{
  "abstract": "Background The effect of alcohol consumption on IBD remains inconclusive, potentially due to the overlooked role of alcohol metabolism.Objective We aimed to investigate the potential modifying role of alcohol metabolic capacity in the associations.Design A prospective cohort study (n=455 417) was used for association analysis between alcohol consumption and IBD risk using Cox proportional hazards regression. An acetaldehyde burden score, using genetic variants of alcohol dehydrogenase and aldehyde dehydrogenase validated by expression quantitative trait loci and proteomic data, was constructed to test effect modification. Genetic and metabolomic analyses, along with mice and human-derived colonic organoid experiments, were conducted to strengthen causal inference.Results The inverse association between alcohol and IBD risk was mainly attributable to red wine. Among individuals with low burden, reflecting low acetaldehyde generation and high acetaldehyde metabolism, per SD increase in red wine consumption (equivalent to 59.4 g/week of pure alcohol intake) was associated with a 20% (95% CI 7% to 31%) reduced Crohn’s disease risk, whereas a 38% (95% CI 13% to 70%) increased risk among those with high burden. Genetic and metabolomic analyses further revealed harmful effects of acetaldehyde and protective effects of acetate. In vivo and in vitro experiments further confirmed these effects and showed that modulation of aldehyde dehydrogenase activity significantly altered colitis outcomes.Conclusion Acetaldehyde metabolism burden modifies susceptibility to alcohol-related IBD and emphasises the importance of considering individual differences in alcohol metabolism when developing precision prevention strategies for IBD.",
  "authors": [
    {
      "affiliations": [
        "Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha, Hunan, China",
        "Xiangya School of Public Health, Central South University, Changsha, China",
        "Postdoctoral Station of Clinical Medicine, Third Xiangya Hospital of Central South University, Changsha, Hunan, China"
      ],
      "name": "Jie Chen"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha, Hunan, China"
      ],
      "name": "Yang Guo"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha, Hunan, China"
      ],
      "name": "Jia Hu"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha, Hunan, China",
        "Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China"
      ],
      "name": "Shuyu Ye"
    },
    {
      "affiliations": [
        "Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Jialu Yao"
    },
    {
      "affiliations": [
        "Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Center District, Israel",
        "Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel"
      ],
      "name": "Henit Yanai"
    },
    {
      "affiliations": [
        "Department of Medicine, Western University, London, Ontario, Canada"
      ],
      "name": "Vipul Jairath"
    },
    {
      "affiliations": [
        "University Hospital of Nancy, Department of Gastroenterology and Inserm NGERE U1256, University of Lorraine, Nancy, Grand Est, France"
      ],
      "name": "Laurent Peyrin-Biroulet"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha, Hunan, China",
        "Ruijin Hospital, Department of Gastroenterology, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China"
      ],
      "name": "Lintao Dan"
    },
    {
      "affiliations": [
        "Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Xue Li"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha, Hunan, China",
        "Xiangya School of Public Health, Central South University, Changsha, China"
      ],
      "name": "Xiaoyan Wang"
    },
    {
      "affiliations": [
        "CINTESIS@RISE Department, Faculdade de Medicina da Universidade do Porto, Porto, Porto District, Portugal"
      ],
      "name": "Fernando Magro"
    }
  ],
  "title": "Combined acetaldehyde metabolism burden modifies IBD susceptibility to alcohol consumption",
  "uid": "3a703645-6653-54c6-971a-9ecc38c11616"
}