{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T23:41:57Z","timestamp":1789342917827,"version":"build-2803163510"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T00:00:00Z","timestamp":1753142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Alcohol is inextricably linked with intestinal microbiota as it was absorbed through gut. While mitochondrial aldehyde dehydrogenase 2 (ALDH2), as the major enzyme responsible for metabolizing toxic acetaldehyde to acetate, is important factor influencing alcohol metabolism. However, it is not yet known the relationship between <jats:italic>ALDH2<\/jats:italic> knockout (KO) and gut microbiota profiles in mice under chronic alcohol exposure. Therefore, this study aimed to investigate the effect of 5% v\/v alcohol exposure on the gut microbiota of <jats:italic>ALDH2<\/jats:italic> knockout (KO-5%) and wild-type (WT-5%) mice. At the end of 10-week experiment, KO-5% mice exhibited a higher serum acetaldehyde concentration and upregulated expression of pro-inflammatory cytokines in intestine tissue than WT-5% mice. Metagenomic results revealed that the KO-5% mice had a significant decrease in alpha diversities. Moreover, KO-5% mice exhibited gut microbiota dysbiosis with the characteristic of a higher abundance of phylum <jats:italic>Proteobacteria<\/jats:italic>, and genera <jats:italic>Stenotrophomonas<\/jats:italic> and <jats:italic>Ralstonia<\/jats:italic>, whereas the level of genera <jats:italic>Lactobacillus<\/jats:italic>, unclassfied <jats:italic>Bacilli<\/jats:italic>, and <jats:italic>Turicibacter<\/jats:italic> were decreased. Additionally, genera <jats:italic>Candidatus Arthromitus<\/jats:italic> and <jats:italic>Ralstonia<\/jats:italic> were the most representatives in the KO-5% mice. Further, chronic alcohol exposure resulted in enriched expression of genes associated with bacterial metabolism and cellular processes in gut from WT mice. Taken together, our findings demonstrated a strong interaction between <jats:italic>ALDH2<\/jats:italic> and the gut microbiota to response to alcohol exposure.<\/jats:p>","DOI":"10.3389\/fmicb.2025.1617673","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T05:30:56Z","timestamp":1753162256000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Host ALDH2 deficiency aggravates acetaldehyde metabolism disturbance and gut microbiota dysbiosis in chronic alcohol exposure mice"],"prefix":"10.3389","volume":"16","author":[{"given":"Xueqin","family":"Tan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beiyi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunzhu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuewen","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,22]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1201","DOI":"10.1016\/j.clinthera.2023.08.018","article-title":"Extrahepatic health effects of alcohol use and alcohol-associated liver disease","volume":"45","author":"Abbas","year":"2023","journal-title":"Clin. Ther."},{"key":"ref2","first-page":"17","article-title":"Drinking patterns and their definitions","volume":"39","year":"2018","journal-title":"Alcohol Res."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"e00191","DOI":"10.1128\/mSystems.00191-16","article-title":"Deblur rapidly resolves single-nucleotide community sequence patterns","volume":"2","author":"Amir","year":"2017","journal-title":"mSystems"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.cld.2018.09.011","article-title":"Epidemiology of alcohol consumption and societal burden of alcoholism and alcoholic liver disease","volume":"23","author":"Axley","year":"2019","journal-title":"Clin. Liver Dis."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1038\/s41587-019-0209-9","article-title":"Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2","volume":"37","author":"Bolyen","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1571","DOI":"10.3390\/nu15071571","article-title":"The influence of alcohol consumption on intestinal nutrient absorption: a comprehensive review","volume":"15","author":"Butts","year":"2023","journal-title":"Nutrients"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.immuni.2017.06.016","article-title":"Peroxisome-mediated metabolism is required for immune response to microbial infection","volume":"47","author":"Cara","year":"2017","journal-title":"Immunity"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1016\/j.cld.2012.08.002","article-title":"Alcohol metabolism","volume":"16","author":"Cederbaum","year":"2012","journal-title":"Clin. Liver Dis."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1152\/physrev.00017.2013","article-title":"Targeting aldehyde dehydrogenase 2: new therapeutic opportunities","volume":"94","author":"Chen","year":"2014","journal-title":"Physiol. Rev."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"102753","DOI":"10.1016\/j.ebiom.2020.102753","article-title":"Novel and prevalent non-east Asian ALDH2 variants; implications for global susceptibility to aldehydes' toxicity","volume":"55","author":"Chen","year":"2020","journal-title":"EBioMedicine"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/978-981-13-6260-6_3","article-title":"ALDH2 and cardiovascular disease","volume":"1193","author":"Chen","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"4067","DOI":"10.2147\/ijgm.S356761","article-title":"ALDH2 polymorphism rs671 *1\/*2 genotype is a risk factor for the development of alcoholic liver cirrhosis in Hakka alcoholics","volume":"15","author":"Chen","year":"2022","journal-title":"Int. J. Gene. Med."