The role of the aryl hydrocarbon receptor and intestinal barrier function in inflammation in CKD

Principle Investigator

Scientific interest within the context of the graduate college:

Chronic kidney dysfunction 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 (Wilck et al. Nature 2017; Bartolomaeus et al.,Circulation 2019; Avery et al., Cardiovasc Res. 2023). CKD is an understudied risk factor for cardiovascular disease. In the long term, microbiome-targeting interventions could help to reduce cardiovascular risk in CKD patients.

Project description:

Introduction: Chronic kidney disease (CKD) is a main contributor to cardiovascular (CV) risk 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., J Am Soc Nephrol. 2022; Holle et al., manuscript in preparation). The aim of the present project is to investigate human cohort material to confirm this hypothesis and to test the microbiome dependency of these changes by means of microbiota transfer into mice.

Aim 1: Analysis of biosamples from a human CKD cohort and correlation with hallmarks of cardiovascular damage. We will use the CARVIDA (CARdioVascular In Depth Assessment in Chronic Kidney Disease) cohort, a subcohort (n=290) of the German Chronic Kidney Disease (GCKD) study. The GCKD study is a prospective cohort study encompassing 5,000 CKD patients with a follow-up of up to 10 years (incl. CV outcomes). CARVIDA additionally provides unique phenotyping of the CV condition of patients enrolled within a time frame of 4 years including cardiac MRI. Dietary protocols and plasma metabolites analyzed by NMR are available. Thus, this cohort is well-suited to identify inflammatory markers associated with CV abnormalities and to explore the relationship between gut barrier dysfunction, inflammation and CVD.

We aim to assess circulating markers of intestinal barrier dysfunction (LPS, sCD14, ZO-1). The AhR-activating potential of patient sera will be analyzed using a reporter cell-based assay and qPCR-based measurement of AhR-target genes. Results will be correlated with available metabolomics data, OLINK proteome data and markers of cardiovascular damage (blood pressure, cardiac hypertrophy, vascular function, atherosclerosis).

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. J Am Soc Nephrol. 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), AhR activity (cell-based reporter assay), inflammation (flow cytometry), as well as CV target organs (heart, vasculature).

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