# The microbiota and allograft rejection: novel investigations into the consequences of obesity

> **NIH NIH U01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $403,766

## Abstract

The extent of genetic disparities between donor and recipients constitutes the main driver that determines
the strength of alloimmunity and subsequent kinetics of graft rejection. In recent years, a role for environmental
factors has emerged. Our preliminary results have identified 2 inter-related environmental factors that can
modulate the strength of the alloimmune response. The first is the microbiota, represented by the communities
of microbes that inhabit the body. Here, we reported that the elimination of microbiota through the use of germ-
free (GF) mice, or a decrease of microbial diversity induced by broad-spectrum antibiotics (Abx) in both donor
and recipient mice prior to transplantation resulted in a reduction of alloreactivity and prolonged graft survival.
Mechanistically, antigen-presenting cells (APCs) from GF and Abx-pre-treated mice had a reduced capacity to
prime donor-reactive T cells. The second environmental factor is high fat diet (HFD). We showed that obese
mice mounted an augmented alloimmunity and rejected transplants faster than lean mice. Mechanistically,
APCs from obese mice had a greater capacity to present alloantigen to T cells compared with APCs from lean
mice, a mirror image of the phenotype observed in GF and Abx-treated mice. Based on established links
between obesity and the gut microbiota, we propose that obesity-dependent dysbiosis super-activates APCs,
which, in turn, induces a more potent priming of alloreactive T cells leading to accelerated kinetics of transplant
rejection. Using metagenomic shotgun sequencing, we have identified increased proportions of Firmicutes and
decreased proportions of Bacteroidetes and Verrucomicrobia in diet-induced obese (DIO) mice. Interestingly,
these changes were reversed in mice treated with bariatric surgery (sleeve gastrectomies, SGx), and in mice
treated with TDCA/valine, co-metabolites that we found to be reduced in the serum of obese mice and restored
by SGx. Of clinical relevance, we detected high levels of B. vulgatus, a commensal species that can metabolize
TDCA, in the stool of an obese patient. Based on these preliminary data, we propose that shaping of microbial
communities by diet modulates alloimmunity. Specifically, we hypothesize that obesity, via its alteration of the
microbiota and through changes of co-metabolites in host/microbiota, enhances DC poising that results in
increased priming of alloreactive T cells and accelerated graft rejection; those effects are reverted by bariatric
surgery or through the restoration of metabolite levels. This hypothesis will be tested in the context of the
following Specific Aims.
 Specific Aim 1. To determine if the microbiota shaped by HFD before and after bariatric surgery
differentially modulates alloimmunity and the kinetics of graft rejection. Specific Aim 2. To investigate the
mechanisms by which the microbiota-dependent metabolites TDCA and valine that are decreased in obesity
and restored by SGx, modulate alloimmu...

## Key facts

- **NIH application ID:** 9928902
- **Project number:** 5U01AI132898-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Maria-Luisa Alegre
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $403,766
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928902

## Citation

> US National Institutes of Health, RePORTER application 9928902, The microbiota and allograft rejection: novel investigations into the consequences of obesity (5U01AI132898-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9928902. Licensed CC0.

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