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Yang Y, Shi X. Big lessons from the little Akkermansia muciniphila in hepatocellular carcinoma. Front Immunol 2025; 16:1524563. [PMID: 40028328 PMCID: PMC11868108 DOI: 10.3389/fimmu.2025.1524563] [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: 11/07/2024] [Accepted: 01/30/2025] [Indexed: 03/05/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequently occurring type of liver tumor and is considered one of the most common primary malignant neoplasms. The prognosis for HCC is dismal because of its complicated etiology and high level of medication resistance. Immunotherapy is presently regarded as one of the most effective therapeutic options for HCC; nevertheless, because of the disturbance of intestinal flora, immunotherapy shows low antitumor efficacy. An increasing body of research indicates that intestinal flora, particularly Akkermansia muciniphila (A. muciniphila), is vital for the treatment of tumors. Studies have demonstrated that the diminished effectiveness of immunotherapy in cancer patients is associated with a reduction in A. muciniphila levels, suggesting that increasing A. muciniphila levels significantly enhance the efficacy of immunotherapy. A. muciniphila functions as a gut probiotic and can treat and prevent a wide range of illnesses, including cancer. Consequently, preserving A. muciniphila abundance is enough to prevent and lower the danger of developing cancer disorders. In this review, we critically evaluate the current body of research on A. muciniphila, with a primary focus on its biological properties and functions. The different illnesses that A. muciniphila treats were then discussed, particularly the way it works with liver cancer. This review aims to give a novel treatment plan for patients with HCC as well as a theoretical foundation for improving HCC immunotherapy.
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Affiliation(s)
- Yanguang Yang
- Laboratory of Integrated Medicine Tumor Immunology, Shanxi University of Chinese Medicine, Taiyuan, China
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Xinli Shi
- Laboratory of Integrated Medicine Tumor Immunology, Shanxi University of Chinese Medicine, Taiyuan, China
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, China
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Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, Qin W, Chen J, Xia Q, Jin H. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther 2025; 10:35. [PMID: 39915447 PMCID: PMC11802921 DOI: 10.1038/s41392-024-02075-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/18/2024] [Accepted: 11/14/2024] [Indexed: 02/09/2025] Open
Abstract
Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.
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Affiliation(s)
- Jiaojiao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Siying Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Zhen Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
| | - René Bernards
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, PR China.
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Haojie Jin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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Monti E, Vianello C, Leoni I, Galvani G, Lippolis A, D’Amico F, Roggiani S, Stefanelli C, Turroni S, Fornari F. Gut Microbiome Modulation in Hepatocellular Carcinoma: Preventive Role in NAFLD/NASH Progression and Potential Applications in Immunotherapy-Based Strategies. Cells 2025; 14:84. [PMID: 39851512 PMCID: PMC11764391 DOI: 10.3390/cells14020084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/07/2025] [Accepted: 01/08/2025] [Indexed: 01/26/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous tumor associated with several risk factors, with non-alcoholic fatty liver disease (NAFLD) emerging as an important cause of liver tumorigenesis. Due to the obesity epidemics, the occurrence of NAFLD has significantly increased with nearly 30% prevalence worldwide. HCC often arises in the background of chronic liver disease (CLD), such as nonalcoholic steatohepatitis (NASH) and cirrhosis. Gut microbiome (GM) alterations have been linked to NAFLD progression and HCC development, with several investigations reporting a crucial role for the gut-liver axis and microbial metabolites in promoting CLD. Moreover, the GM affects liver homeostasis, energy status, and the immune microenvironment, influencing the response to immunotherapy with interesting therapeutic implications. In this review, we summarize the main changes in the GM and derived metabolites (e.g., short-chain fatty acids and bile acids) occurring in HCC patients and influencing NAFLD progression, emphasizing their potential as early diagnostic biomarkers and prognostic tools. We discuss the weight loss effects of diet-based interventions and healthy lifestyles for the treatment of NAFLD patients, highlighting their impact on the restoration of the intestinal barrier and GM structure. We also describe encouraging preclinical findings on the modulation of GM to improve liver functions in CLD, boost the antitumor immune response (e.g., probiotic supplementations or anti-hypercholesterolemic drug treatment), and ultimately delay NAFLD progression to HCC. The development of safe and effective strategies that target the gut-liver axis holds promise for liver cancer prevention and treatment, especially if personalized options will be considered.
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Affiliation(s)
- Elisa Monti
- Department for Life Quality Studies, University of Bologna, Corso d’Augusto 237, 47921 Rimini, Italy; (E.M.); (C.V.); (I.L.); (G.G.); (A.L.); (C.S.)
- Centre for Applied Biomedical Research—CRBA, University of Bologna, 40138 Bologna, Italy
| | - Clara Vianello
- Department for Life Quality Studies, University of Bologna, Corso d’Augusto 237, 47921 Rimini, Italy; (E.M.); (C.V.); (I.L.); (G.G.); (A.L.); (C.S.)
- Centre for Applied Biomedical Research—CRBA, University of Bologna, 40138 Bologna, Italy
| | - Ilaria Leoni
- Department for Life Quality Studies, University of Bologna, Corso d’Augusto 237, 47921 Rimini, Italy; (E.M.); (C.V.); (I.L.); (G.G.); (A.L.); (C.S.)
- Centre for Applied Biomedical Research—CRBA, University of Bologna, 40138 Bologna, Italy
| | - Giuseppe Galvani
- Department for Life Quality Studies, University of Bologna, Corso d’Augusto 237, 47921 Rimini, Italy; (E.M.); (C.V.); (I.L.); (G.G.); (A.L.); (C.S.)
- Centre for Applied Biomedical Research—CRBA, University of Bologna, 40138 Bologna, Italy
| | - Annalisa Lippolis
- Department for Life Quality Studies, University of Bologna, Corso d’Augusto 237, 47921 Rimini, Italy; (E.M.); (C.V.); (I.L.); (G.G.); (A.L.); (C.S.)
| | - Federica D’Amico
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy; (F.D.); (S.R.); (S.T.)
| | - Sara Roggiani
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy; (F.D.); (S.R.); (S.T.)
- Human Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | - Claudio Stefanelli
- Department for Life Quality Studies, University of Bologna, Corso d’Augusto 237, 47921 Rimini, Italy; (E.M.); (C.V.); (I.L.); (G.G.); (A.L.); (C.S.)
| | - Silvia Turroni
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy; (F.D.); (S.R.); (S.T.)
- IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy
| | - Francesca Fornari
- Department for Life Quality Studies, University of Bologna, Corso d’Augusto 237, 47921 Rimini, Italy; (E.M.); (C.V.); (I.L.); (G.G.); (A.L.); (C.S.)
- IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy
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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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Kumar AR, Nair B, Kamath AJ, Nath LR, Calina D, Sharifi-Rad J. Impact of gut microbiota on metabolic dysfunction-associated steatohepatitis and hepatocellular carcinoma: pathways, diagnostic opportunities and therapeutic advances. Eur J Med Res 2024; 29:485. [PMID: 39367507 PMCID: PMC11453073 DOI: 10.1186/s40001-024-02072-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 09/22/2024] [Indexed: 10/06/2024] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) and progression to hepatocellular carcinoma (HCC) exhibits distinct molecular and immune characteristics. These traits are influenced by multiple factors, including the gut microbiome, which interacts with the liver through the "gut-liver axis". This bidirectional relationship between the gut and its microbiota and the liver plays a key role in driving various liver diseases, with microbial metabolites and immune responses being central to these processes. Our review consolidates the latest research on how gut microbiota contributes to MASH development and its progression to HCC, emphasizing new diagnostic and therapeutic possibilities. We performed a comprehensive literature review across PubMed/MedLine, Scopus, and Web of Science from January 2000 to August 2024, focusing on both preclinical and clinical studies that investigate the gut microbiota's roles in MASH and HCC. This includes research on pathogenesis, as well as diagnostic and therapeutic advancements related to the gut microbiota. This evidence emphasizes the critical role of the gut microbiome in the pathogenesis of MASH and HCC, highlighting the need for further clinical studies and trials. This is to refine diagnostic techniques and develop targeted therapies that exploit the microbiome's capabilities, aiming to enhance patient care in liver diseases.
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Affiliation(s)
- Ayana R Kumar
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
| | - Bhagyalakshmi Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
| | - Adithya Jayaprakash Kamath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
- Department of Pharmaceutics, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health. Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India
| | - Lekshmi R Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India.
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania.
| | - Javad Sharifi-Rad
- Universidad Espíritu Santo, Samborondón, 092301, Ecuador.
- Centro de Estudios Tecnológicos y Universitarios del Golfo, Veracruz, Mexico.
- Department of Medicine, College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
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Jarasvaraparn C, Rodrigo M, Hartley C, Karnsakul W. Exploring odevixibat's efficacy in alagille syndrome: insights from recent clinical trials and IBAT inhibitor experiences. Expert Opin Pharmacother 2024; 25:1647-1655. [PMID: 39155775 DOI: 10.1080/14656566.2024.2392873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 08/09/2024] [Accepted: 08/12/2024] [Indexed: 08/20/2024]
Abstract
INTRODUCTION Alagille syndrome (ALGS) is a rare, genetic, multisystem disorder commonly associated with cholestatic liver disease; patients with ALGS may experience elevated serum bile acids and severe pruritus with associated impaired sleep. The ileal bile acid transporter (IBAT) is located on the luminal surface of enterocytes in the terminal ileum; this transport protein mediates resorption of conjugated bile acids for recirculation back to the liver. Inhibition of IBAT disrupts the enterohepatic circulation and leads to fecal elimination of bile acids. AREAS COVERED Here, the role of odevixibat as a novel, nonsurgical approach to interrupting the enterohepatic circulation from the intestine by inhibition of IBAT is reviewed, specifically in reference to currently available data on pharmacologic IBAT inhibition. IBAT inhibition has been shown to reduce serum bile acids and pruritus in trials of cholestatic liver diseases in children including ALGS. EXPERT OPINION Odevixibat or IBAT inhibitor should be considered as a first-line treatment for ALGS to improve pruritis, quality of life and liver-related outcomes including absence of liver transplant, surgical biliary diversion, hepatic decompensation, and death.
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Affiliation(s)
- Chaowapong Jarasvaraparn
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Minna Rodrigo
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA
| | | | - Wikrom Karnsakul
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA
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Li XJ, Fang C, Zhao RH, Zou L, Miao H, Zhao YY. Bile acid metabolism in health and ageing-related diseases. Biochem Pharmacol 2024; 225:116313. [PMID: 38788963 DOI: 10.1016/j.bcp.2024.116313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 05/18/2024] [Accepted: 05/21/2024] [Indexed: 05/26/2024]
Abstract
Bile acids (BAs) have surpassed their traditional roles as lipid solubilizers and regulators of BA homeostasis to emerge as important signalling molecules. Recent research has revealed a connection between microbial dysbiosis and metabolism disruption of BAs, which in turn impacts ageing-related diseases. The human BAs pool is primarily composed of primary BAs and their conjugates, with a smaller proportion consisting of secondary BAs. These different BAs exert complex effects on health and ageing-related diseases through several key nuclear receptors, such as farnesoid X receptor and Takeda G protein-coupled receptor 5. However, the underlying molecular mechanisms of these effects are still debated. Therefore, the modulation of signalling pathways by regulating synthesis and composition of BAs represents an interesting and novel direction for potential therapies of ageing-related diseases. This review provides an overview of synthesis and transportion of BAs in the healthy body, emphasizing its dependence on microbial community metabolic capacity. Additionally, the review also explores how ageing and ageing-related diseases affect metabolism and composition of BAs. Understanding BA metabolism network and the impact of their nuclear receptors, such as farnesoid X receptor and G protein-coupled receptor 5 agonists, paves the way for developing therapeutic agents for targeting BA metabolism in various ageing-related diseases, such as metabolic disorder, hepatic injury, cardiovascular disease, renal damage and neurodegenerative disease.
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Affiliation(s)
- Xiao-Jun Li
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China; Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, No.13, Shi Liu Gang Road, Haizhu District, Guangzhou, Guangdong 510315, China
| | - Chu Fang
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China
| | - Rui-Hua Zhao
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China
| | - Liang Zou
- School of Food and Bioengineering, Chengdu University, No. 2025 Chengluo Avenue, Chengdu, Sichuan 610106, China
| | - Hua Miao
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China.
| | - Ying-Yong Zhao
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China; National Key Laboratory of Kidney Diseases, First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, China.
