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R01: FXR and the Gut Microbiome as Modulators of Non-Alcoholic Fatty Liver Disease

Award Number: U01DK119702
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is emerging as one of the most prevalent chronic liver diseases in the world, with non-alcoholic steatohepatitis (NASH) being an extreme form of NAFLD. Our team proposes to investigate the novel concept that intestine-selective FXR antagonism has the potential to prevent or reverse NAFLD/NASH. FXR is the major bile acid sensor in the body and serves to mediate the dialog between the liver and small intestine regarding bile acid levels, bile acid synthesis, transport, and enterohepatic circulation, and also regulates lipid and glucose levels in the liver. As such, FXR was identified in human trials as a promising target for the prevention and/or amelioration of many metabolic diseases, including NAFLD/NASH. We have recently established intestinal FXR as a major regulator of diet-induced obesity and NAFLD, particularly through antagonism of the receptor with the conjugated bile acid tauro-β-muricholic acid (TβMCA). We reported that tempol, a potent antioxidant, inhibited the FXR signaling pathway, due to accumulation of intestinal TβMCA, an antagonist of FXR, resulting from reduced activity of the Lactobacillus-associated bile salt hydroxylase enzyme. We further developed glycine-β-muricholic acid (GlyβMCA), a potent, intestine-selective FXR antagonist that similarly prevents or reversed NAFLD in diet-induced NAFLD models or genetic models, suggesting intestinal FXR as a promising therapeutic target for NAFLD. These observations have led to the novel central hypothesis: Antagonism of intestinal FXR prevents the development of NAFLD In this proposal we plan to address two fundamental gaps in knowledge with respect to FXR antagonism and NAFLD. First, we will identify using a combination of in vitro and in vivo approaches what chemical features define an FXR antagonist and develop a better understanding for how these modifications influence the absorption, distribution, metabolism, and excretion (ADME) of the antagonist and its pharmacodynamic properties. Second, through the innovative use of cutting-edge techniques—including 16S rRNA gene sequencing, metagenomics, metatranscriptomics, and metabolomics—and unique mouse models, we plan to identify how FXR signaling and the gut microbiota are linked in NAFLD pathogenesis. This combination of approaches will allow us to identify new therapeutic FXR antagonists and to accurately assess how these compounds influence downstream FXR signaling pathways with the ultimate goal of developing new NAFLD therapies.


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: 2024 ( Subtotal = $0 )
2024	2023	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/4/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $352,669 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/23/2023	NON-COMPETING CONTINUATION	$352,669
														Subtotal = $352,669

Issue Date FY: 2022 ( Subtotal = $24,369 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/26/2022	NON-COMPETING CONTINUATION	$24,369
														Subtotal = $24,369

Issue Date FY: 2021 ( Subtotal = $368,652 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	9/14/2021	NON-COMPETING CONTINUATION	$368,652
														Subtotal = $368,652

Issue Date FY: 2020 ( Subtotal = $368,652 )
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	8/4/2020	NON-COMPETING CONTINUATION	$368,652
2020	2019	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/1/2020	NEW	$0
														Subtotal = $368,652

Issue Date FY: 2019 ( Subtotal = $368,652 )
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/21/2019	NEW	$368,652
														Subtotal = $368,652

Grand Total All Awards = $1,482,994

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R01: FXR and the Gut Microbiome as Modulators of Non-Alcoholic Fatty Liver Disease

Award Number: U01DK119702

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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