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Intestinal Biotin Absorption: Physiological and Pathophysiological Aspects

Award Number: R01DK058057
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2000
PERIOD OF PERFORMANCE END DATE: 07/31/2022

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Intestinal Biotin Absorption: Physiological and Pathophysiological Aspects - DESCRIPTION (provided by applicant): The long-term objectives of this renewal application continue to focus on investigating the molecular physiology of the intestinal absorption process of the water- soluble vitamin biotin, the transport system involved, i.e., the Sodium-dependent Multi- Vitamin Transporter (SMVT), and how the absorption process is affected by external/environmental factors and pathophysiological conditions. Biotin is indispensable for normal cellular metabolism, proliferation and survival. The vitamin acts as a co-factor for multiple carboxylases that play critical roles in fatty acid, glucose and amino acid metabolism. Emerging evidence also highlight an important roles for biotin in immune function and in gene expression. Humans and other mammals cannot synthesize biotin, and thus, must obtain the vitamin from exogenous sources via intestinal absorption. Intestinal absorption of biotin occurs via a Na+-dependent and regulated carrier-mediated process. In studies performed during the current funding period, we have generated a conditional (intestine-specific) SMVT- knockout (KO) mouse model to establish the relative contribution of SMVT toward intestinal carrier-mediated biotin absorption and obtained evidence that this system is the only biotin uptake system that operates in the gut. Unexpectedly, however, we came across a very interesting phenomenon in that all the SMVT KO mice developed spontaneous chronic intestinal inflammation, especially in the cecum. In other studies, we found that chronic alcohol exposure significantly inhibit intestinal biotin uptake and that the inhibition is mediated at the level of transcription of the SLC5A6 gene (the gene that encodes SMVT); our new preliminary findings suggest that the latter is, at least in part, mediated via epigenetic mechanism(s). In other new preliminary studies, we found that infecting mice with S. Typhimurium, and exposure to pro-inflammatory cytokines or to bacterial LPS to lead to a significant inhibition in intestinal biotin uptake. Based on our recently published observations and our new preliminary findings, our working hypotheses in this proposal are that the SMVT system is important for the maintenance of normal intestinal immunity and integrity, and that Salmonella infection, as well as exposure of the gut to pro-inflammatory cytokines or to bacterial LPS lead to a significant inhibition in intestinal biotin uptake. We also hypothesize that the inhibition in SLC5A6 transcription by chronic alcohol exposure is mediated, at least in part, via epigenetic mechanism(s). Three specific aims are proposed to test these hypotheses and will utilize state-of-the-art in vitro and n vivo physiological, cellular and molecular approaches. Results of these investigations should provide novel and valuable information regarding the role of SMVT in the maintenance of normal intestinal homeostasis and health, and on how infection with enteric pathogens (Salmonella), as well as exposure to pro-inflammatory cytokines (as in IBD), and to bacterial LPS (as in infection with gram negative bacteria) affect the absorption of the indispensable micronutrient biotin. The results should also shed further light onto how chronic exposure to alcohol (the most common and costly drug abuse, and a significant contributor to many disease categories) affect the normal physiology of intestinal biotin absorption.


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: 2023 ( Subtotal = $0 )
2023	2019	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	3/9/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	5/26/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $630,292 )
2019	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	5/29/2019	NON-COMPETING CONTINUATION	$630,292
														Subtotal = $630,292

Issue Date FY: 2018 ( Subtotal = $724,547 )
2018	2018	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	20	5/15/2018	NON-COMPETING CONTINUATION	$630,292
2018	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	19	3/20/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$613,622
2018	2017	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	3/19/2018	NON-COMPETING CONTINUATION	-$519,367
2018	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	19	5/5/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2018	2016	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	17	5/2/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $724,547

Issue Date FY: 2017 ( Subtotal = $519,367 )
2017	2017	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	9/12/2017	NON-COMPETING CONTINUATION	$519,367
														Subtotal = $519,367

Issue Date FY: 2016 ( Subtotal = $519,367 )
2016	2016	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	7/29/2016	NON-COMPETING CONTINUATION	$519,367
														Subtotal = $519,367

