In 2008, nearly 300,000 infants in China got sick from milk formula tainted with melamine, a plastics additive that was used illegally to bulk up the formula's apparent protein content. Now, a study in rats implicates bacteria living in the gut as unwitting accomplices in this mass poisoning. The work helps clarify how melamine toxicity arises and also drives home the key role that gut bacteria play in human health.
Melamine is an industrial chemical used as a fire retardant and a stabilizer for plastics. In 2007, a rash of kidney stones in dogs and cats in the United States was traced to melamine-contaminated gluten from China. Then in September 2008, scores of infants in China were hospitalized for kidney stones; at least six died. Subsequent investigations uncovered melamine in powdered infant formula and fresh milk produced by more than 2 dozen companies. To stretch profits, milk brokers and other individuals had diluted milk and then added melamine to make the products pass spot checks for required protein content.
Typically, melamine-induced kidney stones are crystals of melamine comingled with a chemical relative called cyanuric acid. "It only takes a small amount of cyanuric acid to trigger the stone formation and kidney toxicity," says Wei Jia, a pharmacologist from the University of North Carolina, Greensboro. The contaminated pet food contained both additives. But cyanuric acid was not in the infant formula, so it was initially unclear why kidney stones formed in the children.
Jia first began to suspect microbes after he and his colleagues noticed that metabolites produced by gut bacteria in rats are different after exposure to melamine. They wondered if bacteria had converted some melamine to cyanuric acid. They tested this idea by giving rats antibiotics for 4 days before exposing them to melamine for 2 weeks. Kidney stones and damage was much less pronounced in those rats compared with rats that didn't get the antibiotics, they report today in Science Translational Medicine. Moreover, the rats on antibiotics excreted twice as much melamine, likely because there were no bacteria present to convert melamine to cyanuric acid.
Jia's team put rat feces in a container with nutrients and melamine. Over 36 hours, the amount of melamine decreased and cyanuric acid appeared in the container, demonstrating that bacteria in the poop were converting melamine to cyanuric acid. The researchers winnowed down the suspects to bacteria called Klebsiella and found that this microbe on its own processed melamine into cyanuric acid and other byproducts. Kidney damage was worse if rats were given these bacteria before they were exposed to melamine, the researchers report.
"They very methodically demonstrated through a huge number of experiments that these products are generated by the gut microbes," says Andrew Patterson, a molecular biologist at Pennsylvania State University, University Park, who was not involved with the work. "That they were able to nail down a culprit out of the whole mess of the bacteria in the gut was very impressive."
During the 2008 adulterated milk incident, less than 1% of infants who drank the tainted dairy products got sick. That's approximately the same percentage of people who carry Klebsiella in their guts, Jia points out. He suspects that only those children with the melamine-converting bacteria were harmed.
"They make a pretty compelling argument," Patterson says, "but it will be a very hard thing to prove unequivocally that this is what happens in humans." Given stepped-up monitoring, the likelihood of another melamine incident is small, adds David Goldfarb, a nephrologist at New York University School of Medicine in New York City. Nonetheless, he says, the study "shows that [gut bacteria are] a very important part of our health."