Microbiota-dependent and -independent effects of obesity on transplant rejection and hyperglycemia

Existing risk factors such as dietary habits and obesity contribute to diabetes not only in the general population but also in transplant patients who are more susceptible to developing diabetes.¹ In solid organ transplantation, accumulating evidence indicates that obesity, a state of chronic low-level inflammation, contributes to shorter graft survival and is associated with an increased risk of postoperative complications.² Furthermore, the use of immunosuppressants contributes to the development of post-transplant diabetes mellitus (PTDM). For example, corticosteroids can promote gluconeogenesis and interfere with insulin signaling, leading to hyperglycemia.^3,Four Tacrolimus may impair pancreatic function $\mathrm{β}$Cellular function is impaired, leading to PTDM.^Five

We previously demonstrated that mice fed a high-fat diet (HFD) develop hyperglycemia and reject allografts more quickly than mice fed a low-fat diet.6–8 HFD induces systemic inflammation, which may contribute to both accelerated and promoted graft rejection.⁹ This leads to the development of insulin resistance.^Ten Concurrently, we and others have shown that the microbiome influences both transplant outcome11,12,13,14 and diabetes susceptibility.¹⁵ Given that diet determines the composition of the microbiota, it is possible that the effect of an HFD on the rate of transplant rejection is partly microbiota-dependent. For example, a diet high in fat and sugar may Oscillibacter valericigenesincreasing the number of MMP12⁺ This reduces macrophages in adipose tissue, leading to insulin resistance.¹⁶

In this study, we aimed to investigate whether the microbiota is responsible for the ability of HFD to accelerate graft rejection and induce hyperglycemia. Results show that HFD accelerated graft rejection through both microbiota-dependent and -independent mechanisms. Meanwhile, HFD-induced hyperglycemia was driven exclusively by the microbiota and did not occur in germ-free (GF) mice fed an HFD. Although HFD-induced dysbiosis caused hyperglycemia, it was not mediated by members of the gut microbial community. Alistipes OnderdonkiWhen supplemented with , specific pathogen-free (SPF) mice without weight loss, it ameliorated both HFD-induced inflammation and HFD-induced glucose intolerance. Our results indicate that both diet alone and diet–microbiota interactions play important roles in regulating alloimmune responses and transplantation outcomes, providing insight into novel solutions in the context of PTDM.