Breast-milk Lacticaseibacillus gasseri FN136 alleviates DSS-induced ulcerative colitis through microbiota-independent metabolite–host interactions

Abstract Chronic, relapsing colonic inflammation defines ulcerative colitis (UC) and heightens long-term colorectal cancer risk. Probiotics, proven beneficial, have emerged as a promising adjunctive strategy for UC management. We conducted a two-tiered evaluation of the breast-milk-derived strain Lacticaseibacillus gasseri FN136. In vitro, FN136 secreted anti-inflammatory amino acids and indoles, displayed pronounced acid- and bile-salt tolerance, and exhibited significant antimicrobial activity. In vivo, daily oral administration of 1 × 10⁹ CFU FN136 markedly attenuated DSS-induced UC: serum l-arginine was restored, splenic Treg frequency increased by 42.09% (P < 0.05), and nitric oxide production was elevated, while disease activity index, body-weight loss, and colonic shortening were all significantly reduced (P < 0.05). Histopathology revealed intact crypt architecture and diminished inflammatory infiltration; systemic inflammation was suppressed as evidenced by decreased interleukin-6, myeloperoxidase, lipopolysaccharide, and FITC-dextran levels (P < 0.05). Critically, 16S rRNA sequencing revealed no significant alterations in global microbial composition, indicating that FN136 exerts protection via a microbiota-independent postbiotic–host axis. Collectively, FN136 mitigates DSS-induced UC by restoring serum arginine and orchestrating immune–barrier homeostasis through a postbiotic pathway, offering a novel framework for precision UC intervention.