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

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.