Issue Date FY: 2015 ( Subtotal = $558,110 )
2015	2015	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	3/24/2015	COMPETING CONTINUATION	$558,110
														Subtotal = $558,110

Issue Date FY: 2014 ( Subtotal = $277,769 )
2014	2014	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	7/17/2014	NON-COMPETING CONTINUATION	$277,769
														Subtotal = $277,769

Issue Date FY: 2013 ( Subtotal = $268,048 )
2013	2013	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	8/6/2013	NON-COMPETING CONTINUATION	$268,048
														Subtotal = $268,048

Issue Date FY: 2012 ( Subtotal = $277,769 )
2012	2012	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	7/27/2012	NON-COMPETING CONTINUATION	$277,769
														Subtotal = $277,769

Issue Date FY: 2011 ( Subtotal = $277,769 )
2011	2011	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	7/25/2011	NON-COMPETING CONTINUATION	$277,769
														Subtotal = $277,769

Issue Date FY: 2010 ( Subtotal = $301,574 )
2010	2010	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	7/5/2010	COMPETING CONTINUATION	$301,574
														Subtotal = $301,574

Issue Date FY: 2009 ( Subtotal = $271,649 )
2009	2009	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	7/22/2009	NON-COMPETING CONTINUATION	$271,649
														Subtotal = $271,649

Issue Date FY: 2008 ( Subtotal = $271,649 )
2008	2008	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Digestive Diseases and Nutrition Research	000	9	7/10/2008	NON-COMPETING CONTINUATION	$271,649
														Subtotal = $271,649

Issue Date FY: 2007 ( Subtotal = $277,192 )
2007	2007	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Digestive Diseases and Nutrition Research	000	8	7/16/2007	NON-COMPETING CONTINUATION	$277,192
														Subtotal = $277,192

Issue Date FY: 2006 ( Subtotal = $285,471 )
2006	2006	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Digestive Diseases and Nutrition Research	000	7	7/18/2006	NON-COMPETING CONTINUATION	$285,471
														Subtotal = $285,471

Issue Date FY: 2005 ( Subtotal = $287,294 )
2005	2005	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	5901 EAST SEVENTH STREET	LONG BEACH	CA	90822	LOS ANGELES	USA	Digestive Diseases and Nutrition Research	000	6	9/26/2005	COMPETING CONTINUATION	$287,294
														Subtotal = $287,294

Issue Date FY: 2004 ( Subtotal = $201,733 )
2004	2004	UNIVERSITY OF CALIFORNIA, IRVINE							Digestive Diseases and Nutrition Research	000	5	8/2/2004	NON-COMPETING CONTINUATION	$201,733
														Subtotal = $201,733

Issue Date FY: 2003 ( Subtotal = $201,733 )
2003	2003	UNIVERSITY OF CALIFORNIA, IRVINE							Digestive Diseases and Nutrition Research	000	4	9/4/2003	NON-COMPETING CONTINUATION	$201,733
														Subtotal = $201,733

Issue Date FY: 2002 ( Subtotal = $201,733 )
2002	2002	UNIVERSITY OF CALIFORNIA, IRVINE	UC IRVINE	IRVINE	CA	92717		USA	Digestive Diseases and Nutrition Research	000	3	8/2/2002	NON-COMPETING CONTINUATION	$201,733
														Subtotal = $201,733

Issue Date FY: 2001 ( Subtotal = $201,733 )
2001	2001	UNIVERSITY OF CALIFORNIA, IRVINE	UC IRVINE	IRVINE	CA	92717		USA	Digestive Diseases and Nutrition Research	000	2	8/31/2001	NON-COMPETING CONTINUATION	$201,733
														Subtotal = $201,733

Issue Date FY: 2000 ( Subtotal = $195,408 )
2000	2000	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Digestive Diseases and Nutrition Research	000	1	9/11/2000	NEW	$195,408
														Subtotal = $195,408

Grand Total All Awards = $6,750,207

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Intestinal Biotin Absorption: Physiological and Pathophysiological Aspects

Award Number: R01DK058057

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2000

PERIOD OF PERFORMANCE END DATE: 07/31/2022

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