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8
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Basthi Mohan P, Lochan R, Shetty S. Biomarker in Hepatocellular Carcinoma. Indian J Surg Oncol 2024; 15:261-268. [PMID: 38817995 PMCID: PMC11133295 DOI: 10.1007/s13193-023-01858-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 11/29/2023] [Indexed: 06/01/2024] Open
Abstract
Liver cancer is one of the most prevalent types of cancer and a major contributor to the socioeconomic burden worldwide. The pathogenesis of hepatocellular carcinoma (HCC) is contributed by various etiological factors like virus infection, excessive alcohol consumption, exposure to toxins, or metabolic disorders. Majority of patients are diagnosed with late-stage HCC, which restricts its management to only palliative care. HCC, if diagnosed early, increases the survival and quality of life. Currently available biomarker (alpha-fetoproteins) have several limitations, that impede the early diagnosis and staging of cancer. This warrants the continous search in pursuit of a novel biomarker. Several research works in diverse areas have contributed to the identification of various novel biomarkers that have shown multifaceted application in early disease diagnosis, which further aid in targeted and effective therapy that can prevent cancer progression. This improves the overall health status of the patient along with significant reduction in caretaker's burden. With the aid of novel technologies, several biomarkers have been investigated and validated in mutliple preliminary research works. Therefore in this review, we have outlined various novel biomarkers that showed promising outcomes in their trials and we have highlighted the developing areas that act as game changers in cancer diagnosis and management.
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Affiliation(s)
- Pooja Basthi Mohan
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
| | - Rajiv Lochan
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
- Lead Consultant Surgeon - HPB and Liver transplantation Surgery, Manipal Hospital, Bengaluru, 560017 Karnataka India
| | - Shiran Shetty
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
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Scarlata GGM, Cicino C, Spagnuolo R, Marascio N, Quirino A, Matera G, Dumitrașcu DL, Luzza F, Abenavoli L. Impact of diet and gut microbiota changes in the development of hepatocellular carcinoma. HEPATOMA RESEARCH 2024. [DOI: 10.20517/2394-5079.2023.122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer that occurs with a frequency of 85% in patients with liver cirrhosis. It is the sixth most common type of cancer globally. Asia is the continent with the highest incidence (72%), followed by Europe (8%) and Africa (5%). Men are four times more likely than women to develop this cancer, especially in the 70-80 age group. Risk factors include alcoholic liver disease, tobacco use, genetic predisposition, dysmetabolic comorbidities such as type 2 diabetes mellitus and obesity, hepatitis B virus and hepatitis C virus infections, and non-alcoholic fatty liver disease. Unhealthy dietary regimens and gut dysbiosis are additional risk factors that have been recently investigated. These two factors are closely related because the gut microbiota performs several biological functions, including nutrient metabolism, a process that promotes gut homeostasis, known as eubiosis. With regard to the correlation between diet, gut microbiota, and HCC development, there are several mechanisms that have not yet been fully elucidated. This narrative review aims to evaluate the impact of diet and gut microbiota changes in the development of HCC. Our analysis, performed on several clinical and pre-clinical studies, showed that a high-fat diet promotes gut dysbiosis and hepatic fat accumulation, leading to the progression from simple steatosis to HCC, while the Mediterranean diet, rich in fiber and monounsaturated fatty acids, had a protective role. For this reason, international employment of this dietary regimen for therapeutic purposes should be encouraged.
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Jiang W, Jin WL, Xu AM. Cholesterol metabolism in tumor microenvironment: cancer hallmarks and therapeutic opportunities. Int J Biol Sci 2024; 20:2044-2071. [PMID: 38617549 PMCID: PMC11008265 DOI: 10.7150/ijbs.92274] [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: 11/16/2023] [Accepted: 02/27/2024] [Indexed: 04/16/2024] Open
Abstract
Cholesterol is crucial for cell survival and growth, and dysregulation of cholesterol homeostasis has been linked to the development of cancer. The tumor microenvironment (TME) facilitates tumor cell survival and growth, and crosstalk between cholesterol metabolism and the TME contributes to tumorigenesis and tumor progression. Targeting cholesterol metabolism has demonstrated significant antitumor effects in preclinical and clinical studies. In this review, we discuss the regulatory mechanisms of cholesterol homeostasis and the impact of its dysregulation on the hallmarks of cancer. We also describe how cholesterol metabolism reprograms the TME across seven specialized microenvironments. Furthermore, we discuss the potential of targeting cholesterol metabolism as a therapeutic strategy for tumors. This approach not only exerts antitumor effects in monotherapy and combination therapy but also mitigates the adverse effects associated with conventional tumor therapy. Finally, we outline the unresolved questions and suggest potential avenues for future investigations on cholesterol metabolism in relation to cancer.
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Affiliation(s)
- Wen Jiang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, P. R. China
| | - Wei-Lin Jin
- Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Lanzhou 730000, P. R. China
| | - A-Man Xu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, P. R. China
- Anhui Public Health Clinical Center, Hefei 230022, P. R. China
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11
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Golonka RM, Yeoh BS, Saha P, Tian Y, Chiang JYL, Patterson AD, Gewirtz AT, Joe B, Vijay-Kumar M. Sex Dimorphic Effects of Bile Acid Metabolism in Liver Cancer in Mice. Cell Mol Gastroenterol Hepatol 2024; 17:719-735. [PMID: 38262588 PMCID: PMC10966305 DOI: 10.1016/j.jcmgh.2024.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 01/15/2024] [Accepted: 01/16/2024] [Indexed: 01/25/2024]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is a male-dominant disease, but targeted sex hormone therapies have not been successful. Bile acids are a potential liver carcinogen and are biomolecules with hormone-like effects. A few studies highlight their potential sex dimorphism in physiology and disease. We hypothesized that bile acids could be a potential molecular signature that explains sex disparity in HCC. METHODS & RESULTS We used the farnesoid X receptor knockout (FxrKO) mouse model to study bile acid-dependent HCC. Temporal tracking of circulating bile acids determined more than 80% of FxrKO females developed spontaneous cholemia (ie, serum total bile acids ≥40 μmol/L) as early as 8 weeks old. Opposingly, FxrKO males were highly resistant to cholemia, with ∼23% incidence even when 26 weeks old. However, FxrKO males demonstrated higher levels of deoxycholate than females. Compared with males, FxrKO females had more severe cholestatic liver injury and further aberrancies in bile acid metabolism. Yet, FxrKO females expressed more detoxification transcripts and had greater renal excretion of bile acids. Intervention with CYP7A1 (rate limiting enzyme for bile acid biosynthesis) deficiency or taurine supplementation either completely or partially normalized bile acid levels and liver injury in FxrKO females. Despite higher cholemia prevalence in FxrKO females, their tumor burden was less compared with FxrKO males. An exception to this sex-dimorphic pattern was found in a subset of male and female FxrKO mice born with congenital cholemia due to portosystemic shunt, where both sexes had comparable robust HCC. CONCLUSIONS Our study highlights bile acids as sex-dimorphic metabolites in HCC except in the case of portosystemic shunt.
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Affiliation(s)
- Rachel M Golonka
- UT Microbiome Consortium, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Beng San Yeoh
- UT Microbiome Consortium, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Piu Saha
- UT Microbiome Consortium, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Yuan Tian
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania
| | - John Y L Chiang
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio
| | - Andrew D Patterson
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania
| | - Andrew T Gewirtz
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia
| | - Bina Joe
- UT Microbiome Consortium, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Matam Vijay-Kumar
- UT Microbiome Consortium, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio.
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12
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Effenberger M, Grander C, Grabherr F, Tilg H. Nonalcoholic Fatty Liver Disease and the Intestinal Microbiome: An Inseparable Link. J Clin Transl Hepatol 2023; 11:1498-1507. [PMID: 38161503 PMCID: PMC10752805 DOI: 10.14218/jcth.2023.00069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 04/21/2023] [Accepted: 07/18/2023] [Indexed: 01/03/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) particularly affects patients with type 2 diabetes and obesity. The incidence of NAFLD has increased significantly over the last decades and is now pandemically across the globe. It is a complex systemic disease comprising hepatic lipid accumulation, inflammation, lipotoxicity, gut dysbiosis, and insulin resistance as main features and with the potential to progress to cirrhosis and hepatocellular carcinoma (HCC). In numerous animal and human studies the gut microbiota plays a key role in the pathogenesis of NAFLD, NAFLD-cirrhosis and NAFLD-associated HCC. Lipotoxicity is the driver of inflammation, insulin resistance, and liver injury. Likewise, western diet, obesity, and metabolic disorders may alter the gut microbiota, which activates innate and adaptive immune responses and fuels hereby hepatic and systemic inflammation. Indigestible carbohydrates are fermented by the gut microbiota to produce important metabolites, such as short-chain fatty acids and succinate. Numerous animal and human studies suggested a pivotal role of these metabolites in the progression of NAFLD and its comorbidities. Though, modification of the gut microbiota and/or the metabolites could even be beneficial in patients with NAFLD, NAFLD-cirrhosis, and NAFLD-associated HCC. In this review we collect the evidence that exogenous and endogenous hits drive liver injury in NAFLD and propel liver fibrosis and the progressing to advanced disease stages. NAFLD can be seen as the product of a complex interplay between gut microbiota, the immune response and metabolism. Thus, the challenge will be to understand its pathogenesis and to develop new therapeutic strategies.
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Affiliation(s)
- Maria Effenberger
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Christoph Grander
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Felix Grabherr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
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13
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Song Y, Lau HCH, Zhang X, Yu J. Bile acids, gut microbiota, and therapeutic insights in hepatocellular carcinoma. Cancer Biol Med 2023; 21:j.issn.2095-3941.2023.0394. [PMID: 38148326 PMCID: PMC10884537 DOI: 10.20892/j.issn.2095-3941.2023.0394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 11/28/2023] [Indexed: 12/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a prevalent and aggressive liver malignancy. The interplay between bile acids (BAs) and the gut microbiota has emerged as a critical factor in HCC development and progression. Under normal conditions, BA metabolism is tightly regulated through a bidirectional interplay between gut microorganisms and BAs. The gut microbiota plays a critical role in BA metabolism, and BAs are endogenous signaling molecules that help maintain liver and intestinal homeostasis. Of note, dysbiotic changes in the gut microbiota during pathogenesis and cancer development can disrupt BA homeostasis, thereby leading to liver inflammation and fibrosis, and ultimately contributing to HCC development. Therefore, understanding the intricate interplay between BAs and the gut microbiota is crucial for elucidating the mechanisms underlying hepatocarcinogenesis. In this review, we comprehensively explore the roles and functions of BA metabolism, with a focus on the interactions between BAs and gut microorganisms in HCC. Additionally, therapeutic strategies targeting BA metabolism and the gut microbiota are discussed, including the use of BA agonists/antagonists, probiotic/prebiotic and dietary interventions, fecal microbiota transplantation, and engineered bacteria. In summary, understanding the complex BA-microbiota crosstalk can provide valuable insights into HCC development and facilitate the development of innovative therapeutic approaches for liver malignancy.
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Affiliation(s)
- Yang Song
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
- Department of Gastroenterology, Zhongshan Hospital Xiamen University, Xiamen 361004, China
| | - Harry CH Lau
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiang Zhang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
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14
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Liu T, Guo Y, Liao Y, Liu J. Mechanism-guided fine-tuned microbiome potentiates anti-tumor immunity in HCC. Front Immunol 2023; 14:1333864. [PMID: 38169837 PMCID: PMC10758498 DOI: 10.3389/fimmu.2023.1333864] [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: 11/06/2023] [Accepted: 12/05/2023] [Indexed: 01/05/2024] Open
Abstract
Microbiome, including bacteria, fungi, and viruses, plays a crucial role in shaping distal and proximal anti-tumor immunity. Mounting evidence showed that commensal microbiome critically modulates immunophenotyping of hepatocellular carcinoma (HCC), a leading cause of cancer-related death. However, their role in anti-tumor surveillance of HCC is still poorly understood. Herein, we spotlighted growing interests in how the microbiome influences the progression and immunotherapeutic responses of HCC via changing local tumor microenvironment (TME) upon translocating to the sites of HCC through different "cell-type niches". Moreover, we summarized not only the associations but also the deep insight into the mechanisms of how the extrinsic microbiomes interplay with hosts to shape immune surveillance and regulate TME and immunotherapeutic responses. Collectively, we provided a rationale for a mechanism-guided fine-tuned microbiome to be neoadjuvant immunotherapy in the near future.
