Kidney Week

Abstract: SA-PO1194

Investigating the Kidney-Gut-Brain Axis in CKD: Effects of Choline Trimethylamine Lyase and SGLT2 Inhibitors

Session Information

• CKD: Mechanisms - 3
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Lee, Su mi, Division of Nephrology, Department of Medicine, University of California-Irvine, Irvine, United States

Su mi Lee, MD, PhD

• Zhao, Yitong, Division of Nephrology, Department of Medicine, University of California-Irvine, Irvine, California, United States

Yitong Zhao, PhD

• Tran, Tiffany, Division of Nephrology, Department of Medicine, University of California-Irvine, Irvine, California, United States

Tiffany Tran

• Vancheeswaran, Nikitha M., Division of Nephrology, Department of Medicine, University of California-Irvine, Irvine, California, United States

Nikitha M. Vancheeswaran

• Tran-Phung, Lily, Division of Nephrology, Department of Medicine, University of California-Irvine, Irvine, California, United States

Lily Tran-Phung

• Jung, Joshua J., Division of Nephrology, Department of Medicine, University of California-Irvine, Irvine, California, United States

Joshua J. Jung

• Hazen, Stanley L., Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, United States

Stanley L. Hazen, MD, PhD

• Fisher, Mark, Department of Neurology, University of California-Irvine, Irvine, California, United States

Mark Fisher, MD

• Lau, Wei Ling, Division of Nephrology, Department of Medicine, University of California-Irvine, Irvine, California, United States

Wei Ling Lau, MD, FASN

Background

Gut dysbiosis in CKD leads to increased uremic toxins including indoxyl sulfate (IS), p-cresyl sulfate (pCS) and trimethylamine N-oxide (TMAO). These toxins are associated with vascular injury and cognitive dysfunction. Choline trimethylamine lyase inhibitors such as iodomethylcholine (IMC) selectively block TMAO generation, while sodium-glucose cotransporter 2 (SGLT2) inhibitors such as canagliflozin have been shown to alter gut microbial composition. In this project, effects of IMC and canagliflozin therapy on the kidney-gut-brain axis were studied in CKD mice.

Methods

CKD was induced in male and female C57Bl/6J mice using dietary adenine. Controls (10-16 mice per group) and CKD animals (31-33 mice per group) were randomized to IMC, canagliflozin or IMC+canagliflozin treatment. Open field behavior test, serum levels of uremic toxins and brain microhemorrhage histology were analyzed.

Results

In CKD mice, serum creatinine was increased 4.5-fold while IS, pCS and TMAO levels were increased 6-fold compared to controls. On open field testing, CKD mice demonstrated decreased locomotor activity; higher serum creatinine, IS and pCS correlated with lower distance traveled. When stratified by sex, these findings remained significant in male mice only. Brain microhemorrhages were increased in CKD mice and correlated with decreased locomotor activity. IMC effectively reduced TMAO levels in CKD mice, but was noted to increase pCS in female CKD animals. Canagliflozin decreased serum TMAO and pCS, and decreased brain microhemorrhages (figure). The drug therapies did not improve locomotor scores.

Conclusion

Oral treatment with IMC or canagliflozin modified levels of gut-derived uremic toxins. The SGLT2 inhibitor decreased brain microhemorrhages but did not improve behavior scores. Further studies are needed to elucidate the role of the kidney-gut-brain axis in CKD-associated cognitive dysfunction.

Funding

• Other NIH Support