Microbiota-derived 4-HPAA alleviates Crohn's disease by stabilizing SIRT1 and reprogramming macrophage immunometabolism.

Crohn's disease (CD) is characterized by mucosal immune dysregulation, gut microbiota disturbance, and epithelial barrier dysfunction. This study investigated whether an Aronia berry polyphenol-rich diet attenuates CD-related intestinal inflammation through microbiota-derived metabolic signals. IL-10-/- and TNBS-induced colitis mouse models were used to evaluate the effects of dietary intervention, bacterial strain supplementation, and candidate metabolite administration. Integrated metagenomic, metabolomic, and transcriptomic analyses were combined with in vivo and in vitro mechanistic experiments to identify diet-responsive microbial taxa, metabolites, and host regulatory pathways. This diet alleviated colitis, reduced mucosal injury, and improved epithelial barrier integrity. Multi-omics analyses identified Flavonifractor plautii enrichment and increased microbiota-derived 4-hydroxyphenylacetic acid (4-HPAA) levels as major diet-associated changes. F. plautii supplementation was associated with increased 4-HPAA production, while 4-HPAA administration partially reproduced the intestinal protective phenotype in vivo. In macrophages, 4-HPAA suppressed pro-inflammatory activation and promoted oxidative metabolic remodeling. Mechanistically, 4-HPAA stabilized SIRT1 by limiting ubiquitination-mediated proteasomal degradation, thereby activating SIRT1-PGC-1α signaling. Myeloid SIRT1 deficiency attenuated the effects of 4-HPAA on macrophage polarization, inflammatory cytokine expression, and epithelial barrier-associated proteins. These findings identify a diet-associated microbial metabolite pathway involving F. plautii, 4-HPAA, and SIRT1 signaling, linking polyphenol-rich dietary intervention to macrophage immunometabolic regulation and intestinal barrier protection. This microbial metabolite-centered mechanism may provide insight into nutritional intervention strategies for CD-related intestinal inflammation.