Exploring the Gut-Kidney Axis in Chronic Kidney Disease: In Vitro Insights into Interorgan Crosstalk

Abstract

Kidney disease affects more than 10% of the global population and is recognized by the World Health Organization (WHO) as one of the top 10 threats to public health. Chronic kidney disease (CKD) is the most common form of kidney disease. Its underlying pathophysiology remains largely unclear, hindering the development of effective treatments. CKD is associated with significant morbidity and mortality, making it essential to investigate the multifactorial mechanisms that drive the onset and progression of the disease. Recent studies have highlighted the importance of the gut-kidney axis bidirectional interaction, regulating both gastrointestinal and kidney functions. Understanding the complex interplay between these organs and the factors contributing to CKD pathogenesis offers new opportunities for exploring therapeutic approaches. The research presented in this thesis focuses on gaining a better understanding of the gut-kidney axis in the development of CKD, with a specific focus on how dysfunction in these interconnected systems contributes to kidney disease. Chapter 2 provides a comprehensive overview of the potential of microphysiological systems (MPSs) to model the gut-kidney axis in CKD, to address the limitations of conventional in vitro systems and animal models and to mimic the (patho)physiological mechanisms of organ interconnections. Chapter 3 focuses on the therapeutic potential of short-chain fatty acids (SCFAs) in improving kidney function by regulating the activity of the organic anion transporter 1 (OAT1). This transporter is involved in the excretion of metabolic waste products and its function is impaired in CKD. The results show that SCFAs significantly enhance OAT1 activity by increasing the expression of the OAT1 gene and protein. These findings suggest that SCFAs can be applied as dietary interventions for CKD, offering a new strategy to improve proximal tubule excretory function and reduce uremic toxin accumulation. Chapter 4 investigates a novel intestinal in vitro system designed to mimic the apical mucus layer on the intestinal epithelium. The intestinal mucus layer is essential for nutrient absorption, intestinal barrier integrity, and homeostasis, and its disruption has been linked to various acute and chronic diseases. This in vitro model offers a robust platform for studying microbiota-derived metabolites and provides insight into the role of the intestinal mucus layer in detoxification and homeostasis. Chapter 5 makes further use of the novel intestinal in vitro system to explore the effects of fecal suspensions (FS) derived from CKD patients and healthy controls on intestinal barrier integrity. The findings show that FS from CKD patients in advanced stages significantly compromise the intestinal barrier, as evidenced by decreased expression of tight-junction proteins which facilitate the diffusion of uremic toxins. Chapter 6 provides a comprehensive summary and discussion of the findings in this thesis, emphasizing the importance of the gut-kidney axis in studying CKD pathogenesis and progression. By clarifying the relationship between gut health and kidney function, gut-targeted interventions (such as enhancing SCFA production, preserving mucus layer integrity, and protecting the intestinal epithelial barrier) can become novel CKD treatments. Overall, this thesis provides a solid foundation for developing integrated therapeutic approaches to address the multifaceted challenges of CKD.