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"2313","DOI":"10.1111\/acer.12900","article-title":"Microbiota protects mice against acute alcohol-induced liver injury","volume":"39","author":"Chen","year":"2015","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1097\/FPC.0b013e32832ecf2e","article-title":"Pharmacokinetic and pharmacodynamic basis for overcoming acetaldehyde-induced adverse reaction in Asian alcoholics, heterozygous for the variant ALDH2*2 gene allele","volume":"19","author":"Chen","year":"2009","journal-title":"Pharmacogenet. Genomics"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1002\/hep.24423","article-title":"Characterization of fecal microbial communities in patients with liver cirrhosis","volume":"54","author":"Chen","year":"2011","journal-title":"Hepatology"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1080\/19490976.2016.1155022","article-title":"Elucidating the role of the host genome in shaping microbiome composition","volume":"7","author":"Davenport","year":"2016","journal-title":"Gut Microbes"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1038\/s41587-020-0548-6","article-title":"PICRUSt2 for prediction of metagenome functions","volume":"38","author":"Douglas","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref18","first-page":"5","article-title":"The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants","volume":"30","author":"Edenberg","year":"2007","journal-title":"Alcohol Res. Health"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/0306-4565(86)90035-5","article-title":"The gastrointestinal microbiome: alcohol effects on the composition of intestinal microbiota","volume":"37","author":"Engen","year":"2015","journal-title":"Alcohol Res."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1111\/j.1467-3010.2006.00588.x","article-title":"Alcohol consumption in the new millennium\u2013weighing up the risks and benefits for our health","volume":"31","author":"Foster","year":"2006","journal-title":"Nutr. Bull."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1146\/annurev-genet-110711-155532","article-title":"The relationship between the human genome and microbiome comes into view","volume":"51","author":"Goodrich","year":"2017","journal-title":"Annu. Rev. Genet."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.nutres.2020.09.004","article-title":"Alcohol use alters the colonic mucosa-associated gut microbiota in humans","volume":"83","author":"Gurwara","year":"2020","journal-title":"Nutr. Res."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1959","DOI":"10.1097\/01.alc.0000187161.07820.21","article-title":"Aldehyde dehydrogenase 2 gene targeting mouse lacking enzyme activity shows high acetaldehyde level in blood, brain, and liver after ethanol gavages","volume":"29","author":"Isse","year":"2005","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1960","DOI":"10.1056\/NEJMc2002496","article-title":"Drug-resistant bacteremia after fecal microbiota transplant","volume":"382","author":"Janket","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1875","DOI":"10.3390\/nu13061875","article-title":"Regulation of alcohol and acetaldehyde metabolism by a mixture of Lactobacillus and Bifidobacterium species in human","volume":"13","author":"Jung","year":"2021","journal-title":"Nutrients"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"869250","DOI":"10.3389\/fmicb.2022.869250","article-title":"Probiotic lactobacilli ameliorate alcohol-induced hepatic damage via gut microbial alteration","volume":"13","author":"Kim","year":"2022","journal-title":"Front. Microbiol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1002\/hep.27036","article-title":"Aldehyde dehydrogenase 2 deficiency ameliorates alcoholic fatty liver but worsens liver inflammation and fibrosis in mice","volume":"60","author":"Kwon","year":"2014","journal-title":"Hepatology"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"108238","DOI":"10.1016\/j.celrep.2020.108238","article-title":"Gut microbiota-induced changes in \u03b2-Hydroxybutyrate metabolism are linked to altered sociability and depression in alcohol use disorder","volume":"33","author":"Leclercq","year":"2020","journal-title":"Cell Rep."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"108800","DOI":"10.1016\/j.foodres.2019.108800","article-title":"Alteration of gut microbiota composition by short-term low-dose alcohol intake is restored by fermented rice liquor in mice","volume":"128","author":"Lee","year":"2020","journal-title":"Food Res. Int."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"106902","DOI":"10.1016\/j.phrs.2023.106902","article-title":"Host ALDH2 deficiency aggravates nonalcoholic steatohepatitis through gut-liver axis","volume":"196","author":"Li","year":"2023","journal-title":"Pharmacol. Res."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1186\/s12944-022-01699-7","article-title":"Alcohol-dependent downregulation of apolipoprotein H exacerbates fatty liver and gut microbiota dysbiosis in mice","volume":"21","author":"Liu","year":"2022","journal-title":"Lipids Health Dis."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1016\/j.yjmcc.2010.03.017","article-title":"Aldehyde dehydrogenase 2 knockout accentuates ethanol-induced cardiac depression: role of protein phosphatases","volume":"49","author":"Ma","year":"2010","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1038\/s41579-021-00562-3","article-title":"Host specificity of the gut microbiome","volume":"19","author":"Mallott","year":"2021","journal-title":"Nat. Rev. Microbiol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"4630","DOI":"10.1038\/s41467-022-31973-2","article-title":"Acetate reprograms gut microbiota during alcohol consumption","volume":"13","author":"Martino","year":"2022","journal-title":"Nat. Commun."