Gut microbiota-derived butyrate orchestrates Astragalus Polysaccharide-mediated colitis remission via macrophage immunometabolic reprogramming

Ulcerative colitis (UC) pathogenesis involves complex interactions between epithelial barrier dysfunction and immune dysregulation. While Astragalus polysaccharide (APS) exhibits anti-inflammatory properties, its mechanistic link to gut microbiota remodeling remains elusive. Using an integrative multi-omics strategy, we demonstrate that APS mitigates dextran sulfate sodium (DSS)-induced colitis by selectively recovering butyrate-producing commensal bacteria, including Ruminococcaceae, Alistipes , Rikenella , and Mucispirillum , thereby increasing fecal butyrate concentrations. Fecal microbiota transplantation (FMT) from APS-treated mice conferred protection against colitis, whereas butyrate supplementation phenocopied the effects of APS. Mechanistically, butyrate inhibited HDAC9 activity, augmenting H3K27ac at the Pparg locus to drive PPARG-ADIPOQ signaling. This epigenetic reprogramming polarized macrophages toward an M2 phenotype, dampened IL-1β/TNF-α production, and restored occludin/claudin-5 expression. Functional recovery experiments further confirmed the necessity of the axis: HDAC9 overexpression or PPARγ/ADIPOQ blockade abolished the therapeutic efficacy of APS. Clinically, human UC biopsy specimens displayed inverse expression patterns between HDAC9 and PPARγ/ADIPOQ, validating the clinical and translational relevance of this epigenetic-metabolic regulatory pathway. Collectively, this study delineates a diet-microbiota-epigenetic interplay wherein microbiota-derived butyrate emerges as a key mediator of APS-induced intestinal mucosal homeostasis through HDAC9/PPARG/ADIPOQ-dependent immunometabolic reprogramming. These results highlight microbiota-driven HDAC inhibition as a promising therapeutic strategy for UC management.