Immunobiotic Bacteria Attenuate Hepatic Fibrosis through the Modulation of Gut Microbiota and the Activation of Aryl-Hydrocarbon Receptors Pathway in Non-Alcoholic Steatohepatitis Mice

ScopeNonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease worldwide that can progress to liver fibrosis (LF). Probiotics have beneficial roles in reducing intestinal inflammation and gut-associated diseases, but their effects and mechanisms beyond the gut in attenuating the progression of LF are remained unclear.Methods and resultsIn a mouse model of NASH/LF induced by a methionine-choline deficient (MCD) diet, immunobiotics are administered to investigate their therapeutic effects. Results show that the MCD diet leads to liver inflammation, steatosis, and fibrosis, which are alleviated by immunobiotics. Immunobiotics reduces serum endotoxin and inflammatory markers while increasing regulatory cytokines and liver weight. They also suppress Th17 cells, known for producing inflammatory cytokines. Furthermore, immunobiotics mitigate collagen deposition and fibrogenic signaling in the liver, while restoring gut-barrier integrity and microbiota composition. Additionally, immunobiotics enhance the activation of the aryl hydrocarbon receptor (AhR) pathway in both colonic and liver tissues.ConclusionsOverall, these results demonstrate a novel insight into the mechanisms through which immunobiotic administration improves the gut health which in turn increases the AhR pathway and inhibits HSCs activation and fibrosis progression beyond the gut in the liver tissue of NASH/LF mice. The MCD diet significantly exacerbates hepatic fibrosis by activating hepatic stellate cells (HSCs) and increasing markers of inflammation and fibrosis, including NASH, inflammatory cytokines, and liver triglycerides (TG). This diet also leads to gut dysbiosis, increased intestinal permeability, bacterial translocation, and elevated endotoxin levels, further aggravating liver damage. Conversely, immunobiotics markedly reduces hepatic fibrosis and HSC activation. It lowers the levels of proinflammatory and profibrogenic markers, enhances the AhR pathway, and improves liver function as indicated by reduced levels of endotoxin, AST, and ALT. Additionally, immunobiotics improve gut health by decreasing intestinal permeability, restoring gut microbiota balance, and enhancing tight junction protein expression. image