Kidney Week

Abstract: TH-PO1100

Depletion of the Gut Microbiota Modulates Metabolome and Immune Profiles in Experimental CKD

Session Information

• CKD: Mechanisms - 1
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Yarritu, Alex, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Alex Yarritu, MSc

• Anders, Wibke, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Wibke Anders

• Kamboj, Sakshi, Universitat Regensburg, Regensburg, Bayern, Germany

Sakshi Kamboj, MSc

• Hassan, Sara A., Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Sara A. Hassan, MSc

• Hoffmann, Carina, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Carina Hoffmann

• Rauch, Ariana, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Ariana Rauch, MS, MSc

• Fuckert, Franziska, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Franziska Fuckert

• Holle, Johannes, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Johannes Holle, DrMed

• Bartolomaeus, Hendrik, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Hendrik Bartolomaeus, MD

• Gronwald, Wolfram, Universitat Regensburg, Regensburg, Bayern, Germany

Wolfram Gronwald

• Wilck, Nicola, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Nicola Wilck, MD

Background

Chronic Kidney Disease (CKD) disrupts the gut microbiome, leading to the production of uremic toxins that impaired kidneys fail to excrete. These toxins potentially increase immune cell activation and senescence, promoting chronic inflammation and exacerbating CKD progression. The exact mechanisms by which gut-derived uremic toxins modulate these alterations remain poorly understood. We hypothesize that microbiome depletion reduces uremic toxin accumulation and immune activation, thereby slowing CKD progression.

Methods

Experimental CKD was induced in 129Sv mice by 5/6 nephrectomy (STNx). Mice were given a non-absorptive antibiotic (Abx) cocktail in drinking water for microbiota depletion or control (Ctrl) throughout the 13-week study period. Plasma, feces, and urine were collected longitudinally to explore metabolite dynamics and CKD progression using untargeted Nuclear Magnetic Resonance (NMR), followed by a targeted approach.

Results

Measurement of 16S gene abundance confirmed the suppression of intestinal microbial load in Abx groups. 16S sequencing of fecal samples showed alterations of bacterial taxa by STNx, with some taxa being reminiscent of human CKD. Abx-STNx mice showed improved kidney function compared to STNx (FITC-sinistrin GFR 113.2 ± 57.21 µl/min vs. 53.32 ± 41.05 µl/min; p = 0.0028). Abx-STNx mice exhibited reduced systemic inflammation, with lower plasma C-reactive protein levels (56.88 ± 16.21 µg/L vs. 78.57 ± 16.57 µg/L; p = 0.0024). Untargeted NMR analysis identified a unique metabolite profile, with higher accumulation of 36.8% the detected metabolome in STNx (p = 0.05) compared to only 18.2% in Abx-STNx (p = 0.05), suggetsing that half of the metabolite accumulation in CKD is microbiome-dependent. To further explore the mechanistic link between metabolite accumulation and inflammation, we assessed the aryl hydrocarbon receptor (AhR)-activating potential. Moreover, organ-specific (blood, spleen, heart, intestine) immune cell composition was analyzed.

Conclusion

Microbiome depletion in experimental CKD improves kidney function. Abx impacted plasma metabolite profiles, leading to reduced inflammation. These proof-of-concept experiments underscore the microbiome as treatment target for in CKD.