In our project, we focus on maladaptive immune responses to prevent multi-morbidity in patients with chronic kidney disease (CKD). Based on our longstanding interest in microbiome-immune interactions in cardiovascular and renal diseases, the planned project involves first proof-of-concept clinical studies side by side with experimental in vitro assays. Our translational project addresses a molecular mechanism that is crucial to maintain health and opens up areas for preventative strategies in line with the Re-Thinking Health program.
Introduction: Patients with chronic kidney disease (CKD) have a 500-1000-fold increase in cardiovascular mortality, irrespective of age (Jankowski et al. Circulation 2021). This heightened risk is in part due to inflammatory processes that result from abnormal immune system status (Ridker et al. European Heart Journal 2022). We recently demonstrated that even very young patients with CKD have specific alterations to their gut microbiome and immune system (Holle et al. JASN 2022). The main disease-associated changes we observed were a reduction of gut microbial production of the short-chain fatty acid (SCFA) propionate and a reduction of circulating regulatory T cells (Treg). Furthermore, we have shown with animal model studies and in vitro assays a potent and Treg-dependent positive effect of propionate in cardiovascular disease (Bartolomaeus et al. Circulation 2019). We offer a project based on well-established previous work by us and others which aims to investigate the effects of propionate on Treg abundance and function in a translational study in healthy participants and CKD patients.
Aim 1: Analyzing the effects of propionate on Treg induction and function in vitro.
Aim 2: Demonstrating the effects of oral propionate treatment on Treg abundance and function in healthy individuals.
Aim 3: Investigating the effects of propionate treatment in a double-blind placebo-controlled study in adolescent patients with CKD.
The clinical studies are approved by the local ethics board. To focus on truly CKD-related effects, children with CKD will be enrolled in a multicenter-fashion, as they do not suffer from additional comorbidities, which might affect our results.