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Affiliation(s)
- Tao Liu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ya Guo
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yanxia Liao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jinping Liu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
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15
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Cameron CM, Richardson B, Golden JB, Phoon YP, Tamilselvan B, Pfannenstiel L, Thapaliya S, Roversi G, Gao XH, Zagore LL, Cameron MJ, Gastman BR. A transcriptional evaluation of the melanoma and squamous cell carcinoma TIL compartment reveals an unexpected spectrum of exhausted and functional T cells. Front Oncol 2023; 13:1200387. [PMID: 38023136 PMCID: PMC10643547 DOI: 10.3389/fonc.2023.1200387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 09/27/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction Significant heterogeneity exists within the tumor-infiltrating CD8 T cell population, and exhausted T cells harbor a subpopulation that may be replicating and may retain signatures of activation, with potential functional consequences in tumor progression. Dysfunctional immunity in the tumor microenvironment is associated with poor cancer outcomes, making exploration of these exhausted T cell subpopulations critical to the improvement of therapeutic approaches. Methods To investigate mechanisms associated with terminally exhausted T cells, we sorted and performed transcriptional profiling of CD8+ tumor-infiltrating lymphocytes (TILs) co-expressing the exhaustion markers PD-1 and TIM-3 from large-volume melanoma tumors. We additionally performed immunologic phenotyping and functional validation, including at the single-cell level, to identify potential mechanisms that underlie their dysfunctional phenotype. Results We identified novel dysregulated pathways in CD8+PD-1+TIM-3+ cells that have not been well studied in TILs; these include bile acid and peroxisome pathway-related metabolism and mammalian target of rapamycin (mTOR) signaling pathways, which are highly correlated with immune checkpoint receptor expression. Discussion Based on bioinformatic integration of immunophenotypic data and network analysis, we propose unexpected targets for therapies to rescue the immune response to tumors in melanoma.
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Affiliation(s)
- Cheryl M. Cameron
- Department of Nutrition, Case Western Reserve University, Cleveland, OH, United States
| | - Brian Richardson
- Department of Nutrition, Case Western Reserve University, Cleveland, OH, United States
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Jackelyn B. Golden
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Yee Peng Phoon
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, United States
| | - Banumathi Tamilselvan
- Department of Nutrition, Case Western Reserve University, Cleveland, OH, United States
| | - Lukas Pfannenstiel
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, United States
| | - Samjhana Thapaliya
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, United States
| | - Gustavo Roversi
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, United States
| | - Xing-Huang Gao
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Leah L. Zagore
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Mark J. Cameron
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Brian R. Gastman
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, United States
- Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, United States
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16
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Abenavoli L, Montori M, Svegliati Baroni G, Argenziano ME, Giorgi F, Scarlata GGM, Ponziani F, Scarpellini E. Perspective on the Role of Gut Microbiome in the Treatment of Hepatocellular Carcinoma with Immune Checkpoint Inhibitors. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1427. [PMID: 37629716 PMCID: PMC10456509 DOI: 10.3390/medicina59081427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 08/02/2023] [Accepted: 08/04/2023] [Indexed: 08/27/2023]
Abstract
Background and Objectives: Hepatocellular carcinoma (HCC) is the leading cause of liver cancer worldwide and has a high mortality rate. Its incidence has increased due to metabolic-associated liver disease (MAFLD) epidemics. Liver transplantation and surgery remain the most resolute measures. Despite the optimistic use of multi-kinase inhibitors, namely sorafenib, the co-existence of chronic liver disease made the response rate low in these patients. Immune checkpoint inhibitors (ICIs) have become a promising hope for certain advanced solid tumors and, also, for advanced HCC. Unfortunately, a large cohort of patients with HCC fail to respond to immunotherapy. Materials and Methods: We conducted a narrative search on the main medical databases for original articles, reviews, meta-analyses, randomized clinical trials, and case series using the following keywords and acronyms and their associations: hepatocellular carcinoma, immunotherapy, checkpoint inhibitors, gut microbiota, and fecal microbiota transplantation. Results: ICIs are a promising and sufficiently safe treatment option for HCC. In detail, they have significantly improved survival and prognosis in these patients vs. sorafenib. Although there are several highlighted mechanisms of resistance, the gut microbiota signature can be used both as a response biomarker and as an effect enhancer. Practically, probiotic dose-finding and fecal microbiota transplantation are the weapons that can be used to increase ICI's treatment-response-reducing resistance mechanisms. Conclusion: Immunotherapy has been a significant step-up in HCC treatment, and gut microbiota modulation is an effective liaison to increase its efficacy.
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Affiliation(s)
- Ludovico Abenavoli
- Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy;
| | - Michele Montori
- Clinic of Gastroenterology and Hepatology, Emergency Digestive Endoscopy, Polytechnics University of Marche, 60126 Ancona, Italy; (M.M.); (M.E.A.)
| | | | - Maria Eva Argenziano
- Clinic of Gastroenterology and Hepatology, Emergency Digestive Endoscopy, Polytechnics University of Marche, 60126 Ancona, Italy; (M.M.); (M.E.A.)
| | - Francesca Giorgi
- Oncology Unit, “Madonna del Soccorso” General Hospital, 63074 San Benedetto del Tronto, Italy;
| | | | - Francesca Ponziani
- Digestive Disease Center (C.E.M.A.D.), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy;
- Translational Medicine and Surgery Department, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Emidio Scarpellini
- Translational Research in GastroIntestinal Disorders (T.A.R.G.I.D.), KU Leuven, Herestraat 49, 3000 Leuven, Belgium;
- Hepatology Outpatient Clinic, “Madonna del Soccorso” General Hospital, 63074 San Benedetto del Tronto, Italy
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17
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Metabolism as a New Avenue for Hepatocellular Carcinoma Therapy. Int J Mol Sci 2023; 24:ijms24043710. [PMID: 36835122 PMCID: PMC9964410 DOI: 10.3390/ijms24043710] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/08/2023] [Accepted: 02/10/2023] [Indexed: 02/16/2023] Open
Abstract
Hepatocellular carcinoma is today the sixth leading cause of cancer-related death worldwide, despite the decreased incidence of chronic hepatitis infections. This is due to the increased diffusion of metabolic diseases such as the metabolic syndrome, diabetes, obesity, and nonalcoholic steatohepatitis (NASH). The current protein kinase inhibitor therapies in HCC are very aggressive and not curative. From this perspective, a shift in strategy toward metabolic therapies may represent a promising option. Here, we review current knowledge on metabolic dysregulation in HCC and therapeutic approaches targeting metabolic pathways. We also propose a multi-target metabolic approach as a possible new option in HCC pharmacology.
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18
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Non-alcoholic Fatty Liver Disease (NAFLD), Type 2 Diabetes, and Non-viral Hepatocarcinoma: Pathophysiological Mechanisms and New Therapeutic Strategies. Biomedicines 2023; 11:biomedicines11020468. [PMID: 36831004 PMCID: PMC9953066 DOI: 10.3390/biomedicines11020468] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 02/01/2023] [Accepted: 02/03/2023] [Indexed: 02/09/2023] Open
Abstract
In recent years, the incidence of non-viral hepatocellular carcinoma (HCC) has increased dramatically, which is probably related to the increased prevalence of metabolic syndrome, together with obesity and type 2 diabetes mellitus (T2DM). Several epidemiological studies have established the association between T2DM and the incidence of HCC and have demonstrated the role of diabetes mellitus as an independent risk factor for the development of HCC. The pathophysiological mechanisms underlying the development of Non-alcoholic fatty liver disease (NAFLD) and its progression to Non-alcoholic steatohepatitis (NASH) and cirrhosis are various and involve pro-inflammatory agents, oxidative stress, apoptosis, adipokines, JNK-1 activation, increased IGF-1 activity, immunomodulation, and alteration of the gut microbiota. Moreover, these mechanisms are thought to play a significant role in the development of NAFLD-related hepatocellular carcinoma. Early diagnosis and the timely correction of risk factors are essential to prevent the onset of liver fibrosis and HCC. The purpose of this review is to summarize the current evidence on the association among obesity, NASH/NAFLD, T2DM, and HCC, with an emphasis on clinical impact. In addition, we will examine the main mechanisms underlying this complex relationship, and the promising strategies that have recently emerged for these diseases' treatments.
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19
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Toh MR, Wong EYT, Wong SH, Ng AWT, Loo LH, Chow PKH, Ngeow JYY. Global Epidemiology and Genetics of Hepatocellular Carcinoma. Gastroenterology 2023; 164:766-782. [PMID: 36738977 DOI: 10.1053/j.gastro.2023.01.033] [Citation(s) in RCA: 185] [Impact Index Per Article: 92.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 01/27/2023] [Accepted: 01/29/2023] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading cancers worldwide. Classically, HCC develops in genetically susceptible individuals who are exposed to risk factors, especially in the presence of liver cirrhosis. Significant temporal and geographic variations exist for HCC and its etiologies. Over time, the burden of HCC has shifted from the low-moderate to the high sociodemographic index regions, reflecting the transition from viral to nonviral causes. Geographically, the hepatitis viruses predominate as the causes of HCC in Asia and Africa. Although there are genetic conditions that confer increased risk for HCC, these diagnoses are rarely recognized outside North America and Europe. In this review, we will evaluate the epidemiologic trends and risk factors of HCC, and discuss the genetics of HCC, including monogenic diseases, single-nucleotide polymorphisms, gut microbiome, and somatic mutations.
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Affiliation(s)
- Ming Ren Toh
- Cancer Genetics Service, National Cancer Centre Singapore, Singapore
| | | | - Sunny Hei Wong
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Alvin Wei Tian Ng
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Lit-Hsin Loo
- Bioinformatics Institute, Agency for Science, Technology, and Research (A∗STAR), Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Pierce Kah-Hoe Chow
- Department of Hepato-Pancreato-Biliary and Transplant Surgery, National Cancer Center Singapore and Singapore General Hospital, Singapore; Duke-NUS Medical School Singapore, Singapore
| | - Joanne Yuen Yie Ngeow
- Cancer Genetics Service, National Cancer Centre Singapore, Singapore; Division of Medical Oncology, National Cancer Centre Singapore, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Duke-NUS Medical School Singapore, Singapore.
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20
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Rigual MDM, Sánchez Sánchez P, Djouder N. Is liver regeneration key in hepatocellular carcinoma development? Trends Cancer 2023; 9:140-157. [PMID: 36347768 DOI: 10.1016/j.trecan.2022.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/05/2022] [Accepted: 10/10/2022] [Indexed: 11/08/2022]
Abstract
The liver is the largest organ of the mammalian body and has the remarkable ability to fully regenerate in order to maintain tissue homeostasis. The adult liver consists of hexagonal lobules, each with a central vein surrounded by six portal triads localized in the lobule border containing distinct parenchymal and nonparenchymal cells. Because the liver is continuously exposed to diverse stress signals, several sophisticated regenerative processes exist to restore its functional status following impairment. However, these stress signals can affect the liver's capacity to regenerate and may lead to the development of hepatocellular carcinoma (HCC), one of the most aggressive liver cancers. Here, we review the mechanisms of hepatic regeneration and their potential to influence HCC development.
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Affiliation(s)
- María Del Mar Rigual
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain
| | - Paula Sánchez Sánchez
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain
| | - Nabil Djouder
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain.
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21
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Yang S, Yu D, Liu J, Qiao Y, Gu S, Yang R, Chai X, Wang W. Global publication trends and research hotspots of the gut-liver axis in NAFLD: A bibliometric analysis. Front Endocrinol (Lausanne) 2023; 14:1121540. [PMID: 36967792 PMCID: PMC10034112 DOI: 10.3389/fendo.2023.1121540] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 02/21/2023] [Indexed: 03/29/2023] Open
Abstract
BACKGROUND Nonalcoholic Fatty Liver Disease(NAFLD)refers to a spectrum of diseases ranging from simple liver steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Bidirectional cross-talk between the gut-liver axis plays an important role in the pathogenesis of NAFLD. To learn more about the gut-liver axis in NAFLD, this study aims to provide a comprehensive analysis from a bibliometric perspective. METHOD Literature related to the gut-liver axis in NAFLD from 1989 to 2022 was extracted from the Web of Science Core Collection. Based on Microsoft Excel, CiteSpace and Vosviewer, we conducted to analyze the number of publications, countries/regions, institutions, authors, journals, references, and keywords. RESULTS A total of 1,891 literature since 2004 was included, with the rapid growth of the number of papers on the gut-liver axis in NAFLD annually. These publications were mainly from 66 countries and 442 institutions. Of the 638 authors analyzed, Bernd Schnabl was the one with the most publications, and Patrice D. Cani was the one with the most co-citations. International Journal of Molecular Sciences is the journal with the most articles published, and Hepatology is the journal with the most citations. The most common keywords are gut microbiota, inflammation, and insulin instance, which are current research hotspots. Short-chain fatty acid, in vitro, randomized controlled trial in clinical, and diabetes mellitus represent the research frontiers in this field and are in a stage of rapid development. CONCLUSION This is the first study to conduct a comprehensive bibliometric analysis of publications related to the gut-liver axis in NAFLD. This study reveals that gut microbiota, inflammation, insulin resistance, short-chain fatty acids, and randomized controlled trial will be the hotspots and new trends in the gut-liver axis in NAFLD research, which could provide researchers with key research information in this field and is helpful for further exploration of new research directions.