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"193","DOI":"10.3389\/fphys.2012.00193","article-title":"Acute alcohol-induced liver injury","volume":"3","author":"Massey","year":"2012","journal-title":"Front. Physiol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1883","DOI":"10.1111\/acer.12462","article-title":"Ethanol reduces lifespan, body weight, and serum alanine aminotransferase level of aldehyde dehydrogenase 2 knockout mouse","volume":"38","author":"Matsumoto","year":"2014","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.alcohol.2022.08.011","article-title":"Changes in gut microbiome correlate with intestinal barrier dysfunction and inflammation following a 3-day ethanol exposure in aged mice","volume":"107","author":"McMahan","year":"2023","journal-title":"Alcohol"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1046\/j.1365-2036.1997.00238.x","article-title":"Use of measurements of ethanol absorption from stomach and intestine to assess human ethanol metabolism","volume":"11","author":"Moreau","year":"1997","journal-title":"Am. J. Physiol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"G966","DOI":"10.1152\/ajpgi.00380.2011","article-title":"Colonic microbiome is altered in alcoholism","volume":"302","author":"Mutlu","year":"2012","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1111\/1751-2980.12375","article-title":"Alcoholic liver disease: focus on prodromal gut health","volume":"17","author":"Park","year":"2016","journal-title":"J. Dig. Dis."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.bbr.2017.01.049","article-title":"Drunk bugs: chronic vapour alcohol exposure induces marked changes in the gut microbiome in mice","volume":"323","author":"Peterson","year":"2017","journal-title":"Behav. Brain Res."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"e7","DOI":"10.1161\/CIR.0000000000001341","article-title":"Alcohol use and cardiovascular disease: a scientific statement from the American Heart Association","volume":"152","author":"Piano","year":"2025","journal-title":"Circulation"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/s41392-023-01577-3","article-title":"NAD+ exhaustion by CD38 upregulation contributes to blood pressure elevation and vascular damage in hypertension","volume":"8","author":"Qiu","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"D590","DOI":"10.1093\/nar\/gks1219","article-title":"The SILVA ribosomal RNA gene database project: improved data processing and web-based tools","volume":"41","author":"Quast","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"102577","DOI":"10.1016\/j.redox.2022.102577","article-title":"ALDH2 deficiency increases susceptibility to binge alcohol-induced gut leakiness, endotoxemia, and acute liver injury in mice through the gut-liver axis","volume":"59","author":"Rungratanawanich","year":"2023","journal-title":"Redox Biol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"R60","DOI":"10.1186\/gb-2011-12-6-r60","article-title":"Metagenomic biomarker discovery and explanation","volume":"12","author":"Segata","year":"2011","journal-title":"Genome Biol."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"e0005224","DOI":"10.1128\/msystems.00052-24","article-title":"Alcohol-induced gut microbiome dysbiosis enhances the colonization of Klebsiella pneumoniae on the mouse intestinal tract","volume":"9","author":"Shen","year":"2024","journal-title":"mSystems"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"430","DOI":"10.18433\/j3990v","article-title":"Moderate-dose regular lifelong alcohol intake changes the intestinal flora, protects against aging, and keeps spatial memory in the senescence-accelerated mouse prone 8 (SAMP8) model","volume":"19","author":"Shimizu","year":"2016","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"206","DOI":"10.3316\/informit.741870194405168","article-title":"The gut microbiome","volume":"46","author":"Sidhu","year":"2017","journal-title":"Aust. Fam. Physician"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1111\/apt.13164","article-title":"Review article: alcohol and gut microbiota - the possible role of gut microbiota modulation in the treatment of alcoholic liver disease","volume":"41","author":"Vassallo","year":"2015","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"13","DOI":"10.15288\/jsa.2000.61.13","article-title":"Hangover symptoms in Asian Americans with variations in the aldehyde dehydrogenase (ALDH2) gene","volume":"61","author":"Wall","year":"2000","journal-title":"J. Stud. Alcohol"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1007\/s12031-024-02259-7","article-title":"Associations between gut microbiota and alcohol abuse: a Mendelian randomisation and bioinformatics study","volume":"74","author":"Wang","year":"2024","journal-title":"J. Mol. Neurosci."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.3390\/cells11081374","article-title":"Key signaling in alcohol-associated liver disease: the role of bile acids","volume":"11","author":"Way","year":"2022","journal-title":"Cells"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1186\/s40168-023-01681-0","article-title":"Gut microbiota-related metabolite alpha-linolenic acid mitigates intestinal inflammation induced by oral infection with toxoplasma gondii","volume":"11","author":"Yang","year":"2023","journal-title":"Microbiome"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1159\/000095013","article-title":"Overview: how is alcohol metabolized by the body?","volume":"29","author":"Zakhari","year":"2006","journal-title":"Alcohol Res. Health"}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2025.1617673\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T05:30:57Z","timestamp":1753162257000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2025.1617673\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,22]]},"references-count":55,"alternative-id":["10.3389\/fmicb.2025.1617673"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2025.1617673","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,22]]},"article-number":"1617673"}}