular carcinoma. Front Immunol 2025; 16:1526967. [PMID: 40070843 PMCID: PMC11893557 DOI: 10.3389/fimmu.2025.1526967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 02/10/2025] [Indexed: 03/14/2025] Open
Abstract
The gut microbiota, a complex microbial ecosystem closely connected to the liver via the portal vein, has emerged as a critical regulator of liver health and disease. Numerous studies have underscored its role in the onset and progression of liver disorders, including alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). This review provides a comprehensive overview of current insights into the influence of the gut microbiota on HCC progression, particularly its effects on immune cells within the HCC tumor microenvironment (TME). Furthermore, we explore the potential of gut microbiota-targeted interventions, such as antibiotics, probiotics, prebiotics, and fecal microbiota transplantation (FMT), to modulate the immune response and improve outcomes of immunotherapy in HCC. By synthesizing insights from recent studies, this review aims to highlight microbiota-based strategies that may enhance immunotherapy outcomes, advancing personalized approaches in HCC treatment.
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Affiliation(s)
- Siqi Ren
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yinping Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xingyue Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Jiahong Su
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xiang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zijun Yuan
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xinyu He
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Sipeng Guo
- Research and Experiment Center, Sichuan College of Traditional Chinese Medicine, Mianyang, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Shuai Deng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Wei Hu
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China
| | - Xiaobing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Research and Experiment Center, Sichuan College of Traditional Chinese Medicine, Mianyang, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
- Gulin Traditional Chinese Medicine Hospital, Luzhou, China
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Sadeghloo Z, Nabavi-Rad A, Zali MR, Klionsky DJ, Yadegar A. The interplay between probiotics and host autophagy: mechanisms of action and emerging insights. Autophagy 2025; 21:260-282. [PMID: 39291740 PMCID: PMC11759520 DOI: 10.1080/15548627.2024.2403277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 07/09/2024] [Accepted: 07/10/2024] [Indexed: 09/19/2024] Open
Abstract
Autophagy, a lysosome-dependent protein degradation mechanism, is a highly conserved catabolic process seen in all eukaryotes. This cell protection system, which is present in all tissues and functions at a basic level, can be up- or downregulated in response to various stresses. A disruption in the natural route of the autophagy process is frequently followed by an interruption in the inherent operation of the body's cells and organs. Probiotics are live bacteria that protect the host through various mechanisms. One of the processes through which probiotics exert their beneficial effects on various cells and tissues is autophagy. Autophagy can assist in maintaining host homeostasis by stimulating the immune system and affecting numerous physiological and pathological responses. In this review, we particularly focus on autophagy impairments occurring in several human illnesses and investigate how probiotics affect the autophagy process under various circumstances.Abbreviation: AD: Alzheimer disease; AKT: AKT serine/threonine kinase; AMPK: 5'AMP-activated protein kinase; ATG: autophagy related; CCl4: carbon tetrachloride; CFS: cell-free supernatant; CMA: chaperone-mediated autophagy; CRC: colorectal cancer; EPS: L. plantarum H31 exopolysaccharide; HD: Huntington disease; HFD: high-fat diet; HPV: human papillomavirus; IFNG/IFN-γ: interferon gamma; IL6: interleukin 6; LGG: L. rhamnosus GG; LPS: lipopolysaccharide; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; PD: Parkinson disease; Pg3G: pelargonidin-3-O-glucoside; PI3K: phosphoinositide 3-kinase; PolyQ: polyglutamine; ROS: reactive oxygen species; SCFAs: short-chain fatty acids; SLAB51: a novel formulation of lactic acid bacteria and bifidobacteria; Slp: surface layer protein (of acidophilus NCFM); SNCA: synuclein alpha; ULK1: unc-51 like autophagy-activating kinase 1; YB: B. longum subsp. infantis YB0411; YFP: yeast fermentate prebiotic.
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Affiliation(s)
- Zahra Sadeghloo
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Nabavi-Rad
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Daniel J Klionsky
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
- Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Dadgar-Zankbar L, Mokhtaryan M, Bafandeh E, Javanmard Z, Asadollahi P, Darbandi T, Afifirad R, Dashtbin S, Darbandi A, Ghanavati R. Microbiome and bladder cancer: the role of probiotics in treatment. Future Microbiol 2025; 20:73-90. [PMID: 39445447 PMCID: PMC11974345 DOI: 10.1080/17460913.2024.2414671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 10/07/2024] [Indexed: 10/25/2024] Open
Abstract
Bladder cancer (BCa) remains a significant global health challenge, with increasing interest in the role of the bladder microbiome in its pathogenesis, progression and treatment outcomes. The complex relationship between bladder cancer and the microbiome, as well as the potential impact of probiotics on treatment effectiveness, is currently under investigation. Research suggests that the microbiota may influence BCa recurrence prevention and enhance the efficacy of the Bacillus Calmette-Guérin (BCG) vaccine. Recent studies reveal differences in the bladder microbiome between individuals without bladder cancer and those with the disease. In the healthy bladder, Streptococcus and Lactobacillus are consistently identified as the most prevalent genera. However, in men, the predominant bacterial genera are Staphylococcus, Corynebacterium and Streptococcus, while in women with bladder cancer, Gardnerella and Lactobacillus are dominant. Probiotics, particularly Lactobacillus spp., can exhibit anti-tumor properties by competing with pathogenic strains involved in carcinogenesis or by producing regulatory substances. They regulate cancer signaling, induce apoptosis, inhibit mutagenic activity, downregulate oncogene expression, induce autophagy, inhibit kinases, reactivate tumor suppressors and prevent metastasis. These mechanisms have shown promising results in both preclinical and some clinical studies.
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Affiliation(s)
- Leila Dadgar-Zankbar
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Mokhtaryan
- Department of Internal Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elnaz Bafandeh
- Molecular Microbiology Research Center, Shahed University, Tehran, Iran
| | - Zahra Javanmard
- Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Parisa Asadollahi
- Microbiology Department, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Taleih Darbandi
- Department of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Roghayeh Afifirad
- Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Shirin Dashtbin
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Atieh Darbandi
- Molecular Microbiology Research Center, Shahed University, Tehran, Iran
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Chen P, Yang C, Ren K, Xu M, Pan C, Ye X, Li L. Modulation of gut microbiota by probiotics to improve the efficacy of immunotherapy in hepatocellular carcinoma. Front Immunol 2024; 15:1504948. [PMID: 39650662 PMCID: PMC11621041 DOI: 10.3389/fimmu.2024.1504948] [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: 10/01/2024] [Accepted: 11/04/2024] [Indexed: 12/11/2024] Open
Abstract
Hepatocellular carcinoma, a common malignancy of the digestive system, typically progresses through a sequence of hepatitis, liver fibrosis, cirrhosis and ultimately, tumor. The interaction between gut microbiota, the portal venous system and the biliary tract, referred to as the gut-liver axis, is crucial in understanding the mechanisms that contribute to the progression of hepatocellular carcinoma. Mechanisms implicated include gut dysbiosis, alterations in microbial metabolites and increased intestinal barrier permeability. Imbalances in gut microbiota, or dysbiosis, contributes to hepatocellular carcinoma by producing carcinogenic substances, disrupting the balance of the immune system, altering metabolic processes, and increasing intestinal barrier permeability. Concurrently, accumulating evidence suggests that gut microbiota has the ability to modulate antitumor immune responses and affect the efficacy of cancer immunotherapies. As a new and effective strategy, immunotherapy offers significant potential for managing advanced stages of hepatocellular carcinoma, with immune checkpoint inhibitors achieving significant advancements in improving patients' survival. Probiotics play a vital role in promoting health and preventing diseases by modulating metabolic processes, inflammation and immune responses. Research indicates that they are instrumental in boosting antitumor immune responses through the modulation of gut microbiota. This review is to explore the relationship between gut microbiota and the emergence of hepatocellular carcinoma, assess the contributions of probiotics to immunotherapy and outline the latest research findings, providing a safer and more cost-effective potential strategy for the prevention and management of hepatocellular carcinoma.
