Significance Here, we report that the kidney has an effective sensing and signaling mechanism to balance microbial metabolite levels in the human body. Using healthy volunteers and in vivo and in vitro assays, we show that the kidney responds to elevated endogenous metabolite levels and stimulates organic anion secretion by AhR and EGFR signaling, controlled by miR-223 and reactive oxygen species. This remote sensing function aids body homeostasis and has important implications for the identification of novel therapeutic targets to preserve kidney function in patients.