The largest study of its kind has revealed for the first time the specific gut bacteria involved in Crohn's disease, which afflicts an estimated 700,000 Americans with chronic, painful diarrhea and bleeding, among other unpleasant symptoms. With a better understanding of how the microbial ecosystem changes in children who suffer from the disease, researchers have gained clues that could someday lead to better diagnosis and treatment.
The Human Microbiome Project has revealed that hundreds of types of bacteria live in a person's gut. The exact species and their relative abundance vary from one person to another, and researchers are increasingly finding that in addition to Crohn’s, abnormal bacterial populations—known as dysbiosis—are linked to diseases ranging from rheumatoid arthritis to diabetes and possibly even autism.
Microbes have been linked to Crohn's in several past studies, typically involving small numbers of patients who had been living with the disease for months or years and were already undergoing treatment. But because patients are often diagnosed in childhood or early adulthood, the new research, published March 12 in Cell Host & Microbe, focused on 668 children as study subjects. It was aimed at developing new tools to predict which patients will develop mild versus severe forms of the disease, and to determine which treatments are likely to be most helpful. Researchers took intestinal biopsy and stool samples from newly diagnosed youngsters at 28 centers across the country. The samples, compared with healthy controls, revealed certain bacterial families were more common, or less common, in Crohn's patients.
The findings tie together and clarify the results of several previous observations. Some of the microbes had been previously associated with inflammatory bowel disease, the umbrella term for Crohn's and ulcerative colitis. One bacterial family also had been implicated in colorectal cancer, a complication of long-term inflammatory bowel disease. And one of the microbes found in the latest study's healthy controls was already known to be anti-inflammatory and tends to be reduced or missing in patients whose condition recurs after surgery.
Those key microbes can't yet be convicted of causing or preventing the disease, says Ramnik Xavier of Massachusetts General Hospital and the Broad Institute of Massachusetts Institute of Technology and Harvard University, who led the study. They may just be microbes that thrive in a diseased gut (or in a healthy system). Either way, they have predictive value as markers for diagnosis: The team developed a formula for calculating a "microbial dysbiosis index" based on all the species present at disease onset. This index reliably indicated which individuals have Crohn's, and patients with the highest scores turned out to have the worst cases. The index is a powerful addition to other diagnostic techniques, says Xavier, who envisions it alongside genetic and blood biomarker tests to predict the course and best treatments of this complex disease.
The study also helps explain why antibiotics are often unsuccessful for Crohn's. Xavier's team found that patients who were taking antibiotics had even less of the good bacteria than their afflicted but antibiotic-free peers. In other words, Xavier says, "giving them antibiotics made the microbial imbalance more pronounced."
Given that microbes are involved but antibiotics aren't effective, it seems logical to give sufferers good bacteria—essentially probiotics—and to make it easier for the bugs to become permanent residents of the gut. Although a treatment called fecal microbial transplantation—in which patients receive a dose of microbes from a healthy donor via enema or colonoscopy—has worked beautifully for those with another digestive disease, infection with Clostridium difficile, the approach isn’t reliable for more complex disorders such as Crohn's. After treatment the healthy appearance of their gut ecosystems proves temporary, Xavier says. Genetic studies provide a clue: Many of the genes linked with the appearance of Crohn's are responsible for immune system recognition of microbes, suggesting that the patient's immune system is missing the essential tools needed either for nurturing good bacteria or for keeping the bad types in check.
In addition to learning more about the influence of the immune response "we need to find out more about these microbes," Xavier says. It's possible that compounds they produce could be developed into drugs that manipulate populations in the gut. But growing human gut microbes in the lab is challenging: many cannot survive in the presence of oxygen, so studying them requires careful techniques and special equipment. Another challenge is that some of the bacteria found in this study correlated with other species in tight-knit groups, suggesting that they can't be isolated for study because they rely on one another to thrive.
Xavier remains eager to peel back the layers of mystery around the complexities of microbiome ecosystems. His group is beginning a longitudinal study of Crohn's patients, sampling their microbiomes every two weeks as they progress through treatment and as they experience the disease's periodic flare-ups. Combine that with an understanding of what chemical compounds the microbes produce, he says, and it should be possible to crack the mystery of their exact role in the disease.