What If Not All Metabolites from the Uremic Toxin Generating Pathways Are Toxic? A Hypothesis

Abstract

The topic of uremic toxicity has received broad attention from the nephrological community over the past few decades. An aspect that is much less often considered is the possibility that the metabolic pathways that generate uremic toxins also may produce molecules that benefit body functions. Here, we discuss this dualism based on the example of tryptophan-derived metabolites, which comprise elements that are mainly toxic, such as indoxyl sulfate, kynurenine and kynurenic acid, but also beneficial compounds, such as indole, melatonin and indole-3-propionic acid, and ambivalent (beneficial for some aspects and harmful for others) compounds such as serotonin. This dualism can also be perceived at the level of the main receptor of the tryptophan-derived metabolites, the aryl hydrocarbon receptor (AHR), which has also been linked to both harm and benefit. We hypothesize that these beneficial effects are the reason why uremic toxin generation remained preserved throughout evolution. This duality is also not unique for the tryptophan-derived metabolites, and in this broader context we discuss the remote sensing and signaling theory (RSST). The RSST proposes that transporters (e.g., organic anion transporter 1-OAT1; ATP-binding cassette transporter G-ABCG2) and drug metabolizing enzymes form a large network of proteins interacting to promote small molecule remote communication at the inter-organ (e.g., gut-liver-heart-brain-kidney) and inter-organismal (e.g., gut microbe-host) levels. These small molecules include gut microbe-derived uremic toxins as well as beneficial molecules such as those discussed here. We emphasize that this positive side of uremic metabolite production needs more attention, and that this dualism especially needs to be considered when assessing and conceiving of therapeutic interventions. These homeostatic considerations are central to the RSST and suggest that interventions be aimed at preserving or restoring the balance between positive and negative components rather than eliminating them all without distinction.

Keywords: aryl hydrocarbon receptor; gut microbiome; indoles; kidney disease; kynurenines; metabolism; remote sensing and signaling theory; tryptophan; uremia; uremic toxins.

Figure 1

Global metabolic pathways of tryptophan according to the most recent insights. Different enzymes are involved in the generation of uremic toxins and activators of aryl hydrocarbon receptor (AhR). (1) Tryptophanase; (2) indoleamine-2,3-dioxygenases (IDOs) and tryptophan-2,3-dioxgenase (TDO) and (3) the newly identified interleukin 4-induced-1 (IL4I1). Indole is further metabolized in the liver (green arrows) by cytochrome P450 family 2 subfamily E member 1 (CYP2E1), resulting in indoxyl and indoxyl sulfate (sulfotransferase) and indole-3-acetic acid (acetate transferase). Both the IDOs/TDO (red arrows) and IL4I1-dependent pathways (purple arrows) are involved in the generation of kynurenic acid. The end-metabolites are excreted by the kidneys (yellow arrows). For the sake of completeness, in grey, (4) the serotonin pathway.

Figure 2

Main metabolites of tryptophan. Extracted from Kyoto Encyclopedia of Genes and Genomes) (KEGG) pathways). The compounds with a colored background are discussed in the paper. Green background: mainly positive effect; red background: mainly negative effect; orange background: ambiguous data. Black frame: kynurenic acid pathway. Upper part: intestinal lumen; lower part: inside the body. Indole-3 propionic acid and Indole-3-(carbox)aldehyde are not mentioned in the KEGG pathways.

Figure 3

Summary of the biological effects of the tryptophan metabolites discussed in this publication. Red: negative effect; green: positive effect; orange: conflicting data. CKD: chronic kidney disease. IxS: indoxyl sulfate; IxG: indoxyl glucuronide; KYN: kynurenine/kynurenic acid; AA: anthranilic acid; QA: quinolinic acid; Trp: tryptophan; Ind: indole; IPA: indole-3-propionic acid; IA: indole-3-(carbox)aldehyde; Mel: melatonin; Nic: nicotinic acid/nicotinamide; Ser: serotonin; IAA: indole-3-acetic acid; 2PY: 1-methyl-2-pyridone-5-carboxamide.

Figure 4

Normal and abnormal (uremic) remote sensing and signaling. Please see text for a detailed explanation of the remote sensing and signaling theory of interorgan and inter-organismal (gut microbe–host) communication via small molecules that regulate metabolism, signaling, and oxidative state. The proteins mediating these effects of small molecules include transporters, drug metabolizing enzymes, and nuclear receptors. Some of the regulated molecules include gut microbe-derived uremic toxins.

Figure 5

Evolutionary time scale of the main elements at play in uremic toxin generation on a 24 h scale. (A) Evolution starting with the vertebrates up to now; (B) enlargement of the boxed section in (A), starting with the hominins until now. If the vertebrates appear at time 0, homo sapiens appear only during the last minutes, and the agricultural revolution is only a fraction of the homo sapiens period. Whereas sulfotransferases appear long before the animals and the intestinal microbiome appears with the invertebrates (i.e., for both before this scale starts), the current conditions leading to an epidemic propensity of CKD appear only very late, with the agricultural revolution. However, this period is long enough to cover several hundreds of generations. The red section in panel (A) and the blue section in panel (B) are enlarged out of proportion to the other sections to allow visibility.