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While the mechanism behind this relationship is multifaceted, recent evidence suggests ethanol-induced changes to the gut microbiome impact the gut\u2013lung axis. To assess this, a chronic\u2013binge ethanol feeding mouse model was used to determine how ethanol altered the gut microbiome, small intestinal epithelial barrier, and immune responses, as well as neutrophil abundance and oxidative stress in the lungs, and how supporting gut health with tributyrin supplementation during chronic\u2013binge ethanol exposure affected these responses. We found that ethanol consumption altered gut bacterial taxa and metabolic processes, distorted small intestinal immune responses, and induced both bacteria and endotoxin translocation into the lymphatic and circulatory systems. These changes were associated with increased neutrophil (Ly6G) presence and markers of oxidative stress, lipocalin-2 and myeloperoxidase, in the lungs. Importantly, tributyrin supplementation during ethanol exposure rescued gut bacterial function (p &lt; 0.05), small intestinal barrier integrity, and immune responses, as well as reducing both Ly6G mRNA (p &lt; 0.05) and lipocalin-2 mRNA (p &lt; 0.01) in the lungs. These data suggest ethanol-associated disruption of gut homeostasis influenced the health of the lungs, and that therapeutics supporting gut health may also support lung health.<\/jats:p>","DOI":"10.3390\/antiox13040472","type":"journal-article","created":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T08:22:44Z","timestamp":1713342164000},"page":"472","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Tributyrin Supplementation Rescues Chronic\u2013Binge Ethanol-Induced Oxidative Stress in the Gut\u2013Lung Axis in Mice"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8381-7072","authenticated-orcid":false,"given":"Anthony","family":"Santilli","sequence":"first","affiliation":[{"name":"Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8667-8861","authenticated-orcid":false,"given":"David","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1937-7871","authenticated-orcid":false,"given":"Yingchun","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2407-769X","authenticated-orcid":false,"given":"Naseer","family":"Sangwan","sequence":"additional","affiliation":[{"name":"Microbial Sequencing & Analytics Resource (MSAAR) Facility, Shared Laboratory Resources (SLR), Lerner Research Institute, Cleveland, OH 44195, USA"},{"name":"Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA"},{"name":"Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5717-7099","authenticated-orcid":false,"given":"Gail A. 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