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Microbiome and Intestinal Innate Immune Response in Alcoholic Liver Disease

Award Number: R37AA020703
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/25/2011
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Microbiome and Intestinal Innate Immune Response in Alcoholic Liver Disease - Project Summary Alcohol abuse and alcohol-related diseases are a major medical burden in industrialized countries. Chronic alcoholism is associated with changes in the intestinal microbiota, increases in intestinal permeability, and elevated systemic levels of bacterial products. We demonstrated that Enterococcus faecalis (E. faecalis) is sufficient to cause mild steatotic liver disease and to exacerbate ethanol-induced liver disease in mice. We identified cytolysin, a two-subunit exotoxin secreted by E. faecalis, to cause hepatocyte death and liver injury. Compared with controls, patients with alcohol use disorder or alcoholic hepatitis have increased fecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with liver disease severity and mortality in patients with alcoholic hepatitis. How chronic alcohol use results in increased intestinal and hepatic numbers of cytolysin-positive E. faecalis is not known. Results from our laboratory suggest that increased intestinal numbers of E. faecalis are facilitated by changes in the intestinal glycocalyx and in particular by reduced (1,2)-fucosylation of glycoproteins on the apical membrane of intestinal epithelial cells. Alcohol- mediated suppression of Fucosyltransferase 2 (Fut2) allows intestinal colonization and bacterial translocation of E. faecalis. Furthermore, translocated E. faecalis is phagocytosed and eliminated by the complement receptor of the immunoglobulin superfamily (CRIg) on Kupffer cells. Patients with chronic alcoholic hepatitis have lower hepatic CRIg expression, which reduces E. faecalis elimination, prolongs exposure to E. faecalis and increases liver damage. Thus, ethanol associated changes in intestinal colonization and hepatic elimination of E. faecalis promotes alcohol-related liver disease. Our experimental approach is to use mouse models of ethanol feeding to investigate the role of Fut2 in limiting intestinal colonization of E. faecalis and reducing liver disease (Aim 1). We will also assess the functional contribution of the phagocytic protein CRIg to E. faecalis elimination and to liver disease (Aim 2). New strategies will be tested to prevent and ameliorate ethanol-induced liver disease in preclinical models. We believe these studies will provide novel insights into the contribution of the microbiota to alcohol-related liver disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $422,582 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	15	8/11/2025	NON-COMPETING CONTINUATION	$422,582
														Subtotal = $422,582

Issue Date FY: 2024 ( Subtotal = $422,582 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	14	6/21/2024	NON-COMPETING CONTINUATION	$422,582
														Subtotal = $422,582

Issue Date FY: 2023 ( Subtotal = $422,582 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	13	6/30/2023	NON-COMPETING CONTINUATION	$422,582
														Subtotal = $422,582

Issue Date FY: 2022 ( Subtotal = $424,655 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	001	12	7/1/2022	NON-COMPETING CONTINUATION	$422,582
2022	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	11	11/17/2021	COMPETING CONTINUATION	$2,073
														Subtotal = $424,655

Issue Date FY: 2021 ( Subtotal = $422,583 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	11	7/21/2021	COMPETING CONTINUATION	$422,583
														Subtotal = $422,583

Grand Total All Awards = $2,114,984

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Microbiome and Intestinal Innate Immune Response in Alcoholic Liver Disease

Award Number: R37AA020703

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/25/2011

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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