Long-term heavy alcohol drinking causes organ injury, and multiple lines of evidence support a critical role of the intestine in alcohol-induced pathogenesis. Alcohol disassembles intestinal tight junctions and increases gut permeability to macromolecules. Alcohol also causes dysbiosis, an increase in pathogenic bacteria and a decrease in commensal bacteria. Consequently, alcohol increases translocation of the pathogenic bacteria and/or bacteria products and induces inflammation in multiple organs, particularly in the liver. Therefore, intestine is a major site to generate systemic factors mediating alcohol-induced organ injury. Recent studies demonstrated that reduced expression of intestinal antimicrobial peptides (AMPs) accounts for the alcohol- induced pathogenic bacteria translocation and the development of hepatitis. However, the mechanisms of how alcohol abuse induces host-microbiota dyshomeostasis remain largely unknown. The intestinal innate immune system plays a crucial role in maintaining the symbiotic balance between the host and gut microbiota by restricting the growth of pathogenic bacteria. In the past granting period, we have shown that alcohol exposure causes accumulation of acetaldehyde (AcH) not only in the liver and plasma but also in the intestinal tissues and lumen contents. The intestinal AcH levels correlated with alcohol-induced gut permeability increase and enteric dysbiosis as well as endotoxemia and hepatic inflammation. Most importantly, we demonstrated that a- defensins and lysozyme produced from the intestinal Paneth cells were reduced by alcohol exposure in association with the development of enteric and hepatic dysbiosis and hepatitis. Our findings suggest that AcH- induced Paneth cell dysfunction may represent an important mechanism underlying alcohol-induced disorders at the gut-liver axis. Paneth cells at the bottom of the intestinal crypts are professional AMP-producing innate immune cells, and the role of Paneth cell dysfunction in alcohol-induced pathogenesis at the gut-liver axis has not been defined. This project aims to determine if Paneth cell dysfunction is a crucial factor in alcohol-induced intestinal overgrowth of pathogenic bacteria, gut permeability increase, bacteria/bacteria products translocation and hepatic inflammation.

Public Health Relevance

Host-microbiota dyshomeostasis plays critical role in initiation and progression of alcohol-induced systemic inflammation and organ injury. This project is to investigate the mechanisms of how alcohol abuse impairs intestinal mucosal immune function and induces dysbiosis in the development of alcoholic hepatitis. The goals of this project are to explore molecular targets for developing therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA020212-09
Application #
10117159
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Orosz, Andras
Project Start
2010-09-30
Project End
2023-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
9
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of North Carolina Greensboro
Department
Nutrition
Type
Sch Allied Health Professions
DUNS #
616152567
City
Greensboro
State
NC
Country
United States
Zip Code
27402
Zhang, Wenliang; Zhong, Wei; Sun, Qian et al. (2018) Adipose-specific lipin1 overexpression in mice protects against alcohol-induced liver injury. Sci Rep 8:408
Hao, Liuyi; Sun, Qian; Zhong, Wei et al. (2018) Mitochondria-targeted ubiquinone (MitoQ) enhances acetaldehyde clearance by reversing alcohol-induced posttranslational modification of aldehyde dehydrogenase 2: A molecular mechanism of protection against alcoholic liver disease. Redox Biol 14:626-636
Zhou, Zhanxiang; Zhong, Wei (2017) Targeting the gut barrier for the treatment of alcoholic liver disease. Liver Res 1:197-207
Sun, Qian; Zhang, Wenliang; Zhong, Wei et al. (2017) Pharmacological inhibition of NOX4 ameliorates alcohol-induced liver injury in mice through improving oxidative stress and mitochondrial function. Biochim Biophys Acta Gen Subj 1861:2912-2921
Sun, Qian; Zhong, Wei; Zhang, Wenliang et al. (2016) Defect of mitochondrial respiratory chain is a mechanism of ROS overproduction in a rat model of alcoholic liver disease: role of zinc deficiency. Am J Physiol Gastrointest Liver Physiol 310:G205-14
Sun, Qian; Zhang, Wenliang; Zhong, Wei et al. (2016) Dietary Fisetin Supplementation Protects Against Alcohol-Induced Liver Injury in Mice. Alcohol Clin Exp Res 40:2076-2084
Wang, Xiaoning; Xie, Guoxiang; Zhao, Aihua et al. (2016) Serum Bile Acids Are Associated with Pathological Progression of Hepatitis B-Induced Cirrhosis. J Proteome Res 15:1126-34
Zhang, Wenliang; Sun, Qian; Zhong, Wei et al. (2016) Hepatic Peroxisome Proliferator-Activated Receptor Gamma Signaling Contributes to Alcohol-Induced Hepatic Steatosis and Inflammation in Mice. Alcohol Clin Exp Res 40:988-99
Dong, Daoyin; Zhong, Wei; Sun, Qian et al. (2016) Oxidative products from alcohol metabolism differentially modulate pro-inflammatory cytokine expression in Kupffer cells and hepatocytes. Cytokine 85:109-19
Zhong, Wei; Li, Qiong; Sun, Qian et al. (2015) Preventing Gut Leakiness and Endotoxemia Contributes to the Protective Effect of Zinc on Alcohol-Induced Steatohepatitis in Rats. J Nutr 145:2690-8

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