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Ray D, Bose P, Mukherjee S, Roy S, Kaity S. Recent drug delivery systems targeting the gut-brain-microbiome axis for the management of chronic diseases. Int J Pharm 2025; 680:125776. [PMID: 40425058 DOI: 10.1016/j.ijpharm.2025.125776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 05/14/2025] [Accepted: 05/24/2025] [Indexed: 05/29/2025]
Abstract
In recent years, the study of microorganisms and the brain has become increasingly connected. The gut-brain-microbiome axis (GBMA), a bi-directional communication system, is the key part of how the body's bacteria and the brain interact. This system can influence the brain and behaviour. Changes in this relationship have been linked to various mental and physical health conditions. The immune system, tryptophan metabolism, the vagus nerve, and the enteric nervous system all facilitate connections between the gut and brain. Microbes produce Peptidoglycans, branched-chain amino acids, and short-chain fatty acids, which are involved in this communication. Studies suggest the gut microbiome may be involved in conditions like autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. Researchers are exploring the gut-brain connection to cure a variety of disorders, such as neurological disorders, cancers, metabolic problems, and liver diseases. Developing novel drug delivery systems is a key focus in GBMA for therapeutic targeting at various disease pathways. Notable platforms attracting significant interest include silica nanoparticle-based delivery systems for probiotic spores, composite hydrogels formulated from protein isolates and citrus pectin, and biomimetic nanosystems designed for targeted therapeutic delivery. This review summarizes different methods of delivering drugs and using dietary interventions to target the GBMA and treat these conditions in a less invasive way. By understanding how the gut and brain communicate, scientists aim to develop new and more effective therapies for these complex chronic diseases.
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Affiliation(s)
- Debjani Ray
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, West Bengal, India
| | - Piyas Bose
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, West Bengal, India
| | - Saptarshi Mukherjee
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, West Bengal, India
| | - Subhadeep Roy
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, West Bengal, India
| | - Santanu Kaity
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, West Bengal, India.
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Shu Y, Jiang H, Gao X, Hong P, Wang Q, Ruan Y, Wu H, He J. Microcystin-LR Induces Lipid Metabolism Disorder in Pelophylax nigromaculatus Tadpoles via the Gut-Liver Axis. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2025; 59:9399-9411. [PMID: 40337926 DOI: 10.1021/acs.est.4c12957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2025]
Abstract
Disruption of lipid homeostasis in aquatic animals poses serious health risks, including tissue damage and systemic metabolic dysfunction. The precise mechanisms by which microcystin-LR, a potent cyanotoxin, disrupts lipid metabolism in amphibian tadpoles remain unclear. In this study, tadpoles (Pelophylax nigromaculatus) were exposed to MC-LR and fecal microbiota transplantation (FMT) experiments were performed to investigate whether or how MC-LR at environmental concentrations interfered with tadpole lipid metabolism from the perspective of the gut microbiota-gut-liver axis. Following exposure, the liver exhibited significant inflammation, hypertrophy, and fibrosis, accompanied by elevated serum lipid levels. Furthermore, the expression levels of the farnesoid X receptor (FXR), a nuclear receptor, were significantly downregulated. Molecular docking and molecular dynamics simulations indicated a strong and stable binding between FXR and MC-LR. Moreover, MC-LR suppressed liver FXR expression or activity, triggering: (1) upregulation of sterol regulatory element-binding protein 1 (SREBP1)-mediated triglyceride (TG) synthesis, (2) inhibition of free fatty acid (FFA) β-oxidation, and (3) activation of SREBP2-dependent bile acid biosynthesis. Moreover, MC-LR altered the composition of gut microbiota and specific bile acid levels (e.g., taurocholic acid and glycochenodeoxycholic acid) in the gut, thereby interfering with hepatic lipid metabolism, as evidenced by FMT-induced hepatic lipid accumulation in recipient tadpoles. These findings identify FXR as a potentially key molecular target for MC-LR and suggest that changes in bile acid levels of intestinal microbiota metabolism also may be an important pathway driving hepatic lipid dysregulation in amphibians exposed to environmental concentrations of MC-LR.
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Affiliation(s)
- Yilin Shu
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002 Anhui, China
| | - Huiling Jiang
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002 Anhui, China
| | - Xianxin Gao
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002 Anhui, China
| | - Pei Hong
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002 Anhui, China
- State Key Laboratory of Marine Pollution (SKLMP), and Department of Chemistry, City University of Hong Kong, Hong Kong SAR 999077, China
| | - Qi Wang
- State Key Laboratory of Marine Pollution (SKLMP), and Department of Chemistry, City University of Hong Kong, Hong Kong SAR 999077, China
| | - Yuefei Ruan
- State Key Laboratory of Marine Pollution (SKLMP), and Department of Chemistry, City University of Hong Kong, Hong Kong SAR 999077, China
| | - Hailong Wu
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002 Anhui, China
| | - Jun He
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002 Anhui, China
- Department of Pathology, Wannan Medical College, Wuhu 241002 Anhui, China
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Li S, Li H, Qi M. Exploring shared pathogenic mechanisms and biomarkers in hepatic fibrosis and inflammatory bowel disease through bioinformatics and machine learning. Front Immunol 2025; 16:1533246. [PMID: 40421012 PMCID: PMC12104268 DOI: 10.3389/fimmu.2025.1533246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 04/22/2025] [Indexed: 05/28/2025] Open
Abstract
Background The coexistence of hepatic fibrosis (HF) and inflammatory bowel disease (IBD) represents a significant clinical concern due to their poorly characterized shared pathogenic mechanisms. Current limitations in identifying common biomarkers for comorbid cases impede early dual diagnosis and therapeutic interventions. Methods Differentially expressed genes (DEGs) were screened, followed by Weighted Gene Co-expression Network Analysis (WGCNA) to identify disease-associated modules. The key diagnostic biomarkers were determined via a protein-protein interaction (PPI) network combined with two machine learning algorithms. The logistic regression model was subsequently developed based on these key genes. Immune cell infiltration profiling of both diseases was assessed via the CIBERSORT algorithm. The construction of genes-miRNAs and genes-TFs (Transcription Factors) regulatory networks were based on the NetworkAnalyst website. Potential drug-gene interactions were predicted utilizing the DSigDB database. The expression and distribution of these genes were validated through single-cell sequencing analysis. Results A sum of 119 up-regulated genes and 17 down-regulated genes were screened, which were enriched in categories associated with immune cell infiltration and chemotaxis, cytokine regulation, metabolic processes, enzymatic activity, and extracellular matrix deposition, based on enrichment analysis. WGCNA revealed four disease-associated gene modules. Four shared diagnostic genes for both diseases were screened, including MMP2, COL1A2, STAT1, and CXCL1. ROC curve analysis confirmed robust diagnostic performance as AUC > 0.7 for individual genes and AUC > 0.85 for combined model. M1 macrophages were significantly increased in both pathologies of diseases. A total of 462 drugs were predicted targeting these biomarkers in the DSigDB database. The four key diagnostic gene expression patterns across diverse cell subpopulations were visualized by single-cell sequencing analysis. Conclusion MMP2, COL1A2, CXCL1, and STAT1 were identified as shared biomarkers for IBD and HF, providing a molecular basis for early diagnosis and precision medicine approaches. It elucidated the similarities between HF and IBD in terms of immunity, metabolism, and fibrosis.
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Affiliation(s)
- Shangkun Li
- Clinical Medicine, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Haoyu Li
- Clinical Medicine, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Mingran Qi
- Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
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Shen TH, Yu X, Zhou C, Liu Y, Li QY, Li W, Jiang TH, Zhu YQ, Liu Y. Review of the mechanisms of the biliary-enteric axis in the development of cholangiocarcinoma. World J Clin Oncol 2025; 16:102374. [PMID: 40290694 PMCID: PMC12019280 DOI: 10.5306/wjco.v16.i4.102374] [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: 10/15/2024] [Revised: 01/07/2025] [Accepted: 02/13/2025] [Indexed: 03/26/2025] Open
Abstract
Cholangiocarcinoma (CCA) is a particularly aggressive and challenging type of cancer, known for its poor prognosis, which is worsened by the complex interplay of various biological and environmental factors that contribute to its development. Recently, researchers have increasingly focused on the significant role of the biliary-enteric communication of liver-gut axis in the pathogenesis of CCA, highlighting a complex relationship that has not been thoroughly explored before. This review aims to summarize the key concepts related to the biliary-enteric communication of liver-gut axis and investigate its potential mechanisms that may lead to the onset and progression of CCA, a disease that presents substantial treatment challenges. Important areas of focus will include the microbiome's profound influence, which interacts with host physiology in ways that may worsen cancer development; changes in bile acid metabolism that can create toxic environments favorable for tumor growth; the regulation of inflammatory processes that may either promote or inhibit tumor progression; the immune system's involvement, which is crucial in the body's response to cancer; and the complex interactions within metabolic pathways that can affect cellular behavior and tumor dynamics. By integrating recent research findings from various studies, we aim to explore the multifaceted roles of the biliary-enteric communication of liver-gut axis in CCA, providing new insights and perspectives for future research while identifying promising therapeutic targets that could lead to innovative treatment strategies aimed at improving patient outcomes in this challenging disease.
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Affiliation(s)
- Tian-Hao Shen
- Department of Interventional Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Xue Yu
- Department of Interventional Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Cheng Zhou
- Department of Interventional Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Yu Liu
- Department of Interventional Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Qiu-Ying Li
- Department of Interventional Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Wei Li
- Department of Hepatological Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Ting-Hui Jiang
- Department of Interventional Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Yong-Qiang Zhu
- Department of Interventional Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Yan Liu
- Department of Interventional Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
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5
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Roth D, Düll MM, Horst LJ, Lindemann A, Malzer X, Koop K, Zundler S, Vetter M, Jefremow A, Atreya R, Geppert C, Weidemann S, Waldner MJ, Dietrich P, Günther C, Munoz LE, Herrmann M, Scheffold A, Neurath MF, Siebler J, Schramm C, Kremer AE, Leppkes M. Integrin αVβ6: Autoantigen and Driver of Epithelial Remodeling in Colon and Bile Ducts in Primary Sclerosing Cholangitis and Inflammatory Bowel Disease. J Crohns Colitis 2025; 19:jjae131. [PMID: 39212221 DOI: 10.1093/ecco-jcc/jjae131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Recently, autoantibodies directed against the epithelial adhesion protein integrin αVβ6 have been identified that are strongly associated with ulcerative colitis (UC). We aimed to elucidate whether anti-integrin αVβ6 (anti-αVβ6) is present in primary sclerosing cholangitis (PSC), its associated inflammatory bowel disease, or other cholestatic liver diseases and their persistence after proctocolectomy. METHODS We detected anti-αVβ6 by an enzyme-linked immunosorbent assay in sera collected at 2 German tertiary centers, including healthy controls (N = 62), UC (N = 36), Crohn's disease (CD, N = 65), PSC-inflammatory bowel diseases (IBD) (78 samples from N = 41 patients), PSC without IBD (PSC, 41 samples from N = 18 patients), primary biliary cholangitis (PBC, N = 24), autoimmune hepatitis (AIH, N = 32), secondary sclerosing cholangitis (SSC, N = 12), and metabolic dysfunction-associated steatotic liver disease (MASLD, N = 24). In addition, sera after proctocolectomy were studied (44 samples/N = 10 patients). Immunofluorescent analyses were performed in tissue samples from liver, large bile duct from surgical resections, and colon of PSC patients. RESULTS Anti-αVβ6 occurred in 91% of UC, 17% of CD, 73% of PSC-IBD, 39% of PSC, 4% of PBC, 14% of AIH, and 0% of healthy controls, SSC, or MASLD. Integrin αVβ6 is selectively expressed in disease-associated epithelia of both bile duct and colon. Anti-αVβ6 levels correlate moderately with intestinal disease activity in PSC-IBD, but only weakly with biliary disease. CONCLUSIONS Anti-αVβ6 frequently occurs in patients suffering from PSC, especially in PSC-IBD. Anti-αVβ6 levels positively correlate to IBD activity in PSC-IBD, but may also occur in the absence of clinically manifest IBD in PSC.