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Affiliation(s)
- Shuangjie Yang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Deshuai Yu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Junjie Liu
- Department of Cardiology, Nanjing Pukou Hospital of Traditional Chinese Medicine, Nanjing, China
| | - Yanfang Qiao
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Shuxiao Gu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Ran Yang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Ran Yang, ; Xinlou Chai, ; Wei Wang,
| | - Xinlou Chai
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Ran Yang, ; Xinlou Chai, ; Wei Wang,
| | - Wei Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Ran Yang, ; Xinlou Chai, ; Wei Wang,
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22
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Zeng D, Zhang L, Luo Q. Celastrol-regulated gut microbiota and bile acid metabolism alleviate hepatocellular carcinoma proliferation by regulating the interaction between FXR and RXRα in vivo and in vitro. Front Pharmacol 2023; 14:1124240. [PMID: 36874033 PMCID: PMC9975715 DOI: 10.3389/fphar.2023.1124240] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 01/31/2023] [Indexed: 02/17/2023] Open
Abstract
Celastrol, a triterpene derived from Thunder God Vine (Tripterygium wilfordii Hook f; Celastraceae), a traditional Chinese herb, has promising anticancer activity. The present study aimed to elucidate an indirect mechanism of celastrol-mediated alleviation of hepatocellular carcinoma (HCC) via gut microbiota-regulated bile acid metabolism and downstream signaling. Here, we constructed a rat model of orthotopic HCC and performed 16S rDNA sequencing and UPLC-MS analysis. The results showed that celastrol could regulate gut bacteria; suppress the abundance of Bacteroides fragilis; raise the levels of glycoursodeoxycholic acid (GUDCA), a bile acid; and alleviate HCC. We found that GUDCA suppressed cellular proliferation and induced the arrest of mTOR/S6K1 pathway-associated cell cycle G0/G1 phase in HepG2 cells. Further analyses using molecular simulations, Co-IP, and immunofluorescence assays revealed that GUDCA binds to farnesoid X receptor (FXR) and regulates the interaction of FXR with retinoid X receptor a (RXRα). Transfection experiments using the FXR mutant confirmed that FXR is essential for GUCDA-mediated suppression of HCC cellular proliferation. Finally, animal experiments showed that the treatment with the combination of celastrol/GUDCA alleviated the adverse effects of celastrol alone treatment on body weight loss and improved survival in rats with HCC. In conclusion, the findings of this study suggest that celastrol exerts an alleviating effect on HCC, in part via regulation of the B. fragilis-GUDCA-FXR/RXRα-mTOR axis.
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Affiliation(s)
- Dequan Zeng
- Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China.,Department of Translational Medicine, Xiamen Institute of Rare Earth Materials, Chinese Academy of Sciences, Xiamen, China.,School of Pharmaceutical Science, Xiamen University, Xiamen, China
| | - Lipen Zhang
- Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China.,Department of Translational Medicine, Xiamen Institute of Rare Earth Materials, Chinese Academy of Sciences, Xiamen, China
| | - Qiang Luo
- Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China.,Department of Translational Medicine, Xiamen Institute of Rare Earth Materials, Chinese Academy of Sciences, Xiamen, China
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23
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Gou H, Liu S, Liu L, Luo M, Qin S, He K, Yang X. Obeticholic acid and 5β-cholanic acid 3 exhibit anti-tumor effects on liver cancer through CXCL16/CXCR6 pathway. Front Immunol 2022; 13:1095915. [PMID: 36605219 PMCID: PMC9807878 DOI: 10.3389/fimmu.2022.1095915] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 12/06/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver malignancy with a high incidence and mortality rate. Previous in vitro and in vivo studies have confirmed that liver sinusoidal endothelial cells (LSEC) secrete CXCL16, which acts as a messenger to increase the hepatic accumulation of CXCR6+ natural killer T (NKT) cells and exert potent antitumor effects. However, evidence for this process in humans is lacking and its clinical significance is still unclear. In this study, by dissecting the human HCC single-cell RNA-seq data, we verified this process through cellphoneDB. NKT cells in patients with high expression of CXCL16 exhibited a higher activation state and produced more interferon-γ (IFN-γ) compared with those with low expression. We next investigated the signaling pathways between activated (CD69 high) and unactivated NKT cells (CD69 low) using NKT cell-developmental trajectories and functional enrichment analyses. In vivo experiments, we found that farnesoid X receptor agonist (obeticholic acid) combined with the takeda G protein coupled receptor 5 antagonist (5β-cholanic acid 3) exhibited significant tumor suppressive effects in the orthotopic liver tumor model and this result may be related to the CXCL16/CXCR6 axis. In conclusion, our study provides the basis and potential strategies for HCC immunotherapy based on NKT cells.
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Affiliation(s)
- Haoxian Gou
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China,Academician Workstation of Sichuan Province, Luzhou, China
| | - Shenglu Liu
- Academician Workstation of Sichuan Province, Luzhou, China
| | - Linxin Liu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Ming Luo
- Academician Workstation of Sichuan Province, Luzhou, China
| | - Shu Qin
- Academician Workstation of Sichuan Province, Luzhou, China
| | - Kai He
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China,Academician Workstation of Sichuan Province, Luzhou, China,*Correspondence: Xiaoli Yang, ; Kai He,
| | - Xiaoli Yang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China,Academician Workstation of Sichuan Province, Luzhou, China,*Correspondence: Xiaoli Yang, ; Kai He,
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24
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Li G, Pu C, Fang T. Analysis of Differential Expression Profiles of Liver Cancer Cell Proteins After Treatment with Bile Acid. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.3208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The pathogenesis of liver cancer has not been fully elucidated yet. Bile acids are components of bile, which are inorganic substances and regulate tumor progression. However, the differential expression profile of liver cancer cell proteins after bile acid treatment remains unclear.
Human hepatoma cell line SMMC7721 was cultured and randomly assigned into control group and bile acid group followed by measuring the protein expression profile by protein fingerprinting. SMMC7721 cells were transfected with UGT2B or UGT2B, followed by analysis of UGT2B expression, cell proliferation,
apoptosis, migration and PI3K/AKT signaling protein expression. The most obvious proteins with an increased expression after bile acid treatment were UGT2B, AAP, APLP2, LAPTM4B, NCOA4 with UGT2B being the most significant one. Overexpression of UGT2B decreased cell proliferation, promoted
cell apoptosis, downregulated migration ability and AKT phosphorylation (P <0.05). UGT2B siRNA transfection significantly down-regulated UGT2B expression, promoted cell proliferation, decreased apoptosis rate, increased migration ability and AKT phosphorylation (P <0.05).
In conclusion, bile acid can alter the protein expressions of liver cancer cells, with UGT2B being changed most obviously. UGT2B can affect liver cancer cell behaviors via modulating PI3K/AKT signaling.
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Affiliation(s)
- Geng Li
- Cancer Radiation Therapy Center, The Second People’s Hospital of Yichang, China Three Gorges University, Yichang, 443000, Hubei, China
| | - Chao’an Pu
- Second Department of Liver, Hubei Provincial Hospital of Tcm, Wuhan, 430000, Hubei, China
| | - Tao Fang
- Department of Hepatobiliary and Pancreatic Surgery, Huangshi Central Hospital (Affiliated Hospital of Hubei Polytechnic University), Huangshi, 435000, Hubei, China
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25
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Das BK. Altered gut microbiota in hepatocellular carcinoma: Insights into the pathogenic mechanism and preclinical to clinical findings. APMIS 2022; 130:719-740. [PMID: 36321381 DOI: 10.1111/apm.13282] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. It is usually the result of pre-existing liver damage caused by hepatitis B and/or C virus infection, alcohol consumption, nonalcoholic steatohepatitis (NASH), aflatoxin exposure, liver cirrhosis, obesity, and diabetes. A growing body of evidence suggests that gut microbes have a role in cancer genesis. More research into the microbiome gut-liver axis has recently contributed to understanding how the gut microbiome facilitates liver disease or even HCC progression. This review focuses on the preclinical results of gut-related hepatocarcinogenesis and probiotics, prebiotics, and antibiotics as therapeutic interventions to maintain gut microbial flora and minimize HCC-associated symptoms. Understanding the mechanistic link between the gut microbiota, host, and cancer progression could aid us in elucidating the cancer-related pathways and drive us toward preventing HCC-associated gut microbiota dysbiosis.
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Affiliation(s)
- Bhrigu Kumar Das
- Department of Pharmacology, Girijananda Chowdhury Institute of Pharmaceutical Science (Assam Science and Technology University), Guwahati, Assam, India
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26
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Influenza Vaccination Reduces the Risk of Liver Cancer in Patients with Chronic Kidney Disease: A Nationwide Population-Based Cohort Study. Vaccines (Basel) 2022; 10:vaccines10122008. [PMID: 36560418 PMCID: PMC9784512 DOI: 10.3390/vaccines10122008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 11/19/2022] [Accepted: 11/23/2022] [Indexed: 11/26/2022] Open
Abstract
Previous studies have indicated that influenza vaccination reduces the development of lung cancer. However, the protective effects of influenza vaccination on primary liver cancer in patients with chronic kidney disease (CKD) are unclear. This cohort study identified 12,985 patients aged at least 55 years who had received a diagnosis of CKD between 1 January 2001 and 31 December 2012 from the National Health Insurance Research Database of Taiwan. The patients were classified according to vaccination status. Propensity score matching was used to reduce selection bias. Cox proportional hazards regression analysis was used to evaluate the correlation between influenza vaccination and primary liver cancer in patients with CKD. The prevalence of primary liver cancer was lower in patients with CKD who had received an influenza vaccine (adjusted hazard ratio: 0.45, 95% confidence interval [CI]: 0.35−0.58, p < 0.001). The protective effects were observed regardless of sex, age, and comorbidities. Moreover, dose-dependent protective effects were observed. In the subgroup analysis, where the patients were classified by the number of vaccinations received, the adjusted hazard ratios for 1, 2−3, and ≥4 vaccinations were 0.86 (95% CI: 0.63−1.17), 0.45 (95% CI: 0.31−0.63), and 0.21 (95% CI: 0.14−0.33), respectively. In conclusion, influenza vaccination was associated with a lower incidence of liver cancer in patients with CKD.
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27
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The Species of Gut Bacteria Associated with Antitumor Immunity in Cancer Therapy. Cells 2022; 11:cells11223684. [PMID: 36429112 PMCID: PMC9688644 DOI: 10.3390/cells11223684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/30/2022] [Accepted: 11/16/2022] [Indexed: 11/22/2022] Open
Abstract
Both preclinical and clinical studies have demonstrated that the modulation of gut microbiota could be a promising strategy for enhancing antitumor immune responses and reducing resistance to immunotherapy in cancer. Various mechanisms, including activation of pattern recognition receptors, gut commensals-produced metabolites and antigen mimicry, have been revealed. Different gut microbiota modulation strategies have been raised, such as fecal microbiota transplantation, probiotics, and dietary selection. However, the identification of gut bacteria species that are either favorable or unfavorable for cancer therapy remains a major challenge. Herein, we summarized the findings related to gut microbiota species observed in the modulation of antitumor immunity. We also discussed the different mechanisms underlying different gut bacteria's functions and the potential applications of these bacteria to cancer immunotherapy in the future.