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Affiliation(s)
- Ping Chen
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan (Hangzhou) Hospital, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Chengchen Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ke Ren
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Mingzhi Xu
- Department of General Medicine, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Chenwei Pan
- Department of Infectious Diseases, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xuewei Ye
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan (Hangzhou) Hospital, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
- Key Laboratory of Pollution Exposure and Health Intervention of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Daniel N, Genua F, Jenab M, Mayén AL, Chrysovalantou Chatziioannou A, Keski-Rahkonen P, Hughes DJ. The role of the gut microbiome in the development of hepatobiliary cancers. Hepatology 2024; 80:1252-1269. [PMID: 37055022 PMCID: PMC11487028 DOI: 10.1097/hep.0000000000000406] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/31/2023] [Accepted: 04/03/2023] [Indexed: 04/15/2023]
Abstract
Hepatobiliary cancers, including hepatocellular carcinoma and cancers of the biliary tract, share high mortality and rising incidence rates. They may also share several risk factors related to unhealthy western-type dietary and lifestyle patterns as well as increasing body weights and rates of obesity. Recent data also suggest a role for the gut microbiome in the development of hepatobiliary cancer and other liver pathologies. The gut microbiome and the liver interact bidirectionally through the "gut-liver axis," which describes the interactive relationship between the gut, its microbiota, and the liver. Here, we review the gut-liver interactions within the context of hepatobiliary carcinogenesis by outlining the experimental and observational evidence for the roles of gut microbiome dysbiosis, reduced gut barrier function, and exposure to inflammatory compounds as well as metabolic dysfunction as contributors to hepatobiliary cancer development. We also outline the latest findings regarding the impact of dietary and lifestyle factors on liver pathologies as mediated by the gut microbiome. Finally, we highlight some emerging gut microbiome editing techniques currently being investigated in the context of hepatobiliary diseases. Although much work remains to be done in determining the relationships between the gut microbiome and hepatobiliary cancers, emerging mechanistic insights are informing treatments, such as potential microbiota manipulation strategies and guiding public health advice on dietary/lifestyle patterns for the prevention of these lethal tumors.
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Affiliation(s)
- Neil Daniel
- Cancer Biology and Therapeutics Laboratory, Conway Institute, School of Biomedical and Biomolecular Sciences, University College Dublin, Dublin, Ireland
| | - Flavia Genua
- Cancer Biology and Therapeutics Laboratory, Conway Institute, School of Biomedical and Biomolecular Sciences, University College Dublin, Dublin, Ireland
| | - Mazda Jenab
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - Ana-Lucia Mayén
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | | | - Pekka Keski-Rahkonen
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - David J. Hughes
- Cancer Biology and Therapeutics Laboratory, Conway Institute, School of Biomedical and Biomolecular Sciences, University College Dublin, Dublin, Ireland
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Iurk VB, Ingles M, Correa GS, Silva CR, Staichak G, Pileggi SAV, Christo SW, Domit C, Pileggi M. The potential influence of microplastics on the microbiome and disease susceptibility in sea turtles. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 946:174298. [PMID: 38944299 DOI: 10.1016/j.scitotenv.2024.174298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 06/10/2024] [Accepted: 06/24/2024] [Indexed: 07/01/2024]
Abstract
Microplastics (MPs) are particles with sizes of ≤5 mm formed when plastic materials break down. These contaminants are often found in marine environments, making it easy for sea turtles to ingest them and for their microbiome to be exposed. MPs can disrupt microbiome balance, leading to dysbiosis and making organisms more susceptible to diseases. Owing to the significance of these processes, it is crucial to dedicate research to studying the metabolic and genetic analysis of the gut microbiome in sea turtles. The objective of this study was to describe the effects of exposure to MPs on the gut microbiome of sea turtles, based on current knowledge. This review also aimed to explore the potential link between MP exposure and disease susceptibility in these animals. We show that the metabolites produced by the gut microbiome, such as short-chain fatty acids (SCFAs), polyamines, and polysaccharide A, can regulate the expression of host genes. Regulation occurs through various mechanisms, including histone acetylation, DNA methylation, and the modulation of cytokine gene expression. These processes are essential for preserving the integrity of the gut mucosa and enhancing the functionality of immune cells. Exposure to MPs disrupts the gut microbiome and alters gene expression, leading to immune system disturbances in sea turtles. This vulnerability makes turtles more susceptible to opportunistic microorganisms such as chelonid alphaherpesvirus 5 (ChAHV5), which is linked to the development of fibropapillomatosis (FP). Additionally, targeted dietary interventions or the use of live microorganisms such as probiotics can help restore microbial biodiversity and recover lost metabolic pathways. The goal of these interventions is to restore the functionality of the immune system in sea turtles undergoing rehabilitation at specialized centers. The gut microbiome plays a crucial role in sea turtle health, sparking discussions and investigations that can potentially lead to promising treatments for these animals.
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Affiliation(s)
- Vitória Bonfim Iurk
- Laboratório de Ecologia e Conservação, Centro de Estudos do Mar, Universidade Federal do Paraná, PR 832555-000, Brazil; Laboratório de Microbiologia Ambiental, Departamento de Biologia Estrutural, Molecular e Genética, Setor de Ciências Biológicas e da Saúde, Universidade Estadual de Ponta Grossa, PR 84030-000, Brazil
| | - Mariana Ingles
- Laboratório de Ecologia e Conservação, Centro de Estudos do Mar, Universidade Federal do Paraná, PR 832555-000, Brazil
| | - Giovana Sequinel Correa
- Laboratório de Virologia Aplicada, Centro de Ciências Biológicas, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, SC 88040-900, Brazil
| | - Caroline Rosa Silva
- Departamento de Biotecnologia, Genética e Biologia Celular, Universidade Estadual de Maringá, PR 87020-900, Brazil
| | - Gabriel Staichak
- Instituto de Biociências da Universidade Federal de Mato Grosso, Universidade Federal do Mato Grosso, MT 79070-900, Brazil
| | - Sônia Alvim Veiga Pileggi
- Laboratório de Microbiologia Ambiental, Departamento de Biologia Estrutural, Molecular e Genética, Setor de Ciências Biológicas e da Saúde, Universidade Estadual de Ponta Grossa, PR 84030-000, Brazil.
| | - Susete Wambier Christo
- Laboratório de Zoologia, Departamento de Biologia Geral, Setor de Ciências Biológicas e da Saúde, Universidade Estadual de Ponta Grossa, PR 84030-000, Brazil
| | - Camila Domit
- Laboratório de Ecologia e Conservação, Centro de Estudos do Mar, Universidade Federal do Paraná, PR 832555-000, Brazil.
| | - Marcos Pileggi
- Laboratório de Microbiologia Ambiental, Departamento de Biologia Estrutural, Molecular e Genética, Setor de Ciências Biológicas e da Saúde, Universidade Estadual de Ponta Grossa, PR 84030-000, Brazil.
