The gut-liver axis: microbial mechanisms and therapeutic implications in MAFLD.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most common chronic liver disease worldwide, currently affecting approximately 32% of the global adult population.Initially presenting as simple hepatic steatosis, MAFLD often progresses to severe cardiovascular complications, imposing significant healthcare and economic burdens. Current clinical management relies primarily on lifestyle interventions, with few targeted pharmacotherapies available, highlighting the urgent need for deeper mechanistic understanding and innovative treatments. A growing body of research highlights the critical role of intestinal homeostasis in the development and progression of MAFLD. Modern studies refer to the bidirectional communication between the gut and liver via the biliary tract, portal vein, and systemic circulation as the "gut-liver axis." This structural connection makes the liver more susceptible to damage from gut-derived microbes, metabolites, endotoxins, and inflammatory mediators, positioning the liver as a key target organ exposed to the intestinal microenvironment. For instance: LPS (endotoxin) a component of Gram-negative bacteria, activates the TLR4 signaling pathway, triggering NF-κB and promoting the release of pro-inflammatory cytokines such as TNF-α and IL-6. This amplifies inflammation and compromises the intestinal barrier, allowing bacteria and their products to enter the liver via the portal vein and induce liver injury. Short-chain fatty acids (SCFAs, e.g., butyrate), produced by the fermentation of dietary fiber, inhibit histone deacetylase (HDAC) and activate G-protein-coupled receptors (e.g., GPR43, GPR109A). These mechanisms promote the differentiation of regulatory T cells (Treg) and the production of IgA antibodies, thereby suppressing inflammation and strengthening the mucosal barrier.Secondary bile acids (e.g., 3-oxoLCA), generated through microbial modification of bile acids, can regulate the Treg/Th17 balance via nuclear receptors such as the vitamin D receptor (VDR). Numerous studies have observed microbial dysbiosis in MAFLD, characterized by an increase in Bacteroidetes and a decrease in Firmicutes.Emerging therapies targeting gut microbiota-including microbial metabolite modulators (HDCA, 4-HPAA) and multi-target traditional Chinese medicines (silymarin, Cornus officinalis glycosides)-demonstrate promising therapeutic potential when combined with interventions like probiotics and fecal microbiota transplantation.