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Xia JK, Tang N, Wu XY, Ren HZ. Deregulated bile acids may drive hepatocellular carcinoma metastasis by inducing an immunosuppressive microenvironment. Front Oncol 2022; 12:1033145. [PMID: 36338764 PMCID: PMC9634065 DOI: 10.3389/fonc.2022.1033145] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/30/2022] [Indexed: 11/22/2022] Open
Abstract
Bile acids (BAs) are physiological detergents that can not only promote the digestion and absorption of lipids, but also may be a potential carcinogen. The accumulation of BAs in the body can lead to cholestatic liver cirrhosis and even liver cancer. Recently, studies demonstrated that BAs are highly accumulated in metastatic lymph nodes, but not in normal healthy lymph nodes or primary tumors. Lymph node metastasis is second only to hematogenous metastasis in liver cancer metastasis, and the survival and prognosis of hepatocellular carcinoma (HCC) patients with lymph node metastasis are significantly worse than those without lymph node metastasis. Meanwhile, component of BAs was found to significantly enhance the invasive potential of HCC cells. However, it is still poorly understood how deregulated BAs fuel the metastasis process of liver cancer. The tumor microenvironment is a complex cellular ecosystem that evolves with and supports tumor cells during their malignant transformation and metastasis progression. Aberrant BAs metabolism were found to modulate tumor immune microenvironment by preventing natural killer T (NKT) cells recruitment and increasing M2-like tumor-associated macrophages (TAMs) polarization, thus facilitate tumor immune escape and HCC development. Based on these available evidence, we hypothesize that a combination of genetic and epigenetic factors in cancerous liver tissue inhibits the uptake and stimulates the synthesis of BAs by the liver, and excess BAs further promote liver carcinogenesis and HCC metastasis by inducing immunosuppressive microenvironment.
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Affiliation(s)
- Jin-kun Xia
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China,Institute of Hepatobiliary Surgery, Nanjing University, Nanjing, China
| | - Ning Tang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Xing-yu Wu
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China,*Correspondence: Hao-zhen Ren, ; Xing-yu Wu,
| | - Hao-zhen Ren
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China,Institute of Hepatobiliary Surgery, Nanjing University, Nanjing, China,*Correspondence: Hao-zhen Ren, ; Xing-yu Wu,
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29
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Khalyfa AA, Punatar S, Yarbrough A. Hepatocellular Carcinoma: Understanding the Inflammatory Implications of the Microbiome. Int J Mol Sci 2022; 23:ijms23158164. [PMID: 35897739 PMCID: PMC9332105 DOI: 10.3390/ijms23158164] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/17/2022] [Accepted: 07/20/2022] [Indexed: 01/25/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. It is well known that repeated inflammatory insults in the liver can cause hepatic cellular injury that lead to cirrhosis and, ultimately, hepatocellular carcinoma. Furthermore, the microbiome has been implicated in multiple inflammatory conditions which predispose patients to malignancy. With this in mind, we explore the inflammatory implications of the microbiome on pathways that lead to HCC. We also focus on how an understanding of these underlying inflammatory principles lead to a more wholistic understanding of this deadly disease, as well as potential therapeutic implications.
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Affiliation(s)
- Ahamed A. Khalyfa
- Department of Internal Medicine, Franciscan Health Olympia Fields, Olympia Fields, IL 60461, USA;
- Correspondence:
| | - Shil Punatar
- Department of Internal Medicine, Franciscan Health Olympia Fields, Olympia Fields, IL 60461, USA;
| | - Alex Yarbrough
- Department of Gastroenterology, Franciscan Health Olympia Fields, Olympia Fields, IL 60461, USA;
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30
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Qin H, Yuan B, Huang W, Wang Y. Utilizing Gut Microbiota to Improve Hepatobiliary Tumor Treatments: Recent Advances. Front Oncol 2022; 12:924696. [PMID: 35924173 PMCID: PMC9339707 DOI: 10.3389/fonc.2022.924696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/20/2022] [Indexed: 11/13/2022] Open
Abstract
Hepatobiliary tumors, which include cholangiocarcinoma, hepatocellular carcinoma (HCC), and gallbladder cancer, are common cancers that have high morbidity and mortality rates and poor survival outcomes. In humans, the microbiota is comprised of symbiotic microbial cells (10-100 trillion) that belong to the bacterial ecosystem mainly residing in the gut. The gut microbiota is a complicated group that can largely be found in the intestine and has a dual role in cancer occurrence and progression. Previous research has focused on the crucial functions of the intestinal microflora as the main pathophysiological mechanism in HCC development. Intestinal bacteria produce a broad range of metabolites that exhibit a variety of pro- and anticarcinogenic effects on HCC. Therefore, probiotic alteration of the gut microflora could promote gut flora balance and help prevent the occurrence of HCC. Recent evidence from clinical and translational studies suggests that fecal microbiota transplant is one of the most successful therapies to correct intestinal bacterial imbalance. We review the literature describing the effects and mechanisms of the microbiome in the gut in the context of HCC, including gut bacterial metabolites, probiotics, antibiotics, and the transplantation of fecal microbiota, and discuss the potential influence of the microbiome environment on cholangiocarcinoma and gallbladder cancer. Our findings are expected to reveal therapeutic targets for the prevention of hepatobiliary tumors, and the development of clinical treatment strategies, by emphasizing the function of the gut microbiota.
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Affiliation(s)
- Hao Qin
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Baowen Yuan
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Huang
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
- *Correspondence: Wei Huang, ; Yan Wang,
| | - Yan Wang
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
- *Correspondence: Wei Huang, ; Yan Wang,
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31
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Vitale G, Mattiaccio A, Conti A, Turco L, Seri M, Piscaglia F, Morelli MC. Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature. Cancers (Basel) 2022; 14:cancers14143421. [PMID: 35884482 PMCID: PMC9322180 DOI: 10.3390/cancers14143421] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/10/2022] [Accepted: 07/12/2022] [Indexed: 02/06/2023] Open
Abstract
The family of inherited intrahepatic cholestasis includes autosomal recessive cholestatic rare diseases of childhood involved in bile acids secretion or bile transport defects. Specific genetic pathways potentially cause many otherwise unexplained cholestasis or hepatobiliary tumours in a healthy liver. Lately, next-generation sequencing and whole-exome sequencing have improved the diagnostic procedures of familial intrahepatic cholestasis (FIC), as well as the discovery of several genes responsible for FIC. Moreover, mutations in these genes, even in the heterozygous status, may be responsible for cryptogenic cholestasis in both young and adults. Mutations in FIC genes can influence serum and hepatic levels of bile acids. Experimental studies on the NR1H4 gene have shown that high bile acids concentrations cause excessive production of inflammatory cytokines, resistance to apoptosis, and increased cell regeneration, all risk conditions for developing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). NR1H4 gene encodes farnesoid X-activated receptor having a pivotal role in bile salts synthesis. Moreover, HCC and CCA can emerge in patients with several FIC genes such as ABCB11, ABCB4 and TJP2. Herein, we reviewed the available data on FIC-related hepatobiliary cancers, reporting on genetics to the pathophysiology, the risk factors and the clinical presentation.
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Affiliation(s)
- Giovanni Vitale
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.T.); (M.C.M.)
- Correspondence:
| | - Alessandro Mattiaccio
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.C.); (M.S.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University di Bologna, 40138 Bologna, Italy
| | - Amalia Conti
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.C.); (M.S.)
| | - Laura Turco
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.T.); (M.C.M.)
| | - Marco Seri
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.C.); (M.S.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University di Bologna, 40138 Bologna, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Maria Cristina Morelli
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.T.); (M.C.M.)
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32
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Shao G, Liu Y, Lu L, Zhang G, Zhou W, Wu T, Wang L, Xu H, Ji G. The Pathogenesis of HCC Driven by NASH and the Preventive and Therapeutic Effects of Natural Products. Front Pharmacol 2022; 13:944088. [PMID: 35873545 PMCID: PMC9301043 DOI: 10.3389/fphar.2022.944088] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 06/20/2022] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is a clinical syndrome with pathological changes that are similar to those of alcoholic hepatitis without a history of excessive alcohol consumption. It is a specific form of nonalcoholic fatty liver disease (NAFLD) that is characterized by hepatocyte inflammation based on hepatocellular steatosis. Further exacerbation of NASH can lead to cirrhosis, which may then progress to hepatocellular carcinoma (HCC). There is a lack of specific and effective treatments for NASH and NASH-driven HCC, and the mechanisms of the progression of NASH to HCC are unclear. Therefore, there is a need to understand the pathogenesis and progression of these diseases to identify new therapeutic approaches. Currently, an increasing number of studies are focusing on the utility of natural products in NASH, which is likely to be a promising prospect for NASH. This paper reviews the possible mechanisms of the pathogenesis and progression of NASH and NASH-derived HCC, as well as the potential therapeutic role of natural products in NASH and NASH-derived HCC.
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Affiliation(s)
- Gaoxuan Shao
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ying Liu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lu Lu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guangtao Zhang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenjun Zhou
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Wu
- Institute of Interdisciplinary Integrative Biomedical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lei Wang
- Department of Hepatology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hanchen Xu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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The Activity of Prebiotics and Probiotics in Hepatogastrointestinal Disorders and Diseases Associated with Metabolic Syndrome. Int J Mol Sci 2022; 23:ijms23137229. [PMID: 35806234 PMCID: PMC9266451 DOI: 10.3390/ijms23137229] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 06/27/2022] [Indexed: 12/11/2022] Open
Abstract
The components of metabolic syndrome (MetS) and hepatogastrointestinal diseases are widespread worldwide, since many factors associated with lifestyle and diet influence their development and correlation. Due to these growing health problems, it is necessary to search for effective alternatives for prevention or adjuvants in treating them. The positive impact of regulated microbiota on health is known; however, states of dysbiosis are closely related to the development of the conditions mentioned above. Therefore, the role of prebiotics, probiotics, or symbiotic complexes has been extensively evaluated; the results are favorable, showing that they play a crucial role in the regulation of the immune system, the metabolism of carbohydrates and lipids, and the biotransformation of bile acids, as well as the modulation of their central receptors FXR and TGR-5, which also have essential immunomodulatory and metabolic activities. It has also been observed that they can benefit the host by displacing pathogenic species, improving the dysbiosis state in MetS. Current studies have reported that paraprobiotics (dead or inactive probiotics) or postbiotics (metabolites generated by active probiotics) also benefit hepatogastrointestinal health.
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Hou Z, Song F, Xing J, Zheng Z, Liu S, Liu Z. Comprehensive fecal metabolomics and gut microbiota for the evaluation of the mechanism of Panax Ginseng in the treatment of Qi-deficiency liver cancer. JOURNAL OF ETHNOPHARMACOLOGY 2022; 292:115222. [PMID: 35341933 DOI: 10.1016/j.jep.2022.115222] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 03/08/2022] [Accepted: 03/21/2022] [Indexed: 06/14/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Qi deficiency liver cancer (QDLC) is an important part of liver cancer research in traditional Chinese medicine (TCM). In the course of its treatment, Panax ginseng is often selected as the main Chinese herbal medicine, and its function has special significance in the tumor treatment of Qi deficiency constitution. However, its mechanism is not clear. AIM OF THE STUDY The research tried to evaluate the mechanism of Panax ginseng in the treatment of QDLC through fecal metabonomics and gut microbiota on the basis of previous pharmacodynamic evaluation. MATERIALS AND METHODS Firstly, biomarkers and related metabolic pathways were screened and identified by metabonomics and Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Then, 16S rRNA sequencing technique was used to investigate the composition, β diversity and key differences of gut microbiota. Finally, the relationship among phenotypes, gut microbiota and fecal metabolites was comprehensively analyzed by spearman correlation coefficient. RESULTS 31 pharmacodynamic potential biomarkers and 20 synergistic potential biomarkers of effective parts of Panax ginseng on QDLC were screened and identified by fecal metabonomics. And then, 6 major metabolic pathways were searched, including bile acid biosynthesis, unsaturated fatty acid biosynthesis, tryptophan metabolism, arachidonic acid metabolism, pyrimidine metabolism, vitamin B6 metabolism. In the study of gut microbiota, at the genus level, 25 species of bacteria with significant differences of effective parts on QDLC and 23 species of bacteria with significant differences of synergistic action of ginsenosides and polysaccharides were screened. In addition, Spearman correlation analysis showed that there was a complex potential relationship among phenotype, gut microbiota and fecal metabolites during the development of QDLC and Panax ginseng intervention, which was mainly reflected in the close potential relationship between bacteria and fecal metabolites such as bile acids, unsaturated fatty acids and indole compounds. CONCLUSION Through the changes of fecal endogenous metabolites and intestinal bacteria, the mechanism of Panax ginseng on QDLC were preliminarily clarified.
