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The composition of the microbiota modulates allograft rejection.

ABSTRACT: Transplantation is the only cure for end-stage organ failure, but without immunosuppression, T cells rapidly reject allografts. While genetic disparities between donor and recipient are major determinants of the kinetics of transplant rejection, little is known about the contribution of environmental factors. Because colonized organs have worse transplant outcome than sterile organs, we tested the influence of host and donor microbiota on skin transplant rejection. Compared with untreated conventional mice, pretreatment of donors and recipients with broad-spectrum antibiotics (Abx) or use of germ-free (GF) donors and recipients resulted in prolonged survival of minor antigen-mismatched skin grafts. Increased graft survival correlated with reduced type I IFN signaling in antigen-presenting cells (APCs) and decreased priming of alloreactive T cells. Colonization of GF mice with fecal material from untreated conventional mice, but not from Abx-pretreated mice, enhanced the ability of APCs to prime alloreactive T cells and accelerated graft rejection, suggesting that alloimmunity is modulated by the composition of microbiota rather than the quantity of bacteria. Abx pretreatment of conventional mice also delayed rejection of major antigen-mismatched skin and MHC class II-mismatched cardiac allografts. This study demonstrates that Abx pretreatment prolongs graft survival, suggesting that targeting microbial constituents is a potential therapeutic strategy for enhancing graft acceptance.

SUBMITTER: Lei YM

PROVIDER: S-EPMC4922695 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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The composition of the microbiota modulates allograft rejection.

Lei Yuk Man YM Chen Luqiu L Wang Ying Y Stefka Andrew T AT Molinero Luciana L LL Theriault Betty B Aquino-Michaels Keston K Sivan Ayelet S AS Nagler Cathryn R CR Gajewski Thomas F TF Chong Anita S AS Bartman Caroline C Alegre Maria-Luisa ML

The Journal of clinical investigation 20160620 7

Transplantation is the only cure for end-stage organ failure, but without immunosuppression, T cells rapidly reject allografts. While genetic disparities between donor and recipient are major determinants of the kinetics of transplant rejection, little is known about the contribution of environmental factors. Because colonized organs have worse transplant outcome than sterile organs, we tested the influence of host and donor microbiota on skin transplant rejection. Compared with untreated conven ...[more]

PMID: 27322054

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Project description:BackgroundNormal mammalian development and homeostasis are dependent upon the gut microbiota. Antibiotics, essential for the treatment and prophylaxis of bacterial infections, can have collateral effects on the gut microbiota composition, which can in turn have far-reaching and potentially deleterious consequences for the host. However, the magnitude and duration of such collateral effects appear to vary between individuals. Furthermore, the degree to which such perturbations affect the host response is currently unclear. We aimed to test the hypothesis that different human microbiomes have different responses to a commonly prescribed antibiotic and that these differences may impact the host response.MethodsGerm-free mice (n = 30) humanized with the microbiota of two unrelated donors (A and B) were subjected to a 7-day antibiotic challenge with amoxicillin-clavulanate ("co-amoxiclav"). Microbiome and colonic transcriptome analysis was performed, pre (day 0) and post antibiotics (day 8) and subsequently into recovery (days 11 and 18).ResultsUnique community profiles were evident depending upon the donor, with donor A recipient mice being dominated by Prevotella and Faecalibacterium and donor B recipient mice dominated by Bacteroides and Parabacteroides. Donor A mice underwent a marked destabilization of their microbiota following antibiotic treatment, while donor B mice maintained a more stable profile. Dramatic and overlapping alterations in the host transcriptome were apparent following antibiotic challenge in both groups. Despite this overlap, donor A mice experienced a more significant alteration in gene expression and uniquely showed correlations between host pathways and key microbial genera.ConclusionsGerm-free mice humanized by different donor microbiotas maintain distinct microbiome profiles, which respond in distinct ways to antibiotic challenge and evince host responses that parallel microbiome disequilibrium. These results suggest that inter-individual variation in the gut microbiota may contribute to personalized host responses following microbiota perturbation.

Dataset Information

The composition of the microbiota modulates allograft rejection.

Publications

The composition of the microbiota modulates allograft rejection.

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