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Affiliation(s)
- Dominik Roth
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, Friedrich Alexander University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Miriam M Düll
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, Friedrich Alexander University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Ludwig J Horst
- Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Aylin Lindemann
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, Friedrich Alexander University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Xenia Malzer
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, Friedrich Alexander University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Kristina Koop
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, Friedrich Alexander University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Sebastian Zundler
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, Friedrich Alexander University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Marcel Vetter
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, Friedrich Alexander University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - André Jefremow
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, Friedrich Alexander University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Raja Atreya
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, Friedrich Alexander University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Carol Geppert
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Sören Weidemann
- Institute of Pathology, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
| | - Maximilian J Waldner
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, Friedrich Alexander University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Peter Dietrich
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, Friedrich Alexander University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Germany
| | - Claudia Günther
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, Friedrich Alexander University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Luis E Munoz
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Department of Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Martin Herrmann
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Department of Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Alexander Scheffold
- Institute of Immunology, Christian-Albrechts-Universität zu Kiel & Universitätsklinik Schleswig-Holstein, Kiel, Germany
| | - Markus F Neurath
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, Friedrich Alexander University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Jürgen Siebler
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, Friedrich Alexander University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Christoph Schramm
- Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas E Kremer
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, Friedrich Alexander University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Department of Hepatology and Gastroenterology, University Hospital Zürich and University Zürich, Zürich, Switzerland
| | - Moritz Leppkes
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, Friedrich Alexander University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
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Kim NH, Kim MY, Yang YM, Jeong WI, Lee HW, Kim W, Kang SG, Han YH. Bacterial components-driven intrahepatic CXCR5 hi B cells are important population for MASH progression through inducing inflammation. FASEB J 2025; 39:e70322. [PMID: 39812617 DOI: 10.1096/fj.202401256r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 12/17/2024] [Accepted: 01/06/2025] [Indexed: 01/16/2025]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by severe liver inflammation and fibrosis due to an imbalanced immune response caused by enhanced bacterial components. The progression of MASH is closely linked to increased permeability of intestinal mucosal barrier facilitating enter of bacterial components into hepatic portal venous system. B cells are important immune cells for adaptive responses and enhance hepatic inflammation through cytokine production and T cell activation. B cells are influenced by gut microbiota, but the specific B cell populations in MASH and their pathologic mechanism remain obscure. Here, we found that the numbers of B cells highly expressing CXCR5, the receptor of CXCL13 chemokine, were increased in the livers of MASH. CXCR5 high B cells are non-proliferating naive B cells with inflammatory features mainly residing in hepatic parenchyma to affect liver pathology. Importantly, we revealed that CXCR5 high B cells were induced by bacterial components stimulating TLRs. These bacterial stimulator-induced CXCR5hi B cells highly express TNFα, CD80, and MHC class II, leading to T cell activation. Consistently, we confirmed that intravenous injection of CXCR5 high B cells enhanced hepatic inflammation in MASH model. Ultimately, this study elucidates the role and mechanisms of CXCR5 high B cells in advancing MASH progression.
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Affiliation(s)
- Nam-Hee Kim
- Department of Pharmacy, College of Pharmacy, Kangwon National University, Chuncheon, South Korea
| | - Mi-Yeon Kim
- Department of Pharmacy, College of Pharmacy, Kangwon National University, Chuncheon, South Korea
| | - Yoon Mee Yang
- Department of Pharmacy, College of Pharmacy, Kangwon National University, Chuncheon, South Korea
- Multidimentional Genomics Research Center, Kangwon National University, Chuncheon, South Korea
| | - Won-Il Jeong
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, South Korea
| | - Hye Won Lee
- Department of Internal Medicine Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Wooseob Kim
- Department of Microbiology, Korea University College of Medicine, Seoul, South Korea
| | - Seung Goo Kang
- Department of Molecular Bioscience/Institute of Bioscience and Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon, South Korea
| | - Yong-Hyun Han
- Department of Pharmacy, College of Pharmacy, Kangwon National University, Chuncheon, South Korea
- Multidimentional Genomics Research Center, Kangwon National University, Chuncheon, South Korea
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7
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Bruneau A, Shevchenko Y, Tacke F, Hammerich L. A comprehensive 26-color immunophenotyping panel to study the role of the gut-liver axis in chronic liver diseases. CYTOMETRY. PART B, CLINICAL CYTOMETRY 2025; 108:15-22. [PMID: 39252408 DOI: 10.1002/cyto.b.22203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 08/19/2024] [Accepted: 08/22/2024] [Indexed: 09/11/2024]
Abstract
The gut-liver axis includes the bidirectional communication between the gut and the liver, and thus covers signals from liver-to-gut and from gut-to-liver. Disruptions of the gut-liver axis have been associated with the progression of chronic liver diseases, including alcohol-related and metabolic dysfunction-associated steatotic liver disease and cholangiopathies. Immune cells and their expression of pattern recognition receptors, activation markers or immune checkpoints might play an active role in the communication between gut and liver. Here, we present a 26-color full spectrum flow cytometry panel for human cells to decipher the role of circulating immune cells in gut-liver communication during the progression of chronic liver diseases in a non-invasive manner, which has been optimized to be used on patient-derived whole blood samples, the most abundantly available clinical material. Our panel focuses on changes in pattern recognition receptors, including toll-like receptors (TLRs) or Dectin-1, and also includes other immunomodulatory molecules such as bile acid receptors and checkpoint molecules. Moreover, this panel can be utilized to follow the progression of chronic liver diseases and could be used as a tool to evaluate the efficiency of therapeutic targets directed against microbial mediators or modulating immune cell activation.
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Affiliation(s)
- Alix Bruneau
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Yaroslava Shevchenko
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Frank Tacke
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Linda Hammerich
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
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8
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Bruneau A, Hammerich L. Slamming hepatocellular carcinoma: targeting immunosuppressive macrophages via SLAMF7 reprograms the tumor microenvironment. Transl Cancer Res 2024; 13:6995-7001. [PMID: 39816568 PMCID: PMC11730195 DOI: 10.21037/tcr-24-876] [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: 05/29/2024] [Accepted: 11/15/2024] [Indexed: 01/18/2025]
Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and one of the leading causes of cancer-related deaths worldwide due to limited treatment options. The tumor microenvironment (TME), which is usually immunosuppressive in HCC, appears to be a decisive factor for response to immunotherapy and strategies aimed at inducing a more inflamed TME hold promise to overcome resistance to immunotherapy. Within the TME, the interplay of various cell types determines whether immunotherapy is successful. Liver macrophages, in particular tumor associated macrophages (TAMs), are known to play a crucial role in tumor progression and represent potential future therapeutic targets. The presence of C-C motif chemokine receptor 2 (CCR2) expressing macrophages is known to be associated with pathogenic angiogenesis and bad prognosis for HCC patients. A recent study published in Cancer Research describes how immunosuppressive macrophages in the TME can be repolarized through targeting Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7)-regulated CC-chemokine ligand 2 (CCL2) signaling, which sensitizes HCC tumors to immunotherapy in a mouse model. This mini-review gives a brief overview about the current knowledge on SLAMF7 in the context of anti-cancer immunity and how the recent findings could be integrated into new therapeutic strategies for HCC.
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Affiliation(s)
- Alix Bruneau
- Department of Hepatology and Gastroenterology, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Linda Hammerich
- Department of Hepatology and Gastroenterology, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
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Kiseleva YV, Zharikova TS, Maslennikov RV, Temirbekov SM, Olsufieva AV, Polyakova OL, Pontes-Silva A, Zharikov YO. Gut Microbiota and Liver Regeneration: A Synthesis of Evidence on Structural Changes and Physiological Mechanisms. J Clin Exp Hepatol 2024; 14:101455. [PMID: 39035190 PMCID: PMC11259939 DOI: 10.1016/j.jceh.2024.101455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 06/05/2024] [Indexed: 07/23/2024] Open
Abstract
Liver regeneration (LR) is a unique biological process with the ability to restore up to 70% of the organ. This allows for the preservation of liver resections for various liver tumors and for living donor liver transplantation (LDLT). However, in some cases, LR is insufficient and interventions that can improve LR are urgently needed. Gut microbiota (GM) is one of the factors influencing LR, as the liver and intestine are intimately connected through the gut-liver axis. Thus, healthy GM facilitates normal LR, whereas dysbiosis leads to impaired LR due to imbalance of bile acids, inflammatory cytokines, microbial metabolites, signaling pathways, etc. Therefore, GM can be considered as a new possible therapeutic target to improve LR. In this review, we critically observe the current knowledge about the influence of gut microbiota (GM) on liver regeneration (LR) and the possibility to improve this process, which may reduce complication and mortality rates after liver surgery. Although much research has been done on this topic, more clinical trials and systemic reviews are urgently needed to move this type of intervention from the experimental phase to the clinical field.
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Affiliation(s)
- Yana V. Kiseleva
- Pirogov Russian National Research Medical University (RNRMU), Moscow, Russia
| | - Tatiana S. Zharikova
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Roman V. Maslennikov
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | | | - Anna V. Olsufieva
- Moscow University for Industry and Finance “Synergy”, Moscow, Russia
| | - Olga L. Polyakova
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - André Pontes-Silva
- Postgraduate Program in Physical Therapy, Department of Physical Therapy, Universidade Federal de São Carlos, São Carlos (SP), Brazil
| | - Yury O. Zharikov
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
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10
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Vu HT, Nguyen VD, Ikenaga H, Matsubara T. Application of PPAR Ligands and Nanoparticle Technology in Metabolic Steatohepatitis Treatment. Biomedicines 2024; 12:1876. [PMID: 39200340 PMCID: PMC11351628 DOI: 10.3390/biomedicines12081876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/10/2024] [Accepted: 08/13/2024] [Indexed: 09/02/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH) is a major disease worldwide whose effective treatment is challenging. Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily and function as ligand-activated transcription factors. To date, three distinct subtypes of PPARs have been characterized: PPARα, PPARβ/δ, and PPARγ. PPARα and PPARγ are crucial regulators of lipid metabolism that modulate the transcription of genes involved in fatty acid (FA), bile acid, and cholesterol metabolism. Many PPAR agonists, including natural (FAs, eicosanoids, and phospholipids) and synthetic (fibrate, thiazolidinedione, glitazar, and elafibranor) agonists, have been developed. Furthermore, recent advancements in nanoparticles (NPs) have led to the development of new strategies for MASLD/MASH therapy. This review discusses the applications of specific cell-targeted NPs and highlights the potential of PPARα- and PPARγ-targeted NP drug delivery systems for MASLD/MASH treatment.
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Affiliation(s)
- Hung Thai Vu
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Osaka, Japan; (H.T.V.); (V.D.N.)
| | - Vien Duc Nguyen
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Osaka, Japan; (H.T.V.); (V.D.N.)
| | - Hiroko Ikenaga
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Osaka, Japan
| | - Tsutomu Matsubara
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Osaka, Japan; (H.T.V.); (V.D.N.)
