Aim: To study the effect of kidney transplantation on gut microbial communities, and investigate the role of dietary fibre in modulating host microbiota to improve graft survival in a murine model of kidney transplant rejection.
Methods: Kidney transplants were performed from BALB/c(H2d) to B6(H2b) or B6(H2b):GPR43-/- mice as allografts, and to BALB/c(H2d) as isografts. Allograft mice received normal chow (WT+NC), a HF diet (WT+HF), or sodium acetate (SA) supplementation (WT+SA; GPR43-/-+SA). Isografts were fed NC only. Gut microbiota composition was assessed by 16S rRNA sequencing prior, at post-transplant day 14, and at post-transplant day 100.
Results: In mice fed NC allograft transplantation resulted in a significant shift in gut microbial composition at day 14 post-transplant, which was not evident in isografts (Fig. 1 & 2).



Allograft transplantation led to dysbiosis in WT+NC mice, with a loss of normal gut microbial diversity at day 14, but not in WT+HF mice where microbial diversity was enhanced. Changes in the microbial communities induced by allograft transplantation were maintained at day 100 post-transplant in both NC and HF fed allograft recipients (Fig. 2).

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Microbial species known to produce short-chain fatty acid (SCFA) by fermentation of dietary fibre and promote the development of T regulatory cells were significantly more abundant in mice fed HF, compared to NC allograft recipients (Bifidobacterium P<0.05 and Clostridiales P<0.0001, Fig. 3).



WT+HF allografts had prolonged survival compared to WT+NC allografts (P<0.01, Fig. 4), and were protected from acute (day 14: lower creatinine P<0.01, less tubulitis (P<0.001)) and chronic (day 100: lower creatinine (P<0.05), less proteinuria (P<0.01) and glomerulosclerosis (P<0.001)) rejection.
In mechanistic experiments, WT+SA allografts exhibited superior graft function to WT controls (lower creatinine (P<0.01), were protected from rejection (reduced tubulitis, P<0.001), and exhibited donor-specific tolerance, confirmed by acceptance of donor strain but rejection of 3rd party skin grafts (P<0.01). The survival benefit conferred by SA was broken by depletion of CD25+ Tregs by using anti-CD25mAb, and SA was ineffective in GPR43-/- allograft recipients (P<0.05, Figure 4).



Conclusions: Kidney transplantation resulted in enduring changes to the gut microbial landscape that were not evident in isografts, suggesting the host-donor immune response as the primary driver of transplant-induced dysbiosis. HF diet prevented transplant-associated dysbiosis and afforded protection against allograft rejection. Protection was mediated, at least in part, by SCFAs and was dependent on a CD4+CD25+Foxp3+ regulatory mechanism and signalling via GPR43. Dietary manipulation of the microbiome warrants evaluation in human transplantation.