Targeting the gut microbial metabolic pathway with small molecules decreases uremic toxin production

Abstract

Uremic toxins are a class of toxins that accumulate in patients with chronic kidney disease (CKD). Indoxyl sulfate (IS), a typical uremic toxin, is not efficiently removed by hemodialysis. Modulation of IS production in the gut microbiota may be a promising strategy for decreasing IS concentration, thus, delaying CKD progression. In the present study, we identified isoquercitrin (ISO) as a natural product that can perturb microbiota-mediated indole production without directly inhibiting the growth of microbes or the indole-synthesizing enzyme TnaA. ISO inhibits the establishment of H proton potential by regulating the gut bacteria electron transport chain, thereby inhibiting the transport of tryptophan and further reducing indole biosynthesis. This non-microbiocidal mechanism may enable ISO to be used as a therapeutic tool, specifically against pathologies triggered by the accumulation of the microbial-produced toxin IS, as in CKD. Herein, we have shown that it is possible to inhibit gut microbial indole production using natural components. Therefore, targeting the uremic toxin metabolic pathway in gut bacteria may be a promising strategy to control host uremic toxin production.

Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets

“…Isoquercitrin, a naturally occurring small molecule, was recently demonstrated to reduce indole production without having microbicidal activity or inhibiting tryptophanase activity. It was proposed that isoquercitrin suppressed indole production by reducing tryptophan transport into bacteria through inhibition of the bacterial electron transport chain protein complex I and weakening the proton motive force [69].…”

Bovine serum albumin aggravates macrophage M1 activation and kidney injury in heterozygous Klotho-deficient mice via the gut microbiota-immune axis

“…The intestine - the main organ of uremic toxin production and discharge 1 , 4 - 8 , 10 - exhibits mechanical, mucous, immune, and biological barriers, which maintain the intestinal tract and the internal environment of the body in a steady state 1 , 4 - 8 , 10 . Among them, the biological barrier is mainly composed of a large number of bacteria, viruses, protozoa, and fungi that parasitize the surface of the intestinal lumen 1 , 4 - 8 , 10 . Under normal circumstances, the intestinal microflora and the body are in dynamic equilibrium; when this balance is disrupted, it may damage the function of the intestinal barrier, leading to a change in the number and proportion of gut bacteria, or translocate them, causing endogenous infection 1 , 4 - 8 , 10 .…”

“…Among them, the biological barrier is mainly composed of a large number of bacteria, viruses, protozoa, and fungi that parasitize the surface of the intestinal lumen 1 , 4 - 8 , 10 . Under normal circumstances, the intestinal microflora and the body are in dynamic equilibrium; when this balance is disrupted, it may damage the function of the intestinal barrier, leading to a change in the number and proportion of gut bacteria, or translocate them, causing endogenous infection 1 , 4 - 8 , 10 . Some uremic toxins (such as AGE, phenols, indoles and TMAO) have strong biological effects 1 , 4 - 8 , 10 ; Mishima and others analyzed the distribution and structure of approximately 190 types of intestinal microorganisms in patients with renal failure and found an imbalance in their abundance; specifically, the abundance of lactic acid bacteria was significantly lower and that of fecal bacteria, Escherichia coli , and other microorganisms was significantly higher 40 .…”

“…Under normal circumstances, the intestinal microflora and the body are in dynamic equilibrium; when this balance is disrupted, it may damage the function of the intestinal barrier, leading to a change in the number and proportion of gut bacteria, or translocate them, causing endogenous infection 1 , 4 - 8 , 10 . Some uremic toxins (such as AGE, phenols, indoles and TMAO) have strong biological effects 1 , 4 - 8 , 10 ; Mishima and others analyzed the distribution and structure of approximately 190 types of intestinal microorganisms in patients with renal failure and found an imbalance in their abundance; specifically, the abundance of lactic acid bacteria was significantly lower and that of fecal bacteria, Escherichia coli , and other microorganisms was significantly higher 40 . An imbalance in the intestinal microecology--a decrease in the number and diversity of intestinal probiotics and an increase in the number and diversity of pathogens-damages the intestinal mucosa barrier, increases the intestinal mucosal permeability, translocates pathogenic bacteria and enterogenous endotoxins into the blood circulation, activates the intestinal mucosal immune system, and induces systemic inflammatory reaction, causing kidney damage.…”

“…Our previous study revealed that ranitidine and finasteride inhibit the synthesis and release of trimethylamine N-oxide and mitigate its cardiovascular and kidney damage through modulating gut microbiota 9 . Indoxyl sulfate is a typical uremic toxin that is not efficiently removed by hemodialysis; modulation of indoxyl sulfate production in the gut microbiota is a promising strategy for decreasing indoxyl sulfate concentration, thus delaying CKD progression 10 . Therefore, exploring the relationship between gut microbiota and kidney disease important for the development of effective therapeutic drugs.…”