Kidney and Gut Microbiome Crosstalk in Response to High Dietary Potassium

Abstract

In this study, we tested the hypothesis that the gut microbiome influences the homeostatic response to a dietary K+ load. Male Specific Pathogen Free (SPF) and Germ‐Free (GF) mice (n = 5 per group) received 5% potassium citrate or K+alimentary matched control diets for 7 days. At the time of sacrifice, blood and urine parameters were compared, and the expression of relevant transporters and signaling molecules was assessed in the kidney by western blotting. No significant differences in whole blood K+ were observed between SPF and GF mice on control or high K+ diets. However, differences in other parameters were observed. Compared to control diet treated SPF mice, K+ loaded SPF mice exhibited a significant decrease in hematocrit (37 vs 39; p ≤ 0.0152) and hemoglobin (12.58 vs 13.26; p ≤ 0.0150), whereas GF mice exhibited no differences in these parameters regardless of dietary maneuver. Blood urea nitrogen (BUN) levels were significantly decreased in SPF mice (23.4mg/dL vs 27; p ≤ 0.0180) on High K+compared to SPF controls, while this was not the case for GF mice. These findings suggest that K+ loaded GF mice were less volume expanded than K+ loaded SPF mice. Consistent with this, plasma aldosterone measurements were higher in K+ loaded GF mice compared to K+ loaded SPF mice (966pg/mL vs 614; p ≤ 0.0155). In whole kidney homogenates, dietary K+ loading markedly increased the cleaved (active) form of the epithelial sodium channel gamma subunit (γENaC) relative to control diet treated mice in both the SPF and GF groups. However, cleaved γENaC was one‐fold higher in the K+ loaded GF mice compared to K+ loaded SPF mice. K+ citrate loading significantly upregulated pendrin in both GF and SPF groups (p ≤ 5.7146E‐05 and p ≤ 5.6654E‐06), likely an effect of the alkaline content of the diet. Interestingly, we also observed a significant 91% increase in Aquaporin 2 (AQP2) levels in the GF high K+ group (p ≤ 0.0168) relative to GF mice treated with control diet, an effect that was not observed in SPF mice (p= 0.165). These findings indicate that male germ‐free mice maintain plasma [K+] in response to a dietary alkaline potassium load, but develop reduced volume status compared to K+ loaded SPF controls. To compensate, germ free mice exhibit plasma elevated aldosterone concentrations, and upregulate cleaved γENaC and AQP2 abundance in the kidney. This suggests that an intact gut microbiome helps to defend against excessive volume depletion during the homeostatic response to alkaline K+ loading.