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Zhang F, Lo EKK, Chen C, Lee JCY, Felicianna, Ismaiah MJ, Leung HKM, Tsang DHL, El-Nezami H. Probiotics Mixture, Prohep: a Potential Adjuvant for Low-Dose Sorafenib in Metabolic Dysfunction-Associated Steatotic Liver Disease-Associated Hepatocellular Carcinoma Suppression Through Modulating Gut Microbiota. Probiotics Antimicrob Proteins 2025:10.1007/s12602-025-10593-4. [PMID: 40405038 DOI: 10.1007/s12602-025-10593-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/11/2025] [Indexed: 05/24/2025]
Abstract
Targeting gut microbiota is an innovative approach to mitigate the development of metabolic dysfunction-associated steatotic liver disease-associated hepatocellular carcinoma (MASLD-HCC). This study aims to investigate the effects of Prohep, a probiotic mixture, both as a prophylactic measure and as an adjuvant therapy for low-dose sorafenib. A MASLD-HCC mice model was established by diethylnitrosamine (DEN) injection with feeding of a high-fat high-cholesterol (HFHC) diet. Gut microbiome profiles were later identified through shotgun sequencing. Our findings demonstrated that Prohep supplementation effectively suppressed MASLD-HCC development in mice. This protective effect was attributed to the modulation of gut microbiota and the increased production of short-chain fatty acids (SCFAs), propionate, and valerate. Prohep also activated AMPK, which decreased lipogenesis, reduced lipid uptake, and enhanced antioxidant enzyme expressions. Additionally, the cancer proliferation pathway PI3K/mTOR was inhibited in response to Prohep treatment. As an adjuvant therapy, Prohep improved the efficacy of low-dose sorafenib, as indicated by reduced tumor counts, alleviated inflammation, and increased hepatic superoxide dismutase (SOD) expression. The combination led to enhanced butyrate production, contributing to the overall therapeutic effects, thanks to the gut microbiota modulatory effects of Prohep. These results underscore Prohep's anti-tumorigenic properties and its potential to enhance the therapeutic outcomes of low-dose sorafenib in MASLD-HCC treatment. The study highlights the importance of gut microbiota modulation for developing effective neoadjuvant therapies and long-term management strategies for MASLD-HCC.
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Affiliation(s)
- Fangfei Zhang
- School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China
| | - Emily Kwun Kwan Lo
- School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China
| | - Congjia Chen
- School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China
| | - Jetty Chung-Yung Lee
- School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China
| | - Felicianna
- School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China
| | - Marsena Jasiel Ismaiah
- School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China
| | - Hoi Kit Matthew Leung
- School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China
| | - Dorothy Hin Lam Tsang
- School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China
| | - Hani El-Nezami
- School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China.
- Institute of Public Health and Clinical Nutrition, School of Medicine, University of Eastern Finland, Kuopio, 70211, Finland.
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Abiru S, Kugiyama Y, Suehiro T, Motoyoshi Y, Saeki A, Nagaoka S, Yamasaki K, Komori A, Yatsuhashi H. Lactitol may improve the prognosis of hepatocellular carcinoma through the proliferation of Megasphaera as well as Bifidobacterium. Front Med (Lausanne) 2025; 12:1567849. [PMID: 40438352 PMCID: PMC12116508 DOI: 10.3389/fmed.2025.1567849] [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: 01/28/2025] [Accepted: 04/28/2025] [Indexed: 06/01/2025] Open
Abstract
Background Increasing evidence suggests that gut microbiota and their metabolites can modulate antitumor immunity. However, sufficient evidence from human studies is lacking. We evaluated the association of lactitol and lactulose as prebiotics with the progression of hepatocellular carcinoma (HCC). Methods In Study 1, the effects of lactitol and lactulose on overall survival (OS) of patients with HCC with Child-Pugh scores of B or C were investigated in patients diagnosed at the Nagasaki Medical Center between 2003 and 2020. In Study 2, the effects of these substances on the gut microbiota of patients with cirrhosis were analyzed. Study 3 examined the effect of these substances on serum albumin levels in patients with cirrhosis. Results In Study 1, a total of 321 patients were evaluated, and 55 pairs of Lactitol and Non-Lactitol groups and 80 pairs of Lactulose and Non-Lactulose groups were created using one to one propensity score matching. The Lactitol group showed a significant improvement (p < 0.05) in OS compared to the Non-Lactitol group, but the Lactulose group did not show any significance compared to the Non-Lactulose group. In Study 2, the number of Bifidobacterium was higher in the Lactitol group and the Lactulose group than in the Control group, but the number of Megasphaera was significantly higher only in the Lactitol group. In addition, in a study of 10 cases in which the gut microbiota was examined before and after lactitol use, an increase in Bifidobacterium and Megasphaera was observed after lactitol use. Study 3 found that lactitol had no beneficial effect on serum albumin levels. Conclusion Lactitol may improve the prognosis of HCC through the proliferation of Megasphaera as well as Bifidobacterium.
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Affiliation(s)
- Seigo Abiru
- Department of Internal Medicine, NHO Saga Hospital, Saga, Japan
- Clinical Research Center, NHO Nagasaki Medical Center, Nagasaki, Japan
| | - Yuki Kugiyama
- Clinical Research Center, NHO Nagasaki Medical Center, Nagasaki, Japan
| | - Tomoyuki Suehiro
- Clinical Research Center, NHO Nagasaki Medical Center, Nagasaki, Japan
| | | | - Akira Saeki
- Clinical Research Center, NHO Nagasaki Medical Center, Nagasaki, Japan
| | - Shinya Nagaoka
- Clinical Research Center, NHO Nagasaki Medical Center, Nagasaki, Japan
| | - Kazumi Yamasaki
- Clinical Research Center, NHO Nagasaki Medical Center, Nagasaki, Japan
| | - Atsumasa Komori
- Clinical Research Center, NHO Nagasaki Medical Center, Nagasaki, Japan
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Guo H, Wang J, Huang S, Sooranna SR, Shu F, Li G. Long-Term Exposure to Microplastics Promotes Early-Stage Hepatocarcinogenesis Induced by Diethylnitrosamine in Rats by Modulation of Their Gut Microbiota. TOXICS 2025; 13:353. [PMID: 40423432 DOI: 10.3390/toxics13050353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2025] [Revised: 04/23/2025] [Accepted: 04/26/2025] [Indexed: 05/28/2025]
Abstract
Hepatocarcinogenesis is linked to environmental factors, with microplastics (MPs) emerging as a global environmental concern that may contribute to liver injury. However, the impact of MPs on the early stages of hepatocarcinogenesis has been largely ignored. Here we investigated the impact of long-term MP exposure on the formation of preneoplastic lesions during hepatocarcinogenesis induced by diethylnitrosamine (DEN) in rats. Rats were injected with DEN to induce preneoplastic lesions, and then they were orally administered with 1 µm MPs 0.5 mg/kg body weight per day for 20 weeks. The results revealed that long-term exposure to MPs did not induce the formation of glutathione S-transferase placental form (GST-P)-positive foci as preneoplastic lesions during hepatocarcinogenesis in these animals, thereby indicating non-carcinogenicity. However, MP exposure resulted in a 1-fold increase in both the number and size of GST-P-positive foci in rats initiated with DEN compared to those treated with DEN alone. Accordingly, MP exposure led to a 0.61-fold increase in the index of proliferating cell nuclear antigen (PCNA)-positive cells in DEN-initiated rats when compared to DEN treatment alone. In addition, the composition of the gut microbiota was significantly altered, accompanied by various levels of short-chain fatty acids. Our results suggest that long-term MP exposure can promote pre-neoplastic lesion formation in DEN-induced rats by increased cell proliferation as well as alterations in the gut microbiota and short-chain fatty acid levels. This highlights the potential health risks associated with hepatocarcinogenesis linked to long-term exposure to MPs.
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Affiliation(s)
- Huina Guo
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise 533000, China
| | - Jianan Wang
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise 533000, China
| | - Shaowen Huang
- Department of Laboratory Medicine, Baise People's Hospital, Baise 533000, China
| | - Suren Rao Sooranna
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London SW10 9NH, UK
| | - Fangyi Shu
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise 533000, China
| | - Genliang Li
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise 533000, China
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Anwer EKE, Ajagbe M, Sherif M, Musaibah AS, Mahmoud S, ElBanbi A, Abdelnaser A. Gut Microbiota Secondary Metabolites: Key Roles in GI Tract Cancers and Infectious Diseases. Biomedicines 2025; 13:100. [PMID: 39857684 PMCID: PMC11762448 DOI: 10.3390/biomedicines13010100] [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: 12/04/2024] [Revised: 12/23/2024] [Accepted: 12/27/2024] [Indexed: 01/27/2025] Open
Abstract
The gut microbiota, a dynamic ecosystem of trillions of microorganisms, produces secondary metabolites that profoundly influence host health. Recent research has highlighted the significant role of these metabolites, particularly short-chain fatty acids, indoles, and bile acids, in modulating immune responses, impacting epigenetic mechanisms, and contributing to disease processes. In gastrointestinal (GI) cancers such as colorectal, liver, and gastric cancer, microbial metabolites can drive tumorigenesis by promoting inflammation, DNA damage, and immune evasion. Conversely, these same metabolites hold therapeutic promise, potentially enhancing responses to chemotherapy and immunotherapy and even directly suppressing tumor growth. In addition, gut microbial metabolites play crucial roles in infectious disease susceptibility and resilience, mediating immune pathways that impact pathogen resistance. By consolidating recent insights into the gut microbiota's role in shaping disease and health, this review underscores the therapeutic potential of targeting microbiome-derived metabolites for treating GI cancers and infectious diseases and calls for further research into microbiome-based interventions.
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Affiliation(s)
- Eman K. E. Anwer
- Biotechnology Graduate Program, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt; (E.K.E.A.); (M.A.); (M.S.)
- Department of Microbiology and Immunology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo 4411601, Egypt
| | - Muhammad Ajagbe
- Biotechnology Graduate Program, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt; (E.K.E.A.); (M.A.); (M.S.)
| | - Moustafa Sherif
- Biotechnology Graduate Program, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt; (E.K.E.A.); (M.A.); (M.S.)
| | - Abobaker S. Musaibah
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt; (A.S.M.); (S.M.)
| | - Shuaib Mahmoud
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt; (A.S.M.); (S.M.)
| | - Ali ElBanbi
- Biology Department, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt;
| | - Anwar Abdelnaser
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt; (A.S.M.); (S.M.)
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Chen P, Yang C, Ren K, Xu M, Pan C, Ye X, Li L. Modulation of gut microbiota by probiotics to improve the efficacy of immunotherapy in hepatocellular carcinoma. Front Immunol 2024; 15:1504948. [PMID: 39650662 PMCID: PMC11621041 DOI: 10.3389/fimmu.2024.1504948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 11/04/2024] [Indexed: 12/11/2024] Open
Abstract
Hepatocellular carcinoma, a common malignancy of the digestive system, typically progresses through a sequence of hepatitis, liver fibrosis, cirrhosis and ultimately, tumor. The interaction between gut microbiota, the portal venous system and the biliary tract, referred to as the gut-liver axis, is crucial in understanding the mechanisms that contribute to the progression of hepatocellular carcinoma. Mechanisms implicated include gut dysbiosis, alterations in microbial metabolites and increased intestinal barrier permeability. Imbalances in gut microbiota, or dysbiosis, contributes to hepatocellular carcinoma by producing carcinogenic substances, disrupting the balance of the immune system, altering metabolic processes, and increasing intestinal barrier permeability. Concurrently, accumulating evidence suggests that gut microbiota has the ability to modulate antitumor immune responses and affect the efficacy of cancer immunotherapies. As a new and effective strategy, immunotherapy offers significant potential for managing advanced stages of hepatocellular carcinoma, with immune checkpoint inhibitors achieving significant advancements in improving patients' survival. Probiotics play a vital role in promoting health and preventing diseases by modulating metabolic processes, inflammation and immune responses. Research indicates that they are instrumental in boosting antitumor immune responses through the modulation of gut microbiota. This review is to explore the relationship between gut microbiota and the emergence of hepatocellular carcinoma, assess the contributions of probiotics to immunotherapy and outline the latest research findings, providing a safer and more cost-effective potential strategy for the prevention and management of hepatocellular carcinoma.
