Can Diet Induce Transplantation Tolerance?

• microbiota; short chain fatty acids
• acetate
• kidney transplantation
• rejection

The induction of tolerance to a transplanted organ, a state that would enable long-term graft acceptance following a short therapy, remains an elusive goal. Indeed, following transplantation, the host’s immune system recognizes genetic disparities between the donor and the recipient and mounts an immune response to eliminate the graft. To prevent graft rejection, transplant recipients need to take immunosuppressive drugs for the rest of their lives, with ensuing side effects and complications from global immunosuppression. In recent years, mounting evidence suggests that environmental factors can modulate the strength of this antigraft immune response. One such factor is the microbiota, the collection of microbes that colonize barrier body surfaces such as the intestine. Importantly, the composition of the gut microbiota is determined in large part by diet and therefore, can be manipulated to promote health. Wu et al.¹ in this issue of JASN demonstrate that a high-fiber diet (HFiD), which results in production of short chain fatty acids (SCFAs), can prolong renal allograft survival in mice. Strikingly, administration of one such SCFA, sodium acetate (SA), was sufficient to induce donor-specific transplantation tolerance.

The authors used a life-sustaining mouse model of fully mismatched renal transplantation in nephrectomized hosts.¹ Although 62% of animals fed normal chow rejected their grafts with a mean survival of 40 days, 71% of mice on an HFiD retained their transplants long term. Graft acceptance on HFiD-fed mice correlated with increased intragraft mRNA expression of the anti-inflammatory cytokine IL-10 at day 14 and reduced histologic signs of chronic rejection at day 100. HFiD resulted in fecal increase of SCFA-producing bacteria, including Bifidobacterium spp. and Bacteroides spp., as determined by 16S rRNA gene sequencing. SCFAs include, among others, acetate, propionate, and butyrate; are produced when dietary fiber is fermented in the colon; and are absorbed through the portal vein. They can bind metabolite-sensing G protein–coupled receptors such as GPR43 expressed on both hematopoietic and nonhematopoietic cells and mediate a variety of effects from activation of the inflammasome to potentiation of regulatory T cell function.

In this report, administration of SA via daily intraperitoneal injection for 14 days starting on the day of transplantation followed by continuous oral supplementation in the drinking water was sufficient to induce long-term renal allograft survival, associated with increased intragraft IL-10 expression. The beneficial effects of HiFD and of SA supplementation were both abrogated in GPR43-deficient mice, though the cell type(s) through which GPR43 signals for this effect and its mechanism of action remain to be elucidated. Remarkably, SA-supplemented mice that had stably accepted their kidney allograft for >200 days had developed donor-specific tolerance as demonstrated by acceptance of a secondary donor-matched skin graft, a robust test of antigen-specific tolerance, while they remained competent to reject a third-party skin graft. Thus, diet can dramatically influence the outcome of an allograft, and a diet high in fiber or supplemented with SA can quite significantly improve transplant survival.

Another study has recently linked hyperglycemic complications of tacrolimus, a calcineurin inhibitor widely used to prevent graft rejection in the clinic, to reduced intestinal butyrate-producing bacteria and diminished butyrate content in mice.² Importantly, butyrate supplementation prevented or corrected hyperglycemia.³ Together, these studies suggest that SCFA dietary supplementation may not only promote transplantation tolerance but also, reduce a common side effect of immunosuppressive therapy. Why butyrate may play a more important role in some models and acetate or other SCFAs in others needs to be further clarified before determining whether supplementation with one or a combination of various SCFAs would be desirable in the clinic. Long-term side effects of such dietary interventions as well as translatability to humans also need to be carefully evaluated.

The intestinal microbial strains that are responsible for the effect of HFiD remain to be identified. Wu et al.¹ found intestinal increases in various SCFA-producing strains, including Bifidobacterium and Bacteroides spp. Which of these strains (or combination of strains) is responsible for the augmented production of SCFAs found after HFiD in this model remains to be discovered. Additionally, which microbial strain plays a role in promoting transplantation tolerance and whether other properties than production of SCFAs are involved in facilitating this process need to be investigated. Administration of Bifidobacterium pseudolongum, a strain enriched in pregnant mice, has been shown to reduce chronic rejection in a mouse model of heart transplantation.³ Additionally, delivery of Bifidobacterium animalis improved glucose tolerance in high-fat diet–fed mice in an SCFA and GPR43-dependent manner.⁴ These studies highlight the Bifidobacterium genus as an attractive probiotic for transplantation, both to promote graft survival and to reduce hyperglycemic complications of immunosuppression. However, it is important to keep in mind that supplementation with Bifidobacterium spp. was associated with improved tumor control in a mouse melanoma model,⁵ suggesting that some bacterial strains of this genus may enhance rather than dampen immunity and therefore, perhaps be detrimental to an allograft. Genetic analysis of each microbial strain and examination of their metabolic potential may help us understand these outcome differences.

Other diets can also affect graft outcome, and high-fat diet in particular was shown to accelerate graft rejection in mice.^6,7 Several studies have also demonstrated a causal link between the microbiota and transplant survival, with specific microbial communities accelerating graft rejection^8,9 and others prolonging graft survival.^3,10,11 However, the manuscript by Wu et al.¹ is unique in linking a dietary intervention and a microbiota-derived metabolite to the development of donor-specific tolerance, rather than only delayed acute or chronic rejection. This may have to do with the fact that, in the mouse, kidney transplantation is conducive to regulatory T cell–dependent tolerance, with some donor/recipient strain combinations resulting in spontaneous kidney allograft acceptance in the absence of immunosuppression. It remains to be determined whether this regimen could lead to tolerance following initial transplantation of other organs, such as cardiac or skin allografts. If tolerance is more elusive in these cases, it may still be of interest to determine if SA might synergize with conventional immunosuppression to improve transplant outcome as another possible translational intervention.

• Copyright © 2020 by the American Society of Nephrology