- Research Institute for Light-induced Acceleration System (RILACS), Osaka Metropolitan University, Sakai 599-8570, Osaka, Japan
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11
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Zhao J, Yue P, Mi N, Li M, Fu W, Zhang X, Gao L, Bai M, Tian L, Jiang N, Lu Y, Ma H, Dong C, Zhang Y, Zhang H, Zhang J, Ren Y, Suzuki A, Wong PF, Tanaka K, Rerknimitr R, Junger HH, Cheung TT, Melloul E, Demartines N, Leung JW, Yao J, Yuan J, Lin Y, Schlitt HJ, Meng W. Biliary fibrosis is an important but neglected pathological feature in hepatobiliary disorders: from molecular mechanisms to clinical implications. MEDICAL REVIEW (2021) 2024; 4:326-365. [PMID: 39135601 PMCID: PMC11317084 DOI: 10.1515/mr-2024-0029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 06/06/2024] [Indexed: 08/15/2024]
Abstract
Fibrosis resulting from pathological repair secondary to recurrent or persistent tissue damage often leads to organ failure and mortality. Biliary fibrosis is a crucial but easily neglected pathological feature in hepatobiliary disorders, which may promote the development and progression of benign and malignant biliary diseases through pathological healing mechanisms secondary to biliary tract injuries. Elucidating the etiology and pathogenesis of biliary fibrosis is beneficial to the prevention and treatment of biliary diseases. In this review, we emphasized the importance of biliary fibrosis in cholangiopathies and summarized the clinical manifestations, epidemiology, and aberrant cellular composition involving the biliary ductules, cholangiocytes, immune system, fibroblasts, and the microbiome. We also focused on pivotal signaling pathways and offered insights into ongoing clinical trials and proposing a strategic approach for managing biliary fibrosis-related cholangiopathies. This review will offer a comprehensive perspective on biliary fibrosis and provide an important reference for future mechanism research and innovative therapy to prevent or reverse fibrosis.
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Affiliation(s)
- Jinyu Zhao
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ping Yue
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ningning Mi
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Matu Li
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Wenkang Fu
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xianzhuo Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Long Gao
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Mingzhen Bai
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Liang Tian
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ningzu Jiang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yawen Lu
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Haidong Ma
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Chunlu Dong
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yong Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Hengwei Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Jinduo Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yanxian Ren
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Azumi Suzuki
- Department of Gastroenterology, Hamamatsu Medical Center, Hamamatsu, Japan
| | - Peng F. Wong
- Department of Vascular Surgery, The James Cook University Hospital, Middlesbrough, UK
| | - Kiyohito Tanaka
- Department of Gastroenterology, Kyoto Second Red Cross Hospital, Kyoto, Japan
| | - Rungsun Rerknimitr
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn, Bangkok, Thailand
- Excellence Center for Gastrointestinal Endoscopy, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Henrik H. Junger
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Tan T. Cheung
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Emmanuel Melloul
- Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Nicolas Demartines
- Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Joseph W. Leung
- Division of Gastroenterology and Hepatology, UC Davis Medical Center and Sacramento VA Medical Center, Sacramento, CA, USA
| | - Jia Yao
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
| | - Jinqiu Yuan
- Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yanyan Lin
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Hans J. Schlitt
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Wenbo Meng
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
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Akkız H, Gieseler RK, Canbay A. Liver Fibrosis: From Basic Science towards Clinical Progress, Focusing on the Central Role of Hepatic Stellate Cells. Int J Mol Sci 2024; 25:7873. [PMID: 39063116 PMCID: PMC11277292 DOI: 10.3390/ijms25147873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 06/28/2024] [Accepted: 06/29/2024] [Indexed: 07/28/2024] Open
Abstract
The burden of chronic liver disease is globally increasing at an alarming rate. Chronic liver injury leads to liver inflammation and fibrosis (LF) as critical determinants of long-term outcomes such as cirrhosis, liver cancer, and mortality. LF is a wound-healing process characterized by excessive deposition of extracellular matrix (ECM) proteins due to the activation of hepatic stellate cells (HSCs). In the healthy liver, quiescent HSCs metabolize and store retinoids. Upon fibrogenic activation, quiescent HSCs transdifferentiate into myofibroblasts; lose their vitamin A; upregulate α-smooth muscle actin; and produce proinflammatory soluble mediators, collagens, and inhibitors of ECM degradation. Activated HSCs are the main effector cells during hepatic fibrogenesis. In addition, the accumulation and activation of profibrogenic macrophages in response to hepatocyte death play a critical role in the initiation of HSC activation and survival. The main source of myofibroblasts is resident HSCs. Activated HSCs migrate to the site of active fibrogenesis to initiate the formation of a fibrous scar. Single-cell technologies revealed that quiescent HSCs are highly homogenous, while activated HSCs/myofibroblasts are much more heterogeneous. The complex process of inflammation results from the response of various hepatic cells to hepatocellular death and inflammatory signals related to intrahepatic injury pathways or extrahepatic mediators. Inflammatory processes modulate fibrogenesis by activating HSCs and, in turn, drive immune mechanisms via cytokines and chemokines. Increasing evidence also suggests that cellular stress responses contribute to fibrogenesis. Recent data demonstrated that LF can revert even at advanced stages of cirrhosis if the underlying cause is eliminated, which inhibits the inflammatory and profibrogenic cells. However, despite numerous clinical studies on plausible drug candidates, an approved antifibrotic therapy still remains elusive. This state-of-the-art review presents cellular and molecular mechanisms involved in hepatic fibrogenesis and its resolution, as well as comprehensively discusses the drivers linking liver injury to chronic liver inflammation and LF.
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Affiliation(s)
- Hikmet Akkız
- Department of Gastroenterology and Hepatology, University of Bahçeşehir, Beşiktaş, Istanbul 34353, Turkey
| | - Robert K. Gieseler
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr University Bochum, In der Schornau 23–25, 44892 Bochum, Germany; (R.K.G.); (A.C.)
| | - Ali Canbay
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr University Bochum, In der Schornau 23–25, 44892 Bochum, Germany; (R.K.G.); (A.C.)
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13
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Alam N, Jia L, Cheng A, Ren H, Fu Y, Ding X, Haq IU, Liu E. Global research trends on gut microbiota and metabolic dysfunction-associated steatohepatitis: Insights from bibliometric and scientometric analysis. Front Pharmacol 2024; 15:1390483. [PMID: 39070791 PMCID: PMC11273336 DOI: 10.3389/fphar.2024.1390483] [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: 02/23/2024] [Accepted: 06/24/2024] [Indexed: 07/30/2024] Open
Abstract
Background Metabolic dysfunction-associated steatohepatitis (MASH) is an inflammatory subtype of metabolic dysfunction-associated steatotic liver disease (MASLD) has recently been proposed as a replacement term for NAFLD, a common, multifactorial and poorly understood liver disease whose incidence is increasing worldwide. In recent years, there has been increasing scientific interest in exploring the relationship between gut microbiota and MASH. To learn more about the gut microbiota in MASH, this study aims to provide a comprehensive analysis of the knowledge structure and research hotspots from a bibliometric perspective. Methods We searched the Web of Science Core Collection for articles and reviews that covered the connections between gut microbiota and MASH over the last decade. The Online Analysis Platforms, VOSviewer, CiteSpace, the R tool "bibliometrix" were used to analyzed existing publications trends and hotspots. Results A total of 4,069 documents related to the interaction between gut microbiota and MASH were retrieved from 2014 to 2023. The number of annual publications increased significantly over the last decade, particularly in the United States and China. The University of California-San Diego was the most productive institution, while researcher Rohit Loomba published the most papers in the field. Younossi ZM was ranked as the first co-cited author and largest contributor of highly cited articles in the field. Gastroenterology and hepatology were the most common specialty category. The most cited journal in the last decade was Hepatology. The Keyword Bursts analysis highlighted the importance of studying the association between gut microbiota and MASH, as well as related factors such as metabolic syndrome, insulin resistance, endotoxemia and overgrowth of gut bacteria. Keyword clusters with co-citation were used to illustrate important topics including intestinal permeability, insulin sensitivity and liver immunology. The most common keywords include insulin resistance, obesity, dysbiosis, inflammation and oxidative stress, which are current hotspots. Conclusion Our analysis highlights key aspects of this field and emphasizes multiorgan crosstalk in MASLD/MASH pathogenesis. In particular, the central role of the gut-liver axis and the significant influence of gut microbiota dysbiosis on disease progression are highlighted. Furthermore, our results highlight the transformative potential of microbiota-specific therapies and cover the way for innovative healthcare and pharmaceutical strategies.
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Affiliation(s)
- Naqash Alam
- Laboratory Animal Center, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
| | - Linying Jia
- Laboratory Animal Center, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
| | - Ao Cheng
- Laboratory Animal Center, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
| | - Honghao Ren
- Laboratory Animal Center, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
| | - Yu Fu
- Laboratory Animal Center, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
| | - Xinhua Ding
- Laboratory Animal Center, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
| | - Ihtisham Ul Haq
- Department of Neurobiology, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
| | - Enqi Liu
- Laboratory Animal Center, School of Basic Medical Sciences, Health Science Center, Xi’an Jiaotong University, Xi’an, China
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14
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Jiang FY, Yue SR, Tan YY, Tang N, Xu YS, Zhang BJ, Mao YJ, Xue ZS, Lu AP, Liu BC, Wang RR. Gynostemma pentaphyllum Extract Alleviates NASH in Mice: Exploration of Inflammation and Gut Microbiota. Nutrients 2024; 16:1782. [PMID: 38892715 PMCID: PMC11174846 DOI: 10.3390/nu16111782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/21/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024] Open
Abstract
NASH (non-alcoholic steatohepatitis) is a severe liver disease characterized by hepatic chronic inflammation that can be associated with the gut microbiota. In this study, we explored the therapeutic effect of Gynostemma pentaphyllum extract (GPE), a Chinese herbal extract, on methionine- and choline-deficient (MCD) diet-induced NASH mice. Based on the peak area, the top ten compounds in GPE were hydroxylinolenic acid, rutin, hydroxylinoleic acid, vanillic acid, methyl vanillate, quercetin, pheophorbide A, protocatechuic acid, aurantiamide acetate, and iso-rhamnetin. We found that four weeks of GPE treatment alleviated hepatic confluent zone inflammation, hepatocyte lipid accumulation, and lipid peroxidation in the mouse model. According to the 16S rRNA gene V3-V4 region sequencing of the colonic contents, the gut microbiota structure of the mice was significantly changed after GPE supplementation. Especially, GPE enriched the abundance of potentially beneficial bacteria such as Akkerrmansia and decreased the abundance of opportunistic pathogens such as Klebsiella. Moreover, RNA sequencing revealed that the GPE group showed an anti-inflammatory liver characterized by the repression of the NF-kappa B signaling pathway compared with the MCD group. Ingenuity Pathway Analysis (IPA) also showed that GPE downregulated the pathogen-induced cytokine storm pathway, which was associated with inflammation. A high dose of GPE (HGPE) significantly downregulated the expression levels of the tumor necrosis factor-α (TNF-α), myeloid differentiation factor 88 (Myd88), cluster of differentiation 14 (CD14), and Toll-like receptor 4 (TLR4) genes, as verified by real-time quantitative PCR (RT-qPCR). Our results suggested that the therapeutic potential of GPE for NASH mice may be related to improvements in the intestinal microenvironment and a reduction in liver inflammation.
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Affiliation(s)
- Feng-Yan Jiang
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (F.-Y.J.); (S.-R.Y.); (Y.-Y.T.); (N.T.); (Y.-S.X.); (B.-J.Z.)
| | - Si-Ran Yue
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (F.-Y.J.); (S.-R.Y.); (Y.-Y.T.); (N.T.); (Y.-S.X.); (B.-J.Z.)
| | - Yi-Yun Tan
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (F.-Y.J.); (S.-R.Y.); (Y.-Y.T.); (N.T.); (Y.-S.X.); (B.-J.Z.)
| | - Nan Tang
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (F.-Y.J.); (S.-R.Y.); (Y.-Y.T.); (N.T.); (Y.-S.X.); (B.-J.Z.)
| | - Yue-Song Xu
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (F.-Y.J.); (S.-R.Y.); (Y.-Y.T.); (N.T.); (Y.-S.X.); (B.-J.Z.)
- Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong 999077, China
| | - Bao-Jun Zhang
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (F.-Y.J.); (S.-R.Y.); (Y.-Y.T.); (N.T.); (Y.-S.X.); (B.-J.Z.)
| | - Yue-Jian Mao
- China Mengniu Dairy Company Limited, Hohhot 010000, China; (Y.-J.M.); (Z.-S.X.)
| | - Zheng-Sheng Xue
- China Mengniu Dairy Company Limited, Hohhot 010000, China; (Y.-J.M.); (Z.-S.X.)
| | - Ai-Ping Lu
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong 999077, China;
| | - Bao-Cheng Liu
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (F.-Y.J.); (S.-R.Y.); (Y.-Y.T.); (N.T.); (Y.-S.X.); (B.-J.Z.)
| | - Rui-Rui Wang
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (F.-Y.J.); (S.-R.Y.); (Y.-Y.T.); (N.T.); (Y.-S.X.); (B.-J.Z.)
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15
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Deng GH, Zhao CC, Cai X, Zhang XQ, Ma MZ, Lv JH, Jiang WL, Peng DY, Wang YY, Xing LH, Yu NJ. Untargeted metabonomics and TLR4/ NF-κB signaling pathway analysis reveals potential mechanism of action of Dendrobium huoshanense polysaccharide in nonalcoholic fatty liver disease. Front Pharmacol 2024; 15:1374158. [PMID: 38887554 PMCID: PMC11180771 DOI: 10.3389/fphar.2024.1374158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 05/10/2024] [Indexed: 06/20/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is marked by hepatic steatosis accompanied by an inflammatory response. At present, there are no approved therapeutic agents for NAFLD. Dendrobium Huoshanense polysaccharide (DHP), an active ingredient extracted from the stems of Dendrobium Huoshanense, and exerts a protective effect against liver injury. However, the therapeutic effects and mechanisms of action DHP against NAFLD remain unclear. DHP was extracted, characterized, and administered to mice in which NAFLD had been induced with a high-fat and high-fructose drinking (HFHF) diet. Our results showed that DHP used in this research exhibits the characteristic polysaccharide peak with a molecular weight of 179.935 kDa and is composed primarily of Man and Glc in a molar ratio of 68.97:31.03. DHP treatment greatly ameliorated NAFLD by significantly reducing lipid accumulation and the levels of liver function markers in HFHF-induced NAFLD mice, as evidenced by decreased serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC) and total triglyceride (TG). Furthermore, DHP administration reduced hepatic steatosis, as shown by H&E and Oil red O staining. DHP also inhibited the Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway expression, thereby reducing levels of hepatic proinflammatory cytokines. Besides, untargeted metabolomics further indicated that 49 metabolites were affected by DHP. These metabolites are strongly associated the metabolism of glycine, serine, threonine, nicotinate and nicotinamide, and arachidonic acid. In conclusion, DHP has a therapeutic effect against NAFLD, whose underlying mechanism may involve the modulation of TLR4/NF-κB, reduction of inflammation, and regulation of the metabolism of glycine, serine, threonine, nicotinate and nicotinamide metabolism, and arachidonic acid metabolism.
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Affiliation(s)
- Guang-hui Deng
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Anhui Academy of Traditional Chinese Medicine and Institute of Conservation and Development of Traditional Chinese Medicine Resources, Hefei, China
| | - Chen-chen Zhao
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Anhui Academy of Traditional Chinese Medicine and Institute of Conservation and Development of Traditional Chinese Medicine Resources, Hefei, China
| | - Xiao Cai
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Anhui Academy of Traditional Chinese Medicine and Institute of Conservation and Development of Traditional Chinese Medicine Resources, Hefei, China
| | - Xiao-qian Zhang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Anhui Academy of Traditional Chinese Medicine and Institute of Conservation and Development of Traditional Chinese Medicine Resources, Hefei, China
| | - Meng-zhen Ma
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Anhui Academy of Traditional Chinese Medicine and Institute of Conservation and Development of Traditional Chinese Medicine Resources, Hefei, China
| | - Jia-hui Lv
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Anhui Academy of Traditional Chinese Medicine and Institute of Conservation and Development of Traditional Chinese Medicine Resources, Hefei, China
| | - Wen-li Jiang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Anhui Academy of Traditional Chinese Medicine and Institute of Conservation and Development of Traditional Chinese Medicine Resources, Hefei, China
| | - Dai-yin Peng
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Anhui Academy of Traditional Chinese Medicine and Institute of Conservation and Development of Traditional Chinese Medicine Resources, Hefei, China
- MOE-Anhui Joint Collaborative Innovation Center for Anhui Genuine Chinese Medicinal Materials, Hefei, China
| | - Yan-yan Wang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Anhui Academy of Traditional Chinese Medicine and Institute of Conservation and Development of Traditional Chinese Medicine Resources, Hefei, China
| | - Li-hua Xing
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Anhui Academy of Traditional Chinese Medicine and Institute of Conservation and Development of Traditional Chinese Medicine Resources, Hefei, China
| | - Nian-jun Yu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Anhui Academy of Traditional Chinese Medicine and Institute of Conservation and Development of Traditional Chinese Medicine Resources, Hefei, China
- MOE-Anhui Joint Collaborative Innovation Center for Anhui Genuine Chinese Medicinal Materials, Hefei, China
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16
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Gao T, Wang S, Zhu Z, Lin L, Luo Y, Lu M, Liao W. Components from Curcuma longa (Turmeric) Against Hepatobiliary Diseases Based on Gut-Liver Axis: Pharmacotherapeutic Properties and Potential Clinical Applications. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2024; 52:387-415. [PMID: 38490808 DOI: 10.1142/s0192415x24500162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/17/2024]
Abstract
Turmeric is widely used worldwide, and there are many examples of its use in treating hepatobiliary diseases. The gut-liver axis is a bidirectional relationship between gut microorganisms and the liver that is closely related to the pathogenesis of hepatobiliary diseases. This review systematically summarizes the components of turmeric. It links the studies on turmeric affecting gut microorganisms to its effects on liver and biliary diseases to explain the potential mechanism of turmeric's regulation of the gut-liver axis. Besides, ethnopharmacology, phytochemicals, and clinical adverse events associated with turmeric have been researched. Furthermore, turmeric is a safe agent with good clinical efficacy and without apparent toxicity at a certain amount. By summarizing the influence of turmeric on the liver by regulating the gut-liver axis, especially the gut microbiota, it provides a preclinical basis for using turmeric as a safe and effective therapeutic agent for the prevention and treatment of hepatobiliary diseases based on the gut-liver axis. However, more efforts should be made to exploit its clinical application further.
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Affiliation(s)
- Tianhui Gao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy/ School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Shuyi Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy/ School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Zongping Zhu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy/ School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Liting Lin
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy/ School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Yirong Luo
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy/ School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Meigui Lu
- Huachiew TCM Hospital, Bangkok 10100, Thailand
| | - Wan Liao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy/ School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
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17
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Sun C, Zhu D, Zhu Q, He Z, Lou Y, Chen D. The significance of gut microbiota in the etiology of autoimmune hepatitis: a narrative review. Front Cell Infect Microbiol 2024; 14:1337223. [PMID: 38404291 PMCID: PMC10884129 DOI: 10.3389/fcimb.2024.1337223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 01/04/2024] [Indexed: 02/27/2024] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory disease of the liver that is mediated by autoimmunity and has complex pathogenesis. Its prevalence has increased globally. Since the liver is the first organ to be exposed to harmful substances, such as gut-derived intestinal microbiota and its metabolites, gut health is closely related to liver health, and the "liver-gut axis" allows abnormalities in the gut microbiota to influence the development of liver-related diseases such as AIH. Changes in the composition of the intestinal microbiota and its resultant disruption of the intestinal barrier and microbial transport are involved in multiple ways in the disruption of immune homeostasis and inflammation, thereby influencing the development of AIH. In terms of the mechanisms involved in immune, the gut microbiota or its metabolites, which is decreased in secondary bile acids, short-chain fatty acids (SCFAs), and polyamines, and increased in lipopolysaccharide (LPS), branched-chain amino acids (BCAA), tryptophan metabolite, amino acid, and bile acid, can disrupt immune homeostasis by activating various immune cells and immune-related signaling pathways, resulting in aberrant activation of the immune system. Clarifying this mechanism has significant clinical implications for the treatment of AIH with drugs that target intestinal microbiota and related signaling pathways. Therefore, this narrative review summarizes the progress in exploring the involvement of gut microbiota in the pathogenesis of AIH, with the aim of helping to improve the precise targeting of therapeutic treatments against AIH for the benefit of clinical AIH treatment.
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Affiliation(s)
- Chen Sun
- Clinical Research Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dongzi Zhu
- Department of General Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qi Zhu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zeping He
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yichao Lou
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Desheng Chen
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Rodrigues SG, van der Merwe S, Krag A, Wiest R. Gut-liver axis: Pathophysiological concepts and medical perspective in chronic liver diseases. Semin Immunol 2024; 71:101859. [PMID: 38219459 DOI: 10.1016/j.smim.2023.101859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/11/2023] [Accepted: 12/04/2023] [Indexed: 01/16/2024]
Affiliation(s)
- Susana G Rodrigues
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Schalk van der Merwe
- Department of Gastroenterology and Hepatology, University hospital Gasthuisberg, University of Leuven, Belgium
| | - Aleksander Krag
- Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; Centre for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark, University of Southern Denmark, Odense, Denmark
| | - Reiner Wiest
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.
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Gruzdev SK, Podoprigora IV, Gizinger OA. Immunology of gut microbiome and liver in non-alcoholic fatty liver disease (NAFLD): mechanisms, bacteria, and novel therapeutic targets. Arch Microbiol 2024; 206:62. [PMID: 38216746 DOI: 10.1007/s00203-023-03752-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/16/2023] [Accepted: 11/16/2023] [Indexed: 01/14/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Most important contributors to its development are diet and obesity. Gut microbiome's importance for immune system and inflammatory pathways more widely accepted as an important component in NAFLD and other liver diseases' pathogenesis. In this article we review potential mechanisms of microbiome alteration of local and systemic immune responses leading to NAFLD's development, and how can modulate them for the treatment. Our review mentions different immune system pathways and microorganisms regulating metabolism, liver inflammation and fibrosis. We specifically point out TLR-4 as a potential key immune pathway activated by bacterial lipopolysaccharides producing pro-inflammatory cytokines in NAFLD. Also, we discuss three endotoxin-producing strains (Enterobacter cloacae B29, Escherichia coli PY102, Klebsiella pneumoniae A7) that can promote NAFLD development via TLR4-dependent immune response activation in animal models and how they potentially contribute to disease progression in humans. Additionally, we discuss their other immune and non-immune mechanisms contributing to NAFLD pathogenesis. In the end we point out gut microbiome researches' future perspective in NAFLD as a potential new target for both diagnostic and treatment.
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Affiliation(s)
- Stanislav Konstantinovich Gruzdev
- Department of Microbiology V.S. Kiktenko, Medical Institute, Peoples' Friendship University of Russia, Miklukho-Maklaya Str. 6, Moscow, 117198, Russia.
| | - Irina Viktorovna Podoprigora
- Department of Microbiology V.S. Kiktenko, Medical Institute, Peoples' Friendship University of Russia, Miklukho-Maklaya Str. 6, Moscow, 117198, Russia
| | - Oksana Anatolievna Gizinger
- Department of Microbiology V.S. Kiktenko, Medical Institute, Peoples' Friendship University of Russia, Miklukho-Maklaya Str. 6, Moscow, 117198, Russia
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Liu S, Liu Y, Zhang D, Li H, Shao X, Xie P, Li J. Novel insights into perfluorinated compound-induced hepatotoxicity: Chronic dietary restriction exacerbates the effects of PFBS on hepatic lipid metabolism in mice. ENVIRONMENT INTERNATIONAL 2023; 181:108274. [PMID: 37879206 DOI: 10.1016/j.envint.2023.108274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 10/13/2023] [Accepted: 10/16/2023] [Indexed: 10/27/2023]
Abstract
Perfluorobutane sulfonates (PFBS) have garnered extensive utilization because of their distinctive physicochemical properties. The liver acts as a key target organ for toxicity within the body and is vital for regulating metabolic processes, particularly lipid metabolism. However, there is currently a significant research gap regarding the influences of PFBS on hepatic lipid metabolism, especially in individuals with different dietary statuses. Here, the objective of this research was to examine the effects of PFBS on hepatic function under different dietary conditions. The results suggested that the levels of liver injury biomarkers were significantly upregulated, e.g., transaminase (GPT, GOT), while liver lipid levels were downregulated after exposure to PFBS at concentration of 50 μg/L for 42 days. Moreover, restricted diet further intensified the adverse effects of PFBS on the liver. Metabolomics analysis identified significant alterations in lipid-related metabolites in PFBS-induced hepatotoxicity, PFBS exposure induced a decrease in lysophosphatidylethanolamine and lysophosphatidylcholine. PFBS exposure caused an increase in aldosterone and prostaglandin f2alpha under restricted diet. In PFBS treatment group, histidine metabolism, beta-alanine metabolism, and arginine biosynthesis were the main pathway for PFBS toxicity. Aldosterone-regulated sodium reabsorption as a vital factor in inducing PFBS toxicity in the RD-PFBS treatment group. The analysis of 16S rRNA sequencing revealed that exposure to PFBS resulted in imbalance of gut microbial communities. PFBS exposure induced a decrease in Akkermansia and Lactobacillus, but an increase in Enterococcus. PFBS exposure caused the abundance of Lachnospiraceae_NK4A136_group was significantly elevated under restricted diet. Additionally, disruptions in the expression of genes involved in lipid production and consumption may significantly contribute to lipid imbalance in the liver. This study underscores the importance of recognizing the harmful impact of PFBS on liver function, along with the biotoxicity of contaminant influenced by dietary habits.