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Affiliation(s)
- Ping Chen
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan (Hangzhou) Hospital, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Chengchen Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ke Ren
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Mingzhi Xu
- Department of General Medicine, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Chenwei Pan
- Department of Infectious Diseases, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xuewei Ye
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan (Hangzhou) Hospital, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
- Key Laboratory of Pollution Exposure and Health Intervention of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Aslam S, Qasim M, Noor F, Shahid M, Ashfaq UA, Munir S, Al-Harthi HF, Mashraqi MM, Waqas U, Khurshid M. Potential Target Metabolites From Gut Microbiota Against Hepatocellular Carcinoma: A Network Pharmacology and Molecular Docking Study. Int J Microbiol 2024; 2024:4286228. [PMID: 39502516 PMCID: PMC11537736 DOI: 10.1155/2024/4286228] [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: 05/20/2024] [Accepted: 10/16/2024] [Indexed: 11/08/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, posing significant challenges and economic burdens on healthcare systems. Gut microbiota metabolites have shown promise in cancer treatment, but the specific active metabolites and their key targets remain unclear. This study employed a network pharmacology-based approach to identify potent metabolites of gut microbiota and their key targets. Active metabolites produced by gut microbiota were retrieved using the database gutMGene, and targets associated with these metabolites were identified using the Swiss Target Prediction tool. HCC-related targets were obtained from the GeneCards database, and overlapping targets were selected through a Venn diagram tool. An integrated metabolites-target-pathway network was analyzed to identify active inhibitors against HCC, including p-cresol glucuronide, secoisolariciresinol, glycocholic acid, enterodiol, and citric acid. Molecular docking tests were performed to validate the findings and assess the binding affinity of the metabolites with their target proteins. The study identified AKT1, EGFR, ALB, and TNF genes as potential therapeutic targets against hepatic cancer. The metabolites, p-cresol glucuronide, secoisolariciresinol, glycocholic acid, enterodiol, and citric acid, exhibited significant binding affinity with their respective target proteins. The study also revealed multiple signaling pathways and biological processes associated with the metabolites, demonstrating their preventive effect against HCC. This research utilizes a network pharmacology-based approach to identify potent metabolites of gut microbiota and their key targets for the treatment of HCC. The findings were validated through molecular docking tests, providing a foundation for future studies on anti-HCC metabolites and their mechanisms of action. Furthermore, this study offers insights into the development of novel anti-HCC drugs utilizing gut microbiota metabolites.
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Affiliation(s)
- Sehar Aslam
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Muhammad Qasim
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Fatima Noor
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
| | - Muhammad Shahid
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Usman Ali Ashfaq
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Samman Munir
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Helal F. Al-Harthi
- Biology Department, Turabah University College, Taif University, Taif 21995, Saudi Arabia
| | - Mutaib M. Mashraqi
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, Najran University, Najran 61441, Saudi Arabia
| | - Umair Waqas
- College of Science and Engineering, Flinders University, Bedford Park, Adelaide, South Australia, Australia
| | - Mohsin Khurshid
- Institute of Microbiology, Government College University Faisalabad, Faisalabad, Pakistan
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Yang Y, Fan G, Lan J, Li X, Li X, Liu R. Polysaccharide-mediated modulation of gut microbiota in the treatment of liver diseases: Promising approach with significant challenges. Int J Biol Macromol 2024:135566. [PMID: 39270901 DOI: 10.1016/j.ijbiomac.2024.135566] [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: 07/09/2024] [Revised: 09/06/2024] [Accepted: 09/09/2024] [Indexed: 09/15/2024]
Abstract
Liver disease represents a significant global health burden, with an increasing prevalence and a lack of efficient treatment options. The microbiota-gut-liver axis involves bidirectional communication between liver function and intestinal microorganisms. A balanced gut flora protects intestinal homeostasis, while imbalances contribute to the development of liver diseases. Distinct alterations in the structure of gut flora during illness are crucial in the management of various liver diseases. Polysaccharides derived from herbal products, fungi, and other sources have been identified to possess diverse biological activities and are well-tolerated in the treatment of liver diseases. This review provides updates on the therapeutic effects of polysaccharides on liver diseases, including fatty liver diseases, acute liver injuries and liver cancers. It also summarizes advancements in understanding the mechanisms involved, particularly from the perspective of gut microbiota and metabolites, by highlighting the changes in the composition of potentially beneficial and harmful bacteria and their correlation with the therapeutic effects of polysaccharides. Additionally, by exploring the structure-activity relationship, our review provides valuable insights for the structural modification of polysaccharides and expanding their applications. In conclusion, this review offers theoretical support and novel perspectives on developing polysaccharides-based therapeutic approaches for the treatment of liver diseases.
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Affiliation(s)
- Yang Yang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Guifang Fan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Jianhang Lan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Xin Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Xiaojiaoyang Li
- School of Life Sciences, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Runping Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China.
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Réthi-Nagy Z, Juhász S. Microbiome's Universe: Impact on health, disease and cancer treatment. J Biotechnol 2024; 392:161-179. [PMID: 39009231 DOI: 10.1016/j.jbiotec.2024.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 05/27/2024] [Accepted: 07/07/2024] [Indexed: 07/17/2024]
Abstract
The human microbiome is a diverse ecosystem of microorganisms that reside in the body and influence various aspects of health and well-being. Recent advances in sequencing technology have brought to light microbial communities in organs and tissues that were previously considered sterile. The gut microbiota plays an important role in host physiology, including metabolic functions and immune modulation. Disruptions in the balance of the microbiome, known as dysbiosis, have been linked to diseases such as cancer, inflammatory bowel disease and metabolic disorders. In addition, the administration of antibiotics can lead to dysbiosis by disrupting the structure and function of the gut microbial community. Targeting strategies are the key to rebalancing the microbiome and fighting disease, including cancer, through interventions such as probiotics, fecal microbiota transplantation (FMT), and bacteria-based therapies. Future research must focus on understanding the complex interactions between diet, the microbiome and cancer in order to optimize personalized interventions. Multidisciplinary collaborations are essential if we are going to translate microbiome research into clinical practice. This will revolutionize approaches to cancer prevention and treatment.
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Affiliation(s)
- Zsuzsánna Réthi-Nagy
- Hungarian Centre of Excellence for Molecular Medicine, Cancer Microbiome Core Group, Budapesti út 9, Szeged H-6728, Hungary
| | - Szilvia Juhász
- Hungarian Centre of Excellence for Molecular Medicine, Cancer Microbiome Core Group, Budapesti út 9, Szeged H-6728, Hungary.
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Kotlyarov S. Importance of the gut microbiota in the gut-liver axis in normal and liver disease. World J Hepatol 2024; 16:878-882. [PMID: 38948437 PMCID: PMC11212653 DOI: 10.4254/wjh.v16.i6.878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 05/01/2024] [Accepted: 05/17/2024] [Indexed: 06/20/2024] Open
Abstract
The gut microbiota is of growing interest to clinicians and researchers. This is because there is a growing understanding that the gut microbiota performs many different functions, including involvement in metabolic and immune processes that are systemic in nature. The liver, with its important role in detoxifying and metabolizing products from the gut, is at the forefront of interactions with the gut microbiota. Many details of these interactions are not yet known to clinicians and researchers, but there is growing evidence that normal gut microbiota function is important for liver health. At the same time, factors affecting the gut microbiota, including nutrition or medications, may also have an effect through the gut-liver axis.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, Ryazan 390026, Russia.
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Ramachandran G, Pottakkat B. Probiotics-A Promising Novel Therapeutic Approach in the Management of Chronic Liver Diseases. J Med Food 2024; 27:467-476. [PMID: 38574254 DOI: 10.1089/jmf.2023.k.0129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/06/2024] Open
Abstract
An increased incidence of liver diseases has been observed in recent years and is associated with gut dysbiosis, which causes bacterial infection, intestinal permeability, and further leads to disease-related complications. Probiotics, active microbial strains, are gaining more clinical importance due to their beneficial effect in the management of many diseases, including liver diseases. Clinical scenarios show strong evidence that probiotics have efficacy in treating liver diseases due to their ability to improve epithelial barrier function, prevent bacterial translocation, and boost the immune system. Moreover, probiotics survive both bile and gastric acid to reach the gut and exert their health benefit. Evidence shows that probiotics are a promising approach to prevent several complications in clinical practice. Herein, we discuss the recent evidence, challenges, and appropriate use of probiotics in managing advanced liver diseases, which may have an impact on future therapeutic strategies. Furthermore, the superior effect of strain-specific probiotics and their efficacy and safety in managing liver diseases are discussed.
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Affiliation(s)
- Gokulapriya Ramachandran
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Biju Pottakkat
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
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Sivaprasadan S, Anila KN, Nair K, Mallick S, Biswas L, Valsan A, Praseedom RK, Nair BKG, Sudhindran S. Microbiota and Gut-Liver Axis: An Unbreakable Bond? Curr Microbiol 2024; 81:193. [PMID: 38805045 DOI: 10.1007/s00284-024-03694-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 04/08/2024] [Indexed: 05/29/2024]
Abstract
The gut microbiota, amounting to approximately 100 trillion (1014) microbes represents a genetic repertoire that is bigger than the human genome itself. Evidence on bidirectional interplay between human and microbial genes is mounting. Microbiota probably play vital roles in diverse aspects of normal human metabolism, such as digestion, immune modulation, and gut endocrine function, as well as in the genesis and progression of many human diseases. Indeed, the gut microbiota has been most closely linked to various chronic ailments affecting the liver, although concrete scientific data are sparse. In this narrative review, we initially discuss the basic epidemiology of gut microbiota and the factors influencing their initial formation in the gut. Subsequently, we delve into the gut-liver axis and the evidence regarding the link between gut microbiota and the genesis or progression of various liver diseases. Finally, we summarise the recent research on plausible ways to modulate the gut microbiota to alter the natural history of liver disease.
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Affiliation(s)
- Saraswathy Sivaprasadan
- Department of Gastrointestinal Surgery and Solid Organ Transplantation, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, India
| | - K N Anila
- Department of Gastrointestinal Surgery and Solid Organ Transplantation, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, India
| | - Krishnanunni Nair
- Department of Gastrointestinal Surgery and Solid Organ Transplantation, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, India
| | - Shweta Mallick
- Department of Gastrointestinal Surgery and Solid Organ Transplantation, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, India
| | - Lalitha Biswas
- Amrita School of Nanosciences and Molecular Medicine, Kochi, India
| | - Arun Valsan
- Department of Hepatology & Gastroenterology, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, India
| | | | | | - Surendran Sudhindran
- Department of Gastrointestinal Surgery and Solid Organ Transplantation, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, India.
