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Gut bacterial metallophores in the development and severity of inflammatory bowel disease

Award Number: R01DK131990
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Gut bacterial metallophores in the development and severity of inflammatory bowel disease - Zinc (Zn) deficiency has emerged as a growing public health problem. In fact, an estimated 17% of the global population is deficient. Animal studies have demonstrated that even marginal zinc deprivation leads to significantly impairs physiological functions. This is especially true in the gut where zinc is required to maintain intestinal homeostasis. Zn deficiency-mediated loss of intestinal homeostasis and microbial dysbiosis have recently been proposed as major mechanistic pathways for the development and severity of inflammatory bowel disease (IBD). Specifically, Zn deficiency is common in patients with IBD with a prevalence ranging from 15% to 40%, likely due to diet deficits and increased intestinal loss. In addition, a common genetic variant of the Zn transporter ZIP8 (rs13107325; A391T) has been associated with an increased risk of Crohn’s disease. In the context of gastrointestinal health, it is also notable that zinc is also an essential nutrient for bacteria. As such, commensals must compete for and scavenge zinc from their host, which likely further effects the host’s ability to acquire adequate levels of zinc. Bacteria utilize numerous strategies to acquire metal, such as the secretion of small molecules known as metallophores (i.e., siderophores and zincophores). Overgrowth of pathobionts, which express high levels of metallophores, is hypothesized to be one mechanism by which the microbiota contributes to IBD pathogenesis. In this application, we propose a new paradigm in which bacterial metallophore production is a key mechanistic pathway leading to accelerated IBD disease severity/inflammation. Specifically, we hypothesize that IBD disease status is associated with a unique subset of microbial metallophores and further hypothesize that IBD-associated metallophores exacerbate disease severity. Four key findings support this hypothesis: First, humans with the A391T allele have and increased prevalence of IBD and have significantly altered intestinal microbial communities. Second, Zip8 393T-KI mice have increased susceptibility to chemically induced colitis. Third, microbial metallophores are associated with the development of adherent-invasive Escherichia coli (AIEC)-mediated colitis. Fourth, a novel class of zinc transporters (zincophores) are produced by a wide-range of known gastrointestinal bacterial species many of which are over-represented in IBD dysbiosis. To test our hypothesis that bacterial zincophore production is a key mechanistic pathway leading to increased IBD disease severity, we propose three research Aims: Aim 1 will establish cross-talk between host genetics, gut microbial composition, bacterial metallophores, and dietary Zn levels as a link to IBD severity. Aim 2 will determine and characterize the effects of bacterial metallophores on intestinal epithelial health. Aim 3 will seek to validate the association of bacterial metallophores with IBD disease using a well characterized IBD biobank.


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 = $587,908 )
2025	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/5/2025	NON-COMPETING CONTINUATION	$587,908
														Subtotal = $587,908

Issue Date FY: 2024 ( Subtotal = $632,070 )
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/20/2024	NON-COMPETING CONTINUATION	$39,505
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/5/2024	NON-COMPETING CONTINUATION	$592,565
														Subtotal = $632,070

Issue Date FY: 2023 ( Subtotal = $660,082 )
2023	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/14/2023	NON-COMPETING CONTINUATION	$660,082
														Subtotal = $660,082

Issue Date FY: 2022 ( Subtotal = $693,330 )
2022	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/27/2022	NEW	$693,330
														Subtotal = $693,330

Grand Total All Awards = $2,573,390

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Gut bacterial metallophores in the development and severity of inflammatory bowel disease

Award Number: R01DK131990

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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