<i>Lactobacillus plantarum</i> Lac16 alleviates dextran sodium sulfate-induced colitis in mice by suppressing NLRP3 inflammasome overactivation through microbiota-derived isobutyric acid

This study establishes that <i>Lactobacillus plantarum</i> Lac16 alleviates DSS-induced colitis through gut microbiota-dependent mechanisms. Lac16 administration significantly ameliorated colitis symptoms while restoring intestinal barrier integrity, promoting anti-inflammatory macrophage polarization, and suppressing NLRP3 inflammasome overactivation. The pseudo-germ-free mouse model provided definitive evidence that Lac16's suppression of NLRP3 inflammasome overactivation requires gut microbiota. Fecal microbiota transplantation verified the causal role of microbiota in mediating Lac16's therapeutic benefits. Notably, Lac16 reshaped microbial composition, elevating beneficial genera (<i>Alloprevotella</i> and <i>Dubosiella</i>) while suppressing pathogenic genera (<i>Bacteroides</i> and <i>Helicobacter</i>). Crucially, Lac16 increased microbiota-derived short-chain fatty acids, particularly isobutyric acid. Both <i>in vivo</i> and <i>in vitro</i> experiments confirmed that isobutyric acid significantly contributes to anticolitic effects and suppresses NLRP3 activation. These findings elucidate a novel mechanism by which Lac16 ameliorates colitis via (i) microbiota-dependent NLRP3 inflammasome modulation and (ii) isobutyric acid-mediated protective effects. This work provides important insights into probiotic mechanisms and supports targeting microbial metabolic networks for IBD intervention.