Indole-3-propionic acid (IPA)

Indole-3-propionic acid (IPA) is a gut-microbiota-derived catabolite of dietary tryptophan produced almost exclusively by the obligate anaerobe Clostridium sporogenes via deamination to indole-3-pyruvate and subsequent reduction. IPA acts through two nuclear receptors — the pregnane X receptor (PXR) in intestinal epithelial cells and liver, and the aryl hydrocarbon receptor (AhR) — and independently as a direct free-radical scavenger. PXR activation upregulates tight-junction proteins (claudin-1, occludin, ZO-1) and mucins (MUC2, MUC4) while suppressing TNF-α and IL-6 via NF-κB inhibition; Venkatesh et al. (2014, Immunity) showed this in a murine colitis model, and Li et al. (2021, J Agric Food Chem) confirmed that IPA raised transepithelial electrical resistance and reduced paracellular flux. Metabolic relevance derives from the Finnish Diabetes Prevention Study (n = 200): Tuomainen et al. (2018, Nutrition & Diabetes) found higher serum IPA at one year was inversely associated with incident type 2 diabetes over a 7-year follow-up and positively linked to preserved insulin secretion; IPA also correlated inversely with IL-6 and hsCRP. In aged animal models, IPA supplementation improved grip strength and bone microarchitecture in mice and extended lifespan in Drosophila in a sex- and genotype-dependent manner (GeroScience, 2025). IPA levels are diet-responsive; tryptophan intake, prebiotic fibre, and antibiotic exposure are established modulators. Human intervention trials are absent; evidence is observational or mechanistic and causal inference has not been established.