Alcohol and Intestinal Inflammatory Response: The Role of Intestinal Microbiota

酒精和肠道炎症反应：肠道微生物群的作用

• 批准号: 9031011
• 负责人: Mashkoor A Choudhry
• 金额: $ 17.93万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-10 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9031011
• 关键词: Adult; Adverse effects; Affect; Alcohol abuse; Alcohol consumption; Alcoholic Intoxication; Alcoholic Liver Diseases; Alcoholism; Alcohols; American; Animals; Bacteria; Bacterial Translocation; Bacteroides fragilis; Burn injury; Cause of Death; Centers for Disease Control and Prevention (U.S.); Critical Illness; Disease; Dose; Economic Burden; Economics; Epithelial; Escherichia coli; Ethanol; Flare; Functional disorder; Funding Opportunities; Gastrointestinal Diseases; Goals; Gram-Negative Bacteria; Growth; Health; Health Care Costs; Health Resources; Homeostasis; Hospitalization; Host Defense; Hour; Immune; Impaired wound healing; Impairment; Infection; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Injury; Interleukin-18; Intestines; Klebsiella; Laboratories; Length of Stay; Lipopolysaccharides; Minor; National Institute on Alcohol Abuse and Alcoholism; Obesity; Organ; Outcome; Pathogenesis; Patients; Physicians; Play; Pre-Clinical Model; Predisposition; Probiotics; Production; Pseudomonas; Public Health; Reporting; Risk Factors; Role; Sepsis; Societies; Sodium Dextran Sulfate; Symptoms; Testing; Tight Junctions; Time; Tissues; Trauma; Traumatic injury; United States; Visit; alcohol exposure; associated symptom; body system; claudin-1 protein; cost; cytokine; disability; effective therapy; gastrointestinal epithelium; gut microbiota; health economics; human disease; immune function; injured; insight; intestinal epithelium; microbiota; mouse model; neglect; novel; novel therapeutic intervention; occludin; pathogen; response

 DESCRIPTION (provided by applicant): Alcohol remains a considerable health and economic burden to American society. The consumption of alcohol is well known for its deleterious effects on gut barrier function and is a potential trigger for inflammatory bowel disease (IBD) flare. According to a recent Center for Disease Control report, IBD is one of the five most prevalent gastrointestinal diseases in the United States, with annual overall health care cost of more than $1.7 billion. IBD alone results in more than 700,000 physician visits, 100,000 hospitalizations, and disability in 119,000 patients (http://www.cdc.gov/ibd/). Excessive production of inflammatory cytokines plays a critical role in the pathogenesis of IBD. Additionally, a recent study suggests that alcohol consumption worsens the symptoms of the disease, however, the mechanism by which alcohol contributes to IBD flares remains largely unexplored. Several lines of evidence suggest that alcohol consumption results in gut bacterial dysbiosis. Such changes in gut microbiota may perturb interactions between bacteria and the host leading to damage of the intestinal epithelium and leakiness, which may exacerbate the symptoms associated with IBD. Therefore, the overall goal of our proposed studies is to determine whether changes in gut bacteria following binge alcohol exposure play a role in altered gut epithelial barrier function, and how this influences intestinal inflammation in response to dextran sodium sulphate (DSS). DSS-induced intestinal inflammation is commonly used in preclinical model to study IBD pathogenesis. Our hypothesis is that binge ethanol intoxication combined with DSS treatment disrupts the normal microbiota resulting in Gram-negative bacterial accumulation within the intestine. This in turn perturbs the microbiota/gut epithelial interactions leading to heightened gut inflammation and exaggerated barrier disruption. The hypothesis will be tested in 2 Aims in a well-established mouse model of binge ethanol exposure and intestinal inflammation. Studies in AIM 1 will determine whether gut inflammation and mucosal damage/leakiness following ethanol intoxication and DSS treatment are related to alterations in gut microflora, and whether treatment with probiotics re-establishes gut microbiota and epithelial barrier integrity. The studies in AIM 2 will delineate the mechanism by which changes in gut bacteria influence epithelial barrier function following ethanol intoxication and DSS exposure. The findings from these studies will reveal a novel role for the gut microbiota in intestinal inflammation and altered intestinal epithelial barrier function following ethanol and DSS exposure, and may help in developing new therapeutic strategies to maintain the gut barrier integrity. Overall, these findings will have wider implications as intestinal barrier dysfunction is often implicated in multiple inflammatory conditions as well as in the pathogenesis associated with alcoholic liver disease and other organ dysfunction.