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Sajjad A, Ali S, Mumtaz S, Summer M, Farooq MA, Hassan A. Chemoprotective and immunomodulatory potential of Lactobacillus reuteri against cadmium chloride-induced breast cancer in mice. J Infect Chemother 2024; 30:838-846. [PMID: 38423298 DOI: 10.1016/j.jiac.2024.02.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 02/15/2024] [Accepted: 02/25/2024] [Indexed: 03/02/2024]
Abstract
INTRODUCTION The current study aimed to investigate the role of probiotic Lactobacillus reuteri for the treatment and prevention of breast cancer. MATERIALS AND METHODS Breast cancer was induced by using Cadmium Chloride (Cd) (2 mg/kg) in group II. Tamoxifen was administered to group III. Group IV was treated with Lactobacillus reuteri. Group V was treated with Cd for one month and divided into three subgroups including VA, VB, and VC which were treated with tamoxifen, Lactobacillus reuteri, and tamoxifen + Lactobacillus reuteri, respectively. RESULTS Significantly higher levels of TNF-α (40.9 ± 4.2 pg/mL), IL-6 (28.0 ± 1.5 pg/mL), IL-10 (60.2 ± 2.0 pg/mL), IFN-γ (60.2 ± 2.0 pg/mL), ALAT (167.2 ± 6.2 U/l), ASAT (451.6 ± 13.9 U/l), and MDA (553.8 ± 19.6 U/l) was observed in Cd group. In comparison, significantly lower levels of TNF-α (18.0 ± 1.1 pg/mL), IL-6 (9.4 ± 0.4 pg/mL), IL-10 (20.8 ± 1.1 pg/mL), IFN-γ (20.8 ± 1.1 pg/mL), ALAT (85.2 ± 3.6 U/l), ASAT (185 ± 6.9 U/l), and MDA (246.0 ± 7.5 U/l) were observed in group Cd + Tam + LR. Liver histopathology of the Cd group showed hemorrhage and ductal aberrations. However, mild inflammation and healthier branched ducts were observed in treatment groups. Furthermore, the renal control group showed normal glomerular tufts, chronic inflammation from the Cd group, and relatively healthier glomerulus with mild inflammation in treatment groups. CONCLUSION Hence, the preventive and anticancerous role of probiotic Lactobacillus reuteri is endorsed by the findings of the current study.
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Affiliation(s)
- Ayesha Sajjad
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, 54000, Pakistan
| | - Shaukat Ali
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, 54000, Pakistan.
| | - Samaira Mumtaz
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, 54000, Pakistan
| | - Muhammad Summer
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, 54000, Pakistan
| | - Muhammad Adeel Farooq
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, 54000, Pakistan
| | - Ali Hassan
- Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, 54000, Pakistan
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10
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Galasso L, Cerrito L, Maccauro V, Termite F, Mignini I, Esposto G, Borriello R, Ainora ME, Gasbarrini A, Zocco MA. Inflammatory Response in the Pathogenesis and Treatment of Hepatocellular Carcinoma: A Double-Edged Weapon. Int J Mol Sci 2024; 25:7191. [PMID: 39000296 PMCID: PMC11241080 DOI: 10.3390/ijms25137191] [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: 06/01/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent among primary liver tumors (90%) and one of the main causes of cancer-related death. It develops usually in a chronically inflamed environment, ranging from compensatory parenchymal regeneration to fibrosis and cirrhosis: carcinogenesis can potentially happen in each of these stages. Inflammation determined by chronic viral infection (hepatitis B, hepatitis C, and hepatitis delta viruses) represents an important risk factor for HCC etiology through both viral direct damage and immune-related mechanisms. The deregulation of the physiological liver immunological network determined by viral infection can lead to carcinogenesis. The recent introduction of immunotherapy as the gold-standard first-line treatment for HCC highlights the role of the immune system and inflammation as a double-edged weapon in both HCC carcinogenesis and treatment. In this review we highlight how the inflammation is the key for the hepatocarcinogenesis in viral, alcohol and metabolic liver diseases.
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Affiliation(s)
- Linda Galasso
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
| | - Lucia Cerrito
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Valeria Maccauro
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
| | - Fabrizio Termite
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
| | - Irene Mignini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Giorgio Esposto
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Raffaele Borriello
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Elena Ainora
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Assunta Zocco
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
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11
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Ramachandran G, Pottakkat B. Probiotics-A Promising Novel Therapeutic Approach in the Management of Chronic Liver Diseases. J Med Food 2024; 27:467-476. [PMID: 38574254 DOI: 10.1089/jmf.2023.k.0129] [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] [Indexed: 04/06/2024] Open
Abstract
An increased incidence of liver diseases has been observed in recent years and is associated with gut dysbiosis, which causes bacterial infection, intestinal permeability, and further leads to disease-related complications. Probiotics, active microbial strains, are gaining more clinical importance due to their beneficial effect in the management of many diseases, including liver diseases. Clinical scenarios show strong evidence that probiotics have efficacy in treating liver diseases due to their ability to improve epithelial barrier function, prevent bacterial translocation, and boost the immune system. Moreover, probiotics survive both bile and gastric acid to reach the gut and exert their health benefit. Evidence shows that probiotics are a promising approach to prevent several complications in clinical practice. Herein, we discuss the recent evidence, challenges, and appropriate use of probiotics in managing advanced liver diseases, which may have an impact on future therapeutic strategies. Furthermore, the superior effect of strain-specific probiotics and their efficacy and safety in managing liver diseases are discussed.
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Affiliation(s)
- Gokulapriya Ramachandran
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Biju Pottakkat
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
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12
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Janota B, Szymanek B. The Influence of Diet and Its Components on the Development and Prevention of Hepatocellular Carcinoma (HCC). Cancers (Basel) 2024; 16:1030. [PMID: 38473387 DOI: 10.3390/cancers16051030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 02/22/2024] [Accepted: 02/28/2024] [Indexed: 03/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is diagnosed annually in nearly a million people worldwide, with approximately half of them being diagnosed at an advanced stage of the disease. Non-infectious risk factors for the development of HCC include an unbalanced lifestyle, including poor dietary choices characterized by a low intake of antioxidants, such as vitamins E and C, selenium, and polyphenols, as well as an excessive consumption of energy and harmful substances. Repeated bad dietary choices that contribute to an unbalanced lifestyle lead to the accumulation of fatty substances in the liver and to it entering an inflammatory state, which, without intervention, results in cirrhosis, the main cause of HCC. This review of the English language literature aims to present the food components that, when included in the daily diet, reduce the risk of developing HCC, as well as identifying foods that may have a carcinogenic effect on liver cells.
