Contributory Role of Gut Microbiota and Their Metabolites Toward Cardiovascular Complications in Chronic Kidney Disease

Abstract

The gut microbiome recently has emerged as a novel risk factor that impacts health and disease. Our gut microbiota can function as an endocrine organ through its unique ability to metabolize various dietary precursors, and can fuel the systemic inflammation observed in chronic disease. This is especially important in the setting of chronic kidney disease, in which microbial metabolism can contribute directly to accumulation of circulating toxins that then can alter and shift the balance of microbiota composition and downstream functions. To study this process, advances in -omics technologies are providing opportunities to understand not only the taxonomy, but also the functional diversity of our microbiome. We also reliably can quantify en masse a wide range of uremic byproducts of microbial metabolism. Herein, we examine the bidirectional relationship between the gut microbiome and the failing kidneys. We describe potential approaches targeting gut microbiota for cardiovascular risk reduction in chronic kidney disease using an illustrative example of a novel gut-generated metabolite, trimethylamine N-oxide.

Keywords: Trimethylamine N-oxide; chronic kidney disease; gut microbiome; uremic toxins.

Figure 1

Dietary precursors are modified by the microbiota to generate an array of uremic toxins through multiple mechanisms at the level of the microbiota, intestinal wall, and liver. Influx of uremic toxins results in microbiota imbalance along with bacterial translocation and inflammation. These factors contribute to the multitude of systemic effects covered in this review.

Figure 2

Overview of TMAO metabolism. Dietary precursors such as red meat, fish, and eggs contain compounds that contain the TMA moiety which is released as TMA, absorbed into circulation and converted to TMAO in the liver. Circulating TMAO has been implicated in processes such as atherosclerosis, platelet activation as well as vascular inflammation. These processes contribute to the development of renal dysfunction. Destruction of tubular secretion mechanisms result in the accumulation of TMAO in the disease setting and contribute to a feed-forward cycle. Modified from Tomlinson et al. 2017.