Mìžnarodnij Endokrinologìčnij Žurnal (Dec 2024)
Targeting Toll-like receptor 4 and microbiota dysregulation: a new frontier in nonalcoholic fatty liver disease management
Abstract
Background. Nonalcoholic fatty liver disease (NAFLD) is a widespread chronic liver condition affecting nearly a quarter of the global population. It encompasses a spectrum of disorders, ranging from simple steatosis to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma, often associated with metabolic syndrome and insulin resistance. Emerging evidence underscores the critical role of gut microbiota dysbiosis and Toll-like receptor 4 (TLR4) activation in the pathogenesis and progression of NAFLD. Gut-derived lipopolysaccharides activate TLR4, initiating inflammatory cascades that exacerbate liver injury. This study purposed to evaluate the relationship between gut microbiota composition, TLR4 levels, and biochemical markers in NAFLD and to assess the efficacy of microbiome-targeted therapy in modulating these factors. Materials and methods. The study included 152 patients with NAFLD and 47 control participants without liver steatosis. NAFLD diagnosis was confirmed by ultrasound, steatometry, and the presence of cardiometabolic risk factors. Microbiota composition was analyzed using quantitative polymerase chain reaction, and TLR4 levels were measured in serum samples. Patients with NAFLD underwent a microbiome-targeted therapy consisting of rifaximin, probiotics, and essential phospholipids over 12 weeks. Biochemical, microbiota, and inflammatory markers were assessed before and after treatment. Statistical analyses included t-tests and correlation analysis to explore associations between microbiota, TLR4, and biochemical parameters. Results. Patients with NAFLD exhibited significant gut microbiota changes, characterized by an increased Firmicutes/Bacteroidetes ratio and elevated Actinobacteria levels compared to controls. TLR4 levels were significantly higher in the NAFLD group, correlating positively with liver function tests and systemic inflammatory markers. Following microbiome-targeted therapy, patients demonstrated a substantial reduction in TLR4 levels, improved liver enzymes (alanine aminotransferase, aspartate aminotransferase), decreased HOMA-IR index, and enhanced gut microbiota composition. Notably, the prevalence of small intestinal bacterial overgrowth decreased from 51 to 20 %. Conclusions. The findings emphasize the critical role of gut microbiota dysbiosis and TLR4 activation in the progression of NAFLD. Microbiome-targeted therapy proved effective in reducing TLR4-driven inflammation, improving metabolic and liver function, and normalizing dysbiotic microbial profiles, supporting the use of microbiota-focused interventions in NAFLD management.
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