Canagliflozin reduces plasma uremic toxins and alters the intestinal microbiota composition in a chronic kidney disease mouse model

Abstract

Accumulation of uremic toxins, which exert deleterious effects in chronic kidney disease, is influenced by the intestinal environment; the microbiota contributes to the production of representative uremic toxins, including p-cresyl sulfate and indoxyl sulfate. Canagliflozin is a sodium-glucose cotransporter (SGLT) 2 inhibitor, and it also exerts a modest inhibitory effect on SGLT1. The inhibition of intestinal SGLT1 can influence the gastrointestinal environment. We examined the effect of canagliflozin on the accumulation of uremic toxins in chronic kidney disease using adenine-induced renal failure mice. Two-week canagliflozin (10 mg/kg po) treatment did not influence the impaired renal function; however, it significantly reduced the plasma levels of p-cresyl sulfate and indoxyl sulfate in renal failure mice (a 75% and 26% reduction, respectively, compared with the vehicle group). Additionally, canagliflozin significantly increased cecal short-chain fatty acids in the mice, suggesting the promotion of bacterial carbohydrate fermentation in the intestine. Analysis of the cecal microbiota showed that canagliflozin significantly altered microbiota composition in the renal failure mice. These results indicate that canagliflozin exerts intestinal effects that reduce the accumulation of uremic toxins including p-cresyl sulfate. Reduction of accumulated uremic toxins by canagliflozin could provide a potential therapeutic option in chronic kidney disease.

What does sodium‐glucose co‐transporter 1 inhibition add: Prospects for dual inhibition

“…Thus, given at high doses, canagliflozin may serve as a dual SGLT1/2 inhibitor and have both direct and indirect effects related to blocking intestinal SGLT1. Further supporting this, canagliflozin significantly increased cecal short‐chain fatty acids (SCFA) in mice with CKD, suggesting increased bacterial carbohydrate fermentation in the intestine . Of note, canagliflozin's SGLT1 inhibitory action might not only be found in the intestine.…”

“…Surprisingly, treatment with a dual SGLT1/2 inhibitor did not affect relative abundance of bacterial orders or bacteria of interest in diabetic rodents . In contrast, in an adenine‐induced CKD mouse model, 2‐week canagliflozin treatment significantly altered microbiota composition in CKD mice . More studies are needed to better understand the role of SGLT1 and/or 2 inhibition on changes in gut microbiota.…”

Dapagliflozin Modulates the Fecal Microbiota in a Type 2 Diabetic Rat Model

“…The latter may augment glucose exposure of the colonic microbiota and formation of metabolites (11). It has been shown that canagliflozin altered the intestinal microbiota composition in mice with chronic kidney disease (12). The effects of dapagliflozin on fecal microbiota remain controversial.…”

Corrigendum: The new views on the state of the gut microbiota in obesity and diabetes mellitus type 2 (Diabetes mellitus. 2019;22(3). doi: 10.14341/DM10194)

“…В исследовании канаглифлозина по влиянию на кишечную микробиоту у животных с нарушением функции почек в группе приема препарата отмечалось увеличение КЦЖК в толстом кишечнике. При анализе микробного состава толстого кишечника не было выявлено значительной разницы в соотношении Firmicutes/Bacteroidetes, однако на уровне родов наблюдалось снижение количества Actinobacteria, Bifidobacterium и Oscillospira по сравнению с контрольной группой [51].…”