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The modes and genomics of gut bacterial specificity to host species

Award Number: R35GM138284
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2030

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The modes and genomics of gut bacterial specificity to host species - Project Summary: Humans and other mammals harbor complex, host-species specific gut bacterial communities, disruption of which has been implicated in a variety of deleterious effects, including human diseases and disorders. Our prior work has shown that predominant gut bacterial strains diversified in parallel (co-diversified) with rodent and primate host species, indicating fidelity of strains to host species over millions of years. We and others have further shown through experiments in germ-free house mice that native gut bacterial strains from house mice outcompete non-native strains from other mouse species and that non-native gut strains stunt host immune and growth phenotypes relative to native strains. These results suggest co- adaptation among gut bacterial strains and host species, but the mechanisms underlying host-species specificity of the gut microbiota remain poorly understood. The proposed research is designed to uncover the fundamental processes and genomic factors that maintain host-species specific gut microbiota within host individuals and populations. Based on our preliminary data, we propose that host-species specificity of gut bacterial strains is mediated by combinations of host innate-immune components (Theme 1), bacteria-bacteria interactions (Theme 2), and host-mediated transmission (Theme 3). In Theme 1, we will test the contribution of host innate immunity to host-species specificity of the gut microbiota. We will conduct experiments in which we compete microbiota from a diverse panel of wild-derived mouse species within wildtype and immune gene- knockout germ-free representatives of the host species. Results will identify the host innate immune components (e.g., Toll-like receptors, antibacterial compounds) that promote the fitness of host-species specific gut bacterial strains. Moreover, population genetic analyses of metagenomic data from these experiments will reveal genomic bases of gut bacterial adaptation to host adaptive and innate immunity. In Theme 2, we will interrogate the extent and molecular underpinnings of co-adaptation among gut bacterial strains within host species. We will employ evolve-and-resequence experiments in which bacterial strains and synthetic communities from a diversity of wild-derived mouse species are grown together in vitro (co-cultured) or in vivo in germ-free mice. Results will discover mutualisms and antagonisms among members of the gut microbiota, quantify how bacterial genomic variation influences the intensity and outcomes of these interactions, and assess how these interactions evolve between host species. In Theme 3, we will elucidate the incipient stages of gut bacterial strain adaptation to host lineages through experimental evolution of mouse populations in outdoor enclosures, in which we will track bacterial strain transmission through host social networks and genealogies. Results will reveal the stability of gut bacterial strains within host maternal lineages, the gut bacterial genomic targets of natural selection within and between host generations, and the effects of host immunity on gut bacterial strain transmission and adaptation.


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 = $451,000 )
2026	2026	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	001	6	4/9/2026	COMPETING CONTINUATION	$451,000
2026	2024	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	5	4/1/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $451,000

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	4	10/23/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $361,557 )
2024	2024	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	001	5	5/3/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$361,557
2024	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	4	5/2/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $361,557

Issue Date FY: 2023 ( Subtotal = $392,076 )
2023	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	4	6/1/2023	NON-COMPETING CONTINUATION	$392,076
														Subtotal = $392,076

Issue Date FY: 2022 ( Subtotal = $392,076 )
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	001	3	7/14/2022	NON-COMPETING CONTINUATION	$39,209
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	3	3/31/2022	NON-COMPETING CONTINUATION	$352,867
														Subtotal = $392,076

Issue Date FY: 2021 ( Subtotal = $392,076 )
2021	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	2	4/5/2021	NON-COMPETING CONTINUATION	$392,076
														Subtotal = $392,076

Issue Date FY: 2020 ( Subtotal = $392,076 )
2020	2020	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	1	6/23/2020	NEW	$392,076
														Subtotal = $392,076

Grand Total All Awards = $2,380,861

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The modes and genomics of gut bacterial specificity to host species

Award Number: R35GM138284

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2030

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