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Chen X, Kou L, Xie X, Su S, Li J, Li Y. Prognostic biomarkers associated with immune checkpoint inhibitors in hepatocellular carcinoma. Immunology 2024; 172:21-45. [PMID: 38214111 DOI: 10.1111/imm.13751] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 12/31/2023] [Indexed: 01/13/2024] Open
Abstract
The treatment of hepatocellular carcinoma (HCC), particularly advanced HCC, has been a serious challenge. Immune checkpoint inhibitors (ICIs) are landmark drugs in the field of cancer therapy in recent years, which have changed the landscape of cancer treatment. In the field of HCC treatment, this class of drugs has shown good therapeutic prospects. For example, atezolizumab in combination with bevacizumab has been approved as first-line treatment for advanced HCC due to significant efficacy. However, sensitivity to ICI therapy varies widely among HCC patients. Therefore, there is an urgent need to search for determinants of resistance/sensitivity to ICIs and to screen biomarkers that can predict the efficacy of ICIs. This manuscript reviews the research progress of prognostic biomarkers associated with ICIs in HCC in order to provide a scientific basis for the development of clinically individualised precision medication regimens.
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Affiliation(s)
- Xiu Chen
- Department of Pharmacy, The Affiliated Hospital, Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Liqiu Kou
- Department of Pharmacy, The Affiliated Hospital, Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xiaolu Xie
- Department of Pharmacy, The Affiliated Hospital, Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Song Su
- Department of Hepatology, The Affiliated Hospital, Southwest Medical University, Luzhou, China
| | - Jun Li
- Department of Traditional Chinese Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, China
| | - Yaling Li
- Department of Pharmacy, The Affiliated Hospital, Southwest Medical University, Luzhou, China
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13
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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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14
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Balouei F, Stefanon B, Martello E, Atuahene D, Sandri M, Meineri G. Supplementation with Silybum marianum Extract, Synbiotics, Omega-3 Fatty Acids, Vitamins, and Minerals: Impact on Biochemical Markers and Fecal Microbiome in Overweight Dogs. Animals (Basel) 2024; 14:579. [PMID: 38396547 PMCID: PMC10886211 DOI: 10.3390/ani14040579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 01/24/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Overweight and obese dogs can develop metabolic dysfunction, characterized by an inflammatory response and involvement of liver functions. If a modulation of the gut microbiome and its interaction with the gut-liver axis is implicated in the development of metabolic dysfunction, exploration becomes necessary. Over the past decade, diverse therapeutic approaches have emerged to target pathogenic factors involved in metabolic dysfunction. This study investigated the impact of a supplement with hepatoprotective activity, containing extracts of Silybum marianum, prebiotics, probiotics, n-3 polyunsaturated fatty acids, vitamins, and minerals on hematological markers of liver functions and inflammation, as well as on the intestinal microbiota of 10 overweight adult dogs over a 35-day time span. Animals underwent clinical and laboratory evaluations every 7 days, both before the administration of the supplement (T0) and after 7, 14, 21, 28, and 35 days (T1, T2, T3, T4, and T5). In comparison to T0, a significant (p < 0.05) decrease in ALP, glucose, direct bilirubin, and CRP was observed from T3 to T5. The alpha diversity of the fecal microbiota significantly decreased (p < 0.05) only at T1, with high variability observed between dogs. Total short-chain fatty acid and lactic acid were also lower at T1 (p < 0.05) compared to the other times of sampling. The beta diversity of the fecal microbiota failed to show a clear pattern in relation to the sampling times. These results of blood parameters in overweight dogs show a reduction of the inflammation and an improvement of metabolic status during the study period, but the effective contribution of the supplement in this clinical outcome deserves further investigation. Furthermore, the considerable individual variability observed in the microbiome hinders the confident detection of supplement effects.
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Affiliation(s)
- Fatemeh Balouei
- Department of Agrifood, Environmental and Animal Science, University of Udine, Via delle Scienze 206, 33100 Udine, Italy; (F.B.); (M.S.)
| | - Bruno Stefanon
- Department of Agrifood, Environmental and Animal Science, University of Udine, Via delle Scienze 206, 33100 Udine, Italy; (F.B.); (M.S.)
| | - Elisa Martello
- Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham City Hospital Campus, Nottingham NG5 1PB, UK;
| | - David Atuahene
- Department of Veterinary Sciences, School of Agriculture and Veterinary Medicine, University of Turin, Grugliasco, 10095 Turin, Italy; (D.A.); (G.M.)
| | - Misa Sandri
- Department of Agrifood, Environmental and Animal Science, University of Udine, Via delle Scienze 206, 33100 Udine, Italy; (F.B.); (M.S.)
| | - Giorgia Meineri
- Department of Veterinary Sciences, School of Agriculture and Veterinary Medicine, University of Turin, Grugliasco, 10095 Turin, Italy; (D.A.); (G.M.)
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15
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Mai Y, Meng L, Deng G, Qin Y. The Role of Type 2 Diabetes Mellitus-Related Risk Factors and Drugs in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2024; 11:159-171. [PMID: 38268569 PMCID: PMC10806369 DOI: 10.2147/jhc.s441672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 01/04/2024] [Indexed: 01/26/2024] Open
Abstract
With changes in modern lifestyles, type 2 diabetes mellitus (T2DM) has become a global epidemic metabolic disease, and hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. T2DM is a complex metabolic disorder and has been considered an independent risk factor for HCC. Growing evidence supports that T2DM-related risk factors facilitate hepatocarcinogenesis via abundant mechanisms. With the wide implementation of microbiomics, transcriptomics, and immunotherapy, the understanding of the complex mechanisms of intestinal flora and immune cell subsets have advanced tremendously in T2DM-related HCC, uncovering new findings in T2DM-related HCC patients. In addition, reports have indicated the different effects of anti-DM drugs on the progression of HCC. In this review, we summarize the effects of major T2DM-related risk factors (including hyperglycemia, hyperinsulinemia, insulin, chronic inflammation, obesity, nonalcoholic fatty liver disease, gut microbiota and immunomodulation), and anti-DM drugs on the carcinogensis and progression of HCC, as well as their potential molecular mechanisms. In addition, other factors (miRNAs, genes, and lifestyle) related to T2DM-related HCC are discussed. We propose a refined concept by which T2DM-related risk factors and anti-DM drugs contribute to HCC and discuss research directions prompted by such evidence worth pursuing in the coming years. Finally, we put forward novel therapeutic approaches to improve the prognosis of T2DM-related HCC, including exploiting novel diagnostic biomarkers, combination therapy with immunocheckpoint inhibitors, and enhancement of the standardized management of T2DM patients.
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Affiliation(s)
- Yuhua Mai
- Department of Endocrinology, The First Affiliated Hospital of GuangXi Medical University, Nanning, Guangxi, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, 530021, People’s Republic of China
| | - Liheng Meng
- Department of Endocrinology, The First Affiliated Hospital of GuangXi Medical University, Nanning, Guangxi, 530021, People’s Republic of China
| | - Ganlu Deng
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, 530021, People’s Republic of China
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China
| | - Yingfen Qin
- Department of Endocrinology, The First Affiliated Hospital of GuangXi Medical University, Nanning, Guangxi, 530021, People’s Republic of China
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16
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Abaturov A, Babуch V. Drug regulation of microRNA. CHILD`S HEALTH 2024; 18:572-583. [DOI: 10.22141/2224-0551.18.8.2023.1657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
The scientific review provides the mechanisms of drug regulation of microRNA in the human body. To write the article, information was searched using Scopus, Web of Science, MEDLINE, PubMed, Google Scholar, Embase, Global Health, The Cochrane Library databases. To restore the reduced functional activity of microRNAs, replacement therapy is used, with modified synthetic analogs of endogenous microRNAs, and drugs that enhance the production of the body’s own microRNAs. The authors state that numerous studies have confirmed the effectiveness of miRNA replacement therapy. It is known that there are several groups of drugs among miRNA inhibitors: anti-miRNA oligonucleotides, miRNA traps, miRNA mimics that prevent miRNA binding; peptide nucleic acids, small-molecule inhibitors. The authors suggest that the expression of drug-metabolizing enzymes is controlled by nuclear receptors and transcription factors, epigenetic regulation such as DNA methylation and histone acetylation, and post-translational modification. It is emphasized that ursodeoxycholic acid modulates the expression of some miRNAs. It is known that probiotic bacteria can modulate the expression level of miRNA genes. The use of probiotics is accompanied by a change in the expression of numerous genes of the body involved in the regulation of the inflammatory response, allergic reactions, metabolism and other biological processes. Thus, modern science is intensively studying the potential of using drugs that restore miRNA content or inhibit miRNA activity for the therapy of miRNA-dependent conditions. The results of scientific research confirmed the therapeutic effect of ursodeoxycholic acid and probiotic preparations due to the effect on the activity of miRNA generation in hepatobiliary diseases. Therefore, the introduction into clinical practice of drugs than can modulate the content and expression of specific miRNAs will certainly open new perspectives in the treatment of patients with hepatobiliary diseases.
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17
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Lv Y, Sun X. Role of miRNA in pathogenesis, diagnosis, and prognosis in hepatocellular carcinoma. Chem Biol Drug Des 2024; 103:e14352. [PMID: 37726253 DOI: 10.1111/cbdd.14352] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 08/27/2023] [Accepted: 09/04/2023] [Indexed: 09/21/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers and is responsible for the second cancer-related death globally. Many treatment regimens have been developed to cure the disease; however, life expectancy is still low. Therefore, there is an urgent need to explore new selective, specific, and robust diagnosis markers for efficient early recognition of the ailment. Along with the diagnosis, the treatment's effectiveness can be determined by prognostic markers, and miRNAs are excellent tools for the diagnosis and prognosis of HCC. In addition, the altered expression profile of a few miRNAs promotes HCC cell migration and invasion, and selective up- or downregulation of these responsible genes may help mitigate the disorder. On one hand, few of the miRNAs have been found to enhance angiogenesis, a crucial step of tumor growth; on the other hand, upregulation of specific miRNAs is reported to suppress angiogenesis and resulting tumor growth of HCC cells. Exosomal miRNAs have significant implications in promoting angiogenesis, increased endothelial cell permeability, tube formation, and metastasis to hepatic and pulmonary tissues. miRNA also attributes to drug resistance toward chemotherapy and the prevention of autophagy also. Identifying novel miRNA and determining their differential expression in HCC tissue may serve as a potential tool for diagnosis, prognosis, and therapy to enhance the life expectancy and quality of life of HCC patients. In the present review, we have summarized the recent advances in HCC-related research.
