Microbes Regulate Glomerular Filtration Rate in Health and Disease in Mice

Background: We hypothesized that the microbiome modulates glomerular filtration rate (GFR). Methods: Microbiota were depleted using antibiotics in drinking water (ABX: ampicillin, neomycin, vancomycin). Germ-free (GF) mice were born in the Johns Hopkins GF Facility. GFR was measured by transcutaneous detection of FITC-sinistrin clearance. Mice were treated with adenine to model chronic kidney disease (CKD). Results: GFR was significantly increased after microbiota depletion (ABX) in both sexes (Table 1, Study I). GFR was also significantly elevated in GF as compared to both control (ctrl) and conventionalized GF (CGF) mice in both sexes (Table 1, Study II). To determine if ABX increases GFR in CKD, mice were given adenine or adenine+ABX (simultaneously). Adenine decreased GFR. In females, adenine+ABX improved GFR (vs adenine) on weeks 4 and 6. In males, GFR improvement was seen on week 2 (Table 1, Study III). Plasma creatinine was significantly increased on adenine but normalized by ABX treatment in females (chow 0.19 mg/dl ±0.03 vs adenine 0.31±0.02, p=0.04; adenine vs adenine+ABX 0.15±0.03, p=0.005, n=7-9) and males (chow 0.17±0.03 vs adenine 0.65±0.07, p<0.0001; adenine vs adenine+ABX 0.40±0.04, p=0.005, n=7-9). Histological studies revealed that adenine increased collagen; ABX suppressed this increase in both females (chow 2.9±2.1 collagen area% vs adenine 7.2±7.4, p=0.0008; adenine vs adenine+ABX 4.5±4.0, p=0.02) and males (chow 2.2±2.1 vs adenine 8.7±6.6, p<0.0001; adenine vs adenine+ABX 6.2±4.6, p=0.02). 16S rRNA analysis on female feces indicated that Akkermansia muciniphila was elevated in adenine than chow diet, but adenine+ABX treatment decreased it. Conclusion: Both the absence (GF) and suppression (ABX) of gut microbes increased GFR in healthy females and males. Moreover, ABX partially improved kidney function in an adenine-induced CKD model. Funding: NIDDK Support