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As the interface between the self and the gut microbiota, IECs serve as hubs of bidirectional cross-talk between host and luminal microbiota. However, the role of mitochondrial-microbiota interaction in the ileum is largely unexplored. Prohibitin 1 (PHB1), a chaperone protein of the inner mitochondrial membrane required for optimal electron transport chain function, is decreased during IBD. We previously demonstrated that mice deficient in PHB1 specifically in IECs (\n                      <jats:italic>Phb1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>i\u2206IEC<\/jats:italic>\n                      <\/jats:sup>\n                      ) exhibited mitochondrial impairment, Paneth cell defects, gut microbiota dysbiosis, and spontaneous inflammation in the ileum (ileitis). Mice deficient in PHB1 in Paneth cells (epithelial secretory cells of the small intestine;\n                      <jats:italic>Phb1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2206PC<\/jats:italic>\n                      <\/jats:sup>\n                      ) also exhibited mitochondrial impairment, Paneth cell defects, and spontaneous ileitis. Here, we determined whether this phenotype is driven by\n                      <jats:italic>Phb1<\/jats:italic>\n                      deficiency-associated ileal microbiota alterations or direct effects of loss of PHB1 in host IECs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Depletion of gut microbiota by broad-spectrum antibiotic treatment in\n                      <jats:italic>Phb1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2206PC<\/jats:italic>\n                      <\/jats:sup>\n                      or\n                      <jats:italic>Phb1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>i\u2206IEC<\/jats:italic>\n                      <\/jats:sup>\n                      mice revealed a necessary role of microbiota to cause ileitis. Using germ-free mice colonized with ileal microbiota from\n                      <jats:italic>Phb1<\/jats:italic>\n                      -deficient mice, we show that this microbiota could not independently induce ileitis without host mitochondrial dysfunction. The luminal microbiota phenotype of\n                      <jats:italic>Phb1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>i\u2206IEC<\/jats:italic>\n                      <\/jats:sup>\n                      mice included a loss of the short-chain fatty acid butyrate. Supplementation of butyrate in\n                      <jats:italic>Phb1-<\/jats:italic>\n                      deficient mice ameliorated Paneth cell abnormalities and ileitis.\n                      <jats:italic>Phb1<\/jats:italic>\n                      -deficient ileal enteroid models suggest deleterious epithelial-intrinsic responses to ileal microbiota that were protected by butyrate.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results suggest a mutual and essential reinforcing interplay of gut microbiota and host IEC, including Paneth cell, mitochondrial health in influencing ileitis. Restoration of butyrate is a potential therapeutic option in Crohn\u2019s disease patients harboring epithelial cell mitochondrial dysfunction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40168-023-01686-9","type":"journal-article","created":{"date-parts":[[2023,11,17]],"date-time":"2023-11-17T01:05:47Z","timestamp":1700183147000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Interplay of gut microbiota and host epithelial mitochondrial dysfunction is necessary for the development of spontaneous intestinal inflammation in mice"],"prefix":"10.1186","volume":"11","author":[{"given":"Kibrom M.","family":"Alula","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander S.","family":"Dowdell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany","family":"LeBere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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