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Affiliation(s)
- Zong Hou
- Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Fengrui Song
- Jilin Provincial Key Laboratory of Chinese Medicine Chemistry and Mass Spectrometry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
| | - Junpeng Xing
- Jilin Provincial Key Laboratory of Chinese Medicine Chemistry and Mass Spectrometry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
| | - Zhong Zheng
- Jilin Provincial Key Laboratory of Chinese Medicine Chemistry and Mass Spectrometry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
| | - Shu Liu
- Jilin Provincial Key Laboratory of Chinese Medicine Chemistry and Mass Spectrometry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China.
| | - Zhiqiang Liu
- Jilin Provincial Key Laboratory of Chinese Medicine Chemistry and Mass Spectrometry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China; State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China.
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Li K, Liu J, Qin X. Research progress of gut microbiota in hepatocellular carcinoma. J Clin Lab Anal 2022; 36:e24512. [PMID: 35719048 PMCID: PMC9279976 DOI: 10.1002/jcla.24512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the sixth most common cancer and the fourth leading cause of cancer-related death in the world. A number of challenges remain for the early detection and effective treatment of HCC. In recent years, microbiota have been proven to be associated with the development of HCC. Many studies have explored the pathogenesis, diagnostic marker, and therapeutic target potential of microbiota in hepatocellular carcinoma. Therefore, we aimed to introduce the research methods and achievements of gut microbiota in hepatocellular carcinoma and discuss the value of gut microbiota in the pathogenesis, diagnosis, and treatment of hepatocellular carcinoma. METHODS Keywords are used to search relevant articles which were mainly published from 2010 to 2021, and we further selected targeted articles and read the full text. RESULTS Gut microbiota involved in promoting the formation and development of hepatocellular carcinoma, and differential gut microbiota and microbial metabolites have the potential to be the biomarkers of hepatocellular carcinoma. Purposefully regulated gut microbiota can improve the prognosis of patients, which is expected to be used in hepatocellular carcinoma. CONCLUSION The study of gut microbiota in hepatocellular carcinoma is definitely worthy of study. In-depth and elaborate research design is crucial for the study of the mechanism of gut microbiota involved in hepatocellular carcinoma, which can provide new directions and targets for the diagnosis, treatment, and prognosis of hepatocellular carcinoma.
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Affiliation(s)
- Keliu Li
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China.,Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China
| | - Jianhua Liu
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China.,Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China
| | - Xiaosong Qin
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China.,Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China
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Yamaguchi T, Yoshida K, Murata M, Suwa K, Tsuneyama K, Matsuzaki K, Naganuma M. Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis. Int J Mol Sci 2022; 23:ijms23116270. [PMID: 35682957 PMCID: PMC9181097 DOI: 10.3390/ijms23116270] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/28/2022] [Accepted: 05/29/2022] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis with insulin resistance, oxidative stress, lipotoxicity, adipokine secretion by fat cells, endotoxins (lipopolysaccharides) released by gut microbiota, and endoplasmic reticulum stress. Together, these factors promote NAFLD progression from steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and eventually end-stage liver diseases in a proportion of cases. Hepatic fibrosis and carcinogenesis often progress together, sharing inflammatory pathways. However, NASH can lead to hepatocarcinogenesis with minimal inflammation or fibrosis. In such instances, insulin resistance, oxidative stress, and lipotoxicity can directly lead to liver carcinogenesis through genetic and epigenetic alterations. Transforming growth factor (TGF)-β signaling is implicated in hepatic fibrogenesis and carcinogenesis. TGF-β type I receptor (TβRI) and activated-Ras/c-Jun-N-terminal kinase (JNK) differentially phosphorylate the mediator Smad3 to create two phospho-isoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). TβRI/pSmad3C signaling terminates cell proliferation, while constitutive Ras activation and JNK-mediated pSmad3L promote hepatocyte proliferation and carcinogenesis. The pSmad3L signaling pathway also antagonizes cytostatic pSmad3C signaling. This review addresses TGF-β/Smad signaling in hepatic carcinogenesis complicating NASH. We also discuss Smad phospho-isoforms as biomarkers predicting HCC in NASH patients with or without cirrhosis.
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Affiliation(s)
- Takashi Yamaguchi
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
- Correspondence: ; Tel.: +81-72-804-0101; Fax: +81-72-804-2524
| | - Katsunori Yoshida
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Miki Murata
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Kanehiko Suwa
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Koichi Tsuneyama
- Department of Pathology & Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan;
| | - Koichi Matsuzaki
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
| | - Makoto Naganuma
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan; (K.Y.); (M.M.); (K.S.); (K.M.); (M.N.)
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Manzoor R, Ahmed W, Afify N, Memon M, Yasin M, Memon H, Rustom M, Al Akeel M, Alhajri N. Trust Your Gut: The Association of Gut Microbiota and Liver Disease. Microorganisms 2022; 10:1045. [PMID: 35630487 PMCID: PMC9146349 DOI: 10.3390/microorganisms10051045] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/08/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023] Open
Abstract
The gut microbiota composition is important for nutrient metabolism, mucosal barrier function, immunomodulation, and defense against pathogens. Alterations in the gut microbiome can disturb the gut ecosystem. These changes may lead to the loss of beneficial bacteria or an increase in potentially pathogenic bacteria. Furthermore, these have been shown to contribute to the pathophysiology of gastrointestinal and extra-intestinal diseases. Pathologies of the liver, such as non-alcoholic liver disease, alcoholic liver disease, cirrhosis, hepatocellular carcinoma, autoimmune hepatitis, viral hepatitis, and primary sclerosing cholangitis have all been linked to changes in the gut microbiome composition. There is substantial evidence that links gut dysbiosis to the progression and complications of these pathologies. This review article aimed to describe the changes seen in the gut microbiome in liver diseases and the association between gut dysbiosis and liver disease, and finally, explore treatment options that may improve gut dysbiosis in patients with liver disease.
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Affiliation(s)
- Ridda Manzoor
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Weshah Ahmed
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Nariman Afify
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Mashal Memon
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Maryam Yasin
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Hamda Memon
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Mohammad Rustom
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Mohannad Al Akeel
- Division of Family Medicine, Department of Health, Abu Dhabi P.O. Box 5674, United Arab Emirates;
| | - Noora Alhajri
- Department of Medicine, Sheikh Shakhbout Medical City (SSMC), Abu Dhabi P.O. Box 11001, United Arab Emirates
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Said I, Ahad H, Said A. Gut microbiome in non-alcoholic fatty liver disease associated hepatocellular carcinoma: Current knowledge and potential for therapeutics. World J Gastrointest Oncol 2022; 14:947-958. [PMID: 35646285 PMCID: PMC9124992 DOI: 10.4251/wjgo.v14.i5.947] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/14/2021] [Accepted: 04/16/2022] [Indexed: 02/06/2023] Open
Abstract
Metabolic diseases such as nonalcoholic fatty liver disease (NAFLD) are rising in incidence and are an increasingly common cause of cirrhosis and hepatocellular carcinoma (HCC). The gut microbiome is closely connected to the liver via the portal vein, and has recently been identified as a predictor of liver disease state. Studies in NAFLD, cirrhosis and HCC have identified certain microbial signatures associated with these diseases, with the disease-associated microbiome changes collectively referred to as dysbiosis. The pathophysiologic underpinnings of these observations are an area of ongoing investigation, with current evidence demonstrating that the gut microbiome can influence liver disease and carcinogenesis via effects on intestinal permeability (leaky gut) and activation of the innate immune system. In the innate immune system, pathogen recognition receptors (Toll like receptors) on resident liver cells and macrophages cause liver inflammation, fibrosis, hepatocyte proliferation and reduced antitumor immunity, leading to chronic liver disease and carcinogenesis. Dysbiosis-associated changes include increase in secondary bile acids and reduced expression of FXR (nuclear receptor), which have also been associated with deleterious effects on lipid and carbohydrate metabolism associated with progressive liver disease. Longitudinal experimental and clinical studies are needed in different populations to examine these questions further. The role of therapeutics that modulate the microbiome is an emerging field with experimental studies showing the potential of diet, probiotics, fecal microbiota transplantation and prebiotics in improving liver disease in experimental models. Clinical studies are ongoing with preliminary evidence showing improvement in liver enzymes and steatosis. The microbial profile is different in responders to cancer immunotherapy including liver cancer, but whether or not manipulation of the microbiome can be utilized to affect response is being investigated.
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Affiliation(s)
- Imaad Said
- Brown University, Providence, RI 02912, United States
| | - Hassan Ahad
- Kansas University, Lawrence, KS 66045, United States
| | - Adnan Said
- Division of Gastroenterology and Hepatology, Department of Medicine, William S. Middleton VAMC, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
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Xie Y, Sun R, Gao L, Guan J, Wang J, Bell A, Zhu J, Zhang M, Xu M, Lu P, Cai X, Ren S, Xu P, Monga SP, Ma X, Yang D, Liu Y, Lu B, Xie W. Chronic Activation of LXRα Sensitizes Mice to Hepatocellular Carcinoma. Hepatol Commun 2022; 6:1123-1139. [PMID: 34981658 PMCID: PMC9035576 DOI: 10.1002/hep4.1880] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/27/2021] [Accepted: 11/18/2021] [Indexed: 01/26/2023] Open
Abstract
The oxysterol receptor liver X receptor (LXR) is a nuclear receptor best known for its function in the regulation of lipid and cholesterol metabolism. LXRs, both the α and β isoforms, have been suggested as potential therapeutic targets for several cancer types. However, there was a lack of report on whether and how LXRα plays a role in the development of hepatocellular carcinoma (HCC). In the current study, we found that systemic activation of LXRα in the VP-LXRα knock-in (LXRαKI) mice or hepatocyte-specific activation of LXRα in the VP-LXRα transgenic mice sensitized mice to liver tumorigenesis induced by the combined treatment of diethylnitrosamine (DEN) and 3,3',5,5'-tetrachloro-1,4-bis (pyridyloxy) benzene (TCPOBOP). Mechanistically, the LXRα-responsive up-regulation of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway and the complement system, and down-regulation of bile acid metabolism, may have contributed to increased tumorigenesis. Accumulations of secondary bile acids and oxysterols were found in both the serum and liver tissue of LXRα activated mice. We also observed an induction of monocytic myeloid-derived suppressor cells accompanied by down-regulation of dendritic cells and cytotoxic T cells in DEN/TCPOBOP-induced liver tumors, indicating that chronic activation of LXRα may have led to the activation of innate immune suppression. The HCC sensitizing effect of LXRα activation was also observed in the c-MYC driven HCC model. Conclusion: Our results indicated that chronic activation of LXRα promotes HCC, at least in part, by promoting innate immune suppressor as a result of accumulation of oxysterols, as well as up-regulation of the IL-6/Janus kinase/STAT3 signaling and complement pathways.