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Affiliation(s)
- Barbara Janota
- Department of Basic Medical Sciences, Faculty of Public Health in Bytom, Medical University of Silesia in Katowice, 41-902 Bytom, Poland
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13
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Thilakarathna WPDW, Rupasinghe HPV. Proanthocyanidins-Based Synbiotics as a Novel Strategy for Nonalcoholic Fatty Liver Disease (NAFLD) Risk Reduction. Molecules 2024; 29:709. [PMID: 38338453 PMCID: PMC10856248 DOI: 10.3390/molecules29030709] [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: 12/23/2023] [Revised: 01/29/2024] [Accepted: 02/01/2024] [Indexed: 02/12/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), the most common liver disease worldwide, is a spectrum of liver abnormalities ranging from steatosis to nonalcoholic steatohepatitis (NASH) characterized by excessive lipid accumulation. The prevalence of NAFLD is predicted to increase rapidly, demanding novel approaches to reduce the global NAFLD burden. Flavonoids, the most abundant dietary polyphenols, can reduce the risk of NAFLD. The majority of dietary flavonoids are proanthocyanidins (PACs), which are oligomers and polymers of the flavonoid sub-group flavan-3-ols. The efficacy of PAC in reducing the NAFLD risk can be significantly hindered by low bioavailability. The development of synbiotics by combining PAC with probiotics may increase effectiveness against NAFLD by biotransforming PAC into bioavailable metabolites. PAC and probiotic bacteria are capable of mitigating steatosis primarily through suppressing de novo lipogenesis and promoting fatty acid β-oxidation. PAC and probiotic bacteria can reduce the progression of steatosis to NASH mainly through ameliorating hepatic damage and inflammation induced by hepatic oxidative stress, endoplasmic reticulum stress, and gut microbiota dysbiosis. Synbiotics of PAC are superior in reducing the risk of NAFLD compared to independent administration of PAC and probiotics. The development of PAC-based synbiotics can be a novel strategy to mitigate the increasing incidence of NAFLD.
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Affiliation(s)
- Wasitha P. D. W. Thilakarathna
- Department of Plant, Food, and Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, NS B2N 5E3, Canada;
| | - H. P. Vasantha Rupasinghe
- Department of Plant, Food, and Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, NS B2N 5E3, Canada;
- Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4H7, Canada
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14
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Xia Q, Lei Y, Wang J, Wang Q. Probiotic management and inflammatory factors as a novel treatment in cirrhosis: A systematic review and meta-analysis. Open Life Sci 2023; 18:20220741. [PMID: 37872967 PMCID: PMC10590617 DOI: 10.1515/biol-2022-0741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 08/18/2023] [Accepted: 09/04/2023] [Indexed: 10/25/2023] Open
Abstract
The interaction between intestinal microecological dysregulation, altered inflammatory factors, and cirrhosis is unclear. The aim of this systematic review and meta-analysis was to synthesize the results of previous studies to assess the efficacy of probiotics in the treatment of cirrhosis and their effect on inflammatory factors, as well as to explore the relationship between gut microecological dysregulation and liver disease to gain a deeper understanding of this interaction. Up to December 2022, eligible studies were identified by searching the following databases: National Knowledge Infrastructure (CNKI), Wanfang Data, Web of Science, PubMed, Embase, Medline, and the Cochrane Library. Statistical analysis was performed using software RevMan Version 5.4. A total of 33 eligible randomized controlled trials were included in the study, and data on probiotic strains, duration of intervention, measures in the control group, and outcomes were extracted and evaluated. Compared to the control group, the experimental group had significant improvements in overall efficacy. The results of the meta-analysis revealed that probiotic use significantly decreased biochemical parameters for liver function, including aspartate transaminase, alanine aminotransferase, and total bilirubin. Similar result was obtained in interleukin-6, tumor necrosis factor-α, and endotoxin. However, probiotic intervention did not significantly affect interleukin-2 and interleukin-10. The current meta-analysis illustrates that probiotic supplementation reduces inflammatory markers and biochemical parameters for liver function in patients with cirrhosis, suggesting that probiotic management may be a novel treatment for cirrhosis. Furthermore, the interaction of the gut microbiota, associated metabolites, and inflammation factors with cirrhosis may provide a promising therapeutic target for the pharmacological and clinical treatment of cirrhosis.
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Affiliation(s)
- Qinglan Xia
- Institute of Infection, Immunology and Tumor Microenvironment, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan430065, China
| | - Yumeng Lei
- Institute of Infection, Immunology and Tumor Microenvironment, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan430065, China
| | - Jiadun Wang
- Institute of Infection, Immunology and Tumor Microenvironment, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan430065, China
| | - Qiang Wang
- Institute of Infection, Immunology and Tumor Microenvironment, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan430065, China
- Asia General Hospital Affiliated to Wuhan University of Science and Technology, Wuhan430056, China
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15
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Gok Yavuz B, Datar S, Chamseddine S, Mohamed YI, LaPelusa M, Lee SS, Hu ZI, Koay EJ, Tran Cao HS, Jalal PK, Daniel-MacDougall C, Hassan M, Duda DG, Amin HM, Kaseb AO. The Gut Microbiome as a Biomarker and Therapeutic Target in Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:4875. [PMID: 37835569 PMCID: PMC10571776 DOI: 10.3390/cancers15194875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 10/03/2023] [Accepted: 10/05/2023] [Indexed: 10/15/2023] Open
Abstract
The microbiome is pivotal in maintaining health and influencing disease by modulating essential inflammatory and immune responses. Hepatocellular carcinoma (HCC), ranking as the third most common cause of cancer-related fatalities globally, is influenced by the gut microbiome through bidirectional interactions between the gut and liver, as evidenced in both mouse models and human studies. Consequently, biomarkers based on gut microbiota represent promising non-invasive tools for the early detection of HCC. There is a growing body of evidence suggesting that the composition of the gut microbiota may play a role in the efficacy of immunotherapy in different types of cancer; thus, it could be used as a predictive biomarker. In this review, we will dissect the gut microbiome's role as a potential predictive and diagnostic marker in HCC and evaluate the latest progress in leveraging the gut microbiome as a novel therapeutic avenue for HCC patients, with a special emphasis on immunotherapy.
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Affiliation(s)
- Betul Gok Yavuz
- Department of Medicine, University of Missouri, St. Louis, MO 63121, USA;
| | - Saumil Datar
- Department of Medicine, University of Texas at Houston, Houston, TX 77030, USA;
| | - Shadi Chamseddine
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (Y.I.M.); (S.S.L.); (Z.I.H.)
| | - Yehia I. Mohamed
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (Y.I.M.); (S.S.L.); (Z.I.H.)
| | - Michael LaPelusa
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Sunyoung S. Lee
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (Y.I.M.); (S.S.L.); (Z.I.H.)
| | - Zishuo Ian Hu
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (Y.I.M.); (S.S.L.); (Z.I.H.)
| | - Eugene J. Koay
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Hop S. Tran Cao
- Hepato-Pancreato-Biliary Section, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Prasun Kumar Jalal
- Division of Gastroenterology, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Carrie Daniel-MacDougall
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (C.D.-M.); (M.H.)
| | - Manal Hassan
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (C.D.-M.); (M.H.)
| | - Dan G. Duda
- Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA;
| | - Hesham M. Amin
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Ahmed O. Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (Y.I.M.); (S.S.L.); (Z.I.H.)
