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Mechanisms that connect ecology to disease in a defined gut microbial community

Award Number: R01DK145694
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: 09/08/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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Mechanisms that connect ecology to disease in a defined gut microbial community - ABSTRACT Perturbations to the ecology of the gut microbiome contribute to a variety of diseases. In the best characterized examples, the pathophysiology is infectious (e.g., C. difficile infection) or immunologic (e.g., E. coli overgrowth in Crohn’s disease). Here, we focus on a third category: biochemical pathophysiology that results in disease. Perturbations to community metabolism are associated with disease, and strategies for reversing these metabolic ‘lesions’ hold promise. However, progress toward this goal is impeded by an incomplete understanding of (and difficulties in modeling) the mechanisms that connect ecology to metabolism. This proposal has two broad goals: to learn more about connections between ecology and metabolism, and to use this knowledge to model and treat disease. In Aim 1, we will construct and metabolically profile a panel of 50 single-strain dropout communities in gnotobiotic mice. We will validate the composition of these dropout communities and use them to colonize germ-free mice; perform deep metagenomic sequencing and high-resolution read analysis to profile the effects of single- and multi-strain dropout on community composition; and analyze feces, urine, and plasma using a microbiome- targeted metabolomics panel to profile the effects of single- and multi-strain dropout on the metabolic output of the gut community. In Aim 2, we will characterize the impact of strain removal and addition on disorders of bile acid metabolism. We will use single and multi-strain dropouts to explore the role of 7a-dehydroxylation and bile salt hydrolase deficiency on IBS-D; use strain dropouts and loss- and gain-of-function mutants to model the effect of ecology on the size and composition of the secondary bile acid pool; and construct candidate therapeutic communities designed to correct lesions in bile acid metabolism and model them using transplantation experiments in gnotobiotic mice. In Aim 3, we will characterize the hydrogenotroph compartment (the strains that consume hydrogen) and its relevance to IBS with bloating. We will use strain dropouts to explore the role of acetogens and sulfate-reducing bacteria in IBS-associated bloating, and construct candidate therapeutic communities designed to correct lesions in hydrogen consumption and model them using transplantation experiments in gnotobiotic mice.


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: 2026 ( Subtotal = $769,846 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/4/2026	NEW	$769,846
														Subtotal = $769,846

Grand Total All Awards = $769,846

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Mechanisms that connect ecology to disease in a defined gut microbial community

Award Number: R01DK145694

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: 09/08/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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