Interplay between gut microbiome, host genetic and epigenetic modifications in MASLD and MASLD-related hepatocellular carcinoma

Ha, Suki; Wong, Vincent Wai-Sun; Zhang, Xiang; Yu, Jun

doi:10.1136/gutjnl-2024-332398

Cited by 7 publications

References 118 publications

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The Association Between Prevotella copri and Advanced Fibrosis in the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease

Leitman,

Zhang,

Pawar

et al. 2024

Preprint

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Metabolic dysfunction-associated steatotic liver disease (MASLD), driven by obesity and metabolic syndrome, is increasingly prevalent and a significant contributor to liver fibrosis, cirrhosis, and liver-related mortality. Emerging research implicates the gut microbiome as a critical player in MASLD progression, yet specific microbial drivers remain poorly understood. Here, we explore the role of Prevotella copri (P. copri) in MASLD progression through both human patient cohorts and a mouse model of diet-induced obesity. Using 16S rRNA sequencing, we identified elevated P. copri abundance in MASLD patients with advanced fibrosis, linked with significant shifts in microbial diversity and bacterial network connectivity. To investigate causality, experimental colonization of P. copri in mice on a high-fat diet worsened MASLD progression, with P. copri-colonized mice showing significant increases in hepatic steatosis, liver triglyceride accumulation, and body weight, independent of caloric intake. At the molecular level, P. copri colonization downregulated key lipid metabolism genes, such as Carnitine Palmitoyltransferase 1, Diacylglycerol Acyltransferase, and Adipose Triglyceride Lipase, and impaired tight intestinal junction integrity through the downregulation of cluadins, occludin, and zonula occludens-1. Collectively, our findings position P. copri as a possible driver of MASLD progression by promoting hepatic steatosis through lipid and triglyceride accumulation and fibrosis through decreased tight junction integrity. These insights suggest a promising therapeutic avenue to target specific microbial signatures like P. copri to curb MASLD progression and mitigate the associated risk of advanced fibrosis.

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The Association Between Prevotella copri and Advanced Fibrosis in the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease

Leitman,

Zhang,

Pawar

et al. 2024

Preprint

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Alterations in Glutathione Redox Homeostasis in Metabolic Dysfunction-Associated Fatty Liver Disease: A Systematic Review

Cesarini,

Grignaffini,

Alisi

et al. 2024

Antioxidants

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Low molecular weight (LMW) thiols, particularly glutathione, play pathogenic roles in various multiorgan diseases. The liver is central for the production and systemic distribution of LMW thiols; thus, it is particularly susceptible to the imbalance of redox status that may determine increased oxidative stress and trigger the liver damage observed in metabolic dysfunction-associated steatotic liver disease (MASLD) models and humans. Indeed, increased LMW thiols at the cellular and extracellular levels may be associated with the severity of MASLD. Here, we present a systematic literature review of recent studies assessing the levels of LMW thiols in MASLD in in vivo and in vitro models and human subjects. Based on the PRISMA 2020 criteria, a search was conducted using PubMed and Scopus by applying inclusion/exclusion filters. The initial search returned 1012 documents, from which 165 eligible studies were selected, further described, and qualitatively analysed. Of these studies, most focused on animal and cellular models, while a minority used human fluids. The analysis of these studies revealed heterogeneity in the methods of sample processing and measurement of LMW thiol levels, which hinder cut-off values for diagnostic use. Standardisation of the analysis and measure of LMW thiol is necessary to facilitate future studies.

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Circulating Gut Microbe-Derived Metabolites Are Associated with Hepatocellular Carcinoma

Banerjee,

Wehrle,

Wang

et al. 2024

Biomedicines

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. The gut microbiome has been implicated in outcomes for HCC, and gut microbe-derived products may serve as potential non-invasive indices for early HCC detection. This study evaluated differences in plasma concentrations of gut microbiota-derived metabolites. Methods: Forty-one patients with HCC and 96 healthy controls were enrolled from surgical clinics at the Cleveland Clinic from 2016 to 2020. Gut microbiota-derived circulating metabolites detectable in plasma were compared between patients with HCC and healthy controls. Hierarchical clustering was performed for generating heatmaps based on circulating metabolite concentrations using ClustVis, with Euclidean and Ward settings and significant differences between metabolite concentrations were tested using a binary logistic regression model. Results: In patients with HCC, 25 (61%) had histologically confirmed cirrhosis. Trimethylamine (TMA)-related metabolites were found at higher concentrations in those with HCC, including choline (p < 0.001), betaine (p < 0.001), carnitine (p = 0.007), TMA (p < 0.001) and trimethylamine N-oxide (TMAO, p < 0.001). Notably, concentrations of P-cresol glucuronide (p < 0.001), indole-lactic acid (p = 0.038), 5-hydroxyindoleacetic acid (p < 0.0001) and 4-hydroxyphenyllactic acid (p < 0.001) were also increased in those with HCC compared to healthy controls. Hierarchical clustering of the metabolite panel separated patients based on the presence of HCC (p < 0.001), but was not able to distinguish between patients with HCC based on the presence of cirrhosis (p = 0.42). Conclusions: Gut microbiota-derived metabolites were differentially abundant in patients with HCC versus healthy controls. The observed perturbations of the TMAO pathway in HCC seem particularly promising as a target of future research and may have both diagnostic and therapeutic implications.

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Interplay between gut microbiome, host genetic and epigenetic modifications in MASLD and MASLD-related hepatocellular carcinoma

Cited by 7 publications

References 118 publications

The Association Between Prevotella copri and Advanced Fibrosis in the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease

The Association Between Prevotella copri and Advanced Fibrosis in the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease

Alterations in Glutathione Redox Homeostasis in Metabolic Dysfunction-Associated Fatty Liver Disease: A Systematic Review

Circulating Gut Microbe-Derived Metabolites Are Associated with Hepatocellular Carcinoma

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