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Affiliation(s)
- Yi Lv
- Hepatobiliary and Pancreatic Surgery, Liuzhou People's Hospital, Liuzhou, Guangxi, China
| | - Xiujuan Sun
- Department of Pathology, Liuzhou People's Hospital, Liuzhou, Guangxi, China
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18
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Nenu I, Baldea I, Coadă CA, Crăciun RC, Moldovan R, Tudor D, Petrushev B, Toma VA, Ştefanescu H, Procopeţ B, Spârchez Z, Vodnar D, Lenghel M, Clichici S, Filip GA. Lactobacillus rhamnosus probiotic treatment modulates gut and liver inflammatory pathways in a hepatocellular carcinoma murine model. A preliminary study. Food Chem Toxicol 2024; 183:114314. [PMID: 38052407 DOI: 10.1016/j.fct.2023.114314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 09/18/2023] [Accepted: 11/28/2023] [Indexed: 12/07/2023]
Abstract
BACKGROUND AND AIMS Hepatocellular carcinoma (HCC) is a growing global concern with an increasing incidence rate. The intestinal microbiota has been identified as a potential culprit in modulating the effects of antitumoral drugs. We aimed to assess the impact of adding Lactobacillus rhamnosus probiotic to regorafenib in mice with HCC. METHODS Cirrhosis and HCCs were induced in 56 male Swiss mice via diethylnitrosamine injection and carbon tetrachloride administration. Mice were divided into four groups: treated with vehicle (VC), regorafenib (Rego), L. rhamnosus probiotic, and a combination of regorafenib and probiotic (Rego-Pro). After 3 weeks of treatment, liver and intestinal fragments were collected for analysis. RESULTS Regorafenib elevated gut permeability, an effect mitigated by probiotic intervention, which exhibited a notable correlation with reduced inflammation (p < 0.01). iNOS levels were also reduced by adding the probiotic with respect to the mice treated with regorafenib only (p < 0.001). Notably, regorafenib substantially increased IL-6, TNF-a and TLR4 in intestinal fragments (p < 0.01). The administration of the probiotic effectively restored IL-6 to its initial levels (p < 0.001). CONCLUSION Reducing systemic and intestinal inflammation by administering L. rhamnosus probiotic may alleviate tumoral resistance and systemic adverse effects.
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Affiliation(s)
- Iuliana Nenu
- Department of Functional Sciences, Physiology Discipline, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania.
| | - Ioana Baldea
- Department of Functional Sciences, Physiology Discipline, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
| | | | - Rareş Călin Crăciun
- Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania.
| | - Remus Moldovan
- Department of Functional Sciences, Physiology Discipline, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
| | - Diana Tudor
- Department of Functional Sciences, Physiology Discipline, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
| | - Bobe Petrushev
- Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania.
| | - Vlad Alexandru Toma
- Department of Molecular Biology and Biotechnologies, Faculty of Biology and Geology, Babeș-Bolyai University, Cluj-Napoca, Romania; Department of Experimental Biology and Biochemistry, Institute of Biological Research, Branch of NIRDBS, Cluj-Napoca, Romania; Department of Molecular and Biomolecular Physics, NIRD for Isotopic and Molecular Technologies, Cluj-Napoca, Romania.
| | - Horia Ştefanescu
- Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania.
| | - Bogdan Procopeţ
- Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania.
| | - Zeno Spârchez
- Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania.
| | - Dan Vodnar
- Department of Food Science University of Agricultural Sciences and Veterinary Medicine, Cluj-Napoca, Romania.
| | - Manuela Lenghel
- Radiology Department, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
| | - Simona Clichici
- Department of Functional Sciences, Physiology Discipline, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
| | - Gabriela Adriana Filip
- Department of Functional Sciences, Physiology Discipline, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
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19
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Romeo M, Dallio M, Scognamiglio F, Ventriglia L, Cipullo M, Coppola A, Tammaro C, Scafuro G, Iodice P, Federico A. Role of Non-Coding RNAs in Hepatocellular Carcinoma Progression: From Classic to Novel Clinicopathogenetic Implications. Cancers (Basel) 2023; 15:5178. [PMID: 37958352 PMCID: PMC10647270 DOI: 10.3390/cancers15215178] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a predominant malignancy with increasing incidences and mortalities worldwide. In Western countries, the progressive affirmation of Non-alcoholic Fatty Liver Disease (NAFLD) as the main chronic liver disorder in which HCC occurrence is appreciable even in non-cirrhotic stages, constitutes a real health emergency. In light of this, a further comprehension of molecular pathways supporting HCC onset and progression represents a current research challenge to achieve more tailored prognostic models and appropriate therapeutic approaches. RNA non-coding transcripts (ncRNAs) are involved in the regulation of several cancer-related processes, including HCC. When dysregulated, these molecules, conventionally classified as "small ncRNAs" (sncRNAs) and "long ncRNAs" (lncRNAs) have been reported to markedly influence HCC-related progression mechanisms. In this review, we describe the main dysregulated ncRNAs and the relative molecular pathways involved in HCC progression, analyzing their implications in certain etiologically related contexts, and their applicability in clinical practice as novel diagnostic, prognostic, and therapeutic tools. Finally, given the growing evidence supporting the immune system response, the oxidative stress-regulated mechanisms, and the gut microbiota composition as relevant emerging elements mutually influencing liver-cancerogenesis processes, we investigate the relationship of ncRNAs with this triad, shedding light on novel pathogenetic frontiers of HCC progression.
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Affiliation(s)
- Mario Romeo
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Marcello Dallio
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Flavia Scognamiglio
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Lorenzo Ventriglia
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Marina Cipullo
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Annachiara Coppola
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Chiara Tammaro
- Biochemistry Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (C.T.); (G.S.)
| | - Giuseppe Scafuro
- Biochemistry Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (C.T.); (G.S.)
| | - Patrizia Iodice
- Division of Medical Oncology, AORN Azienda dei Colli, Monaldi Hospital, Via Leonardo Bianchi, 80131 Naples, Italy
| | - Alessandro Federico
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
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Trivedi Y, Bolgarina Z, Desai HN, Senaratne M, Swami SS, Aye SL, Mohammed L. The Role of Gut Microbiome in Hepatocellular Carcinoma: A Systematic Review. Cureus 2023; 15:e43862. [PMID: 37614827 PMCID: PMC10442465 DOI: 10.7759/cureus.43862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 08/21/2023] [Indexed: 08/25/2023] Open
Abstract
Gut microbiome dysbiosis is common in patients with chronic liver diseases such as hepatocellular carcinoma (HCC) and plays an essential role in developing, diagnosing, and treating HCC. The purpose of this systematic review, which was carried out following the Preferred Reporting Items for Systematic Review and Meta-analyses 2020 guidelines, is to determine the role of the gut microbiome in the pathogenesis, diagnosis, and treatment of HCC. We collected and reviewed articles, including clinical trials, literature reviews, case-control studies, cross-sectional studies, cohort studies, systematic reviews, and meta-analyses, published between May 30, 2013, and May 30, 2023. The databases used to collect these articles included PubMed, Cochrane Library, Google Scholar, and ScienceDirect. After applying appropriate filters, a total of 2,969 studies were identified. They were further screened and subjected to quality assessment tools which finally yielded 17 studies included in this systematic review. This systematic review provides information regarding the gut-liver axis and the relationship between gut microbiome dysbiosis and HCC.
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Affiliation(s)
- Yash Trivedi
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Zoryana Bolgarina
- Obstetrics and Gynecology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Heet N Desai
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Mithum Senaratne
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Shivling S Swami
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Soe Lwin Aye
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Lubna Mohammed
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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21
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Yan X, Bai L, Qi P, Lv J, Song X, Zhang L. Potential Effects of Regulating Intestinal Flora on Immunotherapy for Liver Cancer. Int J Mol Sci 2023; 24:11387. [PMID: 37511148 PMCID: PMC10380345 DOI: 10.3390/ijms241411387] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 06/28/2023] [Accepted: 06/28/2023] [Indexed: 07/30/2023] Open
Abstract
The intestinal flora plays an important role in the occurrence and development of liver cancer, affecting the efficacy and side effects of conventional antitumor therapy. Recently, immunotherapy for liver cancer has been a palliative treatment for patients with advanced liver cancer lacking surgical indications. Representative drugs include immune checkpoint inhibitors, regulators, tumor vaccines, and cellular immunotherapies. The effects of immunotherapy on liver cancer vary because of the heterogeneity of the tumors. Intestinal flora can affect the efficacy and side effects of immunotherapy for liver cancer by regulating host immunity. Therefore, applying probiotics, prebiotics, antibiotics, and fecal transplantation to interfere with the intestinal flora is expected to become an important means of assisting immunotherapy for liver cancer. This article reviews publications that discuss the relationship between intestinal flora and immunotherapy for liver cancer and further clarifies the potential relationship between intestinal flora and immunotherapy for liver cancer.
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Affiliation(s)
- Xiangdong Yan
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China
| | - Liuhui Bai
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China
| | - Ping Qi
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Jin Lv
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Xiaojing Song
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Lei Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, China
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22
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Purdel C, Ungurianu A, Adam-Dima I, Margină D. Exploring the potential impact of probiotic use on drug metabolism and efficacy. Biomed Pharmacother 2023; 161:114468. [PMID: 36868015 DOI: 10.1016/j.biopha.2023.114468] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 02/23/2023] [Accepted: 02/28/2023] [Indexed: 03/05/2023] Open
Abstract
Probiotics are frequently consumed as functional food and widely used as dietary supplements, but are also recommended in treating or preventing various gastrointestinal diseases. Therefore, their co-administration with other drugs is sometimes unavoidable or even compulsory. Recent technological developments in the pharmaceutical industry permitted the development of novel drug-delivery systems for probiotics, allowing their addition to the therapy of severely ill patients. Literature data regarding the changes that probiotics could impose on the efficacy or safety of chronic medication is scarce. In this context, the present paper aims to review probiotics currently recommended by the international medical community, to evaluate the relationship between gut microbiota and various pathologies with high impact worldwide and, most importantly, to assess the literature reports concerning the ability of probiotics to influence the pharmacokinetics/pharmacodynamics of some widely used drugs, especially for those with narrow therapeutic indexes. A better understanding of the potential influence of probiotics on drug metabolism, efficacy and safety could contribute to improving therapy management, facilitating individualized therapy and updating treatment guidelines.
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Affiliation(s)
- Carmen Purdel
- "Carol Davila" University of Medicine and Pharmacy, Faculty of Pharmacy, Department of Toxicology, Traian Vuia 6, Bucharest 020956, Romania
| | - Anca Ungurianu
- "Carol Davila" University of Medicine and Pharmacy, Faculty of Pharmacy, Department of Biochemistry, Traian Vuia 6, Bucharest 020956, Romania.
| | - Ines Adam-Dima
- "Carol Davila" University of Medicine and Pharmacy, Faculty of Pharmacy, Department of Toxicology, Traian Vuia 6, Bucharest 020956, Romania
| | - Denisa Margină
- "Carol Davila" University of Medicine and Pharmacy, Faculty of Pharmacy, Department of Biochemistry, Traian Vuia 6, Bucharest 020956, Romania
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23
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Shi K, Zhang Q, Zhang Y, Bi Y, Zeng X, Wang X. Association between probiotic therapy and the risk of hepatocellular carcinoma in patients with hepatitis B-related cirrhosis. Front Cell Infect Microbiol 2023; 12:1104399. [PMID: 36710968 PMCID: PMC9880196 DOI: 10.3389/fcimb.2022.1104399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 12/30/2022] [Indexed: 01/15/2023] Open
Abstract
Objective Probiotics may offer cancer-prevention benefits, based on experimental investigation results. This study aimed to determine the potential association between probiotics and hepatocellular carcinoma (HCC) in patients with hepatitis B-related cirrhosis (HBC) receiving antiviral therapy. Design This retrospective study included 1267 patients with HBC treated with entecavir or tenofovir between January 2013 and December 2017. The risk of developing HCC was compared between two cohorts of 449 probiotic users (taking a cumulative defined daily doses [cDDD] of ≥ 28) and 818 non-probiotic users (< 28 cDDD). To eliminate the bias caused by confounding factors, propensity score matching (PSM) was used. Results On multivariate regression analysis, probiotic consumption was an independent protective factor for HCC occurrence. After PSM, the incidence of HCC was significantly lower in the probiotic users than that in the nonusers (adjusted hazard ratio [aHR]: 0.70, 95% confidence interval: 0.59-0.83, P < 0.001). The aHRs for probiotics with 28-89, 90-180, and >180 cDDD were 0.58, 0.28, and 0.12, respectively, indicating a dose-response pattern. In 28-89, 90-180, and >180 cDDD, the 3-year cumulative incidence of HCC was 8.7%, 4.7%, and 3.0%, respectively. A multivariate stratified analysis confirmed that the administration of probiotics could help patients. Conclusion Adjuvant probiotic therapy may reduce the risk of HCC in patients receiving antiviral medication for HBC. However, further clinical research is required to confirm these findings.