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Affiliation(s)
- Su Liu
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, China; School of Engineering, China Pharmaceutical University, Nanjing 211198, China
| | - Yafeng Liu
- School of Engineering, China Pharmaceutical University, Nanjing 211198, China
| | - Dong Zhang
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, China
| | - Huan Li
- School of Engineering, China Pharmaceutical University, Nanjing 211198, China; State Key Laboratory of Pollution Control and Resource Reuse, School of Environment, Nanjing University, Nanjing 210023, China
| | - Xicheng Shao
- Faculty of Land and Food Systems, Vancouver Campus, University of British Columbia, Vancouver V6T 1Z4, Canada
| | - Pengfei Xie
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, China
| | - Jianmei Li
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, China.
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21
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Zhang C, Sui Y, Liu S, Yang M. Molecular mechanisms of metabolic disease-associated hepatic inflammation in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. EXPLORATION OF DIGESTIVE DISEASES 2023:246-275. [DOI: https:/doi.org/10.37349/edd.2023.00029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 08/05/2023] [Indexed: 11/27/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide, with a progressive form of non-alcoholic steatohepatitis (NASH). It may progress to advanced liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD/NASH is a comorbidity of many metabolic disorders such as obesity, insulin resistance, type 2 diabetes, cardiovascular disease, and chronic kidney disease. These metabolic diseases are often accompanied by systemic or extrahepatic inflammation, which plays an important role in the pathogenesis and treatment of NAFLD or NASH. Metabolites, such as short-chain fatty acids, impact the function, inflammation, and death of hepatocytes, the primary parenchymal cells in the liver tissue. Cholangiocytes, the epithelial cells that line the bile ducts, can differentiate into proliferative hepatocytes in chronic liver injury. In addition, hepatic non-parenchymal cells, including liver sinusoidal endothelial cells, hepatic stellate cells, and innate and adaptive immune cells, are involved in liver inflammation. Proteins such as fibroblast growth factors, acetyl-coenzyme A carboxylases, and nuclear factor erythroid 2-related factor 2 are involved in liver metabolism and inflammation, which are potential targets for NASH treatment. This review focuses on the effects of metabolic disease-induced extrahepatic inflammation, liver inflammation, and the cellular and molecular mechanisms of liver metabolism on the development and progression of NAFLD and NASH, as well as the associated treatments.
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Affiliation(s)
- Chunye Zhang
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
| | - Yuxiang Sui
- School of Life Science, Shanxi Normal University, Linfen 041004, Shanxi Province, China
| | - Shuai Liu
- The First Affiliated Hospital, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65211, USA
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Saxami G, Kerezoudi EN, Eliopoulos C, Arapoglou D, Kyriacou A. The Gut-Organ Axis within the Human Body: Gut Dysbiosis and the Role of Prebiotics. Life (Basel) 2023; 13:2023. [PMID: 37895405 PMCID: PMC10608660 DOI: 10.3390/life13102023] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/03/2023] [Accepted: 10/06/2023] [Indexed: 10/29/2023] Open
Abstract
The human gut microbiota (GM) is a complex microbial ecosystem that colonises the gastrointestinal tract (GIT) and is comprised of bacteria, viruses, fungi, and protozoa. The GM has a symbiotic relationship with its host that is fundamental for body homeostasis. The GM is not limited to the scope of the GIT, but there are bidirectional interactions between the GM and other organs, highlighting the concept of the "gut-organ axis". Any deviation from the normal composition of the GM, termed "microbial dysbiosis", is implicated in the pathogenesis of various diseases. Only a few studies have demonstrated a relationship between GM modifications and disease phenotypes, and it is still unknown whether an altered GM contributes to a disease or simply reflects its status. Restoration of the GM with probiotics and prebiotics has been postulated, but evidence for the effects of prebiotics is limited. Prebiotics are substrates that are "selectively utilized by host microorganisms, conferring a health benefit". This study highlights the bidirectional relationship between the gut and vital human organs and demonstrates the relationship between GM dysbiosis and the emergence of certain representative diseases. Finally, this article focuses on the potential of prebiotics as a target therapy to manipulate the GM and presents the gaps in the literature and research.
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Affiliation(s)
- Georgia Saxami
- Department of Nutrition and Dietetics, Harokopio University, 17671 Athens, Greece; (E.N.K.); (A.K.)
| | - Evangelia N. Kerezoudi
- Department of Nutrition and Dietetics, Harokopio University, 17671 Athens, Greece; (E.N.K.); (A.K.)
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, SE-701 82 Örebro, Sweden
| | - Christos Eliopoulos
- Institute of Technology of Agricultural Products, Hellenic Agricultural Organization—Demeter, L. Sof. Venizelou 1, 14123 Lykovryssi, Greece; (C.E.); (D.A.)
| | - Dimitrios Arapoglou
- Institute of Technology of Agricultural Products, Hellenic Agricultural Organization—Demeter, L. Sof. Venizelou 1, 14123 Lykovryssi, Greece; (C.E.); (D.A.)
| | - Adamantini Kyriacou
- Department of Nutrition and Dietetics, Harokopio University, 17671 Athens, Greece; (E.N.K.); (A.K.)
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Abstract
Chronic liver diseases such as nonalcoholic fatty liver disease (NAFLD) or viral hepatitis are characterized by persistent inflammation and subsequent liver fibrosis. Liver fibrosis critically determines long-term morbidity (for example, cirrhosis or liver cancer) and mortality in NAFLD and nonalcoholic steatohepatitis (NASH). Inflammation represents the concerted response of various hepatic cell types to hepatocellular death and inflammatory signals, which are related to intrahepatic injury pathways or extrahepatic mediators from the gut-liver axis and the circulation. Single-cell technologies have revealed the heterogeneity of immune cell activation concerning disease states and the spatial organization within the liver, including resident and recruited macrophages, neutrophils as mediators of tissue repair, auto-aggressive features of T cells as well as various innate lymphoid cell and unconventional T cell populations. Inflammatory responses drive the activation of hepatic stellate cells (HSCs), and HSC subsets, in turn, modulate immune mechanisms via chemokines and cytokines or transdifferentiate into matrix-producing myofibroblasts. Current advances in understanding the pathogenesis of inflammation and fibrosis in the liver, mainly focused on NAFLD or NASH owing to the high unmet medical need, have led to the identification of several therapeutic targets. In this Review, we summarize the inflammatory mediators and cells in the diseased liver, fibrogenic pathways and their therapeutic implications.
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Affiliation(s)
- Linda Hammerich
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.
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24
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Yang K, Song M. New Insights into the Pathogenesis of Metabolic-Associated Fatty Liver Disease (MAFLD): Gut-Liver-Heart Crosstalk. Nutrients 2023; 15:3970. [PMID: 37764755 PMCID: PMC10534946 DOI: 10.3390/nu15183970] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/11/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
Metabolism-associated fatty liver disease (MAFLD) is a multifaceted disease that involves complex interactions between various organs, including the gut and heart. It is defined by hepatic lipid accumulation and is related to metabolic dysfunction, obesity, and diabetes. Understanding the intricate interplay of the gut-liver-heart crosstalk is crucial for unraveling the complexities of MAFLD and developing effective treatment and prevention strategies. The gut-liver crosstalk participates in the regulation of the metabolic and inflammatory processes through host-microbiome interactions. Gut microbiota have been associated with the development and progression of MAFLD, and its dysbiosis contributes to insulin resistance, inflammation, and oxidative stress. Metabolites derived from the gut microbiota enter the systemic circulation and influence both the liver and heart, resulting in the gut-liver-heart axis playing an important role in MAFLD. Furthermore, growing evidence suggests that insulin resistance, endothelial dysfunction, and systemic inflammation in MAFLD may contribute to an increased risk of cardiovascular disease (CVD). Additionally, the dysregulation of lipid metabolism in MAFLD may also lead to cardiac dysfunction and heart failure. Overall, the crosstalk between the liver and heart involves a complex interplay of molecular pathways that contribute to the development of CVD in patients with MAFLD. This review emphasizes the current understanding of the gut-liver-heart crosstalk as a foundation for optimizing patient outcomes with MAFLD.
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Affiliation(s)
| | - Myeongjun Song
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
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Lurje I, Gaisa NT, Weiskirchen R, Tacke F. Mechanisms of organ fibrosis: Emerging concepts and implications for novel treatment strategies. Mol Aspects Med 2023; 92:101191. [PMID: 37236017 DOI: 10.1016/j.mam.2023.101191] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023]
Abstract
Fibrosis, or tissue scarring, develops as a pathological deviation from the physiological wound healing response and can occur in various organs such as the heart, lung, liver, kidney, skin, and bone marrow. Organ fibrosis significantly contributes to global morbidity and mortality. A broad spectrum of etiologies can cause fibrosis, including acute and chronic ischemia, hypertension, chronic viral infection (e.g., viral hepatitis), environmental exposure (e.g., pneumoconiosis, alcohol, nutrition, smoking) and genetic diseases (e.g., cystic fibrosis, alpha-1-antitrypsin deficiency). Common mechanisms across organs and disease etiologies involve a sustained injury to parenchymal cells that triggers a wound healing response, which becomes deregulated in the disease process. A transformation of resting fibroblasts into myofibroblasts with excessive extracellular matrix production constitutes the hallmark of disease, however, multiple other cell types such as immune cells, predominantly monocytes/macrophages, endothelial cells, and parenchymal cells form a complex network of profibrotic cellular crosstalk. Across organs, leading mediators include growth factors like transforming growth factor-β and platelet-derived growth factor, cytokines like interleukin-10, interleukin-13, interleukin-17, and danger-associated molecular patterns. More recently, insights into fibrosis regression and resolution of chronic conditions have deepened our understanding of beneficial, protective effects of immune cells, soluble mediators and intracellular signaling. Further in-depth insights into the mechanisms of fibrogenesis can provide the rationale for therapeutic interventions and the development of targeted antifibrotic agents. This review gives insight into shared responses and cellular mechanisms across organs and etiologies, aiming to paint a comprehensive picture of fibrotic diseases in both experimental settings and in human pathology.
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Affiliation(s)
- Isabella Lurje
- Department of Hepatology and Gastroenterology, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Nadine T Gaisa
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, Aachen, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany.
