Exploring the Gut Microbiome in Chronic Kidney Disease

Abstract

Patients with chronic kidney disease (CKD) exhibit a disproportionate burden of cardiovascular disease and other comorbid conditions compared to the general population. It is speculated that this increased burden of comorbid conditions is partially driven by the systemic accumulation of gut-derived bacterial byproducts and the ensuing activation of innate immune pathways. As a result, researchers have directed their attention to the intestinal microbiome as a novel therapeutic target for reducing morbidity and mortality in CKD patients. In this dissertation, I will first summarize the current state of knowledge regarding the complex interactions between the intestinal microbiota and gut barrier function, highlighting how intestinal bacteria and components of the intestinal barrier contribute to the maintenance of an immune tolerant environment. Next, I will review the existing literature regarding the contribution of intestinal dysbiosis to chronic disease states, including CKD. Lastly, I will review the findings from my own experiments focused on: (1) determining how CKD alters the metabolism of trimethylamine N-oxide (TMAO), a novel uremic toxin that correlates with cardiovascular risk in CKD, and (2) characterizing how CKD impacts the expression patterns and activity of intestinal and hepatic alkaline phosphatases, a group of enzymes involved in the detoxification bacterial endotoxins and maintenance of intestinal barrier function.