ESR 9: Renal clearance dynamics of gut bacteria-derived metabolites in chronic kidney disease

Supervisor: Kai-Uwe Eckardt

Short Summary

The impact of chronic kidney disease (CKD) is reflected in various organ systems. In this context, the intestine is highly relevant, whose bacterial colonization is abnormal in CKD. Intestinal bacteria produce a variety of metabolites, which are resorbed by the host and circulate within the blood. If renal function is reduced, as in CKD, these metabolites can accumulate, which is thought to impose an additional burden on CKD progression and the immune system. To date, we have insufficient knowledge about the nature of these metabolites, the dynamics of their accumulation during CKD, as well as their renal clearance modes. In-depth knowledge about these aspects would enhance our understanding of the gut-kidney axis and help to evaluate the role of bacterial metabolites in CKD progression and their utility as biomarkers. For this reason, we aim to use experimental CKD models and different bacterial colonization statuses to answer these questions. We aim to gain a better understanding of gut-derived metabolites and their handling by the kidney. We aim to investigate metabolite landscapes across various body fluids. Human cohort data will be used to verify our findings in CKD patients. Candidate metabolites of particular interest will be investigated further in experimental models.

Scientific strategy

Objectives:

We strive for a better understanding of the spectrum and the accumulation of gut-derived metabolites in CKD and their stage-specific renal clearance dynamics. We want to use this knowledge to therapeutically target microbiota in CKD in the future and to develop novel diagnostic tools to identify CKD patients at a particularly high risk of developing advanced CKD, as well as inflammatory and cardiovascular complications.

Method:

We will induce experimental CKD by using two established mouse models. Most importantly, mice with different colonization statuses will be used to elucidate the impact of the gut microbiota. Metabolite landscapes from faeces, blood, urine and interstitial fluid will be measured in different stages of CKD development. Human cohort data will be used to verify findings in CKD patients. Furthermore, dietary intervention in experimental CKD will be performed in order to beneficially modify the microbial function.

Expected Results:

We expect to better define and understand the spectrum of gut-derived metabolites and their toxic accumulation in different body compartments in CKD. This knowledge could enable novel avenues for the prognostic evaluation and treatment of CKD and its inflammatory and cardiovascular complications.