Akkermansia muciniphila-derived 5-MIAA blunts colitis-associated tumorigenesis by modulating colonic SLC26A3/pSTAT3 signaling

The interaction between gut microbiota and host genetic factors has been implicated in the development of colitis-associated colorectal cancer (CAC). Although Akkermansia muciniphila (Akk) has been studied in CAC, its role and molecular mechanism remain undetermined. In this study, we found that antibiotics treatment effectively inhibited tumorigenesis in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced CAC mice, and was associated with an increase in Akk's relative abundance in feces. Akk supplementation, as well as its conditioned medium, remarkably restrained tumor formation in the CAC model, whereas the original medium did not yield the same results. Further untargeted metabolomics and germ-free mice experiments revealed that Akk generated a tryptophan metabolite 5-methoxyindole-3-acetic acid (5-MIAA), which demonstrated protective effects against CAC proliferation. Mechanistically, 5-MIAA boosted colonic SLC26A3 expression to suppress the phosphorylation of STAT3 (pSTAT3), thus inhibiting CAC proliferation, which was further validated by conditional knockout mice. Collectively, we revealed that a tryptophan metabolite 5-MIAA, derived from Akk, inhibited CAC proliferation through colonic SLC26A3/pSTAT3 signaling pathway, which indicated that Akk and its functional metabolites may serve as novel therapeutic approaches for the prevention and treatment of CAC.