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However, the hydrophobic BA composition in these animals is associated with liver pathology. Although Cyp2c70-ablation has been shown to alter gut microbiome composition, the impact of gut bacteria on liver pathology in Cyp2c70\u2212\/\u2212 mice remains to be established. Therefore, we treated young-adult male and female wild-type (WT) and Cyp2c70\u2212\/\u2212 mice with antibiotics (AB) with broad specificity to deplete the gut microbiota and assessed the consequences on BA metabolism and liver pathology. Female Cyp2c70\u2212\/\u2212 mice did not tolerate AB treatment, necessitating premature termination of the experiment. Male Cyp2c70\u2212\/\u2212 mice did tolerate AB but showed markedly augmented liver pathology after 6 weeks of treatment. Dramatic downregulation of hepatic Cyp8b1 expression (\u221299%) caused a reduction in the proportions of 12\u03b1-hydroxylated BAs in the circulating BA pools of AB-treated male Cyp2c70\u2212\/\u2212 mice. Interestingly, the resulting increased BA hydrophobicity strongly correlated with various indicators of liver pathology. Moreover, genetic inactivation of Cyp8b1 in livers of male Cyp2c70\u2212\/\u2212 mice increased liver pathology, while addition of ursodeoxycholic acid to the diet prevented weight loss and liver pathology in AB-treated female Cyp2c70\u2212\/\u2212 mice. In conclusion, depletion of gut microbiota in Cyp2c70\u2212\/\u2212 mice aggravates liver pathology at least in part by increasing the hydrophobicity of the circulating BA pool. These findings highlight that the potential implications of AB administration to cholestatic patients should be evaluated in a systematic manner.<\/jats:p>","DOI":"10.1042\/cs20230812","type":"journal-article","created":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T15:47:33Z","timestamp":1698853653000},"page":"1637-1650","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Gut microbiota depletion aggravates bile acid-induced liver pathology in mice with a human-like bile acid composition"],"prefix":"10.1042","volume":"137","author":[{"given":"Esther","family":"Verkade","sequence":"first","affiliation":[{"name":"1Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqiang","family":"Shen","sequence":"additional","affiliation":[{"name":"1Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milaine\u00a0V.","family":"Hovingh","sequence":"additional","affiliation":[{"name":"1Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels\u00a0L.","family":"Mulder","sequence":"additional","affiliation":[{"name":"1Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krisztina","family":"de Bruyn","sequence":"additional","affiliation":[{"name":"2Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martijn","family":"Koehorst","sequence":"additional","affiliation":[{"name":"2Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilde\u00a0D.","family":"de Vries","sequence":"additional","affiliation":[{"name":"1Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent\u00a0W.","family":"Bloks","sequence":"additional","affiliation":[{"name":"1Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Folkert","family":"Kuipers","sequence":"additional","affiliation":[{"name":"1Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"},{"name":"3European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6759-3291","authenticated-orcid":false,"given":"Jan\u00a0Freark","family":"de Boer","sequence":"additional","affiliation":[{"name":"1Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"},{"name":"2Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2023,11,10]]},"reference":[{"key":"2023111011151196700_B1","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1038\/nrendo.2014.60","article-title":"Beyond intestinal soap-bile acids in metabolic control","volume":"10","author":"Kuipers","year":"2014","journal-title":"Nat. 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