Therapeutic strategies to limit tryptophan metabolites toxicity during chronic kidney disease

Chronic kidney disease (CKD) is characterized by an accumulation of uremic toxins that interact negatively with biological functions. Among these toxins, tryptophan metabolites are the most representative gut-derived uremic toxins and have emerged as an important therapeutic target. Tryptophan is metabolized via three pathways, leading to serotonin, kynurenines, and indole derivatives. The last one is the precursor of indoxyl sulfate (IS) and indole-3-acetic acid (IAA) by the gut microbial fermentation of dietary tryptophan. There are growing experimental and clinical data that demonstrate the role of IS and IAA on renal disease progression and cardiovascular complications. Also, IS/IAA seems to play a deleterious role in bone metabolism and muscle function. Majority of study found an association between high IAA/IS levels and mortality in CKD and hemodialyzed patients. Indoles act as ligands of the aryl hydrocarbon receptor (AhR). The activation of AhR induces the expression of several enzymes and proteins involved in the inflammation, coagulation state, and oxidative stress. Because the majority of tryptophan metabolites of interest are products by intestinal microbiota, strategies that could modulate its composition appear as an attractive therapeutic. Preliminary data have demonstrated a beneficial effect of the adsorbent AST-120 to reduce the toxic effect of IS/IAA but it was not confirmed in large randomized controlled trials. The capacity of pre/probiotic to reduce tryptophan metabolites accumulation must be determined in large randomized controlled trials. In the future the association of profiling of microbes (metagenomics) with a quantification of TRP catabolites (metabolomics) in stool samples from human CKD cohorts will be innovative data that will enable development of specific tools to modulate intestinal microbiota. With all these new strategies, we hope to decrease the progression of not only CKD but also cardiovascular and bone diseases and sarcopenia.