The largest clinical study of its kind is revealing new insights into the causes of Crohn's disease, a periodic inflammation of the intestines. The research, which involved 668 children, shows that numbers of some beneficial bacteria in the gut decrease in Crohn's patients, while the number of potentially harmful bacteria increases. The study could lead to new, less invasive diagnostic tests; it also shows that antibiotics—which aren't recommended for Crohn's but are often given when patients first present with symptoms—may actually make the disease worse.
Crohn’s disease is one of the two major inflammatory bowel diseases (IBDs); the other is ulcerative colitis, a similar condition that affects only the colon. Both have been on the rise in the developing world since the early 1950s; now, an estimated 1.4 million people suffer from IBD in the United States alone. Symptoms include diarrhea, abdominal pains and cramping, and intestinal ulcers.
Genetic studies have turned up several genes that appear to predispose for IBD, most of them involved in the body’s immune response. But genes alone can't explain the sharp rise in IBD incidence, and scientists have looked at the environment—in particular diet and antibiotic use—for answers.
Several studies have shown that Crohn’s disease is characterized by microbial dysbiosis, a shift in the microbial populations inhabiting the gut, but it's difficult to unravel cause and effect: A change in gut microbiota can cause inflammation, but the reverse can also occur. Complicating the picture is the fact that before being diagnosed with IBD, patients often receive antibiotics to fend off a supposed gut infection that could be causing the symptoms, which also have a powerful impact on the microbial populations living in our guts.
Now, a group headed by Ramnik Xavier, a gastroenterologist at Harvard Medical School in Boston, has collected fecal samples and taken biopsies of the lower part of the small intestine and rectum from 447 children who had just been diagnosed with Crohn's, and a control group of 221 kids who had noninflammatory abdominal symptoms, such as bloating and diarrhea. In contrast with previous studies, the majority of patients had not yet received antibiotics or anti-inflammatory drugs. Based on their genetic material, the researchers determined the relative abundance of a range of microbial species in the samples.
Some potentially harmful microbial species were more abundant in Crohn's patients, such as those belonging to the Enterobacteriaceae, Pasteurellaceae, Veillonellaceae, and Fusobacteriaceae; numbers of the Erysipelotrichales, Bacteroidales, and Clostridiales, generally considered to be beneficial, were lower. The disappearance and appearance of species can be equally important, says Dirk Gevers of the Broad Institute in Cambridge, Massachusetts, who performed most of the work. "There has been a shift in the ecosystem, which affects both types.”
But those differences were found mostly in the biopsy samples; there weren't many differences between the feces from Crohn's patients and the control group. At this early stage of the disease, "the dysbiosis seems not to have reached the stool yet," Gevers says.
The dysbiosis was almost as severe in biopsies from the rectum as in those from the lower part of the small intestine, the team reports today in Cell Host & Microbe. That means that in the future, a diagnostic test of Crohn's might be based on a simple rectal swab rather than a colonoscopy, which is the current standard, Gevers says—a far less stressful procedure for the patient.
The dysbiosis was also more pronounced in patients who had received antibiotics. "This study confirms that these drugs don’t do any good to people with Crohn’s disease," says gastroenterologist Séverine Vermeire of the Catholic University of Leuven in Belgium, who was not involved in the study. "We knew antibiotic use increases the risk to develop the disease; now we know they can worsen it, too."
The results are "very encouraging diagnostic signals," adds Pierre Rimbaud, chief medical officer at Enterome, a Paris-based company that is developing microbiota-based diagnostics. But he emphasizes that the study still doesn't show whether the dysbiosis is the cause or the effect of the inflammation seen in Crohn's disease. Gevers agrees; to find out, scientists could inoculate mice that have been raised in a completely sterile environment, allowing them to test the effect of individual microbial species. One of these microbes, Faecalibacterium prausnitzii, has previously been described as an anti-inflammatory species that could become a so-called probiotic for the treatment of IBD.
Vermeire says it's a "missed opportunity" that the researchers didn't look at the patients' diets. "That could have helped elucidate why this disease occurs so much more in the Western world than elsewhere." In 2011, Vermeire’s group published a study showing that healthy family members of Crohn’s disease patients have a slight dysbiosis as well. Vermeire is convinced that even in these families, it's not genetics but some lifestyle factor that causes the phenomenon. "If we could identify the dysbiosis in an early stage, and we knew the causative factors,” she says, “we could prevent disease occurrence by bringing about lifestyle changes.”