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bioRxiv · 10.1101/2025.11.25.690607

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

Zhu, Y.·Xiang, L.·Luo, W.·Zhang, W.·Lai, W.·Wu, X.·Zhuo, S.·Feng, B.·Chen, S.·Fang, S.·Chen, M.·Bai, P.·Feng, R.
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Abstract

Polyphenols are promising therapeutics for Crohns 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-{gamma} 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-{gamma} agonist with the potential to minimise adverse effects associated with traditional PPAR-{gamma} agonists. This work establishes a foundation for developing microbiota-targeted, polyphenol-based therapeutic strategies for CD patients.

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Zhu, Y., Xiang, L., Luo, W., Zhang, W., Lai, W., Wu, X., Zhuo, S., Feng, B., Chen, S., Fang, S., Chen, M., Bai, P., Feng, R.. 2025-11-26. 3-Phenylpropionic acid, a microbiota-derived polyphenol metabolite linked to hippuric acid, ameliorates colitis as a colon-enriched PPAR-γ agonist. https://doi.org/10.1101/2025.11.25.690607

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