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How gut microbial tryptophan metabolism is directed towards indole, associated with chronic kidney disease, or towards protective indolelactic acid (ILA) and indolepropionic acid (IPA) is unclear. Here we used in vitro culturing and animal experiments to assess gut microbial competition for tryptophan and the resulting metabolites in a controlled three-species defined community and in complex undefined human faecal communities. The generation of specific tryptophan-derived metabolites was not predominantly determined by the abundance of tryptophan-metabolizing bacteria, but rather by substrate-dependent regulation of specific metabolic pathways. Indole-producing <jats:italic>Escherichia coli<\/jats:italic> and ILA- and IPA-producing <jats:italic>Clostridium sporogenes<\/jats:italic> competed for tryptophan within the three-species community in vitro and in vivo. Importantly, fibre-degrading <jats:italic>Bacteroides thetaiotaomicron<\/jats:italic> affected this competition by cross-feeding monosaccharides to <jats:italic>E. coli<\/jats:italic>. This inhibited indole production through catabolite repression, thus making more tryptophan available to <jats:italic>C. sporogenes<\/jats:italic>, resulting in increased ILA and IPA production. The fibre-dependent reduction in indole was confirmed using human faecal cultures and faecal-microbiota-transplanted gnotobiotic mice. Our findings explain why consumption of fermentable fibres suppresses indole production but promotes the generation of other tryptophan metabolites associated with health benefits.<\/jats:p>","DOI":"10.1038\/s41564-024-01737-3","type":"journal-article","created":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T10:07:29Z","timestamp":1719310049000},"page":"1964-1978","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":301,"title":["Dietary fibre directs microbial tryptophan metabolism via metabolic interactions in the gut microbiota"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6051-4930","authenticated-orcid":false,"given":"Anurag K.","family":"Sinha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6017-7121","authenticated-orcid":false,"given":"Martin F.","family":"Laursen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9057-1621","authenticated-orcid":false,"given":"Julius E.","family":"Brinck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten L.","family":"Rybtke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Pii","family":"Hj\u00f8rne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1071-2488","authenticated-orcid":false,"given":"Nicola","family":"Proch\u00e1zkov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikael","family":"Pedersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2504-8313","authenticated-orcid":false,"given":"Henrik M.","family":"Roager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6399-9574","authenticated-orcid":false,"given":"Tine R.","family":"Licht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,25]]},"reference":[{"key":"1737_CR1","doi-asserted-by":"publisher","first-page":"3294","DOI":"10.1038\/s41467-018-05470-4","volume":"9","author":"HM Roager","year":"2018","unstructured":"Roager, H. 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