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Magdy Wasfy R, Mbaye B, Borentain P, Tidjani Alou M, Murillo Ruiz ML, Caputo A, Andrieu C, Armstrong N, Million M, Gerolami R. Ethanol-Producing Enterocloster bolteae Is Enriched in Chronic Hepatitis B-Associated Gut Dysbiosis: A Case-Control Culturomics Study. Microorganisms 2023; 11:2437. [PMID: 37894093 PMCID: PMC10608849 DOI: 10.3390/microorganisms11102437] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 09/25/2023] [Accepted: 09/26/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a global health epidemic that causes fatal complications, leading to liver cirrhosis and hepatocellular carcinoma. The link between HBV-related dysbiosis and specific bacterial taxa is still under investigation. Enterocloster is emerging as a new genus (formerly Clostridium), including Enterocloster bolteae, a gut pathogen previously associated with dysbiosis and human diseases such as autism, multiple sclerosis, and inflammatory bowel diseases. Its role in liver diseases, especially HBV infection, is not reported. METHODS The fecal samples of eight patients with chronic HBV infection and ten healthy individuals were analyzed using the high-throughput culturomics approach and compared to 16S rRNA sequencing. Quantification of ethanol, known for its damaging effect on the liver, produced from bacterial strains enriched in chronic HBV was carried out by gas chromatography-mass spectrometry. RESULTS Using culturomics, 29,120 isolated colonies were analyzed by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry (MALDI-TOF); 340 species were identified (240 species in chronic HBV samples, 254 species in control samples) belonging to 169 genera and 6 phyla. In the chronic HBV group, 65 species were already known in the literature; 48 were associated with humans but had not been previously found in the gut, and 17 had never been associated with humans previously. Six species were newly isolated in our study. By comparing bacterial species frequency, three bacterial genera were serendipitously found with significantly enriched bacterial diversity in patients with chronic HBV: Enterocloster, Clostridium, and Streptococcus (p = 0.0016, p = 0.041, p = 0.053, respectively). However, metagenomics could not identify this enrichment, possibly concerning its insufficient taxonomical resolution (equivocal assignment of operational taxonomic units). At the species level, the significantly enriched species in the chronic HBV group almost all belonged to class Clostridia, such as Clostridium perfringens, Clostridium sporogenes, Enterocloster aldenensis, Enterocloster bolteae, Enterocloster clostridioformis, and Clostridium innocuum. Two E. bolteae strains, isolated from two patients with chronic HBV infection, showed high ethanol production (27 and 200 mM). CONCLUSIONS Culturomics allowed us to identify Enterocloster species, specifically, E. bolteae, enriched in the gut microbiota of patients with chronic HBV. These species had never been isolated in chronic HBV infection before. Moreover, ethanol production by E. bolteae strains isolated from the chronic HBV group could contribute to liver disease progression. Additionally, culturomics might be critical for better elucidating the relationship between dysbiosis and chronic HBV infection in the future.
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Affiliation(s)
- Reham Magdy Wasfy
- IHU Méditerranée Infection, 13005 Marseille, France (M.T.A.); (C.A.)
- MEPHI, IRD, Aix-Marseille Université, 13005 Marseille, France
| | - Babacar Mbaye
- IHU Méditerranée Infection, 13005 Marseille, France (M.T.A.); (C.A.)
- MEPHI, IRD, Aix-Marseille Université, 13005 Marseille, France
| | - Patrick Borentain
- Unité Hépatologie, Hôpital de la Timone, APHM, 13005 Marseille, France;
- Assistance Publique-Hôpitaux de Marseille (APHM), 13005 Marseille, France
| | - Maryam Tidjani Alou
- IHU Méditerranée Infection, 13005 Marseille, France (M.T.A.); (C.A.)
- MEPHI, IRD, Aix-Marseille Université, 13005 Marseille, France
| | - Maria Leticia Murillo Ruiz
- IHU Méditerranée Infection, 13005 Marseille, France (M.T.A.); (C.A.)
- MEPHI, IRD, Aix-Marseille Université, 13005 Marseille, France
| | - Aurelia Caputo
- IHU Méditerranée Infection, 13005 Marseille, France (M.T.A.); (C.A.)
- Assistance Publique-Hôpitaux de Marseille (APHM), 13005 Marseille, France
| | - Claudia Andrieu
- IHU Méditerranée Infection, 13005 Marseille, France (M.T.A.); (C.A.)
- Assistance Publique-Hôpitaux de Marseille (APHM), 13005 Marseille, France
| | - Nicholas Armstrong
- IHU Méditerranée Infection, 13005 Marseille, France (M.T.A.); (C.A.)
- Assistance Publique-Hôpitaux de Marseille (APHM), 13005 Marseille, France
| | - Matthieu Million
- IHU Méditerranée Infection, 13005 Marseille, France (M.T.A.); (C.A.)
- MEPHI, IRD, Aix-Marseille Université, 13005 Marseille, France
- Assistance Publique-Hôpitaux de Marseille (APHM), 13005 Marseille, France
| | - Rene Gerolami
- IHU Méditerranée Infection, 13005 Marseille, France (M.T.A.); (C.A.)
- MEPHI, IRD, Aix-Marseille Université, 13005 Marseille, France
- Unité Hépatologie, Hôpital de la Timone, APHM, 13005 Marseille, France;
- Assistance Publique-Hôpitaux de Marseille (APHM), 13005 Marseille, France
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Huang C, Mei S, Zhang X, Tian X. Inflammatory Milieu Related to Dysbiotic Gut Microbiota Promotes Tumorigenesis of Hepatocellular Carcinoma. J Clin Gastroenterol 2023; 57:782-788. [PMID: 37406184 DOI: 10.1097/mcg.0000000000001883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is an invasive primary liver cancer caused by multiple pathogenic factors and is a significant global health concern. With few effective therapeutic options, HCC is a heterogeneous carcinoma that typically arises in an inflammatory environment. Recent studies have suggested that dysbiotic gut microbiota is involved in hepatocarcinogenesis via multiple mechanisms. In this review, we discuss the effects of gut microbiota, microbial components, and microbiota-derived metabolites on the promotion and progression of HCC by feeding a persistent inflammatory milieu. In addition, we discuss the potential therapeutic modalities for HCC targeting the inflammatory status induced by gut microbiota. A better understanding of the correlation between the inflammatory milieu and gut microbiota in HCC may be beneficial for developing new therapeutic strategies and managing the disease.
