Nutrients Turned into Toxins: Microbiota Modulation of Nutrient Properties in Chronic Kidney Disease

Abstract

In chronic kidney disease (CKD), accumulation of uremic toxins is associated with an increased risk of death. Some uremic toxins are ingested with the diet, such as phosphate and star fruit-derived caramboxin. Others result from nutrient processing by gut microbiota, yielding precursors of uremic toxins or uremic toxins themselves. These nutrients include l-carnitine, choline/phosphatidylcholine, tryptophan and tyrosine, which are also sold over-the-counter as nutritional supplements. Physicians and patients alike should be aware that, in CKD patients, the use of these supplements may lead to potentially toxic effects. Unfortunately, most patients with CKD are not aware of their condition. Some of the dietary components may modify the gut microbiota, increasing the number of bacteria that process them to yield uremic toxins, such as trimethylamine N-Oxide (TMAO), p-cresyl sulfate, indoxyl sulfate and indole-3 acetic acid. Circulating levels of nutrient-derived uremic toxins are associated to increased risk of death and cardiovascular disease and there is evidence that this association may be causal. Future developments may include maneuvers to modify gut processing or absorption of these nutrients or derivatives to improve CKD patient outcomes.

Keywords: caramboxin; carnitine; choline; chronic kidney disease; gut–kidney axis; indoxyl sulfate; microbiota; p-cresyl sulfate; trimethylamine N-Oxide (TMAO); tryptophan; tyrosine.

Figure 1

Microbiota–host interaction and modulation by dietary nutrients. When humans feed themselves, they are also feeding their microbiota. The precise nutrients ingested will favor the growth of bacteria that feed on ingested nutrients, in detriment of bacteria that feed on nutrients that a person is not ingesting. The microbiota competes with the host for certain nutrients, such l-carnitine. Thus, oral l-carnitine supplementation promotes the growth of l-carnitine metabolizing bacteria and may result in decreased l-carnitine absorption. Some waste molecules from bacterial feeding will be absorbed systemically and metabolized to uremic toxins that accumulate if not excreted in urine.

Figure 2

Carambola (star fruit) and caramboxin. CKD patients should be instructed to recognize and avoid carambola because of the risks it entails.

Figure 3

From nutrients to toxins: (A) Metabolic pathways for generation of the uremic toxin TMAO from dietary l-carnitine and choline; (B) metabolic pathways for generation of the uremic toxins p-cresyl-sulfate and p-cresyl-glucuronide from dietary tyrosine; and (C) metabolic pathways for generation of the uremic toxins indoxyl sulfate and indole-3-aldehyde from dietary tryptophan. The uremic toxins thus generated are excreted by the kidneys in healthy subjects but accumulate as uremic toxins in individuals with CKD.

Figure 4

Mechanisms of toxicity for nutrient-derived uremic toxins. The molecular mechanisms of uremic toxin toxicity are starting to be elucidated. The figure represents some key recently described pathways by which they may contribute to the two key consequences of CKD: CKD progression and accelerated cardiovascular aging.