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Sun L, Lu J, Li K, Zhang H, Zhao X, Li G, Li N. Diagnostic and prognostic value of STAP1 and AHNAK methylation in peripheral blood immune cells for HBV-related hepatopathy. Front Immunol 2023; 13:1091103. [PMID: 36713363 PMCID: PMC9880311 DOI: 10.3389/fimmu.2022.1091103] [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: 11/06/2022] [Accepted: 12/19/2022] [Indexed: 01/14/2023] Open
Abstract
Introduction Although we had identified that the methylation of AHNAK was a good diagnostic marker for hepatopathy, here we speculate that there was also another marker, STAP1, whose methylation also involved in the detection of hepatopathy. Methods We investigated the methylation levels of the AHNAK and STAP1 in peripheral blood mononuclear cells of chronic hepatitis B (CHB) patients, compensatory liver cirrhosis (CLC) patients, decompensated liver cirrhosis (DCLC) patients, hepatocellular carcinoma (HCC) patients and healthy controls by methylation-specific PCR. We also evaluated the differences and changes of methylation and expression of AHNAK and STAP1 at different stages of liver disease using the TCGA and GEO public datasets. Results Methylation level of STAP1 in PBMC was positively correlated with the course of liver cancer. The combination of AHNAK and STAP1 methylation was able to predict differrent HBV related hepatopathy. The GEO datasets also supported that the methylation of AHNAK and STAP1 was associated with different types of hepatopathy. The TCGA data showed that the levels of methylation and expression of STAP1 were down-regulated in HCC. We also found the STAP1 methylation level in PBMC and T cells was associated with age, gender, alcohol drinking and anti-HBe. Hyper-methylation of STAP1 was correlated with the poor prognosis of patients but its expression had no association. Conclusion We concluded that combination of AHNAK and STAP1 methylation in peripheral blood immune cells can be used as a diagnostic marker for HBV related hepatopathy and STAP1 methylation may be a potential prognostic marker for HBV related HCC. Our clinical study registration number was ChiCTR2000039860.
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Affiliation(s)
- Libo Sun
- General Surgery Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Junfeng Lu
- Department of Liver Disease Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Kang Li
- Biomedical Information Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Haitao Zhang
- General Surgery Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Xiaofei Zhao
- General Surgery Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Guangming Li
- General Surgery Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China,*Correspondence: Guangming Li, ; Ning Li,
| | - Ning Li
- General Surgery Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China,*Correspondence: Guangming Li, ; Ning Li,
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25
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Liu S, Yang X. Intestinal flora plays a role in the progression of hepatitis-cirrhosis-liver cancer. Front Cell Infect Microbiol 2023; 13:1140126. [PMID: 36968098 PMCID: PMC10034054 DOI: 10.3389/fcimb.2023.1140126] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Accepted: 02/23/2023] [Indexed: 03/29/2023] Open
Abstract
The liver is a vital metabolism and detoxification organ of human body, which is involved in the biotransformation and metabolism of the organism. Hepatitis - cirrhosis - liver cancer are significant and common part of liver diseases. The pathogenesis of liver diseases is generally as followed: inflammation and other pathogenic factors cause persistent damage to the liver, leading to the activation of hepatic stellate cells (HSCs) and excessive deposition of extracellular matrix. Patients with chronic hepatitis have a high risk of developing into liver fibrosis, cirrhosis, and even life-threatening liver cancer, which poses a great threat to public health.As the first organ to come into contact with blood from the gut, the liver is profoundly affected by the intestinal flora and its metabolites, with leaky gut and flora imbalance being the triggers of the liver's pathological response. So far, no one has reviewed the role of intestinal flora in this process from the perspective of the progression of hepatitis-cirrhosis-liver cancer and this article reviews the evidence supporting the effect of intestinal flora in the progression of liver disease.
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Yan F, Zhang Q, Shi K, Zhang Y, Zhu B, Bi Y, Wang X. Gut microbiota dysbiosis with hepatitis B virus liver disease and association with immune response. Front Cell Infect Microbiol 2023; 13:1152987. [PMID: 37201112 PMCID: PMC10185817 DOI: 10.3389/fcimb.2023.1152987] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 04/10/2023] [Indexed: 05/20/2023] Open
Abstract
Background and aims Given hepatitis B virus (HBV)-related hepatocellular carcinoma (HBV-HCC) exhibits unique gut microbiota characteristics and a significant immunosuppressive tumor microenvironment. Thus, a better understanding of the correlation between gut microbiota and the immunosuppressive response may help predict occurrence and prognosis of HBV-HCC. Methods Here, in a cohort of ninety adults (healthy control n=30, HBV-cirrhosis n=30, HBV-HCC n=30) with clinical data, fecal 16S rRNA gene sequencing, matched peripheral blood immune response with flow cytometry analysis. Correlation between the gut microbiome of significantly different in HBV-HCC patients and clinical parameters as well as the peripheral immune response was assessed. Results We found that community structures and diversity of the gut microbiota in HBV-CLD patients become more unbalanced. Differential microbiota analysis that p:Acidobacteriota, p:Proteobacteria, p:Campilobacterota, f:Streptococcaceae, g:Klebsiella associated with inflammation were enriched. The beneficial bacteria of f:Clostridia UCG-014, f:Oscillospiraceae, f:_Rikenellaceae, g:_Barnesiella, g:Prevotella, g:Agathobacter were decreased. Functional analysis of gut microbiota revealed that lipopolysaccharide biosynthesis, lipid metabolism, butanoate metabolism were significantly elevated in HBV-CLD patients. Spearman's correlation analysis showed that Muribaculaceae, Akkermaniacaeae, [Eubacterium]_coprostanoligenes_group, RF39, Tannerellaceae have positive correlation with CD3+T, CD4+T and CD8+T cell counts while negatively correlated with liver dysfunction. Furthermore, paired peripheral blood showed a decreased proportion of CD3+T, CD4+T and CD8+T cells, while an increased T (Treg) cells. The immunosuppressive response of programmed cell death 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), immune receptor tyrosine based inhibitor motor (ITIM) domain (TIGIT), T-cell immune domain, and multiple domain 3 (TIM-3) of CD8+T cells were higher in HBV-HCC patients. They were positively correlated with harmful bacteria, such as Actinobaciota, Myxococota, Streptococcaceae and Eubacterium coprostanoligenes. Conclusions Our study indicated that gut beneficial bacteria, mainly Firmicutes and Bacteroides appeared dysbiosis in HBV-CLD patients. They have negative regulation of liver dysfunction and T cell immune response. It provides potential avenues for microbiome-based prevention and intervention for anti-tumor immune effects of HBV-CLD.
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Kumar M, Kaur R, Kanthaje S, Dhiman RK, Chakraborti A. Bacterial metabolite butyrate in modulating sorafenib-targeted microRNAs to curtail its resistance in hepatocellular carcinoma. J Cancer Res Clin Oncol 2022:10.1007/s00432-022-04544-7. [PMID: 36583742 DOI: 10.1007/s00432-022-04544-7] [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: 09/27/2022] [Accepted: 12/16/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND AIM The host dietary fibre is fermented into short-chain fatty acids (SCFA) by intestinal microbiota as bacterial metabolites like propionate, acetate and butyrate. Among these metabolites, the role of butyrate is well documented to provide energy to intestinal epithelial cells. Also, butyrate has anti-inflammatory and anti-tumour properties and decrease in its level by unbalanced diet can develops cancer. Lately, some research has suggested that sodium butyrate as an inhibitor of histone deacetylase (HDAC) may have anticancer potential for hepatocellular carcinoma (HCC), the most common type of liver cancer. Since, HCC is asymptomatic it is usually diagnosed at its advanced stage. Sorafenib with antiproliferative and antiangiogenic effects is the first line of treatment in advanced HCC. However, prolonged drug treatment to HCC patients develops adaptive resistance towards the sorafenib. Sorafenib resistance can also be enhanced by differentially expressed microRNAs. However, the significance of butyrate in HCC sorafenib resistance and its association with sorafenib-targeted microRNAs is yet to be unfurled. Here, an attempt has been made to explore the role of bacterial metabolite butyrate on sorafenib resistant HCC as well as on sorafenib-targeted microRNAs (miR-7641 and miR-199) to curtail sorafenib resistance in HCC. METHODS Initially, in-silico analysis was performed using Human Metabolome Database (HMDB) so to identify specific butyrate producing faecal bacteria. Then, their specific 16s rRNA expression was compared between HCC patients and healthy individuals using qRT-PCR. Additionally, the cell viability (MTT) and apoptosis assays were performed in both parental and sorafenib resistant HepG2 cells to evaluate the role of sodium butyrate in sorafenib resistant HCC. Moreover, the association of sodium butyrate with sorafenib-targeted miR-7641 and miR-199 was also assessed using real time PCR, cell viability, cell apoptosis and transfection assays. RESULTS In silico analysis demonstrated Roseburia cecical, Roseburia intestinalis, Eubacterium rectal, Faecalibacterium prausnitzii as specific butyrate producing faecal bacteria and their 16s rRNA expression was downregulated in HCC patients. In vitro study revealed the presence of sodium butyrate also decreased the cell viability as well as enhanced cell apoptosis of both parental and resistant HepG2 cells. Interestingly, sodium butyrate also decreased the expression of both sorafenib-targeted miR-7641 and miR-199. Further, combination of both sodium butyrate and antimiR-7641 or antimiR-199 also increased apoptosis and decreased viability of resistant cells. CONCLUSION This is first study to unravel the association of butyrate producing bacteria with HCC patients and the significance of bacterial metabolite butyrate as anti-tumour in sorafenib resistant hepatocellular carcinoma. The study also demonstrated the plausible new aspects of bacterial metabolite butyrate association with sorafenib-targeted miRNAs (miR-7641 and miR-199). Hence, the study highlighted the therapeutic potential of bacterial metabolite butyrate that might improve the clinical management of hepatocellular carcinoma.
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Affiliation(s)
- Mukesh Kumar
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education & Research (PGIMER), Chandigarh, 160012, India
| | - Ramanpreet Kaur
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education & Research (PGIMER), Chandigarh, 160012, India.,Department of Hepatology, Postgraduate Institute of Medical Education & Research (PGIMER), Chandigarh, 160012, India
| | - Shruthi Kanthaje
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education & Research (PGIMER), Chandigarh, 160012, India
| | - Radha K Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education & Research (PGIMER), Chandigarh, 160012, India
| | - Anuradha Chakraborti
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education & Research (PGIMER), Chandigarh, 160012, India.
