Bidirectional microbial regulation by tyrosine metabolism enhances palmatine-mediated colitis protection

Gut microbiota dysbiosis and intestinal immune dysfunction contribute to the disease pathogenesis of ulcerative colitis (UC), therapeutic strategies aim to reshape microbial balance and reduce inflammation. It is unclear that how this bidirectional regulation between microbe-immune system is achieved and what is a possible nexus point for this regulation. Here, we demonstrated that palmatine (PAL) alleviates colitis by modulating interference competition between two microbes through the mediation of microbial tyrosine metabolites. Specifically, PAL directly inhibits <i>B. acidifaciens</i> while indirectly promoting the growth of <i>B. stercorirosoris</i> in mice with DSS-induced colitis. Notably, <i>p</i>-cresol (PC), a crucial microbial metabolite produced by <i>B. acidifaciens,</i> exacerbates colitis by promoting Th17 cells activation and inhibiting the growth of <i>B. stercorirosoris</i>. Furthermore, the immediate reduction in <i>p</i>-hydroxyphenylacetic acid, which is metabolized by <i>B. stercorirosoris</i>, contributes to the aggravation of colitis. Mechanistically, PC significantly inhibited the glycolysis of <i>B. stercorirosoris</i>, with downregulation of gene expression associated with glycolysis. In addition, we found that the inhibitory function of PC was offset by the addition of large amounts of polysaccharide and glucose in the medium of <i>B. stercorirosoris</i>. In summary, this study uncovers the mechanism by which palmatine‒microbiome‒host crosstalk cooperatively alleviate colitis through PC-mediated the bidirectional regulation. These findings propose that microbial metabolites function as regulators of microbiota‒host interactions, offering potential interventions for the treatment or prevention of dysbiosis-driven diseases.