Project Details
Description
Abstract
Defective intestinal epithelial tight junction (TJ) barrier has been postulated to play an important pathogenic
role in a wide variety of inflammatory conditions, including alcoholic liver disease. Our preliminary studies
suggest that chronic alcohol consumption causes an increase in intestinal permeability and that the increase in
intestinal permeability is required for the development of liver disease. The overarching goals of this grant
application are to: a) investigate the pathogenic mechanisms that mediate alcohol consumption - associated
increase in intestinal permeability, b) delineate the causal linkage between defective intestinal TJ barrier and
development of liver inflammation, and c) investigate the therapeutic role of probiotic bacteria Lactobacillus
acidophilus (LA) in targeting the intestinal TJ barrier to prevent liver inflammation. The primary focus of the
grant proposal will be on the gut-liver axis interaction or on the role of defective intestinal TJ barrier in the
pathogenesis of liver inflammation and injury. Based on our compelling preliminary data, we advance a
paradigm-shifting hypothesis that gut-derived bacterial lipopolysaccharide (LPS) is an etiologic factor
responsible for the alcohol consumption-associated increase in intestinal permeability and the subsequent
development of liver disease. We also hypothesize that therapeutic targeting of intestinal TJ barrier is both
sufficient and effective strategy to prevent alcoholic liver disease. We also advance a novel hypothesis that LA
inhibits the alcohol consumption - associated increase in intestinal permeability and the subsequent
development of liver disease via a TLR2 signal transduction pathway suppression (not activation) of enterocyte
NF-KB p50/p65 and MLCK gene activation. Two specific aims are proposed to address the above hypotheses:
1) to determine the pathogenic role of defective intestinal TJ barrier in the development of liver disease and to
delineate the mechanisms that mediate the increase in intestinal TJ permeability and 2) to determine the
therapeutic efficacy of probiotic bacterial targeting of intestinal TJ barrier to prevent or treat liver disease and to
delineate the protective mechanisms involved. The successful completion of the proposed studies will provide
important new insight into the integral role gut-liver axis plays in the pathophysiology of alcohol-induced liver
injury and also provide crucial pre-clinical data needed to support future clinical studies.
Status | Finished |
---|---|
Effective start/end date | 3/18/19 → 12/31/23 |
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases: $474,402.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $490,284.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $425,625.00
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