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Drivers of adaptation and colonization within individual human microbiomes

Award Number: R35GM156282
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: 08/04/2025
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Drivers of adaptation and colonization within individual human microbiomes - LOCAL AND GLOBAL SELECTIVE FORCE WITHIN MICROBIOMES The human microbiome harbors a large capacity for within-person adaptive mutations. Commensal bacterial strains can stably colonize a person for decades, and during this time billions of bacterial mutations are generated daily. Adaptive mutations emerging during colonization might be driven by selective forces that are new to urban industrialized societies, vary across individuals, or vary across times within an individual. These changes could alter the impact of strains on the immune system, the metabolism of particular nutrients or drugs, and the stability of the microbiome to invasions or perturbations. Despite this potential, still little is known about the extent of evolution within human microbiomes or its interplay with ecological forces. This knowledge gap emerges from limitations of traditional approaches; metagenomics does not provide the resolution needed to accurately identify de novo mutations, and model animal microbiomes have relatively limited potential for adaptation due to their shorter lifespans, smaller microbial population sizes, and constrained environmental complexity. To overcome these limitations, my lab studies in vivo evolution using high-throughput culture-dependent methods. Using this approach to we have discovered evidence that, even in the absence of antibiotic treatment, adaptive de novo mutations reach high frequency within healthy people. However, it is unknown if such adaptation is common across species or capable of spreading person-to-person. This proposal outlines a long-term strategy to develop the intuition, rules, and exceptions regarding ongoing adaptation and selective forces within human microbiomes. First, we will use a culture-dependent genomic approach to characterize within-person evolution over a dozen species in human microbiomes, including residents of the skin, vagina, and large intestine. We will characterize niche traits that predict the balance of neutral and adaptive forces across species, as well as elucidate the role of person-specific selective forces in evolution and initial engraftment of migrating strains. Second, we will characterize across-person evolution using PHLAME, a computational platform for phylogenomics we developed that leverages rapidly accruing public metagenomic data. We will identify bacterial strains with recent success within and across human environments. We expect to uncover principles underlying adaptive evolution of commensals within and across humans and to lay the groundwork for a microbiome framework that integrates both evolutionary and ecological forces, which will pave the way towards more successful microbiome-targeted therapies.


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 = $524,900 )
2026	2026	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	2	4/28/2026	NON-COMPETING CONTINUATION	$524,900
														Subtotal = $524,900

Issue Date FY: 2025 ( Subtotal = $557,900 )
2025	2025	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	8/1/2025	NEW	$557,900
														Subtotal = $557,900

Grand Total All Awards = $1,082,800

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Drivers of adaptation and colonization within individual human microbiomes

Award Number: R35GM156282

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: 08/04/2025

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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