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Affiliation(s)
- Caizhi Huang
- Department of Internal Medicine, College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine
- Department of Laboratory Medicine, Hunan Children's Hospital
| | - Si Mei
- Department of Physiology, Hunan University of Chinese Medicine
| | - Xue Zhang
- Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention & Treatment, Hunan University of Chinese Medicine
| | - Xuefei Tian
- Department of Internal Medicine, College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine
- Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention & Treatment, Hunan University of Chinese Medicine
- Hunan Province University Key Laboratory of Oncology of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
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18
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Trivedi Y, Bolgarina Z, Desai HN, Senaratne M, Swami SS, Aye SL, Mohammed L. The Role of Gut Microbiome in Hepatocellular Carcinoma: A Systematic Review. Cureus 2023; 15:e43862. [PMID: 37614827 PMCID: PMC10442465 DOI: 10.7759/cureus.43862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 08/21/2023] [Indexed: 08/25/2023] Open
Abstract
Gut microbiome dysbiosis is common in patients with chronic liver diseases such as hepatocellular carcinoma (HCC) and plays an essential role in developing, diagnosing, and treating HCC. The purpose of this systematic review, which was carried out following the Preferred Reporting Items for Systematic Review and Meta-analyses 2020 guidelines, is to determine the role of the gut microbiome in the pathogenesis, diagnosis, and treatment of HCC. We collected and reviewed articles, including clinical trials, literature reviews, case-control studies, cross-sectional studies, cohort studies, systematic reviews, and meta-analyses, published between May 30, 2013, and May 30, 2023. The databases used to collect these articles included PubMed, Cochrane Library, Google Scholar, and ScienceDirect. After applying appropriate filters, a total of 2,969 studies were identified. They were further screened and subjected to quality assessment tools which finally yielded 17 studies included in this systematic review. This systematic review provides information regarding the gut-liver axis and the relationship between gut microbiome dysbiosis and HCC.
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Affiliation(s)
- Yash Trivedi
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Zoryana Bolgarina
- Obstetrics and Gynecology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Heet N Desai
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Mithum Senaratne
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Shivling S Swami
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Soe Lwin Aye
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Lubna Mohammed
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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19
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Lee YT, Fujiwara N, Yang JD, Hoshida Y. Risk stratification and early detection biomarkers for precision HCC screening. Hepatology 2023; 78:319-362. [PMID: 36082510 PMCID: PMC9995677 DOI: 10.1002/hep.32779] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/25/2022] [Accepted: 08/28/2022] [Indexed: 12/08/2022]
Abstract
Hepatocellular carcinoma (HCC) mortality remains high primarily due to late diagnosis as a consequence of failed early detection. Professional societies recommend semi-annual HCC screening in at-risk patients with chronic liver disease to increase the likelihood of curative treatment receipt and improve survival. However, recent dynamic shift of HCC etiologies from viral to metabolic liver diseases has significantly increased the potential target population for the screening, whereas annual incidence rate has become substantially lower. Thus, with the contemporary HCC etiologies, the traditional screening approach might not be practical and cost-effective. HCC screening consists of (i) definition of rational at-risk population, and subsequent (ii) repeated application of early detection tests to the population at regular intervals. The suboptimal performance of the currently available HCC screening tests highlights an urgent need for new modalities and strategies to improve early HCC detection. In this review, we overview recent developments of clinical, molecular, and imaging-based tools to address the current challenge, and discuss conceptual framework and approaches of their clinical translation and implementation. These encouraging progresses are expected to transform the current "one-size-fits-all" HCC screening into individualized precision approaches to early HCC detection and ultimately improve the poor HCC prognosis in the foreseeable future.
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Affiliation(s)
- Yi-Te Lee
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California
| | - Naoto Fujiwara
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California; Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, Los Angeles, California; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Yujin Hoshida
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
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20
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Shi K, Zhang Q, Zhang Y, Bi Y, Zeng X, Wang X. Association between probiotic therapy and the risk of hepatocellular carcinoma in patients with hepatitis B-related cirrhosis. Front Cell Infect Microbiol 2023; 12:1104399. [PMID: 36710968 PMCID: PMC9880196 DOI: 10.3389/fcimb.2022.1104399] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 12/30/2022] [Indexed: 01/15/2023] Open
Abstract
Objective Probiotics may offer cancer-prevention benefits, based on experimental investigation results. This study aimed to determine the potential association between probiotics and hepatocellular carcinoma (HCC) in patients with hepatitis B-related cirrhosis (HBC) receiving antiviral therapy. Design This retrospective study included 1267 patients with HBC treated with entecavir or tenofovir between January 2013 and December 2017. The risk of developing HCC was compared between two cohorts of 449 probiotic users (taking a cumulative defined daily doses [cDDD] of ≥ 28) and 818 non-probiotic users (< 28 cDDD). To eliminate the bias caused by confounding factors, propensity score matching (PSM) was used. Results On multivariate regression analysis, probiotic consumption was an independent protective factor for HCC occurrence. After PSM, the incidence of HCC was significantly lower in the probiotic users than that in the nonusers (adjusted hazard ratio [aHR]: 0.70, 95% confidence interval: 0.59-0.83, P < 0.001). The aHRs for probiotics with 28-89, 90-180, and >180 cDDD were 0.58, 0.28, and 0.12, respectively, indicating a dose-response pattern. In 28-89, 90-180, and >180 cDDD, the 3-year cumulative incidence of HCC was 8.7%, 4.7%, and 3.0%, respectively. A multivariate stratified analysis confirmed that the administration of probiotics could help patients. Conclusion Adjuvant probiotic therapy may reduce the risk of HCC in patients receiving antiviral medication for HBC. However, further clinical research is required to confirm these findings.
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21
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Noor S, Ali S, Riaz S, Sardar I, Farooq MA, Sajjad A. Chemopreventive role of probiotics against cancer: a comprehensive mechanistic review. Mol Biol Rep 2023; 50:799-814. [PMID: 36324027 DOI: 10.1007/s11033-022-08023-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 10/10/2022] [Indexed: 11/06/2022]
Abstract
Probiotics use different mechanisms such as intestinal barrier improvement, bacterial translocation and maintaining gut microbiota homeostasis to treat cancer. Probiotics' ability to induce apoptosis against tumor cells makes them more effective to treat cancer. Moreover, probiotics stimulate immune function through an immunomodulation mechanism that induces an anti-tumor effect. There are different strains of probiotics, but the most important ones are lactic acid bacteria (LAB) having antagonistic and anti-mutagenic activities. Live and dead probiotics have anti-inflammatory, anti-proliferative, anti-oxidant and anti-metastatic properties which are useful to fight against different diseases, especially cancer. The main focus of this article is to review the anti-cancerous properties of probiotics and their role in the reduction of different types of cancer. However, further investigations are in progress to improve the efficiency of probiotics in cancer treatment.
