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Dynamic metabolic rewiring determines immune outcomes of chronic cardiac transplant outcomes

Award Number: R01AI189709
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/03/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Dynamic metabolic rewiring determines immune outcomes of chronic cardiac transplant outcomes - PROJECT SUMMARY Cardiac transplant recipients ubiquitously develop cardiac allograft vasculopathy (CAV), interstitial fibrosis and chronic inflammation, with post-transplant mortality rate unchanged for the past two decades. Immune-mediated damage is the primary cause of long-term graft failure. The pathophysiology of chronic graft rejection is still poorly understood; and tools to predict, prevent, and treat graft chronic inflammation and fibrosis are largely lacking. Emerging evidence indicates that the microbiome and microbiome-regulated metabolic compounds critically impact alloimmunity, consequently promoting or inhibiting graft survival. We developed a clinically relevant murine model of chronic cardiac rejection, characterized by full MHC mismatch, administration of clinically relevant chronic immunosuppression, and development of chronic cardiac lesions. With this model we showed pro- and anti-inflammatory bacteria and whole gut microbiota can be defined by their effects on graft outcome: anti-inflammatory Bifidobacterium (Bifido) improved long-term graft outcome, while pro-inflammatory Desulfovibrio (Desulfo) impaired graft survival, each influencing lymph node (LN) structure, lymphocyte trafficking and regulatory T cell (Treg) differentiation. Bifido and Desulfo distinctively reprogrammed metabolic activities in gut lumen and circulation, affecting amino acid, carbohydrate and nucleotide metabolism, and trimethylamine biosynthesis. Remarkably, FMT from a human-sourced cardiac transplant recipient with CAV, using this murine model, resulted in pro-inflammatory responses akin to those seen with Desulfo FMT. We hypothesize that changes in gut metabolic activities, due to altered gut microbiome, shift the immune balance of Tregs vs. effector T cells, thereby inhibiting or promoting transplant rejection. Specifically, gut metabolic activities regulate the LN microenvironment where the Treg/Teff ratio is determined. The goal of this study is to determine microbiome-mediated changes that serve as key determinants of alloimmune modulation and CAV development. We will use our clinically relevant murine model to derive insights pertinent to metabolic and immunological parameters of human transplantation. In Aim 1, we will define microbiome-induced metabolic reprogramming in cardiac transplantation. In Aim 2, we will determine metabolically driven alloantigen-specific responses in lymphoid tissues and grafts. In Aim 3, we will characterize the metabolic and alloimmune responses induced by fecal microbiota transfer sourced from human cardiac transplant recipients under immune regulatory (non-CAV) or activated (CAV) conditions. The results of this study will define translatable microbial- and metabolite-informed targets for monitoring, diagnostics and therapeutics in transplantation, and discern the complex dialogue between microbiome and alloimmunity.


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 = $770,199 )
2026	2026	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	1	8/3/2026	NEW	$770,199
														Subtotal = $770,199

Grand Total All Awards = $770,199

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Dynamic metabolic rewiring determines immune outcomes of chronic cardiac transplant outcomes

Award Number: R01AI189709

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/03/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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