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Zhang L, Zi L, Kuang T, Wang K, Qiu Z, Wu Z, Liu L, Liu R, Wang P, Wang W. Investigating causal associations among gut microbiota, metabolites, and liver diseases: a Mendelian randomization study. Front Endocrinol (Lausanne) 2023; 14:1159148. [PMID: 37476494 PMCID: PMC10354516 DOI: 10.3389/fendo.2023.1159148] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 04/13/2023] [Indexed: 07/22/2023] Open
Abstract
Objective There is some evidence for an association between gut microbiota and nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and viral hepatitis, but no studies have explored their causal relationship. Methods Instrumental variables of the gut microbiota (N = 13266) and gut microbiota-derived metabolites (N = 7824) were acquired, and a Mendelian randomization study was performed to explore their influence on NAFLD (1483 European cases and 17,781 European controls), ALD (2513 European cases and 332,951 European controls), and viral hepatitis risk (1971 European cases and 340,528 European controls). The main method for examining causality is inverse variance weighting (IVW). Results IVW results confirmed that Anaerotruncus (p = 0.0249), Intestinimonas (p = 0.0237), Lachnoclostridium (p = 0.0245), Lachnospiraceae NC2004 group (p = 0.0083), Olsenella (p = 0.0163), and Peptococcus (p = 0.0472) were protective factors for NAFLD, and Ruminococcus 1 (p = 0.0120) was detrimental for NAFLD. The higher abundance of three genera, Lachnospira (p = 0.0388), Desulfovibrio (p = 0.0252), and Ruminococcus torques group (p = 0.0364), was correlated with a lower risk of ALD, while Ruminococcaceae UCG 002 level was associated with a higher risk of ALD (p = 0.0371). The Alistipes (p = 0.0069) and Ruminococcaceae NK4A214 group (p = 0.0195) were related to a higher risk of viral hepatitis. Besides, alanine (p = 0.0076) and phenyllactate (p = 0.0100) were found to be negatively correlated with NAFLD, while stachydrine (Op = 0.0244) was found to be positively associated with NAFLD. The phenylacetate (p = 0.0353) and ursodeoxycholate (p = 0.0144) had a protective effect on ALD, while the threonate (p = 0.0370) exerted a detrimental influence on ALD. The IVW estimates of alanine (p = 0.0408) and cholate (p = 0.0293) showed their suggestive harmful effects against viral hepatitis, while threonate (p = 0.0401) displayed its suggestive protective effect against viral hepatitis. Conclusion In conclusion, our research supported causal links between the gut microbiome and its metabolites and NAFLD, ALD, and viral hepatitis.
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Affiliation(s)
- Lilong Zhang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, Hubei, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Liuliu Zi
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, Hubei, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Tianrui Kuang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, Hubei, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Kunpeng Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, Hubei, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zhendong Qiu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, Hubei, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zhongkai Wu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, Hubei, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Li Liu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, Hubei, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Rongqiang Liu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, Hubei, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Peng Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, Hubei, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Weixing Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, Hubei, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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Xu GX, Wei S, Yu C, Zhao SQ, Yang WJ, Feng YH, Pan C, Yang KX, Ma Y. Activation of Kupffer cells in NAFLD and NASH: mechanisms and therapeutic interventions. Front Cell Dev Biol 2023; 11:1199519. [PMID: 37261074 PMCID: PMC10228659 DOI: 10.3389/fcell.2023.1199519] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 05/05/2023] [Indexed: 06/02/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are emerging as the leading causes of liver disease worldwide. These conditions can lead to cirrhosis, liver cancer, liver failure, and other related ailments. At present, liver transplantation remains the sole treatment option for end-stage NASH, leading to a rapidly growing socioeconomic burden. Kupffer cells (KCs) are a dominant population of macrophages that reside in the liver, playing a crucial role in innate immunity. Their primary function includes phagocytosing exogenous substances, presenting antigens, and triggering immune responses. Moreover, they interact with other liver cells during the pathogenesis of NAFLD, and this crosstalk may either delay or exacerbate disease progression. Stimulation by endogenous signals triggers the activation of KCs, resulting in the expression of various inflammatory factors and chemokines, such as NLRP3, TNF-α, IL-1B, and IL-6, and contributing to the inflammatory cascade. In the past 5 years, significant advances have been made in understanding the biological properties and immune functions of KCs in NAFLD, including their interactions with tissue molecules, underlying molecular mechanisms, signaling pathways, and relevant therapeutic interventions. Having a comprehensive understanding of these mechanisms and characteristics can have enormous potential in guiding future strategies for the prevention and treatment of NAFLD.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Yong Ma
- *Correspondence: Kun-Xing Yang, ; Yong Ma,
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Vonderlin J, Chavakis T, Sieweke M, Tacke F. The Multifaceted Roles of Macrophages in NAFLD Pathogenesis. Cell Mol Gastroenterol Hepatol 2023; 15:1311-1324. [PMID: 36907380 PMCID: PMC10148157 DOI: 10.1016/j.jcmgh.2023.03.002] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 03/03/2023] [Accepted: 03/03/2023] [Indexed: 03/14/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome. NAFLD constitutes a spectrum of pathologies ranging from simple hepatic steatosis (nonalcoholic fatty liver) to the more progressive form of steatohepatitis and fibrosis, which can culminate in liver cirrhosis and hepatocellular carcinoma. Macrophages play multiple roles in the context of NAFLD pathogenesis by regulating inflammatory responses and metabolic homeostasis in the liver and thereby may represent an attractive therapeutic target. Advances in high-resolution methods have highlighted the extraordinary heterogeneity and plasticity of hepatic macrophage populations and activation states thereof. Harmful/disease-promoting as well as beneficial/restorative macrophage phenotypes co-exist and are dynamically regulated, thus this complexity must be taken into consideration in strategies concerning therapeutic targeting. Macrophage heterogeneity in NAFLD includes their distinct ontogeny (embryonic Kupffer cells vs bone marrow-/monocyte-derived macrophages) as well as their functional phenotype, for example, inflammatory phagocytes, lipid- and scar-associated macrophages, or restorative macrophages. Here, we discuss the multifaceted role of macrophages in the pathogenesis of NAFLD in steatosis, steatohepatitis, and transition to fibrosis and hepatocellular carcinoma, focusing on both their beneficial and maladaptive functions at different disease stages. We also highlight the systemic aspect of metabolic dysregulation and illustrate the contribution of macrophages in the reciprocal crosstalk between organs and compartments (eg, the gut-liver axis, adipose tissue, and cardiohepatic metabolic interactions). Furthermore, we discuss the current state of development of pharmacologic treatment options targeting macrophage biology.
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Affiliation(s)
- Joscha Vonderlin
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Michael Sieweke
- Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
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Aseem SO, Hylemon PB, Zhou H. Bile Acids and Biliary Fibrosis. Cells 2023; 12:cells12050792. [PMID: 36899928 PMCID: PMC10001305 DOI: 10.3390/cells12050792] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/22/2023] [Accepted: 02/24/2023] [Indexed: 03/06/2023] Open
Abstract
Biliary fibrosis is the driving pathological process in cholangiopathies such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Cholangiopathies are also associated with cholestasis, which is the retention of biliary components, including bile acids, in the liver and blood. Cholestasis may worsen with biliary fibrosis. Furthermore, bile acid levels, composition and homeostasis are dysregulated in PBC and PSC. In fact, mounting data from animal models and human cholangiopathies suggest that bile acids play a crucial role in the pathogenesis and progression of biliary fibrosis. The identification of bile acid receptors has advanced our understanding of various signaling pathways involved in regulating cholangiocyte functions and the potential impact on biliary fibrosis. We will also briefly review recent findings linking these receptors with epigenetic regulatory mechanisms. Further detailed understanding of bile acid signaling in the pathogenesis of biliary fibrosis will uncover additional therapeutic avenues for cholangiopathies.
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Affiliation(s)
- Sayed Obaidullah Aseem
- Stravitz-Sanyal Institute for Liver Disease & Metabolic Health, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA
- Correspondence:
| | - Phillip B. Hylemon
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA
- Central Virginia Veterans Healthcare System, Richmond, VA 23249, USA
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA
- Central Virginia Veterans Healthcare System, Richmond, VA 23249, USA
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Drummer C, Saaoud F, Jhala NC, Cueto R, Sun Y, Xu K, Shao Y, Lu Y, Shen H, Yang L, Zhou Y, Yu J, Wu S, Snyder NW, Hu W, Zhuo J‘J, Zhong Y, Jiang X, Wang H, Yang X. Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages. Front Immunol 2023; 14:1113883. [PMID: 36776889 PMCID: PMC9909353 DOI: 10.3389/fimmu.2023.1113883] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 01/06/2023] [Indexed: 01/27/2023] Open
Abstract
Introduction Non-alcoholic fatty liver disease (NAFLD) has a global prevalence of 25% of the population and is a leading cause of cirrhosis and hepatocellular carcinoma. NAFLD ranges from simple steatosis (non-alcoholic fatty liver) to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs) and monocyte-derived macrophages, act as key players in the progression of NAFLD. Caspases are a family of endoproteases that provide critical connections to cell regulatory networks that sense disease risk factors, control inflammation, and mediate inflammatory cell death (pyroptosis). Caspase-11 can cleave gasdermin D (GSDMD) to induce pyroptosis and specifically defends against bacterial pathogens that invade the cytosol. However, it's still unknown whether high fat diet (HFD)-facilitated gut microbiota-generated cytoplasmic lipopolysaccharides (LPS) activate caspase-11 and promote NAFLD. Methods To examine this hypothesis, we performed liver pathological analysis, RNA-seq, FACS, Western blots, Seahorse mitochondrial stress analyses of macrophages and bone marrow transplantation on HFD-induced NAFLD in WT and Casp11-/- mice. Results and Discussion Our results showed that 1) HFD increases body wight, liver wight, plasma cholesterol levels, liver fat deposition, and NAFLD activity score (NAS score) in wild-type (WT) mice; 2) HFD increases the expression of caspase-11, GSDMD, interleukin-1β, and guanylate-binding proteins in WT mice; 3) Caspase-11 deficiency decreases fat liver deposition and NAS score; 4) Caspase-11 deficiency decreases bone marrow monocyte-derived macrophage (MDM) pyroptosis (inflammatory cell death) and inflammatory monocyte (IM) surface GSDMD expression; 5) Caspase-11 deficiency re-programs liver transcriptomes and reduces HFD-induced NAFLD; 6) Caspase-11 deficiency decreases extracellular acidification rates (glycolysis) and oxidative phosphorylation (OXPHOS) in inflammatory fatty acid palmitic acid-stimulated macrophages, indicating that caspase-11 significantly contributes to maintain dual fuel bioenergetics-glycolysis and OXPHOS for promoting pyroptosis in macrophages. These results provide novel insights on the roles of the caspase-11-GSDMD pathway in promoting hepatic macrophage inflammation and pyroptosis and novel targets for future therapeutic interventions involving the transition of NAFLD to NASH, hyperlipidemia, type II diabetes, metabolic syndrome, metabolically healthy obesity, atherosclerotic cardiovascular diseases, autoimmune diseases, liver transplantation, and hepatic cancers.