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Affiliation(s)
- Yang Xie
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Runzi Sun
- Department of ImmunologyUniversity of PittsburghPittsburghPAUSA
| | - Li Gao
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
- Department of GastroenterologyPeking University People’s HospitalBeijingChina
| | - Jibin Guan
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Jingyuan Wang
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Aaron Bell
- Division of Experimental PathologyDepartment of PathologyUniversity of PittsburghPittsburghPAUSA
| | - Junjie Zhu
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Min Zhang
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Meishu Xu
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Peipei Lu
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Xinran Cai
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Songrong Ren
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Pengfei Xu
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Satdarshan P. Monga
- Division of Experimental PathologyDepartment of PathologyUniversity of PittsburghPittsburghPAUSA
- Pittsburgh Liver Research CenterUniversity of Pittsburgh Medical Center and University of Pittsburgh School of MedicinePittsburghPAUSA
| | - Xiaochao Ma
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Da Yang
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Yulan Liu
- Department of GastroenterologyPeking University People’s HospitalBeijingChina
| | - Binfeng Lu
- Department of ImmunologyUniversity of PittsburghPittsburghPAUSA
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
- Department of Pharmacology and Chemical BiologyUniversity of PittsburghPittsburghPAUSA
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Luo Y, Decato BE, Charles ED, Shevell DE, McNaney C, Shipkova P, Apfel A, Tirucherai GS, Sanyal AJ. Pegbelfermin selectively reduces secondary bile acid concentrations in patients with non-alcoholic steatohepatitis. JHEP REPORTS : INNOVATION IN HEPATOLOGY 2022; 4:100392. [PMID: 34977519 PMCID: PMC8689226 DOI: 10.1016/j.jhepr.2021.100392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 10/08/2021] [Accepted: 10/26/2021] [Indexed: 11/30/2022]
Abstract
Background & Aims Increased serum bile acids (BAs) have been observed in patients with non-alcoholic steatohepatitis (NASH). Pegbelfermin (PGBF), a polyethylene glycol-modified (PEGylated) analogue of human fibroblast growth factor 21 (FGF21), significantly decreased hepatic steatosis and improved fibrosis biomarkers and metabolic parameters in patients with NASH in a phase IIa trial. This exploratory analysis evaluated the effect of PGBF on serum BAs and explored potential underlying mechanisms. Methods Serum BAs and 7α-hydroxy-4-cholesten-3-one (C4) were measured by HPLC-mass spectrometry (MS) using serum collected in studies of patients with NASH (NCT02413372) and in overweight/obese adults (NCT03198182) who received PGBF. Stool samples were collected in NCT03198182 to evaluate faecal BAs by liquid chromatography (LC)-MS and the faecal microbiome by metagenetic and metatranscriptomic analyses. Results Significant reductions from baseline in serum concentrations of the secondary BA, deoxycholic acid (DCA), and conjugates, were observed with PGBF, but not placebo, in patients with NASH; primary BA concentrations did not significantly change in any arm. Similar effects of PGBF on BAs were observed in overweight/obese adults, allowing for an evaluation of the effects of PGBF on the faecal microbiome and BAs. Faecal transcriptomic analysis showed that the relative abundance of the gene encoding choloylglycine hydrolase, a critical enzyme for secondary BA synthesis, was reduced after PGBF, but not placebo, administration. Furthermore, a trend of reduction in faecal secondary BAs was observed. Conclusions PGBF selectively reduced serum concentrations of DCA and conjugates in patients with NASH and in healthy overweight/obese adults. Reduced choloylglycine hydrolase gene expression and decreased faecal secondary BA levels suggest a potential role for PGBF in modulating secondary BA synthesis by gut microbiome. The clinical significance of DCA reduction post-PGBF treatment warrants further investigation. Lay summary Pegbelfermin (PGBF) is a hormone that is currently being studied in clinical trials for the treatment of non-alcoholic fatty liver disease. In this study, we show that PGBF treatment can reduce bile acids that have previously been shown to have toxic effects on the liver. Additional studies to understand how PGBF regulates bile acids may provide additional information about its potential use as a treatment for fatty liver.
Bile acids are elevated in patients with non-alcoholic steatohepatitis. Pegbelfermin, a PEGylated human FGF21 analogue, is in phase II trials for non-alcoholic steatohepatitis. Pegbelfermin treatment was associated with secondary, but not primary, bile acid reductions. Pegbelfermin reduced expression of a gene responsible for secondary bile acid synthesis. Further study is needed to assess the clinical significance of these observations.
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Key Words
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- ApoA1, apolipoprotein A1
- BA, bile acid
- BSH, bile salt hydrolase
- Bile salt hydrolase
- Biomarkers
- C4
- C4, 7α-hydroxy-4-cholesten-3-one
- CA, cholic acid
- CDCA, chenodeoxycholic acid
- CYP7A1, cytochrome P450 7A1
- DCA, deoxycholic acid
- Deoxycholic acid
- FGF21
- FGF21, fibroblast growth factor 21
- FXR, farnesoid X receptor
- GCA, glyco-cholic acid
- GCDCA, glyco-chenodeoxycholic acid
- GDCA, glyco-deoxycholic acid
- GUDCA, glyco-ursodeoxycholic acid
- HFF, hepatic fat fraction
- HbA1c, glycated haemoglobin
- LC, liquid chromatography
- LCA, lithocholic acid
- MS, mass spectrometry
- Microbiome
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- PEGylated, polyethylene glycol-conjugated
- PGBF, pegbelfermin
- PRO-C3, N-terminal type III collagen propeptide
- QD, once daily
- QW, once weekly
- T2DM, type 2 diabetes mellitus
- TCA, tauro-cholic acid
- TCDCA, tauro-chenodeoxycholic acid
- TDCA, tauro-deoxycholic acid
- UDCA, ursodeoxycholic acid
- baiCD, 7α-hydroxy-3-oxo-delta4-cholenoic acid oxidoreductase
- baiH, 7β-hydroxy-3-oxo-delta4-cholenoic acid oxidoreductase
- hdhA, 7-alpha-hydroxysteroid dehydrogenase
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Affiliation(s)
- Yi Luo
- Bristol Myers Squibb, Princeton, NJ, USA
| | | | | | | | | | | | | | | | - Arun J Sanyal
- Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, VA, USA
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Ni Y, Lu M, Xu Y, Wang Q, Gu X, Li Y, Zhuang T, Xia C, Zhang T, Gou XJ, Zhou M. The Role of Gut Microbiota-Bile Acids Axis in the Progression of Non-alcoholic Fatty Liver Disease. Front Microbiol 2022; 13:908011. [PMID: 35832821 PMCID: PMC9271914 DOI: 10.3389/fmicb.2022.908011] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/06/2022] [Indexed: 02/05/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), an emerging global health problem affecting 25-30% of the total population, refers to excessive lipid accumulation in the liver accompanied by insulin resistance (IR) without significant alcohol intake. The increasing prevalence of NAFLD will lead to an increasing number of cirrhosis patients, as well as hepatocellular carcinoma (HCC) requiring liver transplantation, while the current treatments for NAFLD and its advanced diseases are suboptimal. Accordingly, it is necessary to find signaling pathways and targets related to the pathogenesis of NAFLD for the development of novel drugs. A large number of studies and reviews have described the critical roles of bile acids (BAs) and their receptors in the pathogenesis of NAFLD. The gut microbiota (GM), whose composition varies between healthy and NAFLD patients, promotes the transformation of more than 50 secondary bile acids and is involved in the pathophysiology of NAFLD through the GM-BAs axis. Correspondingly, BAs inhibit the overgrowth of GM and maintain a healthy gut through their antibacterial effects. Here we review the biosynthesis, enterohepatic circulation, and major receptors of BAs, as well as the relationship of GM, BAs, and the pathogenesis of NAFLD in different disease progression. This article also reviews several therapeutic approaches for the management and prevention of NAFLD targeting the GM-BAs axis.
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Affiliation(s)
- Yiming Ni
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Central Laboratory, Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mengna Lu
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuan Xu
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- School of Pharmacy, Shaanxi University of Traditional Chinese Medicine, Xianyang, China
| | - Qixue Wang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of Traditional Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xinyi Gu
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of Traditional Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ying Li
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of Traditional Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tongxi Zhuang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of Traditional Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chenyi Xia
- Department of Physiology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ting Zhang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of Traditional Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiao-jun Gou
- Central Laboratory, Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Xiao-jun Gou,
| | - Mingmei Zhou
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of Traditional Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Mingmei Zhou,
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Bi C, Xiao G, Liu C, Yan J, Chen J, Si W, Zhang J, Liu Z. Molecular Immune Mechanism of Intestinal Microbiota and Their Metabolites in the Occurrence and Development of Liver Cancer. Front Cell Dev Biol 2021; 9:702414. [PMID: 34957088 PMCID: PMC8693382 DOI: 10.3389/fcell.2021.702414] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 11/11/2021] [Indexed: 12/12/2022] Open
Abstract
Intestinal microorganisms are closely associated with immunity, metabolism, and inflammation, and play an important role in health and diseases such as inflammatory bowel disease, diabetes, cardiovascular disease, Parkinson’s disease, and cancer. Liver cancer is one of the most fatal cancers in humans. Most of liver cancers are slowly transformed from viral hepatitis, alcoholic liver disease, and non-alcoholic fatty liver disease. However, the relationship between intestinal microbiota and their metabolites, including short-chain fatty acids, bile acids, indoles, and ethanol, and liver cancer remains unclear. Here, we summarize the molecular immune mechanism of intestinal microbiota and their metabolites in the occurrence and development of liver cancer and reveal the important role of the microbiota-gut-liver axis in liver cancer. In addition, we describe how the intestinal flora can be balanced by antibiotics, probiotics, postbiotics, and fecal bacteria transplantation to improve the treatment of liver cancer. This review describes the immunomolecular mechanism of intestinal microbiota and their metabolites in the occurrence and development of hepatic cancer and provides theoretical evidence support for future clinical practice.
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Affiliation(s)
- Chenchen Bi
- Department of Pharmacology, Medical College of Shaoxing University, Shaoxing, China
| | - Geqiong Xiao
- Department of Oncology, Affiliated Hospital of Shaoxing University, Shaoxing, China
| | - Chunyan Liu
- Department of Clinical Medicine, Shaoxing People's Hospital, Shaoxing, China
| | - Junwei Yan
- Department of Pharmacology, Medical College of Shaoxing University, Shaoxing, China
| | - Jiaqi Chen
- Department of Pharmacology, Medical College of Shaoxing University, Shaoxing, China
| | - Wenzhang Si
- Department of General Surgery, Affiliated Hospital of Shaoxing University, Shaoxing, China
| | - Jian Zhang
- Department of Pharmacology, Medical College of Shaoxing University, Shaoxing, China
| | - Zheng Liu
- Department of Pharmacology, Medical College of Shaoxing University, Shaoxing, China
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Abstract
The microbiome modulates key processes in metabolism, inflammation, and immunity and plays pivotal roles in many gastrointestinal and liver diseases. Recent experimental studies have demonstrated a key role of the microbiome in hepatocarcinogenesis. Dysfunctions of the gut bacterial flora have a significant effect on liver disease. Dysbiosis is found to be associated with chronic liver diseases. Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related mortality. The majority of HCC develops in patients with chronic liver disease, caused by chronic viral hepatitis, nonalcoholic fatty liver disease (NAFLD), and alcohol-related fatty liver disease. This review discusses molecular mechanisms of gut microbiome-related hepatocarcinogenesis and the impact of dysbiosis on chronic liver disease progression.
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Affiliation(s)
- Hikmet Akkız
- Department of Gastroenterology and Hepatology, The University of Çukurova, Adana, Turkey.
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44
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Grgurevic I, Bozin T, Mikus M, Kukla M, O’Beirne J. Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease: From Epidemiology to Diagnostic Approach. Cancers (Basel) 2021; 13:5844. [PMID: 34830997 PMCID: PMC8616369 DOI: 10.3390/cancers13225844] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 11/14/2021] [Accepted: 11/17/2021] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is becoming the leading cause of liver morbidity worldwide and, as such, represents the pathogenic background for the increasing incidence of hepatocellular carcinoma (HCC). The annual incidence of NAFLD-related HCC is expected to increase by 45-130% by 2030. Diabetes mellitus is the most important risk factor for HCC development in NAFLD, with the risk further increased when associated with other metabolic traits, such as obesity, arterial hypertension and dyslipidemia. The highest risk of HCC exists in patients with advanced fibrosis or cirrhosis, although 20-50% of HCC cases arise in NAFLD patients with an absence of cirrhosis. This calls for further investigation of the pathogenic mechanisms that are involved in hepatocarcinogenesis, including genetics, metabolomics, the influence of the gut microbiota and immunological responses. Early identification of patients with or at risk of NAFLD is of utmost importance to improve outcomes. As NAFLD is highly prevalent in the community, the identification of cases should rely upon simple demographic and clinical characteristics. Once identified, these patients should then be evaluated for the presence of advanced fibrosis or cirrhosis and subsequently enter HCC surveillance programs if appropriate. A significant problem is the early recognition of non-cirrhotic NAFLD patients who will develop HCC, where new biomarkers and scores are potential solutions to tackle this issue.
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Affiliation(s)
- Ivica Grgurevic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10 000 Zagreb, Croatia;
- Faculty of Pharmacy and Biochemistry, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia
| | - Tonci Bozin
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10 000 Zagreb, Croatia;
| | - Mislav Mikus
- Department of Obstetrics and Gynecology, University Hospital Centre Zagreb, 10 000 Zagreb, Croatia;
| | - Michal Kukla
- Department of Internal Medicine and Geriatrics, Faculty of Medicine, Jagiellonian University Medical College, 30688 Cracow, Poland;
| | - James O’Beirne
- Department of Hepatology, University of the Sunshine Coast, Sunshine Coast 4556, Australia;
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45
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Giraud J, Saleh M. Host-Microbiota Interactions in Liver Inflammation and Cancer. Cancers (Basel) 2021; 13:cancers13174342. [PMID: 34503151 PMCID: PMC8430654 DOI: 10.3390/cancers13174342] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 08/20/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is a difficult to treat liver cancer that generally arises in individuals suffering from alcoholic or non-alcoholic fatty liver diseases. Inflammation, tissue injury and fibrosis are important precursors of HCC. In this review, we explore the links between the microbiota, inflammation and carcinogenesis in the context of HCC. We discuss how the gut and liver communicate and how microbial molecules, including structural components and metabolites, elicit inflammation and tumorigenesis in the liver. A better understanding of microbiota-dependent mechanisms of liver cancer development might lead to novel microbial-based therapeutic approaches. Abstract Hepatocellular carcinoma (HCC) is a classical inflammation-promoted cancer that occurs in a setting of liver diseases, including nonalcoholic fatty liver disease (NAFLD) or alcoholic liver disease (ALD). These pathologies share key characteristics, notably intestinal dysbiosis, increased intestinal permeability and an imbalance in bile acids, choline, fatty acids and ethanol metabolites. Translocation of microbial- and danger-associated molecular patterns (MAMPs and DAMPs) from the gut to the liver elicits profound chronic inflammation, leading to severe hepatic injury and eventually HCC progression. In this review, we first describe how the gut and the liver communicate and discuss mechanisms by which the intestinal microbiota elicit hepatic inflammation and HCC. We focus on the role of microbial products, e.g., MAMPs, host inflammatory effectors and host–microbiome-derived metabolites in tumor-promoting mechanisms, including cell death and senescence. Last, we explore the potential of harnessing the microbiota to treat liver diseases and HCC.
