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 alloimmunity and graft rejection.
Specific Aim 3. To determine the effects of bariatric surgery on the microbiota, TDCA/valine serum levels, and APC tuning in a pilot human study.

Public Health Relevance

We have found that the communities of microbes that inhabit the intestine of lean mice can causally modulate the kinetics of solid organ transplant rejection. Moreover, the communities of microbes associated with obese mice correlate with an accelerated transplant rejection; bariatric surgery not only results in modifications of these communities but also in prolongation of graft survival. In this application, we will investigate the causal impact of various microbial communities on alloimmunity, and the metabolic basis for their effects, as well as propose therapeutic modalities to overcome the deleterious impact of obese-associated microbiota on transplant outcomes.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAI1)
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Nabavi, Nasrin N
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Brigham and Women's Hospital
United States
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Metwally, Ahmed A; Yang, Jie; Ascoli, Christian et al. (2018) MetaLonDA: a flexible R package for identifying time intervals of differentially abundant features in metagenomic longitudinal studies. Microbiome 6:32
Uehara, Hirofumi; Minami, Koichiro; Quante, Markus et al. (2018) Recall features and allorecognition in innate immunity. Transpl Int 31:6-13