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Affiliation(s)
- Charles Drummer
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Fatma Saaoud
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Nirag C. Jhala
- Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Ramon Cueto
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Yu Sun
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Keman Xu
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Ying Shao
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Yifan Lu
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Huimin Shen
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Ling Yang
- Department of Medical Genetics and Molecular Biochemistry, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Yan Zhou
- Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Temple Health, Philadelphia, PA, United States
| | - Jun Yu
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Sheng Wu
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Nathaniel W. Snyder
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Wenhui Hu
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Jia ‘Joe’ Zhuo
- Tulane Hypertension & Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States
| | - Yinghui Zhong
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, United States
| | - Xiaohua Jiang
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Hong Wang
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Xiaofeng Yang
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
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Li ZJ, Gou HZ, Zhang YL, Song XJ, Zhang L. Role of intestinal flora in primary sclerosing cholangitis and its potential therapeutic value. World J Gastroenterol 2022; 28:6213-6229. [PMID: 36504550 PMCID: PMC9730442 DOI: 10.3748/wjg.v28.i44.6213] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 10/31/2022] [Accepted: 11/10/2022] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is an autoimmune disease characterized by chronic cholestasis, a persistent inflammation of the bile ducts that leads to sclerotic occlusion and cholestasis. Gut microbes, consisting of microorganisms colonized in the human gut, play an important role in nutrient intake, metabolic homeostasis, immune regulation, and immune regulation; however, their presence might aid PSC development. Studies have found that gut-liver axis interactions also play an important role in the pathogenesis of PSC. Patients with PSC have considerably reduced intestinal flora diversity and increased abundance of potentially pathogenic bacteria. Dysbiosis of the intestinal flora leads to increased intestinal permeability, homing of intestinal lymphocytes, entry of bacteria and their associated metabolites, such as bile acids, into the liver, stimulation of hepatic immune activation, and promotion of PSC. Currently, PSC effective treatment is lacking. However, a number of studies have recently investigated the targeted modulation of gut microbes for the treatment of various liver diseases (alcoholic liver disease, metabolic fatty liver, cirrhosis, and autoimmune liver disease). In addition, antibiotics, fecal microbiota transplantation, and probiotics have been reported as successful PSC therapies as well as for the treatment of gut dysbiosis, suggesting their effectiveness for PSC treatment. Therefore, this review briefly summarizes the role of intestinal flora in PSC with the aim of providing new insights into PSC treatment.
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Affiliation(s)
- Zhen-Jiao Li
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
- Laboratory of Biological Therapy and Regenerative Medicine Transformation Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Hong-Zhong Gou
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
- Laboratory of Biological Therapy and Regenerative Medicine Transformation Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Yu-Lin Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
- Laboratory of Biological Therapy and Regenerative Medicine Transformation Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Xiao-Jing Song
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
- Laboratory of Biological Therapy and Regenerative Medicine Transformation Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Lei Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
- Laboratory of Biological Therapy and Regenerative Medicine Transformation Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
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Zhou Z, Pan X, Li L. Crosstalk between liver macrophages and gut microbiota: An important component of inflammation-associated liver diseases. Front Cell Dev Biol 2022; 10:1070208. [PMID: 36483677 PMCID: PMC9723159 DOI: 10.3389/fcell.2022.1070208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 11/10/2022] [Indexed: 08/30/2023] Open
Abstract
Hepatic macrophages have been recognized as primary sensors and responders in liver inflammation. By processing host or exogenous biochemical signals, including microbial components and metabolites, through the gut-liver axis, hepatic macrophages can both trigger or regulate inflammatory responses. Crosstalk between hepatic macrophages and gut microbiota is an important component of liver inflammation and related liver diseases, such as acute liver injury (ALI), alcoholic liver disease (ALD), and nonalcoholic fatty liver disease (NAFLD). This review summarizes recent advances in knowledge related to the crosstalk between hepatic macrophages and gut microbiota, including the therapeutic potential of targeting hepatic macrophages as a component of gut microecology in inflammation-associated liver diseases.
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Affiliation(s)
| | | | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Liang T, Li D, Zunong J, Li M, Amaerjiang N, Xiao H, Khattab NM, Vermund SH, Hu Y. Interplay of Lymphocytes with the Intestinal Microbiota in Children with Nonalcoholic Fatty Liver Disease. Nutrients 2022; 14:nu14214641. [PMID: 36364902 PMCID: PMC9657134 DOI: 10.3390/nu14214641] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 10/24/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
Abnormally high lymphocyte counts are seen in persons with nonalcoholic fatty liver disease (NAFLD). Gut microbiota dysbiosis is a risk factor for NAFLD. We assessed the gut microbiota of 63 healthy children and 63 children with NAFLD using 16S rRNA gene and metagenomic sequencing to explore the relationships. Compared with healthy children (HC group), the Bacteroidetes, Verrucomicrobia, and Akkermansia were less abundant, while the Actinobacteria were more abundant in children with NAFLD (FLD group). To understand the effect of lymphocytes on the gut microbiota of children with NAFLD, we compared the microbiota of 41 children with NAFLD and high numbers of lymphocytes (FLD_HL group) and 22 children with NAFLD and low numbers of lymphocytes (FLD_LL group). The abundances of Bacteroidetes, Verrucobacterium, and Akkermansia increased and Actinobacteria decreased in the FLD_LL group compared to the FLD_HL group. Akkermansia was negatively correlated with lymphocyte count. NAFLD may disturb the gut microbiota in children through reducing the abundance of Akkermansia and increasing the abundance of proinflammatory bacteria, such as Escherichia-Shigella. Conclusions: High lymphocyte counts are associated with disturbances of gut microbiota and emergence of opportunistic pathogens in children with NAFLD.
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Affiliation(s)
- Tian Liang
- Department of Child, Adolescent Health and Maternal Care, School of Public Health, Capital Medical University, Beijing 100069, China
| | - Dan Li
- Yale School of Public Health, Yale University, New Haven, CT 06510-3201, USA
| | - Jiawulan Zunong
- Department of Child, Adolescent Health and Maternal Care, School of Public Health, Capital Medical University, Beijing 100069, China
| | - Menglong Li
- Department of Child, Adolescent Health and Maternal Care, School of Public Health, Capital Medical University, Beijing 100069, China
| | - Nubiya Amaerjiang
- Department of Child, Adolescent Health and Maternal Care, School of Public Health, Capital Medical University, Beijing 100069, China
| | - Huidi Xiao
- Department of Child, Adolescent Health and Maternal Care, School of Public Health, Capital Medical University, Beijing 100069, China
| | - Nourhan M. Khattab
- Department of Child, Adolescent Health and Maternal Care, School of Public Health, Capital Medical University, Beijing 100069, China
| | - Sten H. Vermund
- Yale School of Public Health, Yale University, New Haven, CT 06510-3201, USA
| | - Yifei Hu
- Department of Child, Adolescent Health and Maternal Care, School of Public Health, Capital Medical University, Beijing 100069, China
- Correspondence: or ; Tel.: +86-10-83911747
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Chen X, Liu M, Tang J, Wang N, Feng Y, Ma H. Research Progress on the Therapeutic Effect of Polysaccharides on Non-Alcoholic Fatty Liver Disease through the Regulation of the Gut-Liver Axis. Int J Mol Sci 2022; 23:11710. [PMID: 36233011 PMCID: PMC9570256 DOI: 10.3390/ijms231911710] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/26/2022] [Accepted: 09/28/2022] [Indexed: 11/22/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease affecting global public health at present, which can induce cirrhosis and liver cancer in serious cases. However, NAFLD is a multifactorial disease, and there is still a lack of research on its mechanism and therapeutic strategy. With the development of the gut-liver axis theory, the association between the gut-liver axis and the pathogenesis of NAFLD has been gradually disclosed. Polysaccharides, as a kind of natural product, have the advantages of low toxicity, multi-target and multi-pathway action. It has been reported that polysaccharides can affect the gut-liver axis at multiple interrelated levels, such as maintaining the ecological balance of gut microbiota (GM), regulating the metabolites of GM and improving the intestinal barrier function, which thereby plays a protective role in NAFLD. These studies have great scientific significance in understanding NAFLD based on the gut-liver axis and developing safe and effective medical treatments. Herein, we reviewed the recent progress of polysaccharides in improving nonalcoholic fatty liver disease (NAFLD) through the gut-liver axis.
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Affiliation(s)
- Xiang Chen
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
| | - Menghan Liu
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
| | - Jun Tang
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong 999077, China
| | - Yibin Feng
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong 999077, China
| | - Haotian Ma
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
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Effect of DSS-Induced Ulcerative Colitis and Butyrate on the Cytochrome P450 2A5: Contribution of the Microbiome. Int J Mol Sci 2022; 23:ijms231911627. [PMID: 36232929 PMCID: PMC9569822 DOI: 10.3390/ijms231911627] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/27/2022] [Accepted: 09/27/2022] [Indexed: 12/02/2022] Open
Abstract
Several studies have indicated the beneficial anti-inflammatory effect of butyrate in inflammatory bowel disease (IBD) therapy implying attempts to increase butyrate production in the gut through orally administered dietary supplementation. Through the gut-liver axis, however, butyrate may reach directly the liver and influence the drug-metabolizing ability of hepatic enzymes, and, indirectly, also the outcome of applied pharmacotherapy. The focus of our study was on the liver microsomal cytochrome P450 (CYP) 2A5, which is a mouse orthologue of human CYP2A6 responsible for metabolism of metronidazole, an antibiotic used to treat IBD. Our findings revealed that specific pathogen-free (SPF) and germ-free (GF) mice with dextran sulfate sodium (DSS)-induced colitis varied markedly in enzyme activity of CYP2A and responded differently to butyrate pre-treatment. A significant decrease (to 50%) of the CYP2A activity was observed in SPF mice with colitis; however, an administration of butyrate prior to DSS reversed this inhibition effect. This phenomenon was not observed in GF mice. The results highlight an important role of gut microbiota in the regulation of CYP2A under inflammatory conditions. Due to the role of CYP2A in metronidazole metabolism, this phenomenon may have an impact on the IBD therapy. Butyrate administration, hence, brings promising therapeutic potential for improving symptoms of gut inflammation; however, possible interactions with drug metabolism need to be further studied.
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Smith MM, Melrose J. Xylan Prebiotics and the Gut Microbiome Promote Health and Wellbeing: Potential Novel Roles for Pentosan Polysulfate. Pharmaceuticals (Basel) 2022; 15:ph15091151. [PMID: 36145372 PMCID: PMC9503530 DOI: 10.3390/ph15091151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/17/2022] [Accepted: 09/09/2022] [Indexed: 12/12/2022] Open
Abstract
This narrative review highlights the complexities of the gut microbiome and health-promoting properties of prebiotic xylans metabolized by the gut microbiome. In animal husbandry, prebiotic xylans aid in the maintenance of a healthy gut microbiome. This prevents the colonization of the gut by pathogenic organisms obviating the need for dietary antibiotic supplementation, a practice which has been used to maintain animal productivity but which has led to the emergence of antibiotic resistant bacteria that are passed up the food chain to humans. Seaweed xylan-based animal foodstuffs have been developed to eliminate ruminant green-house gas emissions by gut methanogens in ruminant animals, contributing to atmospheric pollution. Biotransformation of pentosan polysulfate by the gut microbiome converts this semi-synthetic sulfated disease-modifying anti-osteoarthritic heparinoid drug to a prebiotic metabolite that promotes gut health, further extending the therapeutic profile and utility of this therapeutic molecule. Xylans are prominent dietary cereal components of the human diet which travel through the gastrointestinal tract as non-digested dietary fibre since the human genome does not contain xylanolytic enzymes. The gut microbiota however digest xylans as a food source. Xylo-oligosaccharides generated in this digestive process have prebiotic health-promoting properties. Engineered commensal probiotic bacteria also have been developed which have been engineered to produce growth factors and other bioactive factors. A xylan protein induction system controls the secretion of these compounds by the commensal bacteria which can promote gut health or, if these prebiotic compounds are transported by the vagal nervous system, may also regulate the health of linked organ systems via the gut–brain, gut–lung and gut–stomach axes. Dietary xylans are thus emerging therapeutic compounds warranting further study in novel disease prevention protocols.