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FAN Y, ZHAO H, ZHANG Y, Yani Z, DU J, LING C. Effectiveness of Jiedu granule on gut microbiota in patients with advanced hepatocellular carcinoma: a randomized controlled trial. J TRADIT CHIN MED 2022; 42:988-996. [PMID: 36378058 PMCID: PMC9924752 DOI: 10.19852/j.cnki.jtcm.20220902.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 01/05/2022] [Indexed: 12/30/2022]
Abstract
OBJECTIVE To observe whether Jiedu granule (, JDG) modulates the composition of the gut microbiota during advanced hepatocellular carcinoma (HCC). METHODS A randomized controlled trial was conducted. Sixty-two advanced HCC participants were randomly allocated to receive JDG or placebo. The median overall survival (OS) times of patients and the variation of relative abundance of bacteria over time were used as main outcome measures. RESULTS Patients who received JDG demonstrated significantly longer median OS times compared with the placebo group. Pyrosequencing of the V3 regions of 16S rRNA genes revealed a dose dependent deviation of gut microbiota in response to JDG treatment. Redundancy analysis identified and Peptostre-ptococcaceae which related to the onset of liver cancer disappeared after 1-month and 2-month JDG treatment, while in control group, no significant changes of these two bacteria were found. The variation tendency of relative abundance of (essential in immunoblocking therapy of tumor) in JDG group was not obvious while in control group, it was decreased significantly with time. The relative abundance of (correlated with the occurrence of liver cancer) was increased in JDG group and was decreased in control group over time. CONCLUSION Changes in the gut microbiota may be associated with the efficiency of JDG on survival period of advanced HCC patients. Trial registration：Chinese Clinical TRIAL Registry ChiCTR-OOC-16008002.
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Affiliation(s)
- Yifu FAN
- School of Traditional Chinese Medicine, Navy Medical University, Shanghai 200433, China
| | - Hetong ZHAO
- School of Traditional Chinese Medicine, Navy Medical University, Shanghai 200433, China
| | - Yani ZHANG
- School of Traditional Chinese Medicine, Navy Medical University, Shanghai 200433, China
| | - Zifei Yani
- School of Traditional Chinese Medicine, Navy Medical University, Shanghai 200433, China
| | - Juan DU
- School of Traditional Chinese Medicine, Navy Medical University, Shanghai 200433, China
| | - Changquan LING
- School of Traditional Chinese Medicine, Navy Medical University, Shanghai 200433, China
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29
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Jiang H, Peng Y, Zhang W, Chen Y, Jiang Q, Zhou Y. Gut microbiome-targeted therapies in liver cirrhosis: a protocol for systematic review and meta-analysis. Syst Rev 2022; 11:181. [PMID: 36042459 PMCID: PMC9429623 DOI: 10.1186/s13643-022-02059-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 08/23/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Microbiome-targeted therapies (MTTs), including probiotics, prebiotics, synbiotics, and fecal microbiota transplantation (FMT), have been proposed as a potential treatment for cirrhosis via modulation of gut microbiome, while the impact of gut microflora alteration on liver function in cirrhosis trajectory is unclear, and no related systematic review has been published. We aim to comprehensively assess the effects of MTTs in patients with liver cirrhosis. METHODS We will search databases of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) with no time restriction. Only randomized controlled trials published in English will be included. Two independent reviewers will be responsible for study identification and selection, data extraction, and risk of bias assessment, with discrepancies resolved by consensus or referral to a third author. Heterogeneity of studies will be examined using Cochrane Q-test and I2 statistics. The data will be pooled using either a fixed- or random-effects model based on I2 statistics. The results will be presented as risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CI). We will perform subgroup analysis on the type of MTTs and assess the reporting biases. Sensitivity analysis will be conducted to test the stability of each outcome result. DISCUSSION There is no current study about the role of MTTs in developing the liver function, and the therapeutic effects of MTTs are inconsistent. By investigating the liver-specific indicators when treating with multiple MTTs on course of cirrhosis, our findings will give more conclusive and stronger evidence about the efficacy of MTTs and provide new insight into the action mechanisms of these MTTs. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42021253198.
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Affiliation(s)
- Honglin Jiang
- Fudan University School of Public Health, Building 8, 130 Dong'an Road, Shanghai, 200032, China.,Key Laboratory of Public Health Safety, Fudan University, Ministry of Education, Building 8, 130 Dong'an Road, Shanghai, 200032, China.,Fudan University Center for Tropical Disease Research, Building 8, 130 Dong'an Road, Shanghai, 200032, China
| | - Yan Peng
- Department of Nutrition, Beijing Fangshan District Liangxiang Hospital, No. 45 Gongchen Street, Fangshan, Beijing, 102401, China
| | - Wei Zhang
- Department of Reference, Medical Library of Fudan University, Building 8, 130 Dong'an Road, Shanghai, 200032, China
| | - Yue Chen
- School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, 600 Peter Morand Crescent, Ottawa, Ontario, K1G 5Z3, Canada
| | - Qingwu Jiang
- Fudan University School of Public Health, Building 8, 130 Dong'an Road, Shanghai, 200032, China.,Key Laboratory of Public Health Safety, Fudan University, Ministry of Education, Building 8, 130 Dong'an Road, Shanghai, 200032, China.,Fudan University Center for Tropical Disease Research, Building 8, 130 Dong'an Road, Shanghai, 200032, China
| | - Yibiao Zhou
- Fudan University School of Public Health, Building 8, 130 Dong'an Road, Shanghai, 200032, China. .,Key Laboratory of Public Health Safety, Fudan University, Ministry of Education, Building 8, 130 Dong'an Road, Shanghai, 200032, China. .,Fudan University Center for Tropical Disease Research, Building 8, 130 Dong'an Road, Shanghai, 200032, China.
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30
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Beyoğlu D, Idle JR. The gut microbiota - a vehicle for the prevention and treatment of hepatocellular carcinoma. Biochem Pharmacol 2022; 204:115225. [PMID: 35998677 DOI: 10.1016/j.bcp.2022.115225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) arises principally against a background of cirrhosis and these two diseases are responsible globally for over 2 million deaths a year. There are few treatment options for liver cirrhosis and HCC, so it is vital to arrest these pathologies early in their development. To do so, we propose dietary and therapeutic solutions that involve the gut microbiota and its consequences. Integrated dietary, environmental and intrinsic signals result in a bidirectional connection between the liver and the gut with its microbiota, known as the gut-liver axis. Numerous lifestyle factors can result in dysbiosis with a change in the functional composition and metabolic activity of the microbiota. A panoply of metabolites can be produced by the microbiota, including ethanol, secondary bile acids, trimethylamine, indole, quinolone, phenazine and their derivatives and the quorum sensor acyl homoserine lactones that may contribute to HCC but have yet to be fully investigated. Gram-negative bacteria can activate the pattern recognition receptor toll-like receptor 4 (TLR4) in the liver leading to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, which can contribute to HCC initiation and progression. The goal in preventing HCC should be to ensure a healthy gut microbiota using probiotic supplements containing beneficial bacteria and prebiotic plant fibers such as oligosaccharides that stimulate their growth. The clinical development of TLR4 antagonists is urgently needed to counteract the pathological effects of dysbiosis on the liver and other organs. Further nutrigenomic studies are required to understand better how the diet influences the gut microbiota and its adverse effects on the liver.
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Affiliation(s)
- Diren Beyoğlu
- Arthur G. Zupko Institute for Systems Pharmacology and Pharmacogenomics, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, New York 11201, USA
| | - Jeffrey R Idle
- Arthur G. Zupko Institute for Systems Pharmacology and Pharmacogenomics, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, New York 11201, USA.
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Liakina V, Strainiene S, Stundiene I, Maksimaityte V, Kazenaite E. Gut microbiota contribution to hepatocellular carcinoma manifestation in non-alcoholic steatohepatitis. World J Hepatol 2022; 14:1277-1290. [PMID: 36158907 PMCID: PMC9376773 DOI: 10.4254/wjh.v14.i7.1277] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 04/27/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
Recently, the gut microbiota has been recognized as an obvious active player in addition to liver steatosis/steatohepatitis in the pathophysiological mechanisms of the development of hepatocellular carcinoma (HCC), even in the absence of cirrhosis. Evidence from clinical and experimental studies shows the association of specific changes in the gut microbiome and the direct contribution to maintaining liver inflammation and/or cancerogenesis in nonalcoholic fatty liver disease-induced HCC. The composition of the gut microbiota differs significantly in obese and lean individuals, especially in the abundance of pro-inflammatory lipopolysaccharide-producing phyla, and, after establishing steatohepatitis, it undergoes minor changes during the progression of the disease toward advanced fibrosis. Experimental studies proved that the microbiota of obese subjects can induce steatohepatitis in normally fed mice. On the contrary, the transplantation of healthy microbiota to obese mice relieves steatosis. However, further studies are needed to confirm these findings and the mechanisms involved. In this review, we have evaluated well-documented clinical and experimental research on the role of the gut microbiota in the manifestation and promotion of HCC in nonalcoholic steatohepatitis (NASH). Furthermore, a literature review of microbiota alterations and consequences of dysbiosis for the promotion of NASH-induced HCC was performed, and the advantages and limitations of the microbiota as an early marker of the diagnosis of HCC were discussed.
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Affiliation(s)
- Valentina Liakina
- Centre of Hepatology, Gastroenterology and Dietetics, Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius 01513, Lithuania
- Department of Chemistry and Bioengineering, Faculty of Fundamental Sciences, Vilnius Gediminas Technical University (VILNIUS TECH), Vilnius 10223, Lithuania.
| | - Sandra Strainiene
- Faculty of Medicine, Vilnius University, Vilnius 01513, Lithuania
- Therapeutic and Radiological Department, Antakalnis Polyclinic, Vilnius 10207, Lithuania
| | - Ieva Stundiene
- Centre of Hepatology, Gastroenterology and Dietetics, Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius 01513, Lithuania
| | - Vaidota Maksimaityte
- Centre of Hepatology, Gastroenterology and Dietetics, Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius 01513, Lithuania
| | - Edita Kazenaite
- Centre of Hepatology, Gastroenterology and Dietetics, Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius 01513, Lithuania
- Department of Pathology, Forensic Medicine and Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius 01513, Lithuania
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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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Russo E, Fiorindi C, Giudici F, Amedei A. Immunomodulation by probiotics and prebiotics in hepatocellular carcinoma. World J Hepatol 2022; 14:372-385. [PMID: 35317185 PMCID: PMC8891667 DOI: 10.4254/wjh.v14.i2.372] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/21/2021] [Accepted: 01/25/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent primary malignancy in patients suffering from chronic liver diseases and cirrhosis. Recent attention has been paid to the involvement of the gut-liver axis (GLA) in HCC pathogenesis. This axis results from a bidirectional, anatomical and functional relationship between the gastrointestinal system and the liver. Moreover, the complex network of interactions between the intestinal microbiome and the liver plays a crucial role in modulation of the HCC-tumor microenvironment, contributing to the pathogenesis of HCC by exposing the liver to pathogen-associated molecular patterns, such as bacterial lipopolysaccharides, DNA, peptidoglycans and flagellin. Indeed, the alteration of gut microflora may disturb the intestinal barrier, bringing several toll-like receptor ligands to the liver thus activating the inflammatory response. This review explores the new therapeutic opportunities that may arise from novel insights into the mechanisms by which microbiota immunomodulation, represented by probiotics, and prebiotics, affects HCC through the GLA.
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Affiliation(s)
- Edda Russo
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Tuscany, Italy
| | - Camila Fiorindi
- Department of Health Professions, Dietary Production Line and Nutrition, University Hospital of Careggi, Florence 50134, Italy
| | - Francesco Giudici
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Tuscany, Italy
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Tuscany, Italy.
