Microbes and Glomerular Filtration Rate in Health and CKD in Mice.

Abstract

BACKGROUND Microbes are implicated in a variety of host physiological and pathophysiological processes. In this study, we tested the hypothesis that microbes modulate glomerular filtration rate (GFR) in health and chronic kidney disease. METHODS To uncover the effect of gut microbiota on kidney function in health and in a chronic kidney disease (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 antibiotics also increased GFR. In females on an adenine diet, antibiotics increased GFR versus adenine alone on weeks 4 and 6. In males, antibiotics elevated GFR on week 2. Adenine diet significantly increased plasma creatinine and kidney fibrosis; this was suppressed by 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 antibiotic-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 which partially involves tubuloglomerular feedback, and, suppressing gut microbes can elevate GFR even in CKD mice.