Role of the Gut Microbiome in Uremia: A Potential Therapeutic Target

Abstract

Also known as the "second human genome," the gut microbiome plays important roles in both the maintenance of health and the pathogenesis of disease. The symbiotic relationship between host and microbiome is disturbed due to the proliferation of dysbiotic bacteria in patients with chronic kidney disease (CKD). Fermentation of protein and amino acids by gut bacteria generates excess amounts of potentially toxic compounds such as ammonia, amines, thiols, phenols, and indoles, but the generation of short-chain fatty acids is reduced. Impaired intestinal barrier function in patients with CKD permits translocation of gut-derived uremic toxins into the systemic circulation, contributing to the progression of CKD, cardiovascular disease, insulin resistance, and protein-energy wasting. The field of microbiome research is still nascent, but is evolving rapidly. Establishing symbiosis to treat uremic syndrome is a novel concept, but if proved effective, it will have a significant impact on the management of patients with CKD.

Keywords: Gut microbiome; amine; ammonia; chronic kidney disease (CKD); end-stage renal disease (ESRD); indole; metabolome; microbial metabolite; p-cresyl sulfate (PCS); phenol; review; thiol; urea; uremic syndrome; uremic toxin.

Figure 1

Schematic representation of the association between uremia, dysbiotic gut microbiome, gut-derived uremic toxins, and the clinical manifestations of these uremic toxins.

Figure 2

Schematic showing some of the major toxic metabolites originating from synthesis by dysbiotic gut microbiome and potential pathways linking their accumulations to pathophysiological consequences in CKD, including in ESRD. Increased intestinal concentration of uremic toxins associated with the progression of CKD leads to microbial dysbiosis. p-Cresol, produced by the intestinal microbiota from the amino acid tyrosine, inhibits colonocyte respiration and proliferation, and at higher concentrations, increases DNA damage and becomes genotoxic towards colonocytes. Overgrowth of pathogenic bacteria, the loss of barrier integrity, and the breach in the epithelia barrier lead to endotoxemia. Circulating endotoxin, also referred to as lipopolysaccharide (LPS), activates production of inflammatory cytokines. Endotoxin translocation from the gut has been suggested as one of the causes of inflammation in CKD.^, Amongst the most studied uremic toxins are phospholipid metabolites and bacterial products of choline degradation, such as TMAO, which has been associated with CVD. TMAO causes alteration of cholesterol and sterol metabolism, promotes foam cell formation by increasing expression of scavenger receptors on macrophages, and leads to alternations in bile acid metabolism and sterol transporters both within the liver and intestine. Other uremic toxins include cometabolites of phenols (eg, PCS), and indoles (eg, IS), which have been associated with progression of CKD, CVD, and mortality in hemodialysis patients. Accumulation of PCS in human tubular cells leads to Nox4-dependent ROS generation via upregulation of Nox4 and p22phox, which subsequently enhance the expression of inflammatory cytokines and profibrotic factors, resulting in cell injury. Activation of PI3-K and PKC mediate the stimulatory effect of PCS on Nox4 and NADPH oxidase. IS induces nephrotoxicity via organic anion transporter–mediated uptake in the basolateral membrane of renal proximal tubular cells, where it activates NF-κB and plasminogen activator inhibitor type 1 expression. ROS, reactive oxygen species

Figure 3

Schematic illustration of amino acid, ammonia (NH₃), and urea flux between the gastrointestinal tract and liver. Urea is produced via the urea cycle in the liver from dietary amino acids and by their catabolism in peripheral tissues. Urea is then excreted into the gastrointestinal system and into the urine. Within the intestinal tract, gut bacteria, particularly coliforms and anaerobes in the colon and cecum, convert dietary amino acids and urea into ammonia and CO₂, using microbial urease. Some of this ammonia is, in turn, converted to ammonium hydroxide which raises the luminal fluid’s pH before being excreted in feces. The remaining ammonia is absorbed into the portal circulation and converted back to urea via the urea cycle in the liver. Of the total ammonia produced, the majority enters the urea cycle, with the remaining smaller proportions being metabolized by peripheral tissues.

Figure 4

The cause-consequence relationship between gut dysbiosis and CKD. Human genome affects gut microbiome, and together, in presence of a specific dysbiotic microbiome or absence of protective microbiome, they can increases the susceptibility to kidney disease when exposed to insult. Subsequent maladaptive changes of microbiome in response to uremic state, and in association with traditional risk factors, lead to further increased generation of uremic toxins and disease progression.