3-Phenylpropionic acid, a microbiota-derived polyphenol metabolite linked to hippuric acid, ameliorates colitis as a colon-enriched PPAR-γ agonist

Abstract Polyphenols are promising therapeutics for Crohn’s disease (CD), yet their bioavailability is largely dependent on the gut microbiome. The bioactive metabolites, metabolic pathways, and anti-inflammatory mechanisms underlying their effects remain poorly defined. We identified hippuric acid (HIPA) as a biomarker of polyphenol–microbiome interaction. HIPA is a meta-organismal metabolite produced through a cross-organ pathway that involves synthesis from gut microbial polyphenol metabolism via 3-phenylpropionic acid (3-PPA), followed by renal clearance. We found that CD is characterised by impaired polyphenol metabolism, resulting in deficient colonic 3-PPA and reduced serum hippuric acid relative to healthy individuals. Furthermore, we demonstrate that 3-PPA is a colon-enriched, mild PPAR-γ agonist that ameliorates colitis in murine model. Systemic bioinformatic profiling of metagenomic data suggested the existence of undiscovered 3-PPA producers. Through targeted microbial incubation with polyphenols, we identified the probiotic Bifidobacterium breve and a lab isolate Escherichia coli FAH as novel 3-PPA producers. Collectively, our findings establish 3-PPA as a diet-dependent, colon-produced, mild PPAR-γ agonist with the potential to minimise adverse effects associated with traditional PPAR-γ agonists. This work establishes a foundation for developing microbiota-targeted, polyphenol-based therapeutic strategies for CD patients. Competing Interest Statement The First Affiliated Hospital of Sun Yat-sen University has a patent pending for PPAR-γ targeted therapeutics, on which R. F., Y. Z., P. B., W. Lai, W. Luo, and W.Z. are listed as co-inventors. Y.Z has received research funds from Wecare Probiotics. Shuguang Fang is the founder of Wecare Probiotics Co., Ltd. All other authors declare that they have no competing financial or personal interests related to the subject matter of this manuscript. Footnotes Leading author: zhuyj67{at}mail.sysu.edu.cn (Y.Z.)