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Rifaximin is a pregnane X receptor (PXR) agonist with low systemic and high intestinal bioavailability. The mechanisms by which it alleviates HE are unclear. We used human small intestinal (hSI) organoids to study whether rifaximin, via PXR activation, affects the epithelial biotransformation machinery, and to gain understanding of its low systemic availability.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We generated PXR knockdown hSI organoids via lentiviral delivery of short hairpin RNAs. Organoids were cultured for 24\u2009h with rifaximin or rifampicin. RNA\u2010sequencing and metabolomics were performed to analyse gene expression and amino acid metabolism. Luminal rifaximin was quantified by photospectrometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Treatment of wild\u2010type hSI organoids with rifaximin resulted in &gt;twofold differential expression of 131 genes compared to DMSO. These effects were largely PXR independent and related to amino acid metabolism. Rifaximin decreased expression of glutaminase\u20102 and increased expression of asparagine synthetase and solute carrier 7A11, thereby increasing intracellular glutamine and asparagine concentrations, indicating active ammonia detoxification. Rifaximin was apically excreted into the lumen in an ATP binding cassette B1 (ABCB1)\u2010dependent manner.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Rifaximin\u2014after uptake into enterocytes\u2014stimulates intracellular nitrogen detoxification by PXR\u2010independent mechanisms. Active apical excretion of rifaximin by ABCB1 into the intestinal lumen explains its low systemic bioavailability. Our study implies that rifaximin, next to modulation of the microbiome, has direct effects on ammonia scavenging in the human small intestinal epithelium.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15491","type":"journal-article","created":{"date-parts":[[2022,12,4]],"date-time":"2022-12-04T09:08:25Z","timestamp":1670144905000},"page":"649-659","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Rifaximin stimulates nitrogen detoxification by <scp>PXR<\/scp>\u2010independent mechanisms in human small intestinal organoids"],"prefix":"10.1111","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8472-8549","authenticated-orcid":false,"given":"Koos","family":"de Wit","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Amsterdam UMC University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5114-7799","authenticated-orcid":false,"given":"Ulrich","family":"Beuers","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Amsterdam UMC University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6542-8695","authenticated-orcid":false,"given":"Anna","family":"Mukha","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine UMC Utrecht, Utrecht University  Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5970-4668","authenticated-orcid":false,"given":"Edwin C. 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