Gut-Derived Metabolites and Their Role in Immune Dysfunction in Chronic Kidney Disease

Abstract

Several of the uremic toxins, which are difficult to remove by dialysis, originate from the gut bacterial metabolism. This opens opportunities for novel targets trying to decrease circulating levels of these toxins and their pathophysiological effects. The current review focuses on immunomodulatory effects of these toxins both at their side of origin and in the circulation. In the gut end products of the bacterial metabolism such as p-cresol, trimethylamine and H₂S affect the intestinal barrier structure and function while in the circulation the related uremic toxins stimulate cells of the immune system. Both conditions contribute to the pro-inflammatory status of patients with chronic kidney disease (CKD). Generation and/or absorption of these toxin precursors could be targeted to decrease plasma levels of their respective uremic toxins and to reduce micro-inflammation in CKD.

Keywords: chronic kidney disease; gut; immune; uremic toxins.

Figure 1

End products of the intestinal bacterial metabolism (I, IAA, pC, TMA, H₂S) are transported as such or after detoxification (sulfatation and glucuronidation) towards the liver via the portal vein where the remaining pC and I are conjugated and TMA is oxygenated. The end products of the bacterial and human metabolism are taken up into the circulation (IxS, IAA, pCS, pCG, TMAO, H₂S) where some bind to albumin (IxS, IAA, pCS and to a lesser extend pCG). H₂S is also generated by different tissues throughout the body. Finally, these compounds are excreted into the urine. Trp: tryptophan; Tyr: tyrosine; Cys: cysteine; I: indole; IAA: indole-3-acetic acid; pC: p-cresol; TMA: trimethylamine; TMAO: trimethylamine N-oxide; pCS: p-cresyl sulfate; pCG: p-cresyl glucuronide; IxS: indoxyl sulfate.