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Publicly available databases show marked down-regulation of HMGCS2 in colonic tissues in Crohn's disease and ulcerative colitis. This led us to investigate the expression and function of this pathway in colon and its relevance to colonic inflammation in mice. Hmgcs2 is expressed in cecum and colon. As global deletion of Hmgcs2 showed significant postnatal mortality, we used a conditional knockout mouse with enzyme deletion restricted to intestinal tract. These mice had no postnatal mortality. Fasting blood ketones were lower in these mice, indicating contribution of colonic ketogenesis to circulating ketones. There was also evidence of gut barrier breakdown and increased susceptibility to experimental colitis with associated elevated levels of IL-6, IL-1\u03b2, and TNF-\u03b1 in circulation. Interestingly, many of these phenomena were mostly evident in male mice. Hmgcs2 expression in colon is controlled by colonic microbiota as evidenced from decreased expression in germ-free mice and antibiotic-treated conventional mice and from increased expression in a human colonic epithelial cell line upon treatment with aqueous extracts of cecal contents. Transcriptomic analysis of colonic epithelia from control mice and Hmgcs2-null mice indicated an essential role for colonic ketogenesis in the maintenance of optimal mitochondrial function, cholesterol homeostasis, and cell-cell tight-junction organization. These findings demonstrate a sex-dependent obligatory role for ketogenesis in protection against colonic inflammation in mice.<\/jats:p>","DOI":"10.1042\/bcj20230403","type":"journal-article","created":{"date-parts":[[2024,2,19]],"date-time":"2024-02-19T11:21:40Z","timestamp":1708341700000},"page":"295-312","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Colonic ketogenesis, a microbiota-regulated process, contributes to blood ketones and protects against colitis in mice"],"prefix":"10.1042","volume":"481","author":[{"given":"Kevin","family":"Bass","sequence":"first","affiliation":[{"name":"1Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9230-0144","authenticated-orcid":false,"given":"Sathish","family":"Sivaprakasam","sequence":"additional","affiliation":[{"name":"1Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunadharini","family":"Dharmalingam-Nandagopal","sequence":"additional","affiliation":[{"name":"1Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4202-1638","authenticated-orcid":false,"given":"Muthusamy","family":"Thangaraju","sequence":"additional","affiliation":[{"name":"2Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0799-6018","authenticated-orcid":false,"given":"Vadivel","family":"Ganapathy","sequence":"additional","affiliation":[{"name":"1Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2024,2,19]]},"reference":[{"key":"2024021911212042100_BCJ-2023-0403C1","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1016\/j.cmet.2016.12.022","article-title":"Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics","volume":"25","year":"2017","journal-title":"Cell Metab."},{"key":"2024021911212042100_BCJ-2023-0403C2","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1186\/s12916-021-02185-0","article-title":"Ketone bodies: from enemy to friend and guardian angel","volume":"19","year":"2021","journal-title":"BMC Med."},{"key":"2024021911212042100_BCJ-2023-0403C3","doi-asserted-by":"publisher","first-page":"788","DOI":"10.3390\/nu12030788","article-title":"Modulation of cellular biochemistry, epigenetics and metabolomics by ketone bodies. implications of the ketogenic diet in the physiology of the organism and pathological states","volume":"12","year":"2020","journal-title":"Nutrients"},{"key":"2024021911212042100_BCJ-2023-0403C4","doi-asserted-by":"publisher","first-page":"dgaa370","DOI":"10.1210\/clinem\/dgaa370","article-title":"Ketone body, 3-hydroxybutyrate: minor metabolite \u2013 major medical manifestations","volume":"105","year":"2020","journal-title":"J. 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