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Amedei A, Gitto S, Campani C, Marra F. Probiotics and the gut-liver axis. PROBIOTICS 2022:467-481. [DOI: 10.1016/b978-0-323-85170-1.00003-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Kang J, Li C, Gao X, Liu Z, Chen C, Luo D. Metformin inhibits tumor growth and affects intestinal flora in diabetic tumor-bearing mice. Eur J Pharmacol 2021; 912:174605. [PMID: 34757071 DOI: 10.1016/j.ejphar.2021.174605] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 10/19/2021] [Accepted: 10/26/2021] [Indexed: 12/31/2022]
Abstract
Many studies have found that diabetes increases the risk of some cancers such as hepatocellular carcinoma. However, there are few studies on the relationship between the two diseases and their effects on intestinal flora. Therefore, we used streptozotocin and high-fat diet to establish a mouse model of type 2 diabetes, and then inoculated the Huh-7 hepatocellular carcinoma cells to obtain mouse diabetic tumor model. Mice inoculated with Huh-7 cells alone served as control. The tumor size in the diabetic tumor group was significantly higher than that in the tumor group. Our study also showed that the expression levels of inflammation-related factors (TNFα, IL-1β, IL-6, TLR4 and MCP1) in the diabetic tumor group were significantly higher than that in the tumor group. We found that metformin alleviated blood glucose level, reduced the expressions of inflammation-related factors and retarded xenograft tumor growth in the diabetic tumor group, but it couldn't reduce the tumor growth in the tumor group. Subsequent studies found that the content of some short chain fatty acids (SCFAs) including acetic acid, propionic acid and isobutyric acid decreased significantly in diabetic tumor group. Metformin increased short chain fatty acid levels (acetic acid, butyic acid and valeric acid) and enriched the abundance of SCFA-producing bacterial genera such as Ruminococcaceae, Clostridiales, Anaerovorax, Odoribacter and Marvinbryantia. In conclusion, type 2 diabetes could promote the growth of hepatoma cells in mice. Metformin could inhibit the growth of tumor under the condition of diabetes and play a role in the intestinal homeostasis in mice.
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Affiliation(s)
- Jie Kang
- College of Life Science, Hebei University, Key Laboratory of Microbial Diversity Research and Application of Hebei Province, Institute of Life Science and Green Development, Hebei University, Baoding, Hebei, 071002, China
| | - Chunqing Li
- College of Life Science, Hebei University, Key Laboratory of Microbial Diversity Research and Application of Hebei Province, Institute of Life Science and Green Development, Hebei University, Baoding, Hebei, 071002, China
| | - Xuehui Gao
- College of Life Science, Hebei University, Key Laboratory of Microbial Diversity Research and Application of Hebei Province, Institute of Life Science and Green Development, Hebei University, Baoding, Hebei, 071002, China
| | - Zhiqin Liu
- College of Life Science, Hebei University, Key Laboratory of Microbial Diversity Research and Application of Hebei Province, Institute of Life Science and Green Development, Hebei University, Baoding, Hebei, 071002, China
| | - Chuan Chen
- College of Life Science, Hebei University, Key Laboratory of Microbial Diversity Research and Application of Hebei Province, Institute of Life Science and Green Development, Hebei University, Baoding, Hebei, 071002, China.
| | - Duqiang Luo
- College of Life Science, Hebei University, Key Laboratory of Microbial Diversity Research and Application of Hebei Province, Institute of Life Science and Green Development, Hebei University, Baoding, Hebei, 071002, China.
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Neag MA, Mitre AO, Catinean A, Buzoianu AD. Overview of the microbiota in the gut-liver axis in viral B and C hepatitis. World J Gastroenterol 2021; 27:7446-7461. [PMID: 34887642 PMCID: PMC8613744 DOI: 10.3748/wjg.v27.i43.7446] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 08/13/2021] [Accepted: 11/03/2021] [Indexed: 02/06/2023] Open
Abstract
Viral B and C hepatitis are a major current health issue, both diseases having a chronic damaging effect on the liver and its functions. Chronic liver disease can lead to even more severe and life-threatening conditions, such as liver cirrhosis and hepatocellular carcinoma. Recent years have uncovered an important interplay between the liver and the gut microbiome: the gut-liver axis. Hepatitis B and C infections often cause alterations in the gut microbiota by lowering the levels of ‘protective’ gut microorganisms and, by doing so, hinder the microbiota ability to boost the immune response. Treatments aimed at restoring the gut microbiota balance may provide a valuable addition to current practice therapies and may help limit the chronic changes observed in the liver of hepatitis B and C patients. This review aims to summarize the current knowledge on the anato-functional axis between the gut and liver and to highlight the influence that hepatitis B and C viruses have on the microbiota balance, as well as the influence of treatments aimed at restoring the gut microbiota on infected livers and disease progression.
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Affiliation(s)
- Maria Adriana Neag
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy of Cluj-Napoca, Cluj-Napoca 400337, Romania
| | - Andrei Otto Mitre
- Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy of Cluj-Napoca, Cluj-Napoca 400012, Romania
| | - Adrian Catinean
- Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy of Cluj-Napoca, Cluj-Napoca 400006, Romania
| | - Anca Dana Buzoianu
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy of Cluj-Napoca, Cluj-Napoca 400337, Romania
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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: 36] [Impact Index Per Article: 9.0] [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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Singh D, Khan MA, Siddique HR. Therapeutic implications of probiotics in microbiota dysbiosis: A special reference to the liver and oral cancers. Life Sci 2021; 285:120008. [PMID: 34606851 DOI: 10.1016/j.lfs.2021.120008] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/20/2021] [Accepted: 09/28/2021] [Indexed: 02/07/2023]
Abstract
The microbiota plays an important role in maintaining the body's homeostasis. Imbalance in the microbiota is referred to as microbiota dysbiosis. Microbiota dysbiosis leads to pro-inflammatory immune response and progression of cancer- one of the leading causes of mortality globally. Accumulating evidence suggest the role of microbiota-dysbiosis in the liver and oral carcinogenesis and the therapeutic role of probiotic strains against these diseases. Probiotics are active microbial strains that have recently gained clinical importance due to their beneficial effects on the human body associated with the prevention and treatment of different diseases, including cancer. Multiple researchers have reported the use of probiotic strains in the modulation of microbiota and immune responses for cancer prevention and management. Clinical trials have also highlighted the efficacy of probiotic strains in reducing the side effects of microbiota dysbiosis related to cancer. In this context, the probiotic-mediated modulation to reverse microbiota dysbiosis is now considered one of the possible novel strategies for cancer prevention and management. In this article, we review the association between microbiota dysbiosis and liver/oral cancer. This review highlights the research advances on the anti-cancer activity of probiotic strains and their metabolites in the management of liver and oral cancers.
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Affiliation(s)
- Deepti Singh
- Molecular Cancer Genetics & Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh 202002, India
| | - Mohammad Afsar Khan
- Molecular Cancer Genetics & Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh 202002, India
| | - Hifzur R Siddique
- Molecular Cancer Genetics & Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh 202002, India.
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Bartolini I, Risaliti M, Tucci R, Muiesan P, Ringressi MN, Taddei A, Amedei A. Gut microbiota and immune system in liver cancer: Promising therapeutic implication from development to treatment. World J Gastrointest Oncol 2021; 13:1616-1631. [PMID: 34853639 PMCID: PMC8603449 DOI: 10.4251/wjgo.v13.i11.1616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/25/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is a leading cause of death worldwide, and hepatocellular carcinoma (HCC) is the most frequent primary liver tumour, followed by cholangiocarcinoma. Notably, secondary tumours represent up to 90% of liver tumours. Chronic liver disease is a recognised risk factor for liver cancer development. Up to 90% of the patients with HCC and about 20% of those with cholangiocarcinoma have an underlying liver alteration. The gut microbiota-liver axis represents the bidirectional relationship between gut microbiota, its metabolites and the liver through the portal flow. The interplay between the immune system and gut microbiota is also well-known. Although primarily resulting from experiments in animal models and on HCC, growing evidence suggests a causal role for the gut microbiota in the development and progression of chronic liver pathologies and liver tumours. Despite the curative intent of "traditional" treatments, tumour recurrence remains high. Therefore, microbiota modulation is an appealing therapeutic target for liver cancer prevention and treatment. Furthermore, microbiota could represent a non-invasive biomarker for early liver cancer diagnosis. This review summarises the potential role of the microbiota and immune system in primary and secondary liver cancer development, focusing on the potential therapeutic implications.
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Affiliation(s)
- Ilenia Bartolini
- Department of Experimental and Clinical Medicine, University of Florence, Azienda Ospedaliero Universitaria Careggi (AOUC), Florence 50134, Italy
| | - Matteo Risaliti
- Department of Experimental and Clinical Medicine, University of Florence, Azienda Ospedaliero Universitaria Careggi (AOUC), Florence 50134, Italy
| | - Rosaria Tucci
- Department of Experimental and Clinical Medicine, University of Florence, Azienda Ospedaliero Universitaria Careggi (AOUC), Florence 50134, Italy
| | - Paolo Muiesan
- Department of Experimental and Clinical Medicine, University of Florence, Azienda Ospedaliero Universitaria Careggi (AOUC), Florence 50134, Italy
| | - Maria Novella Ringressi
- Department of Experimental and Clinical Medicine, University of Florence, Azienda Ospedaliero Universitaria Careggi (AOUC), Florence 50134, Italy
| | - Antonio Taddei
- Department of Experimental and Clinical Medicine, University of Florence, Azienda Ospedaliero Universitaria Careggi (AOUC), Florence 50134, Italy
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, SOD of Interdisciplinary Internal Medicine, Azienda Ospedaliero Universitaria Careggi (AOUC), Florence 50134, Italy
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Prevention of NAFLD-associated HCC: Role of lifestyle and chemoprevention. J Hepatol 2021; 75:1217-1227. [PMID: 34339764 DOI: 10.1016/j.jhep.2021.07.025] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/13/2021] [Accepted: 07/15/2021] [Indexed: 02/07/2023]
Abstract
In many countries worldwide, the burden of hepatocellular carcinoma (HCC) associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing. Preventive strategies are needed to counteract this trend. In this review, we provide an overview of the evidence on preventive strategies in NAFLD-associated HCC. We consider the impact of lifestyle factors such as weight loss, physical activity, smoking, dietary patterns and food items, including coffee and alcohol, on both HCC and NAFLD/NASH. Furthermore, evidence on chemopreventive treatments, including aspirin, antidiabetic treatments and statins is summarised. The role of adjuvant therapies for tertiary prevention of HCC is briefly reviewed.
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41
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Food-grade lactic acid bacteria and probiotics as a potential protective tool against erythrotoxic dietary xenobiotics. Trends Food Sci Technol 2021. [DOI: 10.1016/j.tifs.2021.09.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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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: 35] [Impact Index Per Article: 8.8] [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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Zhou D, Luan J, Huang C, Li J. Tumor-Associated Macrophages in Hepatocellular Carcinoma: Friend or Foe? Gut Liver 2021; 15:500-516. [PMID: 33087588 PMCID: PMC8283292 DOI: 10.5009/gnl20223] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 08/21/2020] [Accepted: 08/22/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and it has diverse etiologies with multiple mechanisms. The diagnosis of HCC typically occurs at advanced stages when there are limited therapeutic options. Hepatocarcinogenesis is considered a multistep process, and hepatic macrophages play a critical role in the inflammatory process leading to HCC. Emerging evidence has shown that tumor-associated macrophages (TAMs) are crucial components defining the HCC immune microenvironment and represent an appealing option for disrupting the formation and development of HCC. In this review, we summarize the current knowledge of the polarization and function of TAMs in the pathogenesis of HCC, as well as the mechanisms underlying TAM-related anti-HCC therapies. Eventually, novel insights into these important aspects of TAMs and their roles in the HCC microenvironment might lead to promising TAM-focused therapeutic strategies for HCC.
