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The alcohol dehydrogenase 1B (ADH1B) gene plays a crucial role in alcohol catabolism, where rs1229984 variant carriers (CT\/TT) catabolize ethanol at an 80-fold faster rate than non-carriers (CC). This study investigates the relationships between ADH1B gene rs1229984 mutation, alcohol consumption, gut microbiota, and insulin resistance. Methods: We performed cross-sectional analysis on fecal metagenomic sequencing data from diabetes-free participants in a longitudinal cohort of the Hispanic Community Health Study\/Study of Latinos. We used Analysis of Composition of Microbiomes to identify gut microbial species associated with alcohol consumption in non-carriers (n = 1399) and carriers (n = 193). We constructed genotype-specific gut microbiome scores (GMSs) based on the identified species associated with alcohol consumption to examine how gut microbiota may influence the relationship between alcohol consumption and insulin resistance across ADH1B genotypes. Insulin resistance was defined as Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) &gt; 2.5. Results: Distinct microbial species associated with alcohol consumption were identified in non-carriers (54 species) and carriers (16 species). In non-carriers, the genotype-specific GMS modified the relationship between alcohol consumption and insulin resistance (Pinteraction = 0.011). The odds ratios (OR) for insulin resistance with increasing alcohol consumption levels across low, moderate, and high tertiles of GMS were 0.75 (95%CI 0.58\u20130.96), 0.82 (0.67\u20131), and 1.13 (0.93\u20131.39), respectively. We identified that individual alcohol-related species, such as Prevotella copri, Ruminococcus callidus, and Erysipelatoclostridium ramosum, modified the relationship between alcohol consumption and insulin resistance in non-carriers. Conclusions: This study suggests that the ADH1B gene rs1229984 mutation is associated with gut microbiota profiles altered by alcohol consumption. Our findings also suggest a potential role of gut microbiota in the protective association between alcohol consumption and insulin resistance in the ADH1B variant non-carriers.<\/jats:p>","DOI":"10.3390\/nu17162669","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T15:34:53Z","timestamp":1755531293000},"page":"2669","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Interplays of ADH1B Genotype, Alcohol Consumption, and Gut Microbiota in Relation to Insulin Resistance"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1144-9594","authenticated-orcid":false,"given":"Brian","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brandilyn A.","family":"Peters-Samuelson","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Cordero","sequence":"additional","affiliation":[{"name":"Department of Psychology, University of Miami, Miami, FL 33124, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2906-0261","authenticated-orcid":false,"given":"Krista M.","family":"Perreira","sequence":"additional","affiliation":[{"name":"Department of Social Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amber","family":"Pirzada","sequence":"additional","affiliation":[{"name":"Institute for Minority Health Research, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martha L.","family":"Daviglus","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicine and Population Health, NYU Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert C.","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert D.","family":"Burk","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qibin","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/nature05488","article-title":"Abdominal obesity and metabolic syndrome","volume":"444","author":"Despres","year":"2006","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1001\/jama.2021.9883","article-title":"Trends in prevalence of diabetes and control of risk factors in diabetes among US adults, 1999\u20132018","volume":"326","author":"Wang","year":"2021","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1016\/S0140-6736(17)30058-2","article-title":"Type 2 diabetes","volume":"389","author":"Chatterjee","year":"2017","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nrendo.2014.29","article-title":"Insulin resistance and hyperglycaemia in cardiovascular disease development","volume":"10","author":"Laakso","year":"2014","journal-title":"Nat. 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