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Affiliation(s)
- Shehzeen Noor
- Applied Entomology and Medical Toxicology and Laboratory, Department of Zoology, Government College University, Lahore, Pakistan
| | - Shaukat Ali
- Applied Entomology and Medical Toxicology and Laboratory, Department of Zoology, Government College University, Lahore, Pakistan.
| | - Shumaila Riaz
- Applied Entomology and Medical Toxicology and Laboratory, Department of Zoology, Government College University, Lahore, Pakistan
| | - Iqra Sardar
- Applied Entomology and Medical Toxicology and Laboratory, Department of Zoology, Government College University, Lahore, Pakistan
| | - Muhammad Adeel Farooq
- Applied Entomology and Medical Toxicology and Laboratory, Department of Zoology, Government College University, Lahore, Pakistan
| | - Ayesha Sajjad
- Applied Entomology and Medical Toxicology and Laboratory, Department of Zoology, Government College University, Lahore, Pakistan
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22
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Budu O, Banciu C, Pinzaru I, Sarău C, Lighezan D, Șoica C, Dehelean C, Drăghici G, Dolghi A, Prodea A, Mioc M. A Combination of Two Probiotics, Lactobacillus sporogenes and Clostridium butyricum, Inhibits Colon Cancer Development: An In Vitro Study. Microorganisms 2022; 10:microorganisms10091692. [PMID: 36144294 PMCID: PMC9506018 DOI: 10.3390/microorganisms10091692] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/16/2022] [Accepted: 08/22/2022] [Indexed: 11/30/2022] Open
Abstract
Cancer remains a leading cause of death worldwide and, even though several advances have been made in terms of specific treatment, the late-stage detection and the associated side effects of the conventional drugs sustain the search for better treatment alternatives. Probiotics are live microorganisms that have been proven to possess numerous health benefits for human hosts, including anticancer effects. In the present study, the in vitro effect of the association of two probiotic strains (PBT), Lactobacillus sporogenes and Clostridium butyricum, were tested against colon (HT-29 and HCT 116), lung (A549), and liver (HepG2) cancer cell lines, alone or in combination with 5-fluorouracil (5FU). Moreover, the underlying mechanism of PBT and PBT-5FU against the HT-29 cell line was evaluated using the Hoechst 33342 staining, revealing characteristic apoptotic modifications, such as chromatin condensation, nuclear fragmentation, and membrane blebbing. Furthermore, the increase in the expression of pro-apoptotic Bax, Bid, Bad, and Bak proteins and the inhibition of the anti-apoptotic Bcl-2 and Bcl-XL proteins were recorded. Collectively, these findings suggest that the two strains of probiotic bacteria, alone or in association with 5FU, induce apoptosis in colon cancer cells and may serve as a potential anticancer treatment.
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Affiliation(s)
- Oana Budu
- Department of Internal Medicine IV, Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania
| | - Christian Banciu
- Department of Internal Medicine IV, Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania
| | - Iulia Pinzaru
- Department of Toxicology and Drug Industry, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania
- Research Centre for Pharmaco-Toxicological Evaluation, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania
- Correspondence: (I.P.); (C.S.); Tel.: +40-256-494-604
| | - Cristian Sarău
- Department of Medical Semiology I, Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania
- Correspondence: (I.P.); (C.S.); Tel.: +40-256-494-604
| | - Daniel Lighezan
- Department of Medical Semiology I, Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania
| | - Codruța Șoica
- Research Centre for Pharmaco-Toxicological Evaluation, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania
| | - Cristina Dehelean
- Department of Toxicology and Drug Industry, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania
- Research Centre for Pharmaco-Toxicological Evaluation, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania
| | - George Drăghici
- Department of Toxicology and Drug Industry, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania
- Research Centre for Pharmaco-Toxicological Evaluation, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania
| | - Alina Dolghi
- Department of Toxicology and Drug Industry, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania
- Research Centre for Pharmaco-Toxicological Evaluation, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania
| | - Alexandra Prodea
- Research Centre for Pharmaco-Toxicological Evaluation, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania
| | - Marius Mioc
- Research Centre for Pharmaco-Toxicological Evaluation, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania
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23
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Schemczssen-Graeff Z, Pileggi M. Probiotics and live biotherapeutic products aiming at cancer mitigation and patient recover. Front Genet 2022; 13:921972. [PMID: 36017495 PMCID: PMC9395637 DOI: 10.3389/fgene.2022.921972] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 07/13/2022] [Indexed: 11/13/2022] Open
Abstract
Molecular biology techniques allowed access to non-culturable microorganisms, while studies using analytical chemistry, as Liquid Chromatography and Tandem Mass Spectrometry, showed the existence of a complex communication system among bacteria, signaled by quorum sensing molecules. These approaches also allowed the understanding of dysbiosis, in which imbalances in the microbiome diversity, caused by antibiotics, environmental toxins and processed foods, lead to the constitution of different diseases, as cancer. Colorectal cancer, for example, can originate by a dysbiosis configuration, which leads to biofilm formation, production of toxic metabolites, DNA damage in intestinal epithelial cells through the secretion of genotoxins, and epigenetic regulation of oncogenes. However, probiotic strains can also act in epigenetic processes, and so be use for recovering important intestinal functions and controlling dysbiosis and cancer mitigation through the metabolism of drugs used in chemotherapy, controlling the proliferation of cancer cells, improving the immune response of the host, regulation of cell differentiation and apoptosis, among others. There are still gaps in studies on the effectiveness of the use of probiotics, therefore omics and analytical chemistry are important approaches to understand the role of bacterial communication, formation of biofilms, and the effects of probiotics and microbiome on chemotherapy. The use of probiotics, prebiotics, synbiotics, and metabiotics should be considered as a complement to other more invasive and hazard therapies, such chemotherapy, surgery, and radiotherapy. The study of potential bacteria for cancer treatment, as the next-generation probiotics and Live Biotherapeutic Products, can have a controlling action in epigenetic processes, enabling the use of these bacteria for the mitigation of specific diseases through changes in the regulation of genes of microbiome and host. Thus, it is possible that a path of medicine in the times to come will be more patient-specific treatments, depending on the environmental, genetic, epigenetic and microbiome characteristics of the host.
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Affiliation(s)
- Zelinda Schemczssen-Graeff
- Comparative Immunology Laboratory, Department of Microbiology, Parasitology and Pathology, Federal University of Paraná, Curitiba, Brazil
| | - Marcos Pileggi
- Environmental Microbiology Laboratory, Structural and Molecular Biology and Genetics Department, Life Sciences and Health Institute, Ponta Grossa State University, Ponta Grossa, Brazil
- *Correspondence: Marcos Pileggi,
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24
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Li YG, Yu ZJ, Li A, Ren ZG. Gut microbiota alteration and modulation in hepatitis B virus-related fibrosis and complications: Molecular mechanisms and therapeutic inventions. World J Gastroenterol 2022; 28:3555-3572. [PMID: 36161048 PMCID: PMC9372803 DOI: 10.3748/wjg.v28.i28.3555] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 06/06/2022] [Accepted: 06/24/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) has posed a threat to public health, mainly resulting in liver damage. With long-term accumulation of extracellular matrix, patients with chronic hepatitis B are at high risk of developing into liver fibrosis and cirrhosis and even life-threatening hepatic carcinoma. The occurrence of complications such as spontaneous bacterial peritonitis and hepatic encephalopathy greatly increases disability and mortality. With deeper understanding of the bidirectional interaction between the liver and the gut (gut-liver axis), there is a growing consensus that the human health closely relates to the gut microbiota. Supported by animal and human studies, the gut microbiota alters as the HBV-related liver fibrosis initials and progresses, characterized as the decrease of the ratio between "good" and "potentially pathogenic" microbes. When the primary disease is controlled via antiviral treatment, the gut microbiota dysfunction tends to be improved. Conversely, the recovery of gut microbiota can promote the regression of liver fibrosis. Therapeutic strategies targeted on gut microbiota (rifaximin, probiotics, engineered probiotics and fecal microbiota transplantation) have been applied to animal models and patients, obtaining satisfactory results.
