Microbes and GFR in Health and CKD in Mice

Key Points – Microbes regulate GFR in health and CKD in mice. Tubuloglomerular feedback initially contributes to the microbial modulation of GFR. Background – Microbes are implicated in a variety of host physiologic and pathophysiologic processes. In this study, we tested the hypothesis that microbes modulate GFR in health and CKD.Methods – To uncover the effect of gut microbiota on kidney function in health and in a CKD model, we examined GFR, plasma creatinine, and kidney histology in mice when gut microbes were manipulated.Results – In healthy mice, GFR was significantly increased when gut microbiota were either suppressed (oral antibiotics) or absent (germ-free). In mice challenged with adenine diet to induce CKD with impaired GFR, suppressing gut microbes with oral antibiotics also increased GFR. In females on an adenine diet, oral antibiotics increased GFR versus adenine alone on weeks 4 and 6. In males, oral antibiotics elevated GFR on week 2. Adenine diet significantly increased plasma creatinine and kidney fibrosis; this was suppressed by oral antibiotics in both sexes. To explore the mechanism, we tested the hypothesis that altered tubuloglomerular feedback contributes to elevated GFR using the sodium-glucose cotransporter 2 inhibitor empagliflozin; empagliflozin impairs Na⁺ reabsorption in the proximal tubule, altering tubuloglomerular feedback. Empagliflozin impaired antibiotics-induced GFR increases on week 3 but not week 5, suggesting that altered tubuloglomerular feedback contributes to the initial increase in GFR.Conclusions – The microbiome plays a key role in “setting” baseline GFR by a mechanism that partially involves tubuloglomerular feedback, and suppressing gut microbes can elevate GFR even in CKD mice.