Novel cross-feeding human gut microbes metabolizing tryptophan to indole-3-propionate

Tryptophan-derived indoles produced by the gut microbiota, particularly indole-3-propionate (IPA), are key compounds associated with gastrointestinal balance and overall health. Reduced levels of IPA have been associated with inflammatory bowel disease, type 2 diabetes, and colorectal cancer. Since fiber-rich diets have been shown to promote IPA, we aimed to decipher fiber-specific effects and identify associated IPA-producing taxa in a range of healthy individuals. We cultured fecal microbiota from 16 adults with tryptophan and eight different dietary fibers and monitored community shifts by 16S rRNA gene amplicon sequencing and tryptophan-derived indoles using targeted liquid chromatography with diode array detection. The concentrations and types of indoles produced were donor-specific, with pectin strongly promoting IPA production in certain donors. IPA production was not associated with any known IPA producer but with the pectin-utilizing species <i>Lachnospira eligens</i>, which produced indole-3-lactate (ILA) <i>in vitro</i>, the IPA precursor. Supplementation of ILA in additional fecal microbiota cultures (<i>n</i> = 6) revealed its effective use as a substrate for IPA production. We identified a novel IPA producer, <i>Enterocloster aldenensis</i>, which produced IPA exclusively from ILA but not from tryptophan. Co-culture of <i>L. eligens</i> and <i>E. aldenensis</i> resulted in IPA production, providing new evidence for an ILA cross-feeding mechanism that may contribute to the IPA-promoting effects observed with pectin. Overall, we highlight the potential for targeted dietary interventions to promote beneficial gut taxa and metabolites.