Chronic gastrointestinal problems may begin with what is in a patient’s mouth. In a study published Thursday in Science, an international team of researchers—including one from Harvard—reported on strains of oral bacteria that, when swallowed in the 1.5 liters of saliva that people ingest every day, can lodge in the gut and trigger inflammatory bowel conditions like Crohn’s disease and ulcerative colitis.
“For some time now, we’ve noticed that when we look at the microbiome of patients with inflammatory bowel disease, or IBD, we’ve found microbes there that normally reside in the oral cavity,” says study co-author Ramnik Xavier, chief of gastroenterology at Massachusetts General Hospital (MGH), a member of the Broad Institute of MIT and Harvard, and co-director of MIT’s Center for Microbiome Informatics and Therapeutics.
“Over the years,” Xavier explains, “we’ve spent a lot of time identifying genes associated with inflammatory bowel disease—basically, identifying genetic variants that increase patients’ risk of disease.” Simultaneously, “There’s always been this other search, asking, ‘Are there pathobionts?’”—in other words, microbes that live innocuously in one part of the body but can turn pathogenic when moved to another. “For some time we have been looking for pathobiont organisms for Crohn’s and colitis.”
The researchers believe they have found them: two strains of Klebsiella bacteria, microbes commonly found in the mouth. In the study, led by Koji Atarashi from Japan’s Keio University, scientists administered saliva from two patients with Crohn’s disease to two groups of germ-free mice. Although one group did not get sick, the other developed a strong immune response associated with Crohn’s. Sorting through the bacteria in that group’s saliva sample, the researchers pinpointed a strain of Klebsiella pneumoniae as the trigger for the immune response. A subsequent experiment using samples from two ulcerative colitis patients turned up another inflammation-causing strain, of Klebsiella aeromobilis.
“So then we asked the question,” Xavier says, “is this unique to two-plus-two patients in Japan, or do we see these same pathobionts in other clinical centers?” Checking databases of thousands of IBD patients at MGH and the Hospital of the University of Pennsylvania, Xavier and others found that people with inflammatory bowel conditions had significantly more Klebsiella bacteria in their gut microbiome than healthy patients did. Most likely, he explains, oral bacteria, including Klebsiella, traffics through everyone’s gut in the saliva we swallow. Usually it passes through harmlessly; but in people with a genetic susceptibility to IBD that alters the gut microbiome, the Klebsiella has a chance to take hold in the intestine and proliferate, inducing an immune response that causes the disease. “This is a clear, elegant example of gene-microbe interaction,” Xavier says.
And there is another twist: Klebsiella bacteria are often extremely resistant to multiple antibiotics. That explains, Xavier says, “why antibiotics have limited value in treating patients with Crohn’s disease and ulcerative colitis. And with this bug, the more antibiotic resistance it acquired, the more likely it was to persist in the gut and cause this immune response.” In their experiments, when the researchers introduced saliva from IBD patients to healthy, normal mice, the Klebsiella generally failed to colonize the gut; but when those mice had been given antibiotics beforehand to which the bacteria had resistance, the Klebsiella did persist and multiply in the intestine. “For a long time, I’ve tried to discourage patients from taking antibiotics for inflammatory bowel disease,” Xavier says. “Because we also showed in a 2014 paper that patients who took antibiotics—and this has been seen in the old clinical data accumulated before the microbiome was even examined in IBD—that patients who took antibiotics early in the disease had more complicated outcomes.”
There is more research to be done to confirm and extend the results of this study, but Xavier believes this paper opens a useful path for other disease investigation. “This is a direction that research on the role of the microbiome in inflammatory bowel disease—and many other diseases—should take,” he says. “Because once you identify these types of bugs, then you have a target.” Already, he adds, other teams are working on therapies to kill or remove these two Klebsiella strains. With this paper and others forthcoming that are related to it, “We’ll be in a good position to define what the microbiome changes are in inflammatory bowel disease and where we can intervene.”
