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Microbiome-induced intestinal Th17 cells and microbiome independent gamma delta T cells improve fracture healing

Award Number: R01AR085595
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2025
PERIOD OF PERFORMANCE END DATE: 07/31/2030

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Microbiome-induced intestinal Th17 cells and microbiome independent gamma delta T cells improve fracture healing - PROJECT SUMMARY Fractures are a common traumatic injury in humans. Fracture healing is often complicated by delayed unions and non-unions, creating a need for innovative strategies for fracture healing. We reported that the intestinal microbiome and gut permeability are potent factors governing the efficiency of fracture repair. We found that microbiome depletion by antibiotic treatment impairs fracture healing in mice. We also found that optimal fracture repair occurs in the presence of segmented filamentous bacteria (SFB) in the gut microbiome. SFB are gut commensal bacteria that are potent inducers of Th17 cell generation – a population of IL-17 producing CD4+ cells. Based on published and preliminary data, we hypothesize that early after a fracture, cytokines released by γδ T cells and other inflammatory cells within the fracture site increase local and circulating levels of inflammatory cytokines. Circulating cytokines induce a leaky gut phenotype, which, together with a microbiota containing SFB, results in the heightened expansion of intestinal Th17 cells. Attracted by chemokine gradients induced by callus inflammation, intestinal Th17 cells migrate to the to the fracture callus, where they further increase local IL-17 levels. The combined production of IL-17 by γδ T cells and Th17 cells originating from the gut shortens and optimizes fracture repair. Attesting to the relevance of γδ T cells and Th17 cells for fracture repair, mice lacking γδ T cells or mice with a paucity of Th17 cells exhibit suboptimal fracture healing. Given the importance of specific bacterial taxa for the expansion of intestinal Th17 cells, and thus for fracture repair, we further hypothesize that induction of Th17 cells by specific live microbial biotherapeutics may improve fracture healing. Because the specific phenotype of the γδ T cells that function in fracture healing is unknown, that the relative contribution of Th17 cells to fracture repair is unknown, and if fracture healing is expedited by IL-17A or IL-17F is unknown, in Aim 1 we will identify the subsets of γδ T cells relevant for fracture healing, investigate the contribution of Th17 cells to fracture repair, and to determine the relevance of IL-17A and IL-17F for fracture repair. In Aim 2, we will determine the contribution of increased gut permeability to fracture repair and comprehensively characterize the mechanisms involved. This will be achieved by preventing or enhancing the increased in gut permeability induced by fractures using pharmacological agents. In Aim 3 we will determine if precision probiotic treatment using sequential supplementation with bacteria known to expand intestinal Th17 cells in humans followed by an anti-inflammatory probiotic will expedite and/or improve fracture healing. The phenotypic characterization of T cells implicated in fracture repair, the definition of mechanisms whereby fractures increase gut permeability, and an assessment of the effects of precision probiotic treatment will yield essential data to inform novel strategies for optimizing fracture healing.


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 = $663,901 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/25/2025	NEW	$663,901
														Subtotal = $663,901

Grand Total All Awards = $663,901

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Microbiome-induced intestinal Th17 cells and microbiome independent gamma delta T cells improve fracture healing

Award Number: R01AR085595

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2025

PERIOD OF PERFORMANCE END DATE: 07/31/2030

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