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Affiliation(s)
- Yao-Guang Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zu-Jiang Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Ang Li
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zhi-Gang Ren
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250000, Shandong Province, China
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25
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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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26
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Kubota N, Fujiwara N, Hoshida Y. Liver cancer risk-predictive molecular biomarkers specific to clinico-epidemiological contexts. Adv Cancer Res 2022; 156:1-37. [PMID: 35961696 PMCID: PMC7616039 DOI: 10.1016/bs.acr.2022.01.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Hepatocellular carcinoma (HCC) risk prediction is increasingly important because of the low annual HCC incidence in patients with the rapidly emerging non-alcoholic fatty liver disease or cured HCV infection. To date, numerous clinical HCC risk biomarkers and scores have been reported in literature. However, heterogeneity in clinico-epidemiological context, e.g., liver disease etiology, patient race/ethnicity, regional environmental exposure, and lifestyle-related factors, obscure their real clinical utility and applicability. Proper characterization of these factors will help refine HCC risk prediction according to certain clinical context/scenarios and contribute to improved early HCC detection. Molecular factors underlying the clinical heterogeneity encompass various features in host genetics, hepatic and systemic molecular dysregulations, and cross-organ interactions, which may serve as clinical-context-specific biomarkers and/or therapeutic targets. Toward the goal to enable individual-risk-based HCC screening by incorporating the HCC risk biomarkers/scores, their assessment in patient with well-defined clinical context/scenario is critical to gauge their real value and to maximize benefit of the tailored patient management for substantial improvement of the poor HCC prognosis.
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Affiliation(s)
- Naoto Kubota
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Naoto Fujiwara
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States; Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yujin Hoshida
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States.
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27
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MiR-29a Curbs Hepatocellular Carcinoma Incidence via Targeting of HIF-1α and ANGPT2. Int J Mol Sci 2022; 23:ijms23031636. [PMID: 35163556 PMCID: PMC8835722 DOI: 10.3390/ijms23031636] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/25/2022] [Accepted: 01/28/2022] [Indexed: 12/11/2022] Open
Abstract
A high-fat diet is responsible for hepatic fat accumulation that sustains chronic liver damage and increases the risks of steatosis and hepatocellular carcinoma (HCC). MicroRNA-29a (miR-29a), a key regulator of cellular behaviors, is present in anti-fibrosis and modulator tumorigenesis. However, the increased transparency of the correlation between miR-29a and the progression of human HCC is still further investigated. In this study, we predicted HIF-1α and ANGPT2 as regulators of HCC by the OncoMir cancer database and showed a strong positive correlation with HIF-1α and ANGPT2 gene expression in HCC patients. Mice fed the western diet (WD) while administered CCl4 for 25 weeks induced chronic liver damage and higher HCC incidence than without fed WD mice. HCC section staining revealed signaling upregulation in ki67, severe fibrosis, and steatosis in WD and CCl4 mice and detected Col3a1 gene expressions. HCC tissues significantly attenuated miR-29a but increased in HIF-1α, ANGPT2, Lox, Loxl2, and VEGFA expression. Luciferase activity analysis confirms that miR-29a specific binding 3′UTR of HIF-1α and ANGPT2 to repress expression. In summary, miR-29a control HIF-1α and ANGPT2 signaling in HCC formation. This study insight into a novel molecular pathway by which miR-29a targeting HIF-1α and ANGPT2 counteracts the incidence of HCC development.
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28
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Sankarapandian V, Venmathi Maran BA, Rajendran RL, Jogalekar MP, Gurunagarajan S, Krishnamoorthy R, Gangadaran P, Ahn BC. An Update on the Effectiveness of Probiotics in the Prevention and Treatment of Cancer. Life (Basel) 2022; 12:59. [PMID: 35054452 PMCID: PMC8779143 DOI: 10.3390/life12010059] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 12/29/2021] [Indexed: 12/15/2022] Open
Abstract
Probiotics are living microbes that play a significant role in protecting the host in various ways. Gut microbiota is one of the key players in maintaining homeostasis. Cancer is considered one of the most significant causes of death worldwide. Although cancer treatment has received much attention in recent years, the number of people suffering from neoplastic syndrome continues to increase. Despite notable improvements in the field of cancer therapy, tackling cancer has been challenging due to the multiple properties of cancer cells and their ability to evade the immune system. Probiotics alter the immunological and cellular responses by enhancing the epithelial barrier and stimulating the production of anti-inflammatory, antioxidant, and anticarcinogenic compounds, thereby reducing cancer burden and growth. The present review focuses on the various mechanisms underlying the role of probiotics in the prevention and treatment of cancer.
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Affiliation(s)
- Vidya Sankarapandian
- Department of Microbiology, Srimad Andavan Arts and Science College, Bharathidasan University, Trichy 620005, India;
| | | | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea;
| | - Manasi P. Jogalekar
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA;
| | - Sridharan Gurunagarajan
- Department of Biochemistry, Srimad Andavan Arts and Science College, Bharathidasan University, Trichy 620005, India;
| | - Rajapandiyan Krishnamoorthy
- Nanobiotechnology and Molecular Biology Research Lab, Department of Food Science and Nutrition, College of Food and Agriculture Sciences, King Saud University, Riyadh 4545, Saudi Arabia;
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea;
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea;
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, Korea
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Amedei A, Gitto S, Campani C, Marra F. Probiotics and the gut-liver axis. PROBIOTICS 2022:467-481. [DOI: 10.1016/b978-0-323-85170-1.00003-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Zou R, Wang Y, Ye F, Zhang X, Wang M, Cui S. Mechanisms of primary and acquired resistance to PD-1/PD-L1 blockade and the emerging role of gut microbiome. Clin Transl Oncol 2021; 23:2237-2252. [PMID: 34002348 DOI: 10.1007/s12094-021-02637-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 05/06/2021] [Indexed: 12/12/2022]
Abstract
As a very promising immunotherapy, PD-1/PD-L1 blockade has revolutionized the treatment of a variety of tumor types, resulting in significant clinical efficacy and lasting responses. However, these therapies do not work for a large proportion of patients initially, which is called primary resistance. And more frustrating is that most patients eventually develop acquired resistance after an initial response to PD-1/PD-L1 blockade. The mechanisms that lead to primary and acquired resistance to PD-1/PD-L1 inhibition have remained largely unclear. Recently, the gut microbiome has emerged as a potential regulator for PD-1/PD-L1 blockade. This review elaborates on the current understanding of the mechanisms in terms of PD-1 related signaling pathways and necessary factors. Moreover, this review discusses new strategies to increase the efficacy of immunotherapy from the perspectives of immune markers and gut microbiome.
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Affiliation(s)
- R Zou
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Y Wang
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - F Ye
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - X Zhang
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - M Wang
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - S Cui
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
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