Host-derived nitrate fuels indole production by <i>Escherichia coli</i> to drive chronic kidney disease progression.

Abstract

Chronic kidney disease (CKD) is linked to an elevated fecal abundance of <i>Enterobacteriaceae</i>, but the ecological drivers of this shift and its impact on disease progression remain unclear. The uremic toxin indoxyl sulfate is produced from microbiota-derived indole in the liver. Here, we found that in mice with adenine-induced CKD, impaired clearance of indoxyl sulfate elevated mucosal expression of the gene encoding inducible nitric oxide synthase (iNOS). The resulting rise in luminal nitrate levels promoted <i>Escherichia coli</i> growth by means of nitrate respiration. Fecal microbiota from CKD patients generated more indole than feces of healthy controls during anaerobic culture, but only in the presence of nitrate. Nitrate enhanced indole production by <i>E. coli</i>, thereby worsening renal pathology in CKD mice, which was mitigated by iNOS inhibition.