Melamine poisoning has become widely publicized after a recent
occurrence of renal injury in infants and children exposed to
melamine-tainted milk in China. This renal damage is believed to result
from kidney stones formed from melamine and uric acid or from melamine
and its cocrystallizing chemical derivative, cyanuric acid. However, the
composition of the stones and the mechanism by which the stones are
formed in the renal tubules are unknown. We report that cyanuric acid
can be produced in the gut by microbial transformation of melamine and
serves as an integral component of the kidney stones responsible for
melamine-induced renal toxicity in rats. Melamine-induced toxicity in
rats was attenuated, and melamine excretion decreased after antibiotic
suppression of gut microbial activity. We further demonstrated that
melamine is converted to cyanuric acid in vitro by bacteria cultured
from normal rat feces; Klebsiella was subsequently identified in fecal
samples by 16S ribosomal DNA sequencing. In culture, Klebsiella
terrigena was shown to convert melamine to cyanuric acid directly. Rats
colonized by K. terrigena showed exacerbated melamine-induced
nephrotoxicity. Cyanuric acid was detected in the kidneys of rats
administered melamine alone, and the concentration after Klebsiella
colonization was increased. These findings suggest that the observed
toxicity of melamine may be conditional on the exact composition and
metabolic activities of the gut microbiota.