Abstract
<title>Abstract</title> <p> Ulcerative colitis (UC), a chronic and relapsing inflammatory disorder of the colon, stems from dysregulated interactions between host immunity and the gut microbiota. However, precise pharmacomicrobiomics targets that modulate this interaction remain poorly characterized. Here, we identify Tetramethylpyrazine (TMP) as a potent suppressor of intestinal inflammation in murine colitis models, a protective effect contingent upon the induction of anti-inflammatory macrophage M2 polarization. Integrated 16S rRNA sequencing reveals that TMP reconfigures the gut microbial architecture, augmenting both α- and β-diversity while selectively enriching <italic>Bifidobacterium pseudolongum</italic> . Crucially, <italic>B. pseudolongum</italic> abundance inversely correlates with disease severity. Using gnotobiotic mouse models and fecal microbiota transplantation (FMT), we causally demonstrate that the anti-inflammatory efficacy of TMP is strictly microbiota-dependent and can be recapitulated by <italic>B. pseudolongum</italic> alone. Untargeted metabolomics further uncovers that <italic>B. pseudolongum</italic> remodels the host metabolic landscape, specifically promoting the accumulation of taurine and N-stearoyl taurine. Mechanistically, we delineate how <italic>B. pseudolongum</italic> reprograms host taurine metabolism to activate the Foxo1-mediated oxidative stress response, culminating in the upregulation of Sesn3, Sod2, and Cat antioxidant defenses that orchestrate macrophage M2 polarization. This immunomodulatory cascade proves indispensable for TMP-mediated protection against colitis. Collectively, our findings unveil a previously unrecognized gut microbiota-host metabolic circuit wherein TMP ameliorates UC through <italic>B. pseudolongum</italic> -driven taurine metabolism and subsequent macrophage M2 polarization, highlighting novel therapeutic avenues for targeting microbial-metabolic-immune networks in inflammatory diseases. </p>