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Protein fermentation by colonic microbiota may impair barrier function by increasing toxic metabolite production. We previously identified sex-by-protein interactions affecting the microbiota and its metabolites in vitro. Do sex-by-protein interactions in colonic protein fermentation lead to a sexually dimorphic response in gut barrier function in vivo? We hypothesised that high-protein diets would elicit sex-specific effects on microbiota and barrier function. Twenty sibling-matched male (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200910) and female (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200910) piglets were fed high-protein (28%) or standard-protein (SP; 18%) diets for four weeks. Bacterial populations were assessed using 16\u00a0S rRNA sequencing, urinary metabolites via SPME\/GC-MS, and gut barrier proteins via quantitative fluorescence immunohistology. High-protein diets increased bacteria-derived\n                    <jats:italic>p-<\/jats:italic>\n                    cresol and reduced E-cadherin and CD45\u2009+\u2009protein expression without altering microbiota composition. Females on high-protein diets had greater abundances of\n                    <jats:italic>Staphylococcus<\/jats:italic>\n                    and\n                    <jats:italic>Chryseobacterium<\/jats:italic>\n                    , elevated\n                    <jats:italic>p-<\/jats:italic>\n                    cresol, and reduced ZO-1 expression compared to males. High-protein diets appear to reduce barrier function and increase protein-associated toxic metabolite production in sexually dimorphic manners in pigs. If these results are replicated in humans, it indicates requirements for sex-specific nutritional strategies.\n                  <\/jats:p>","DOI":"10.1007\/s00394-025-03885-6","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T07:39:45Z","timestamp":1770881985000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["High-protein diets increase microbiota associated p-cresol production in the colon and reduce gut barrier function in a sex-dependent manner"],"prefix":"10.1007","volume":"65","author":[{"given":"Daniel","family":"James","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Batool","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Poveda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeynep","family":"Hayirli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chloe","family":"Callow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Munawar","family":"Abbas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Linden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Gibson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce A.","family":"Griffin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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