# Immunological and functional consequences triggered by the gut microbiota regulate alloimmunity and cardiac transplant outcome

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $578,734

## Abstract

Project Summary
 Many aspects of the innate and adaptive immunity are critically regulated by the microbiota. Microbial
cells, their metabolites and nucleic acids engage various immune cells, resulting in pro- or anti-inflammatory
signals that differ based on chemical structures, cellular receptors, and physiological context. The microbiota
not only influences local immunity, but also has distant effects on systemic immunity. Local microbiota
stimulation of innate and adaptive immune cells results in those cells or their products to migrate or traffic
through lymphatics or blood, and influence diseases. However, the precise causal pathways linking microbiota
components to immune cells and downstream effectors in most cases remain to be defined.
 Solid organ transplantation has made significant progress over the past 35 years and has become a
routine procedure. Cardiac transplantation is a common and successful transplant, with graft survival after one
year exceeding 80-90%. Despite advances in all aspects of allografting, the rate of decline of cardiac and other
graft function beyond the first year after transplant has not changed in over 20 years. All allografts eventually
succumb to chronic vascular, interstitial or epithelial changes. Despite critical improvements in
immunosuppressive regimens, immunologic monitoring, and molecular classification of organ pathology,
chronic rejection still persists and its primary cause is not understood. Prior work has focused on distal events
of fibrosis and inflammation, but not on proximal causes of inflammation and immunity.
 We previously showed in renal transplantation, large and persistent shifts in the composition and
complexity of the gut microbiota as a result of immunosuppression and antibiotics. Such shifts in the microbiota
are indicative of all organ transplants, including cardiac transplants. We therefore hypothesized that these
changes could critically affect graft outcome. Our current studies dissected the interactions between the enteric
microbiota and innate and adaptive immunity, in clinically-relevant cardiac transplantation models of acute and
chronic rejection. Our results show that both pro-inflammatory and anti-inflammatory microbiota populations, as
well as single bacteria, can be defined by their effects on the long-term outcome of the grafts. Mechanistic
explorations suggest a differential stimulation of myeloid cells (i.e. macrophages and DC), resulting in changes
in LN structure that influence allogeneic immunity. Thus, we hypothesize that the microbiota directly regulates
innate immunity, which in turn regulates systemic inflammation and adaptive immunity, thereby determining the
occurrence and progression of graft fibrosis, inflammation and graft survival. To investigate this hypothesis, we
will take advantage of our expertise in microbiota analysis and in molecular and cellular transplant
immunology. The definition of pro-inflammatory and anti-inflammatory microbiota and strai...

## Key facts

- **NIH application ID:** 10439697
- **Project number:** 5R01HL148672-04
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Jonathan S Bromberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $578,734
- **Award type:** 5
- **Project period:** 2019-07-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439697

## Citation

> US National Institutes of Health, RePORTER application 10439697, Immunological and functional consequences triggered by the gut microbiota regulate alloimmunity and cardiac transplant outcome (5R01HL148672-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10439697. Licensed CC0.

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