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We sought to test the hypothesis that alcohol affects intestinal stem cells using an in\u00a0vivo model and ex\u00a0vivo organoids generated from jejunum and colon from mice fed chronic alcohol.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Mice were fed a control or an alcohol diet. Intestinal permeability, liver steatosis\u2013inflammation, and stool short\u2010chain fatty acids (<jats:styled-content style=\"fixed-case\">SCFA<\/jats:styled-content>s) were measured. Jejunum and colonic organoids and tissue were stained for stem cell, cell lineage, and apical junction markers with assessment of <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> by <jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\u2010seq. Ch<jats:styled-content style=\"fixed-case\">IP<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content> analysis was carried out for <jats:italic>Notch1<\/jats:italic> using an antibody specific for acetylated histone 3.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Alcohol\u2010fed mice exhibited colonic (but not small intestinal) hyperpermeability, steatohepatitis, and decreased butyrate\/total <jats:styled-content style=\"fixed-case\">SCFA<\/jats:styled-content> ratio in stool. Stem cell, cell lineage, and apical junction marker staining in tissue or organoids from jejunum tissue were not impacted by alcohol. Only chromogranin A (Chga) was increased in jejunum organoids by <jats:styled-content style=\"fixed-case\">qPCR<\/jats:styled-content>. However, colonic tissue and organoid staining exhibited an alcohol\u2010induced significant decrease in cytokeratin 20+\u00a0 (Krt20+) absorptive lineage enterocytes, a decrease in occludin and E\u2010cadherin apical junction proteins, an increase in Chga, and an increase in the Lgr5 stem cell marker. <jats:styled-content style=\"fixed-case\">qPCR<\/jats:styled-content> revealed an alcohol\u2010induced decrease in colonic organoid and tissue <jats:italic>Notch1<\/jats:italic>,<jats:italic> Hes1<\/jats:italic>, and <jats:italic>Krt20<\/jats:italic> and increased <jats:italic>Chga,<\/jats:italic> supporting an alteration in stem cell fate due to decreased <jats:italic>Notch1<\/jats:italic> expression. Colonic tissue Ch<jats:styled-content style=\"fixed-case\">IP<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content> revealed alcohol feeding suppressed <jats:italic>Notch1 <\/jats:italic><jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> expression (via deacetylation of histone H3) and decreased Notch1 tissue staining.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Data support a model for alcohol\u2010induced colonic hyperpermeability via epigenetic effects on <jats:italic>Notch1,<\/jats:italic> and thus <jats:italic>Hes1,<\/jats:italic> suppression through a mechanism involving histone H3 deacetylation at the <jats:italic>Notch1<\/jats:italic> locus. This decreased enterocyte and increased enteroendocrine cell colonic stem cell fate and decreased apical junctional proteins leading to hyperpermeability.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.13519","type":"journal-article","created":{"date-parts":[[2017,10,9]],"date-time":"2017-10-09T19:42:43Z","timestamp":1507578163000},"page":"2100-2113","source":"Crossref","is-referenced-by-count":34,"title":["Alcohol Feeding in Mice Promotes Colonic Hyperpermeability and Changes in Colonic Organoid Stem Cell Fate"],"prefix":"10.1111","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4690-7751","authenticated-orcid":false,"given":"Christopher B.","family":"Forsyth","sequence":"first","affiliation":[{"name":"Department of Internal Medicine Section\u00a0of Gastroenterology Rush University Medical Center Chicago Illinois"},{"name":"Department of Biochemistry Rush University Chicago 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