Effect of SGLT1 inhibition in the gut on the renal function

Sodium-dependent glucose cotransporters (SGLTs) have attracted considerable attention as a new target for T2DM. In the kidney, inhibition of SGLT2 in the proximal tubules show reno-protective effects. On the other hand, SGLT1 is the primary transporter for glucose absorption from the gastrointestinal tract, but the effect of SGLT1 inhibition in the gut on the renal function was unclear. Here we examined the effect of SGL5213, a novel and potent intestinal SGLT1 inhibitor, in a renal failure model. SGL5213 improved renal function and reduced gut-derived uremic toxins (phenyl sulfate and trimethylamine-N-oxide) in an adenine-induced renal failure model. Histological analysis revealed that SGL5213 ameliorated renal fibrosis and inflammation. SGL5213 also reduced gut inflammation and fibrosis in the ileum which is a primary target of SGL5213. Examining the gut microbiota community revealed that the Firmicutes/Bacteroidetes ratio, which suggests gut dysbiosis, was increased in renal failure and SGL5213 rebalanced the ratio through increasing Bacteroidetes and reducing Firmicutes. At the genus level, Allobaculum (a major component of Erysipelotrichaceae) was significantly increased in the RF group, and the increase was cancelled by SGL5213.