The role of the gut microbiome in mediating kidney disease associated comorbidities

Principal Investigator

Scientific interest within the context of the graduate college:

Chronic kidney disease is a major global health concern of increasing prevalence, driving a plethora of secondary comorbidities. A mechanistic understanding of the driving factors is essential to develop preventive and therapeutic concepts. Our research group investigates microbiome-mediated mechanisms of cardiovascular risk (e.g. Wilck et al. Nature 2017, Bartolomaeus et al. Circulation 2019, Avery et al. Cardiovascular Research 2023; see below for more). We believe that CKD is an understudied risk factor for cardiovascular disease, characterized by changes in microbiome composition. In the long term, microbiome-targeting interventions could help to reduce cardiovascular risk in CKD patients.

Project description:

Chronic kidney disease (CKD) is a main contributor to cardiovascular (CV) risk, inflammation and subsequent multimorbid conditions. CKD associates with dysbiotic alterations of the gut microbiome, a resulting dysbalance of gut bacterial metabolites, an impaired intestinal barrier function and resulting chronic systemic inflammation driving CV disease. We have recently shown that intestinal barrier dysfunction and increased AhR activity may drive inflammation and cardiovascular remodeling (Holle et al. JASN 2022; Holle et al. manuscript in preparation). The aim of the present project is to investigate the transmission of CKD-associated traits by microbiome transfer from humans to mice. Further biomaterials from human cohort materials will be used to understand if the human microbiome in mice can be compared to the “real world”.

Aim 1: Fecal microbiota transfer (FMT) of human microbiota into mice. We have prior experience in FMT experiments. As such, mice can be used as an experimental platform to understand the efficacy of microbiome-targeting interventions. We therefore use mice (colonized with microbiota from CKD patients and controls) to perform dietary interventions to improve microbiome dysbiosis and associated pathologies (gut barrier dysfunction, inflammation etc.). In the present experiment we aim to investigate the potential of dietary fiber to improve CKD-associated microbiome dysbiosis. We aim to analyze the microbiome by sequencing, the immune phenotype (flow cytometry) as well as cardiovascular alterations (e.g. cardiac hypertrophy and fibrosis by histology, gene expression). These initial data will inform further in-depth analyses.

Aim 2: Investigation of the influence of CKD candidate bacterial species on AhR and the intestinal barrier. Gnotobiotic mice, i.e. mice with known, defined gut bacteria, provide an opportunity to mechanistically study the impact of specific bacteria on the host organism. In previous microbiome analyses (Holle et al. JASN 2022; Holle et al. manuscript in preparation), we have identified CKD-specific candidate species that we would like to investigate by colonizing germ-free mice. The analysis will focus on the intestinal barrier (immunohistology, gene expression), aryl hydrocarbon receptor activity (cell-based reporter assay) and inflammation (flow cytometry from whole blood, spleen, intestine, heart and kidney).

Aim 3: Analysis of biosamples from a human CKD cohort. We conducted a fiber-intervention (placebo-controlled) in dialysis patients. We aim to analyze the microbiome, markers of a “leaky” gut as well as the immune phenotype (flow cytometry). The results will be compared to the data generated in mice.

Application details

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