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Affiliation(s)
- Margaret M. Smith
- Raymond Purves Laboratory of Bone and Joint Research, Kolling Institute of Medical Research, Faculty of Health and Science, University of Sydney at Royal North Shore Hospital, St. Leonards, NSW 2065, Australia
| | - James Melrose
- Raymond Purves Laboratory of Bone and Joint Research, Kolling Institute of Medical Research, Faculty of Health and Science, University of Sydney at Royal North Shore Hospital, St. Leonards, NSW 2065, Australia
- Graduate School of Biomedical Engineering, University of New South Wales, Sydney, NSW 2052, Australia
- Sydney Medical School, Northern Campus, University of Sydney at Royal North Shore Hospital, St. Leonards, NSW 2065, Australia
- Correspondence:
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Tan YY, Yue SR, Lu AP, Zhang L, Ji G, Liu BC, Wang RR. The improvement of nonalcoholic steatohepatitis by Poria cocos polysaccharides associated with gut microbiota and NF-κB/CCL3/CCR1 axis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 103:154208. [PMID: 35691078 DOI: 10.1016/j.phymed.2022.154208] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 05/18/2022] [Accepted: 05/24/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Nonalcoholic steatohepatitis (NASH) has been linked to inflammation induced by intestinal microbiota. Poria cocos polysaccharides (PCP) possesses anti-inflammation and immunomodulation functions; however, its preventive effects against NASH and potential mechanisms need to be explored. METHODS The composition of PCP was determined using ion chromatography. C57BL/6 mice were administered the methionine and choline deficient (MCD) diet for 4 weeks to establish the NASH model or methionine-choline-sufficient (MCS) diet to serve as the control. Mice were assigned to the MCS group, MCD group, low-dose PCP (LP) group, and high-dose PCP (HP) group, and were administered the corresponding medications via gavage. Serum biochemical index analysis and liver histopathology examination were performed to verify the successful establishment of NASH model and to evaluate the efficacy of PCP. The composition of intestinal bacteria was profiled through 16S rRNA gene sequencing. Hepatic RNA sequencing (RNA-Seq) was performed to explore the potential mechanisms, which were further confirmed using qPCR, western blot, and immunohistochemistry. RESULTS PCP consists of glucose, galactose, mannose, D-glucosamine hydrochloride, xylose, arabinose, and fucose. PCP could significantly alleviate symptoms of NASH, including histological liver damage, impaired hepatic function, and increased oxidative stress. Meanwhile, HP could reshape the composition of intestinal bacteria by significantly increasing the relative abundance of Faecalibaculum and decreasing the level of endotoxin load derived from gut bacteria. PCP could also downregulate the expression of pathways associated with immunity and inflammation, including the chemokine signaling pathway, Toll-like receptor signaling pathway, and NF-kappa B signaling pathway. The expression levels of CCL3 and CCR1 (involved in the chemokine signaling pathway), Tlr4, Cd11b, and NF-κb (involved in the NF-kappa B signaling pathway), and Tnf-α (involved in the TNF signaling pathway) were significantly reduced in the HP group compared to the MCD group. CONCLUSIONS PCP could prevent the development of NASH, which may be associated with the modulation of intestinal microbiota and the downregulation of the NF-κB/CCL3/CCR1 axis.
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Affiliation(s)
- Yi-Yun Tan
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Si-Ran Yue
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Ai-Ping Lu
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Lei Zhang
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Guang Ji
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
| | - Bao-Cheng Liu
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
| | - Rui-Rui Wang
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
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38
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Zhao YY. Recent advances of gut microbiota in chronic kidney disease patients. EXPLORATION OF MEDICINE 2022:260-274. [DOI: 10.37349/emed.2022.00090] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/21/2022] [Indexed: 01/23/2025] Open
Abstract
Chronic kidney disease (CKD) is a worldwide public health issue and has ultimately progressed to an end-stage renal disease that requires life-long dialysis or renal transplantation. However, the underlying molecular mechanism of these pathological development and progression remains to be fully understood. The human gut microbiota is made up of approximately 100 trillion microbial cells including anaerobic and aerobic species. In recent years, more and more evidence has indicated a clear association between dysbiosis of gut microbiota and CKD including immunoglobulin A (IgA) nephropathy, diabetic kidney disease, membranous nephropathy, chronic renal failure and end-stage renal disease. The current review describes gut microbial dysbiosis and metabolites in patients with CKD thus helping to understand human disease. Treatment with prebiotics, probiotics and natural products can attenuate CKD through improving dysbiosis of gut microbiota, indicating a novel intervention strategy in patients with CKD. This review also discusses therapeutic options, such as prebiotics, probiotics and natural products, for targeting dysbiosis of gut microbiota in patients to provide more specific concept-driven therapy strategy for CKD treatment.
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Affiliation(s)
- Ying-Yong Zhao
- Faculty of Life Science & Medicine, Northwest University, Xi’an 710069, Shaanxi, China
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39
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Rui L, Lin JD. Reprogramming of Hepatic Metabolism and Microenvironment in Nonalcoholic Steatohepatitis. Annu Rev Nutr 2022; 42:91-113. [PMID: 35584814 PMCID: PMC10122183 DOI: 10.1146/annurev-nutr-062220-105200] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD), a spectrum of metabolic liver disease associated with obesity, ranges from relatively benign hepatic steatosis to nonalcoholic steatohepatitis (NASH). The latter is characterized by persistent liver injury, inflammation, and liver fibrosis, which collectively increase the risk for end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. Recent work has shed new light on the pathophysiology of NAFLD/NASH, particularly the role of genetic, epigenetic, and dietary factors and metabolic dysfunctions in other tissues in driving excess hepatic fat accumulation and liver injury. In parallel, single-cell RNA sequencing studies have revealed unprecedented details of the molecular nature of liver cell heterogeneity, intrahepatic cross talk, and disease-associated reprogramming of the liver immune and stromal vascular microenvironment. This review covers the recent advances in these areas, the emerging concepts of NASH pathogenesis, and potential new therapeutic opportunities. Expected final online publication date for the Annual Review of Nutrition, Volume 42 is August 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Liangyou Rui
- Department of Molecular and Integrated Physiology and Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA;
| | - Jiandie D Lin
- Life Sciences Institute and Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA;
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40
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Manzoor R, Ahmed W, Afify N, Memon M, Yasin M, Memon H, Rustom M, Al Akeel M, Alhajri N. Trust Your Gut: The Association of Gut Microbiota and Liver Disease. Microorganisms 2022; 10:1045. [PMID: 35630487 PMCID: PMC9146349 DOI: 10.3390/microorganisms10051045] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/08/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023] Open
Abstract
The gut microbiota composition is important for nutrient metabolism, mucosal barrier function, immunomodulation, and defense against pathogens. Alterations in the gut microbiome can disturb the gut ecosystem. These changes may lead to the loss of beneficial bacteria or an increase in potentially pathogenic bacteria. Furthermore, these have been shown to contribute to the pathophysiology of gastrointestinal and extra-intestinal diseases. Pathologies of the liver, such as non-alcoholic liver disease, alcoholic liver disease, cirrhosis, hepatocellular carcinoma, autoimmune hepatitis, viral hepatitis, and primary sclerosing cholangitis have all been linked to changes in the gut microbiome composition. There is substantial evidence that links gut dysbiosis to the progression and complications of these pathologies. This review article aimed to describe the changes seen in the gut microbiome in liver diseases and the association between gut dysbiosis and liver disease, and finally, explore treatment options that may improve gut dysbiosis in patients with liver disease.
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Affiliation(s)
- Ridda Manzoor
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Weshah Ahmed
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Nariman Afify
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Mashal Memon
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Maryam Yasin
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Hamda Memon
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Mohammad Rustom
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Mohannad Al Akeel
- Division of Family Medicine, Department of Health, Abu Dhabi P.O. Box 5674, United Arab Emirates;
| | - Noora Alhajri
- Department of Medicine, Sheikh Shakhbout Medical City (SSMC), Abu Dhabi P.O. Box 11001, United Arab Emirates
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41
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Salvati A, Poelstra K. Drug Targeting and Nanomedicine: Lessons Learned from Liver Targeting and Opportunities for Drug Innovation. Pharmaceutics 2022; 14:217. [PMID: 35057111 PMCID: PMC8777931 DOI: 10.3390/pharmaceutics14010217] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 02/08/2023] Open
Abstract
Drug targeting and nanomedicine are different strategies for improving the delivery of drugs to their target. Several antibodies, immuno-drug conjugates and nanomedicines are already approved and used in clinics, demonstrating the potential of such approaches, including the recent examples of the DNA- and RNA-based vaccines against COVID-19 infections. Nevertheless, targeting remains a major challenge in drug delivery and different aspects of how these objects are processed at organism and cell level still remain unclear, hampering the further development of efficient targeted drugs. In this review, we compare properties and advantages of smaller targeted drug constructs on the one hand, and larger nanomedicines carrying higher drug payload on the other hand. With examples from ongoing research in our Department and experiences from drug delivery to liver fibrosis, we illustrate opportunities in drug targeting and nanomedicine and current challenges that the field needs to address in order to further improve their success.
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Affiliation(s)
- Anna Salvati
- Correspondence: (A.S.); (K.P.); Tel.: +31-503639831 (A.S.); +31-503633287 (K.P.)
| | - Klaas Poelstra
- Correspondence: (A.S.); (K.P.); Tel.: +31-503639831 (A.S.); +31-503633287 (K.P.)
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42
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Maccioni L, Leclercq IA, Schnabl B, Stärkel P. Host Factors in Dysregulation of the Gut Barrier Function during Alcohol-Associated Liver Disease. Int J Mol Sci 2021; 22:12687. [PMID: 34884492 PMCID: PMC8657823 DOI: 10.3390/ijms222312687] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/18/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic alcohol consumption and alcohol-associated liver disease (ALD) represent a major public health problem worldwide. Only a minority of patients with an alcohol-use disorder (AUD) develop severe forms of liver disease (e.g., steatohepatitis and fibrosis) and finally progress to the more advanced stages of ALD, such as severe alcohol-associated hepatitis and decompensated cirrhosis. Emerging evidence suggests that gut barrier dysfunction is multifactorial, implicating microbiota changes, alterations in the intestinal epithelium, and immune dysfunction. This failing gut barrier ultimately allows microbial antigens, microbes, and metabolites to translocate to the liver and into systemic circulation. Subsequent activation of immune and inflammatory responses contributes to liver disease progression. Here we review the literature about the disturbance of the different host defense mechanisms linked to gut barrier dysfunction, increased microbial translocation, and impairment of liver and systemic inflammatory responses in the different stages of ALD.
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Affiliation(s)
- Luca Maccioni
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, UCLouvain, Unversité Catholique de Louvain, 1200 Brussels, Belgium; (L.M.); (I.A.L.)
| | - Isabelle A. Leclercq
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, UCLouvain, Unversité Catholique de Louvain, 1200 Brussels, Belgium; (L.M.); (I.A.L.)
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA;
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA 92161, USA
| | - Peter Stärkel
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, UCLouvain, Unversité Catholique de Louvain, 1200 Brussels, Belgium; (L.M.); (I.A.L.)
- Department of Hepato-Gastroenterology, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
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43
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De Muynck K, Vanderborght B, Van Vlierberghe H, Devisscher L. The Gut-Liver Axis in Chronic Liver Disease: A Macrophage Perspective. Cells 2021; 10:2959. [PMID: 34831182 PMCID: PMC8616442 DOI: 10.3390/cells10112959] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 10/25/2021] [Accepted: 10/26/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic liver disease (CLD) is a growing health concern which accounts for two million deaths per year. Obesity, alcohol overconsumption, and progressive cholestasis are commonly characterized by persistent low-grade inflammation and advancing fibrosis, which form the basis for development of end-stage liver disease complications, including hepatocellular carcinoma. CLD pathophysiology extends to the intestinal tract and is characterized by intestinal dysbiosis, bile acid dysregulation, and gut barrier disruption. In addition, macrophages are key players in CLD progression and intestinal barrier breakdown. Emerging studies are unveiling macrophage heterogeneity and driving factors of their plasticity in health and disease. To date, in-depth investigation of how gut-liver axis disruption impacts the hepatic and intestinal macrophage pool in CLD pathogenesis is scarce. In this review, we give an overview of the role of intestinal and hepatic macrophages in homeostasis and gut-liver axis disruption in progressive stages of CLD.
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Affiliation(s)
- Kevin De Muynck
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium; (K.D.M.); (B.V.)
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium;
| | - Bart Vanderborght
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium; (K.D.M.); (B.V.)
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium;
| | - Hans Van Vlierberghe
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium;
| | - Lindsey Devisscher
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium; (K.D.M.); (B.V.)
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