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Genomic and metabolomic foundations of human-microbial symbiosis in the gut

Award Number: R01DK030292
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: 01/01/1982
PERIOD OF PERFORMANCE END DATE: 01/31/2030

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Genomic and metabolomic foundations of human-microbial symbiosis in the gut - ABSTRACT Acute malnutrition (wasting) affects >45M children under the age of 5; two-thirds suffer from moderate acute malnutrition (MAM) while the remainder have severe acute malnutrition (SAM). Besides accounting for 21% of life-years lost among children younger than 5 years, undernutrition leads to long term growth impairments, immune and metabolic dysfunction, and altered CNS development. Current treatments have limited effectiveness. We found that MAM and SAM are associated with impaired gut microbial community development (microbiota immaturity). We then screened Bangladeshi complementary foods in gnotobiotic animals for their capacity to improve the fitness and expressed beneficial functions of key growth-promoting bacterial taxa underrepresented in the microbiota of children with malnutrition. This yielded a `microbiota- directed complementary food' formulation (MDCF-2) that in a randomized controlled clinical trial (RCT), repaired the microbiota of 12-18-month-old Bangladeshi children with MAM and accelerated weight gain/ameliorated stunting compared to an existing ready-to-use supplementary food (RUSF) that was 15% more calorically dense. The efficacy of MDCF-2 was confirmed in a second RCT. We identified metabolic pathways in metagenome-assembled genomes (MAGs) belonging to specific strains of Prevotella copri that are differentially expressed in response to MDCF-2 and positively associated with growth (weight-for-length Z score; WLZ); this differential expression was associated with the metabolism of specific glycan structures in MDCF-2 and with the magnitude of clinical response to treatment. Tests of MDCF-2 derivatives in which single ingredients were replaced by `glyco-equivalent' food staples, conducted in gnotobiotic mice harboring MAM- donor microbiota, followed by a pilot translational study in Bangladeshi children with MAM, further highlighted glycan structures targeting P. copri. We will use 2 specific aims to build on these findings. Aim1-Perform a pan-genome analysis to define features of P. copri MAGs positively associated with WLZ in our RCTs that are highly conserved in P. copri strains we culture from Bangladeshi children, and strains obtained from other countries. Combine in vitro growth assays, microbial RNA-Seq and mass spectrometry to test the effects of lead glycan structures obtainable at scale singly and in combination, on cultured P. copri strains with carbohydrate utilization machinery exemplifying the different strains documented in the pan-genome analysis. Results will identify strains/glycan combinations that approximate the MAG expression profiles observed in our RCTs and gnotobiotic models and refine selection of prebiotic candidates. Aim2-Use a gnotobiotic mouse model of intergenerational microbiota transmission to perform mechanistic studies (microbial RNA-Seq/host bulk and snRNA-Seq/microbial community and host targeted MS-based metabolomics) of the effects of prebiotic single or combination glycan leads from Aim1 on targeted P. copri strains and on host growth and expression of metabolic/signaling pathways in intestinal cell lineages distributed along the length of the gut.


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 = $817,317 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	40	1/19/2026	NON-COMPETING CONTINUATION	$817,317
														Subtotal = $817,317

Issue Date FY: 2025 ( Subtotal = $863,192 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	39	5/20/2025	COMPETING CONTINUATION	$108,606
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	39	1/21/2025	COMPETING CONTINUATION	$754,586
2025	2021	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	38	11/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $863,192

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	38	7/11/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $708,899 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	38	6/17/2021	NON-COMPETING CONTINUATION	$708,899
														Subtotal = $708,899

Issue Date FY: 2020 ( Subtotal = $705,658 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	37	7/11/2020	NON-COMPETING CONTINUATION	$705,658
														Subtotal = $705,658

Issue Date FY: 2019 ( Subtotal = $758,885 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	36	6/21/2019	NON-COMPETING CONTINUATION	$758,885
														Subtotal = $758,885

Issue Date FY: 2018 ( Subtotal = $779,524 )
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	35	6/28/2018	COMPETING CONTINUATION	$769,114
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	35	8/23/2018	COMPETING CONTINUATION	$10,410
														Subtotal = $779,524

Issue Date FY: 2005 ( Subtotal = $385,000 )
2005	2005	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Digestive Diseases and Nutrition Research	000	24	3/21/2005	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2004 ( Subtotal = $385,000 )
2004	2004	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Digestive Diseases and Nutrition Research	000	23	3/10/2004	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2003 ( Subtotal = $385,000 )
2003	2003	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Digestive Diseases and Nutrition Research	000	22		NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2002 ( Subtotal = $385,000 )
2002	2002	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Digestive Diseases and Nutrition Research	000	21	3/8/2002	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2001 ( Subtotal = $385,313 )
2001	2001	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Digestive Diseases and Nutrition Research	000	20	5/7/2001	COMPETING CONTINUATION	$385,313
														Subtotal = $385,313

Grand Total All Awards = $6,558,788

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Genomic and metabolomic foundations of human-microbial symbiosis in the gut

Award Number: R01DK030292

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: 01/01/1982

PERIOD OF PERFORMANCE END DATE: 01/31/2030

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