Crosstalk between gut microbiota-associated metabolites and adaptive immunity in cholecystitis: a conceptual mechanistic framework and potential therapeutic implications

Abstract

The pathogenesis of cholecystitis involves the complex interplay of bile stasis, microbial dysbiosis, metabolic disturbances, and immune responses. Gut microbiota-associated metabolites can modulate adaptive immune components, including T helper 17 (Th17) cells, regulatory T (Treg) cells, CD8+ T cells, and B cells, through receptor-mediated signaling, immunometabolic reprogramming, and epigenetic regulation. Conversely, T cell-mediated immune selection and B cell-IgA responses can reshape microbial community structure and metabolic activity, thereby establishing a bidirectional microbiota-immune regulatory network. The immunological effects of metabolic signals, including secondary bile acids, short-chain fatty acids, tryptophan-related metabolites, polyamines, and lactate, are highly context dependent and may vary according to metabolite concentration, target cell type, receptor engagement, and the local tissue microenvironment. Importantly, direct mechanistic evidence specific to cholecystitis remains limited. Most of the mechanistic pathways discussed in this review are derived from studies of cholelithiasis, cholestasis, and other hepatobiliary or inflammatory disorders; therefore, several proposed links between microbial metabolism and adaptive immunity should currently be regarded as conceptual extrapolations rather than established mechanisms in cholecystitis. Focusing on this bidirectional crosstalk, we discuss its potential roles across distinct pathological settings, including gallstone-associated disease, acute inflammation, and chronic inflammation with tissue remodeling. We further summarize candidate therapeutic strategies targeting microbial ecology, bile acid metabolism, specific metabolic pathways, and adaptive immune responses. This conceptual framework may provide a basis for future mechanistic studies and facilitate the development of more precise therapeutic approaches for cholecystitis.