The Intestinal Bug Hypothesis in Crohn's Disease Gets a Reboot

The etiology of Crohn’s disease remains a mystery of modern medicine. Since Burrill Crohn, MD, and his associates first characterized this disease of “regional enteritis”

at Mount Sinai Hospital in 1932,¹ it has been recognized as an inflammatory process that primarily affects the small intestine. The “skip pattern” of inflammation seen on radiologic barium exams perplexed clinicians, but it has served as a key diagnostic sign: one section of the bowel appears highly affected while the adjacent sections appear healthy.

Speculation on what causes Crohn’s disease has evolved over time. Once thought to be the result of simple inflammation, in which the body overreacts to its own stimuli, as in autoimmune disease, theories progressed toward a specific type of inflammatory response. Today’s research is concerned with what might be causing the inflammation. This historical track has been paralleled by the evolution of therapies. When Crohn was a practicing gastroenterologist, the only option was surgery. Then, as inflammation was better understood, agents were developed to shut down the body’s response to inflammation generally (eg, prednisone), to immunosuppression (eg, azathioprine, cyclosporine), to addressing individual factors in the inflammatory process (eg, TNF-alpha inhibitors).

The Unsolved Mystery

Although effective therapies for treating Crohn’s have been introduced for 50 years, the actual cause of bowel inflammation remains unknown. A combination of factors may be responsible, including food, the environment, and genetics, but scientists have made little progress on key questions. Why does the disease suddenly emerge in adolescence? What causes flare-ups after medical treatment successfully induces a symptomatic remission? And, why do the skip patterns exist, in which only parts of the bowel seem to be susceptible to the disease?

With these questions in mind, researchers are revisiting an older concept: what if a microbe, or microbes, are causing the inflammation? According to unpublished reports, Crohn himself voiced suspicions that a microbe, specifically Mycobacterium paratuberculosis, may play a critical role in this disease. Considering treatment costs and the side effects associated with Crohn’s disease as well as the biologic agents used for treatment, the thought of a simple antibiotic cure would be welcomed by patients, providers, and payers.

The Search for Causation

Crohn could not directly evaluate the presence of M paratuberculosis in his day, as the technology needed to detect the organism did not exist. Although a gold standard to culture the microorganism does not exist,² more recent studies have been successful in detecting it in humans.

However, use of these detection methods has not settled the question, and several groups of investigators have obtained mixed results. In 2004, researchers found that 50% of patients with Crohn’s disease and 22% of those with ulcerative colitis tested positive for M paratuberculosis in the blood, whereas none of the controls (who did

not have inflammatory bowel disease) tested positive.³

Others showed that higher levels of this pathogen were not detected in patients with recent—onset Crohn’s disease compared with controls. However, it was found to be present in greater amounts in patients with established disease.⁴

To complicate matters, other investigators failed to establish a link. A 2013 study of intestinal granuloma and lymphatic samples from patients with active Crohn’s disease

and healthy controls, revealed no evidence of M paratuberculosis.⁵ Also, the use of anti-infective therapy targeted to this organism, in patients with active Crohn’s disease, has not produced beneficial clinical results.⁶

It remains unclear whether the presence of M paratuberculosis is the result of an incidental association or indicates a causative agent.⁷ However, the evidence does seem to be mounting that this pathogen is not the “smoking gun” that Crohn and others have sought for the better part of a century.

Deciphering the Microbiome

If not M paratuberculosis, then what? Some have focused on other singular Helicobacter, Enterobacter, and Campylobacter species, as they all reside close to the intestinal mucosa.⁸ In fact, it now seems unlikely that a single pathogen will be implicated as the cause.

Perhaps the situation is far more complicated. A theory that has received support is that the overall gut microbiome may play a pivotal role in patients with Crohn’s disease. A 2012 review by Mann and Saeed⁴ commented that adherentinvasive Escherichia coli, Campylobacter species, and Clostridium difficile had been prevalent in previous studies of patients with Crohn’s disease. The authors conclude, “The majority of recent studies support a role for the ability of intestinal pathogens to promote chronic inflammation in individuals with genetic susceptibility and/or other environmental factors which remain to be identified. These factors may include subsets of commensal microflora.”⁴ If this is the case, antibiotics in use today may destroy many of the necessary microbes found in the gut or increase the population of pathologic bugs.

The question may not be whether a single pathogen is at work in causing inflammation, but rather, whether the body’s reaction to normal gut bacteria has gone awry. Each person has a combination of microbes in the intestinal tract; some may be responsible for bowel inflammation, while others protect against it. To investigate this, researchers from 28 centers throughout the United States and Canada attempted to characterize the entire microbiome of 447 patients with Crohn’s disease. They compared their results with the microbiome of 221 controls. The samples were collected from throughout the small and large bowel of the patient.⁹

In patients with Crohn’s disease, very few of the beneficial microorganisms were found residing in the gut, while too many pathologic microbes were discovered. Higher numbers of Enterobacteriaceae, Pasteurellacaea, Veillonellaceae, and Fusobacteriaceae, and decreased numbers of Erysipelotrichales, Bacteroides, and Clostridiales were often found in patients with Crohn’s disease. Dirk Gevers, PhD, the lead investigator, told Evidence-Based Immunology and Infectious Disease that the real issue may not be the existence of pathologic organisms in the gut. The real problem may be the relationship between the normal organisms and the bowel environment.

Gevers, the group leader of Microbial Systems and Communities in the Broad Institute’s Genome Sequencing and Analysis Program, said, “The organisms are present in both healthy subjects and patients with Crohn’s disease, but only in patients these organisms are present in an imbalanced state, also called dysbiosis.” He added, “This dysbiosis is linked to the disease, but no causative relation has been demonstrated so far. What we were able to show in our work is that a more severe disease state has a more extreme dysbiosis. This might suggest that reversing this dysbiosis could be a potential route for treatment, a route that is actively being explored by several

groups.”

The theory of dysbiosis received support from a study of patients who relapsed after receiving infliximab therapy. Researchers found that a look back through the patients’ microbiomes revealed markers that predicted relapse. Low concentrations of certain Clostridium species as well as Bacteroides, and Faecalibacterium prausnitzii predicted relapse.¹⁰

Are We Looking in the Wrong Place for a Cure?

If the theory of dysbiosis is true, then treatment options might be in 1 of 2 areas: (1) rebalancing the microbiome through methods such as fecal implantation (such as that used to successfully treat Clostridium difficile infection)¹¹ or perhaps by using targeted antibiotics to reduce, but not eliminate, the levels of certain organisms along with probiotics to increase the levels of others or (2) an approach that is aimed at restoring the normal relationship between the organisms and the intestinal lining.

“Instead of wiping out a whole gut microbiome with broad spectrum antibiotics,” said Gevers, “new directions that can be explored are those that target the host—microbe interaction with a more subtle approach, either correcting the imbalance or modulating the dysfunctional response of the host to organisms that are otherwise well tolerated by healthy people.”

EBIID

Uncertainty remains whether the dysbiosis seen in patients in Crohn’s disease is an association or a cause. However, research is proceeding rapidly down this path, and there is much enthusiasm an answer to this riddle of Burrill Crohn’s disease may be on the horizon.