Microbial-Derived Tryptophan Catabolites, Kidney Disease and Gut Inflammation

Abstract

Uremic metabolites, molecules either produced by the host or from the microbiota population existing in the gastrointestinal tract that gets excreted by the kidneys into urine, have significant effects on both health and disease. Tryptophan-derived catabolites are an important group of bacteria-produced metabolites with an extensive contribution to intestinal health and, eventually, chronic kidney disease (CKD) progression. The end-metabolite, indoxyl sulfate, is a key contributor to the exacerbation of CKD via the induction of an inflammatory state and oxidative stress affecting various organ systems. Contrastingly, other tryptophan catabolites positively contribute to maintaining intestinal homeostasis and preventing intestinal inflammation-activities signaled through nuclear receptors in particular-the aryl hydrocarbon receptor (AhR) and the pregnane X receptor (PXR). This review discusses the origins of these catabolites, their effect on organ systems, and how these can be manipulated therapeutically in the future as a strategy to treat CKD progression and gut inflammation management. Furthermore, the use of biotics (prebiotics, probiotics, synbiotics) as a means to increase the presence of beneficial short-chain fatty acids (SCFAs) to achieve intestinal homeostasis is discussed.

Keywords: CKD; SCFAs; biotics; indoles; indoxyl sulfate; intestinal inflammation; tryptophan derivatives.

Figure 1

(A). Classification of uremic metabolites based on origin. Uremic metabolites have three possible origins, either endogenous metabolism, microbial metabolism, or from exogenous intake. (B). Classification of uremic metabolites sourced from microbial metabolism. Uremic metabolites sourced from microbial metabolism are further classified according to the involvement of microbiota in their synthesis; they are either the result of dietary component metabolism, produced by host and biochemically modified by microbiota or synthesised de novo by the microbiota. SCFAs: short chain fatty acids; PSA: polysaccharide-A [4].

Figure 2

Depiction of metabolic pathways of tryptophan. Serotonin, and kynurenine pathways (in yellow boxes) are processes occurring endogenously within host metabolism. Indole pyruvate pathway occurs intestinally as a result of enzymatic degradations performed by the microbiota population in three separate pathways; tryptophan dehydrogenase pathway, tryptophanase pathway, and the aromatic amino acid transaminase pathway. All catabolites are produced intestinally with the exception of indoxyl sulfate (in the grey box), which is produced hepatically [34].

Figure 3

Depiction of future experimental perspectives. The use of biotics represents an important therapeutic target to achieve eubiosis and reduce intestinal inflammation, either through the promotion of the synthesis of beneficial indole metabolites or through the enhanced synthesis of SCFAs. A decrease in the levels of deleterious metabolites such as indoxyl sulfate is warranted for the reduction of intestinal homeostasis.