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Affiliation(s)
- Dexi Zhou
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, China.,Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, China.,School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Jiajie Luan
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, China.,Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, China.,School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Cheng Huang
- School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Hefei, China
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Fianchi F, Liguori A, Gasbarrini A, Grieco A, Miele L. Nonalcoholic Fatty Liver Disease (NAFLD) as Model of Gut-Liver Axis Interaction: From Pathophysiology to Potential Target of Treatment for Personalized Therapy. Int J Mol Sci 2021; 22:6485. [PMID: 34204274 PMCID: PMC8233936 DOI: 10.3390/ijms22126485] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 06/13/2021] [Accepted: 06/14/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide, affecting both adults and children and will result, in the near future, as the leading cause of end-stage liver disease. Indeed, its prevalence is rapidly increasing, and NAFLD is becoming a major public health concern. For this reason, great efforts are needed to identify its pathogenetic factors and new therapeutic approaches. In the past decade, enormous advances understanding the gut-liver axis-the complex network of cross-talking between the gut, microbiome and liver through the portal circulation-have elucidated its role as one of the main actors in the pathogenesis of NAFLD. Indeed, evidence shows that gut microbiota is involved in the development and progression of liver steatosis, inflammation and fibrosis seen in the context of NAFLD, as well as in the process of hepatocarcinogenesis. As a result, gut microbiota is currently emerging as a non-invasive biomarker for the diagnosis of disease and for the assessment of its severity. Additionally, to its enormous diagnostic potential, gut microbiota is currently studied as a therapeutic target in NAFLD: several different approaches targeting the gut homeostasis such as antibiotics, prebiotics, probiotics, symbiotics, adsorbents, bariatric surgery and fecal microbiota transplantation are emerging as promising therapeutic options.
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Affiliation(s)
- Francesca Fianchi
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.F.); (A.L.); (A.G.); (A.G.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, 00168 Rome, Italy
| | - Antonio Liguori
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.F.); (A.L.); (A.G.); (A.G.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.F.); (A.L.); (A.G.); (A.G.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, 00168 Rome, Italy
| | - Antonio Grieco
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.F.); (A.L.); (A.G.); (A.G.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, 00168 Rome, Italy
| | - Luca Miele
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.F.); (A.L.); (A.G.); (A.G.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, 00168 Rome, Italy
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Khedr OMS, El-Sonbaty SM, Moawed FSM, Kandil EI, Abdel-Maksoud BE. Lactobacillus acidophilus ATCC 4356 Exopolysaccharides Suppresses Mediators of Inflammation through the Inhibition of TLR2/STAT-3/P38-MAPK Pathway in DEN-Induced Hepatocarcinogenesis in Rats. Nutr Cancer 2021; 74:1037-1047. [PMID: 34085875 DOI: 10.1080/01635581.2021.1934490] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Probiotics have been suggested as a safe and cost-effective approach to prevent or treat hepatocellular carcinoma (HCC). Some of the exopolysaccharides (EPSs) produced by lactic acid bacteria confer health benefits such as immunomodulatory and antitumor activities. The present study was therefore aimed to investigate the immunomodulatory effect of Lactobacillus acidophilus ATCC 4356 EPSs against diethylnitrosamine (DEN) and gamma radiation (IR) induced HCC either as prevention or treatment in male rats' model. Biochemical results revealed a significant increase in serum ALT and γ-GT activities as well as MDA, IL-17, TGF-β1, signal transducer and activator of transcription-3 protein (STAT3), mitogen-activated protein kinase p38 (p38MAPK) levels in the liver tissue. The gene expression level of the liver toll-like receptor 2 (TLR-2) gene was also increased. However, prevention and treatment with EPSs ameliorated most of the investigated parameters. The histopathological observations of liver tissues were in agreement with restored biochemical results. In conclusion, Lactobacillus acidophilus ATCC 4356 EPSs are efficacious control against HCC throughout the regulation of TLR2/STAT-3/P38-MAPK Pathway associated with inflammation. Therefore, our novel EPSs ATCC 4356 could be used as a good, safe and effective probiotic to prevent hepatocarcinogenesis in suspected patients.
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Affiliation(s)
- Ola M S Khedr
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Sawsan M El-Sonbaty
- Microbiology Department, National Centre for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt
| | - Fatma S M Moawed
- Health Radiation Research Department, National Centre for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt
| | - Eman I Kandil
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
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Beyaz Coşkun A, Sağdiçoğlu Celep AG. Therapeutic modulation methods of gut microbiota and gut-liver axis. Crit Rev Food Sci Nutr 2021; 62:6505-6515. [PMID: 33749411 DOI: 10.1080/10408398.2021.1902263] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Liver diseases are considered global health problems that cause more than 1 million deaths each year. Due to the increase in the prevalence of liver diseases worldwide, studies on different treatment methods have increased. Some of these methods is diagnostic and therapeutic applications based on the examination of the intestinal and intestinal microbiota. In this study, research articles, systematic review and review in the literature were examined in order to determine gut-liver axis relationship and treatment methods for liver diseases with gut modulation methods. Studies related to the subject have been searched in Google Scholar and Pubmed databases. The keywords "liver disease" and "gut-liver axis" and "microbiota" and "gut modulation methods" or "probiotic" or "prebiotic" or "symbiotic" or "antibiotic" or "bile acid regulation" or "adsorbent" or "fecal microbiota transplantation" were used in the searches. Improvements have been achieved in biomarkers of liver diseases by providing intestinal modulation with probiotic, prebiotic, symbiotic, antibiotic and adsorbents applications, bile acid regulation and fecal microbiota transplantation. In the results of experimental and clinical studies, it was seen that the therapeutic potential of the treatments performed by applying probiotics, prebiotics and symbiotics was higher.
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Affiliation(s)
- Ayfer Beyaz Coşkun
- Department of Nutrition and Dietetics, Faculty of Health Science, Fırat University, Elazığ, Turkey
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Mechanisms by Which Probiotic Bacteria Attenuate the Risk of Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:ijms22052606. [PMID: 33807605 PMCID: PMC7961993 DOI: 10.3390/ijms22052606] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 03/03/2021] [Accepted: 03/04/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the second leading cause of cancer-related deaths worldwide. Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV), alcoholic liver disease (ALD), and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) are the major extrinsic risk factors of HCC development. Genetic background is pivotal in HCC pathogenesis, and both germline mutations and single nucleotide polymorphism (SNP) are intrinsic risk factors of HCC. These HCC risk factors predispose to hepatic injury and subsequent activation of fibrogenesis that progresses into cirrhosis and HCC. Probiotic bacteria can mitigate HCC risk by modulating host gut microbiota (GM) to promote growth of beneficial microbes and inhibit HCC-associated dysbiosis, thus preventing pathogen-associated molecular patterns (PAMPs)-mediated hepatic inflammation. Probiotics have antiviral activities against HBV and HCV infections, ameliorate obesity and risk of NAFLD/NASH, and their antioxidant, anti-proliferative, anti-angiogenic, and anti-metastatic effects can prevent the HCC pathogenesis. Probiotics also upregulate the expression of tumor suppressor genes and downregulate oncogene expression. Moreover, metabolites generated by probiotics through degradation of dietary phytochemicals may mitigate the risk of HCC development. These multiple anticancer mechanisms illustrate the potential of probiotics as an adjuvant strategy for HCC risk management and treatment.
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Shi T, Kobara H, Oura K, Masaki T. Mechanisms Underlying Hepatocellular Carcinoma Progression in Patients with Type 2 Diabetes. J Hepatocell Carcinoma 2021; 8:45-55. [PMID: 33604315 PMCID: PMC7886236 DOI: 10.2147/jhc.s274933] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) ranks third in cancer-related deaths from solid tumors worldwide. The incidence of type 2 diabetes mellitus (T2DM) has increased worldwide in conjunction with the expansion of the Western lifestyle. Furthermore, patients with T2DM have been documented to have an increased risk of HCC, as well as bile tract cancer. Growing evidence shows that T2DM is a strong additive metabolic risk factor for HCC, but how diabetes affects the incidence of HCC requires additional investigation. In this review, we discuss the underlying mechanisms of HCC in patients with T2DM. Topics covered include abnormal glucose and lipid metabolism, hyperinsulinemia, and insulin resistance; the effect of activated platelets; hub gene expression associated with HCC; inflammation and signaling pathways; miRNAs; altered gut microbiota and immunomodulation. The evidence suggests that reducing obesity, diabetes, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis through efficient measures of prevention may lead to decreased rates of T2DM-related HCC.
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Affiliation(s)
- Tingting Shi
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa, 761-0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa, 761-0793, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa, 761-0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa, 761-0793, Japan
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McPherson AC, Pandey SP, Bender MJ, Meisel M. Systemic Immunoregulatory Consequences of Gut Commensal Translocation. Trends Immunol 2021; 42:137-150. [PMID: 33422410 PMCID: PMC10110348 DOI: 10.1016/j.it.2020.12.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 12/04/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023]
Abstract
One major determinant of systemic immunity during homeostasis and in certain complex multifactorial diseases (e.g. cancer and autoimmune conditions), is the gut microbiota. These commensals can shape systemic immune responses via translocation of metabolites, microbial cell wall components, and viable microbes. In the last few years, bacterial translocation has revealed itself as playing a key, and potentially causal role in mediating immunomodulatory processes in nongastrointestinal diseases. Moreover, recent observations regarding the presence of complex microbial communities and viable bacteria within gut-distal tissues during homeostasis challenge the current paradigm that healthy mammals are entirely sterile at nonmucosal sites. This review discusses our current understanding of how the gut microbiota orchestrates systemic immunity during noninfectious extraintestinal diseases and homeostasis, focusing on the translocation of viable bacteria to gut-distal sites.
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Affiliation(s)
- Alex C McPherson
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Surya P Pandey
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Mackenzie J Bender
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Marlies Meisel
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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Atypical immunometabolism and metabolic reprogramming in liver cancer: Deciphering the role of gut microbiome. Adv Cancer Res 2020; 149:171-255. [PMID: 33579424 DOI: 10.1016/bs.acr.2020.10.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related mortality worldwide. Much recent research has delved into understanding the underlying molecular mechanisms of HCC pathogenesis, which has revealed to be heterogenous and complex. Two major hallmarks of HCC include: (i) a hijacked immunometabolism and (ii) a reprogramming in metabolic processes. We posit that the gut microbiota is a third component in an entanglement triangle contributing to HCC progression. Besides metagenomic studies highlighting the diagnostic potential in the gut microbiota profile, recent research is pinpointing the gut microbiota as an instigator, not just a mere bystander, in HCC. In this chapter, we discuss mechanistic insights on atypical immunometabolism and metabolic reprogramming in HCC, including the examination of tumor-associated macrophages and neutrophils, tumor-infiltrating lymphocytes (e.g., T-cell exhaustion, regulatory T-cells, natural killer T-cells), the Warburg effect, rewiring of the tricarboxylic acid cycle, and glutamine addiction. We further discuss the potential involvement of the gut microbiota in these characteristics of hepatocarcinogenesis. An immediate highlight is that microbiota metabolites (e.g., short chain fatty acids, secondary bile acids) can impair anti-tumor responses, which aggravates HCC. Lastly, we describe the rising 'new era' of immunotherapies (e.g., immune checkpoint inhibitors, adoptive T-cell transfer) and discuss for the potential incorporation of gut microbiota targeted therapeutics (e.g., probiotics, fecal microbiota transplantation) to alleviate HCC. Altogether, this chapter invigorates for continuous research to decipher the role of gut microbiome in HCC from its influence on immunometabolism and metabolic reprogramming.
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