Th173 - Altered Intestinal Barrier and Immunoregulatory Gut-derived Metabolites Contribute to Acute Rejection in Renal Transplantation

Amber Vaitkute – UCL; Meryl Attrill – UCL; Stephanie Chong – Royal Free Hospital; Hibo Mahdi – Royal Free Hospital; Alan Salama – Royal Free Hospital; Simon Eaton – UCL; Hannah Bradford – UCL; Chris Piper – UCL; Mona Bajaj-Elliott – UCL; Claudia Mauri – UCL; Anne Pesenacker – UCL; Reza Motallebzadeh – UCL

Abstract Text:

Introduction: Long-term graft survival in renal transplantation remains a challenge. Gastrointestinal microbiota can impact extra-intestinal health. We aim to identify the interplay between the gut microbiota and recipient immunity in renal transplantation. Our hypothesis is that increased gut permeability and reduced availability of bacterial-derived metabolites associated with immunoregulation promotes a less tolerogenic environment that increases the risk of acute rejection (AR).

Methods: Transplant recipients (n=92) and live-donors (n=23) were recruited into a longitudinal study, with urine, stool and blood samples collected at baseline and up to 12-months after surgery. Flow cytometry was used to assess B-regs (CD45+CD19+IL10+). Gut permeability was assessed by measuring plasma intestinal fatty acid binding protein (i-FABP). 16s rRNA sequencing and mass spectrometry was used to assess the gut microbiome and metabolome.

Results: Recipients with biopsy-proven AR had evidence of increased permeability before transplantation and decreased indole derivatives. In AR, a decreased IL-10:TNF ratio in CD19+ B-cells was observed, particularly within the transitional B-cell compartment (CD45+CD19+CD24hiCD38hiIL10+), at 3-months (0.14±0.107 vs 0.08±0.04; p< 0.05) and 6-months (0.11±0.05 vs 0.07±0.05; p< 0.05) compared to non-rejectors. Furthermore, we observed an increased frequency of B-regs in non-rejectors after transplantation when compared to baseline (2.66%±1.86% vs 4.62%±1.99%; p=0.01), and at 6-months when compared to rejectors (2.96%±1.69% vs 1.75%±1.25%; p< 0.05).

Discussion: Increased gut permeability and reduced immunoregulatory metabolites are associated with reduction in IL-10+ B-regs, predisposing patients to AR. We postulate that decreased responsiveness or availability of indoles and SCFAs may impact B-reg generation and maintenance resulting in reduced immunological tolerance that contributes to AR.