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Affiliation(s)
- Julie Giraud
- ImmunoConcEpT, CNRS, UMR 5164, University of Bordeaux, F-33000 Bordeaux, France;
| | - Maya Saleh
- ImmunoConcEpT, CNRS, UMR 5164, University of Bordeaux, F-33000 Bordeaux, France;
- Department of Medicine, McGill University, Montreal, QC H3G 0B1, Canada
- Correspondence:
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Visekruna A, Luu M. The Role of Short-Chain Fatty Acids and Bile Acids in Intestinal and Liver Function, Inflammation, and Carcinogenesis. Front Cell Dev Biol 2021; 9:703218. [PMID: 34381785 PMCID: PMC8352571 DOI: 10.3389/fcell.2021.703218] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/06/2021] [Indexed: 12/12/2022] Open
Abstract
During the past decade, researchers have investigated the role of microbiota in health and disease. Recent findings support the hypothesis that commensal bacteria and in particular microbiota-derived metabolites have an impact on development of inflammation and carcinogenesis. Major classes of microbial-derived molecules such as short-chain fatty acids (SCFA) and secondary bile acids (BAs) were shown to have immunomodulatory potential in various autoimmune, inflammatory as well as cancerous disease models and are dependent on diet-derived substrates. The versatile mechanisms underlying both beneficial and detrimental effects of bacterial metabolites comprise diverse regulatory pathways in lymphocytes and non-immune cells including changes in the signaling, metabolic and epigenetic status of these. Consequently, SCFAs as strong modulators of immunometabolism and histone deacetylase (HDAC) inhibitors have been investigated as therapeutic agents attenuating inflammatory and autoimmune disorders. Moreover, BAs were shown to modulate the microbial composition, adaptive and innate immune response. In this review, we will discuss the recent findings in the field of microbiota-derived metabolites, especially with respect to the molecular and cellular mechanisms of SCFA and BA biology in the context of intestinal and liver diseases.
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Affiliation(s)
- Alexander Visekruna
- Institute for Medical Microbiology and Hygiene, Philipps-University Marburg, Marburg, Germany
| | - Maik Luu
- Institute for Medical Microbiology and Hygiene, Philipps-University Marburg, Marburg, Germany.,Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
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47
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Temraz S, Nassar F, Kreidieh F, Mukherji D, Shamseddine A, Nasr R. Hepatocellular Carcinoma Immunotherapy and the Potential Influence of Gut Microbiome. Int J Mol Sci 2021; 22:ijms22157800. [PMID: 34360566 PMCID: PMC8346024 DOI: 10.3390/ijms22157800] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 06/30/2021] [Accepted: 06/30/2021] [Indexed: 02/06/2023] Open
Abstract
Disruptions in the human gut microbiome have been associated with a cycle of hepatocyte injury and regeneration characteristic of chronic liver disease. Evidence suggests that the gut microbiota can promote the development of hepatocellular carcinoma through the persistence of this inflammation by inducing genetic and epigenetic changes leading to cancer. As the gut microbiome is known for its effect on host metabolism and immune response, it comes as no surprise that the gut microbiome may have a role in the response to therapeutic strategies such as immunotherapy and chemotherapy for liver cancer. Gut microbiota may influence the efficacy of immunotherapy by regulating the responses to immune checkpoint inhibitors in patients with hepatocellular carcinoma. Here, we review the mechanisms by which gut microbiota influences hepatic carcinogenesis, the immune checkpoint inhibitors currently being used to treat hepatocellular carcinoma, as well as summarize the current findings to support the potential critical role of gut microbiome in hepatocellular carcinoma (HCC) immunotherapy.
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Affiliation(s)
- Sally Temraz
- Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, Beirut 1107 2020, Lebanon; (F.N.); (F.K.); (D.M.); (A.S.)
- Correspondence: (S.T.); (R.N.)
| | - Farah Nassar
- Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, Beirut 1107 2020, Lebanon; (F.N.); (F.K.); (D.M.); (A.S.)
| | - Firas Kreidieh
- Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, Beirut 1107 2020, Lebanon; (F.N.); (F.K.); (D.M.); (A.S.)
| | - Deborah Mukherji
- Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, Beirut 1107 2020, Lebanon; (F.N.); (F.K.); (D.M.); (A.S.)
| | - Ali Shamseddine
- Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, Beirut 1107 2020, Lebanon; (F.N.); (F.K.); (D.M.); (A.S.)
| | - Rihab Nasr
- Department of Anatomy, Cell Biology and Physiology, American University of Beirut Medical Center, Riad El Solh, Beirut 1107 2020, Lebanon
- Correspondence: (S.T.); (R.N.)
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48
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Yeh H, Chiang CC, Yen TH. Hepatocellular carcinoma in patients with renal dysfunction: Pathophysiology, prognosis, and treatment challenges. World J Gastroenterol 2021; 27:4104-4142. [PMID: 34326614 PMCID: PMC8311541 DOI: 10.3748/wjg.v27.i26.4104] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/17/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
The population of patients with hepatocellular carcinoma (HCC) overlaps to a high degree with those for chronic kidney disease (CKD) and end-stage renal disease (ESRD). The degrees of renal dysfunction vary, from the various stages of CKD to dialysis-dependent ESRD, which often affects the prognosis and treatment choice of patients with HCC. In addition, renal dysfunction makes treatment more difficult and may negatively affect treatment outcomes. This study summarized the possible causes of the high comorbidity of HCC and renal dysfunction. The possible mechanisms of CKD causing HCC involve uremia itself, long-term dialysis status, immunosuppressive agents for postrenal transplant status, and miscellaneous factors such as hormone alterations and dysbiosis. The possible mechanisms of HCC affecting renal function include direct tumor invasion and hepatorenal syndrome. Finally, we categorized the risk factors that could lead to both HCC and CKD into four categories: Environmental toxins, viral hepatitis, metabolic syndrome, and vasoactive factors. Both CKD and ESRD have been reported to negatively affect HCC prognosis, but more research is warranted to confirm this. Furthermore, ESRD status itself ought not to prevent patients receiving aggressive treatments. This study then adopted the well-known Barcelona Clinic Liver Cancer guidelines as a framework to discuss the indicators for each stage of HCC treatment, treatment-related adverse renal effects, and concerns that are specific to patients with pre-existing renal dysfunction when undergoing aggressive treatments against CKD and ESRD. Such aggressive treatments include liver resection, simultaneous liver kidney transplantation, radiofrequency ablation, and transarterial chemoembolization. Finally, focusing on patients unable to receive active treatment, this study compiled information on the latest systemic pharmacological therapies, including targeted and immunotherapeutic drugs. Based on available clinical studies and Food and Drug Administration labels, this study details the drug indications, side effects, and dose adjustments for patients with renal dysfunction. It also provides a comprehensive review of information on HCC patients with renal dysfunction from disease onset to treatment.
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Affiliation(s)
- Hsuan Yeh
- Department of Nephrology, Chang Gung Memorial Hospital and Chang Gung University, Taipei 105, Taiwan
| | - Chun-Cheng Chiang
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Tzung-Hai Yen
- Department of Nephrology, Chang Gung Memorial Hospital and Chang Gung University, Taipei 105, Taiwan
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49
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Korlepara V, Kumar N, Banerjee S. Gut Microbiota And Inflammatory Disorders. Curr Drug Targets 2021; 23:156-169. [PMID: 34165407 DOI: 10.2174/1389450122666210623125603] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/14/2021] [Accepted: 03/18/2021] [Indexed: 11/22/2022]
Abstract
The gut has been colonized with bacteria, fungi, viruses, archaea, eukarya. The human and bacterial cells are found in a 1:1 ratio, while the variance in the diversity of gut microbiota may result in Dysbiosis. Gut dysbiosis may result in various pathological manifestations. Beneficial gut microbiota may synthesize short-chain fatty acids like acetate, butyrate, propionate, while -gram-negative organisms are the primary source of LPS, a potent pro-inflammatory mediator. Both gut microbiota and microbial products may be involved in immunomodulation as well as inflammation. Prebiotics and probiotics are being explored as therapeutic agents against various inflammatory and autoimmune disorders. Here we discuss the molecular mechanisms involved in gut bacteria-mediated modulation of various inflammatory and autoimmune disorders.
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Affiliation(s)
- Vamsi Korlepara
- Department of Pharmacology and Toxicology National Institute of Pharmaceutical Education and Research, Kolkata, India
| | - Naveen Kumar
- Department of Pharmacology and Toxicology National Institute of Pharmaceutical Education and Research, Kolkata, India
| | - Sugato Banerjee
- Department of Pharmacology and Toxicology National Institute of Pharmaceutical Education and Research, Kolkata, India
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50
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Xu J, Zhan Q, Fan Y, Lo EKK, Zhang F, Yu Y, El-Nezami H, Zeng Z. Clinical Aspects of Gut Microbiota in Hepatocellular Carcinoma Management. Pathogens 2021; 10:pathogens10070782. [PMID: 34206200 PMCID: PMC8308793 DOI: 10.3390/pathogens10070782] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 06/13/2021] [Accepted: 06/18/2021] [Indexed: 01/02/2023] Open
Abstract
Liver cancer, predominantly hepatocellular carcinoma (HCC), is the third leading cause of cancer-related deaths worldwide. Emerging data highlight the importance of gut homeostasis in the pathogenesis of HCC. Clinical and translational studies revealed the patterns of dysbiosis in HCC patients and their potential role for HCC diagnosis. Research on underlying mechanisms of dysbiosis in HCC development pointed out the direction for improving the treatment and prevention. Despite missing clinical studies, animal models showed that modulation of the gut microbiota by probiotics may become a new way to treat or prevent HCC development.
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Affiliation(s)
- Jinghang Xu
- Department of Infectious Diseases, Peking University First Hospital, Peking University, Beijing 100034, China; (J.X.); (Q.Z.); (Y.F.); (Y.Y.)
| | - Qiao Zhan
- Department of Infectious Diseases, Peking University First Hospital, Peking University, Beijing 100034, China; (J.X.); (Q.Z.); (Y.F.); (Y.Y.)
| | - Yanan Fan
- Department of Infectious Diseases, Peking University First Hospital, Peking University, Beijing 100034, China; (J.X.); (Q.Z.); (Y.F.); (Y.Y.)
| | - Emily Kwun Kwan Lo
- School of Biological Sciences, University of Hong Kong, Pokfulam 999077, Hong Kong, China; (E.K.K.L.); (F.Z.)
| | - Fangfei Zhang
- School of Biological Sciences, University of Hong Kong, Pokfulam 999077, Hong Kong, China; (E.K.K.L.); (F.Z.)
| | - Yanyan Yu
- Department of Infectious Diseases, Peking University First Hospital, Peking University, Beijing 100034, China; (J.X.); (Q.Z.); (Y.F.); (Y.Y.)
| | - Hani El-Nezami
- School of Biological Sciences, University of Hong Kong, Pokfulam 999077, Hong Kong, China; (E.K.K.L.); (F.Z.)
- Institute of Public Health and Clinical Nutrition, School of Medicine, University of Eastern Finland, FI-70211 Kuopio, Finland
- Correspondence: (H.E.-N.); (Z.Z.)
| | - Zheng Zeng
- Department of Infectious Diseases, Peking University First Hospital, Peking University, Beijing 100034, China; (J.X.); (Q.Z.); (Y.F.); (Y.Y.)
- Correspondence: (H.E.-N.); (Z.Z.)
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