Postbiotic Limosilactobacillus reuteri cultured with Polygonatum kingianum polysaccharides ameliorates high-fat-high-sugar-deteriorated colitis and associated hepatobiliary disorders

Unhealthy diet exacerbates inflammatory bowel disease and its associated hepatic disruptions. The present study demonstrated the superior efficacy of the heat-inactivated Limosilactobacillus reuteri WX-94 (L. reuteri), cultured with Polygonatum kingianum polysaccharides (PKP postbiotic) in ameliorating a high-fat-high-sugar (HFHS)- deteriorated colitis in rats, which outperforming PKP alone, its symbiotic form, and inactivated L. reuteri cultured without PKP. HFHS deteriorated liver functions in rats following a DSS administration, which were reversed by PKP postbiotic. PKP postbiotic exclusively enriched Prevotella and Lactobacillus while decreasing Escherichia.coil, along with the elevation in fecal short-chain fatty acids, serum bile acids (e.g., taurocholic acid, taurallocholic acid and tauroursocholic acid), indole derivatives (e.g., indolepropionic acid, indoleacetic acid, indolelactic acid) and phospholipids. Mechanistically, PKP postbiotic suppressed colonic inflammation and hepatobiliary disorders through regulating tryptophan catabolism-activated AHR/IL-22 signaling and bile acids-activated TLR4/NFκB/NLRP3 signaling. Furthermore, we utilized human data sourced from Gene Expression Omnibus databases to confirm the involvement of key pathways regulated by PKP postbiotic in the colitis pathogenesis. Mendelian randomization-derived causal associations were observed between PKP postbiotic-elevated indole lactic acid with both colitis and nonalcoholic fatty liver disease. Our study presents compelling evidence of a novel property of PKP that augments the health-promoting benefits of inactivated L. reuteri.