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New Developments in Basic IBD Research Until Crohn's disease and ulcerative colitis are completely eradicated, the pace of research will never be fast enough for those suffering from these devastating inflammatory diseases. However, a stunning array of discoveries over the past several years has begun to bear fruit. In expanding our understanding of inflammatory bowel disease (IBD) in all its complexity, CCFA-affiliated researchers are moving toward a cure.
However, the idea of a single cure is actually a misconception. Experts now foresee many avenues potentially capable of halting the disease in its tracks, healing intestinal damage, and, eventually, preventing IBD altogether. Multiple "cures" will be needed to deal with a group of diseases that is far more complex than earlier believed.
This article provides an overview of the major trends in basic research -- research performed in the laboratory that is the underpinning for improved diagnostics and treatments.
Throughout most of the 20th century, Crohn's disease and ulcerative colitis were seen as two diseases with some overlap, and doctors tended to lump patients into one category or the other. Now, as scientists continue to uncover the genetics and immunology behind IBD, they're discovering that what they thought were just two diseases are turning out to be more numerous. In other words, there are several types of Crohn's and several types of colitis.
Immunologic BiomarkersAs researchers have grown more aware of the complexity of IBD, they've stepped up the search for immunologic biomarkers -- measurable patterns or substances in the blood, stool, or elsewhere in the body that help identify the disease subtype. Each subtype, in turn, is associated with a particular set of symptoms and potential complications. One type of Crohn's disease, for example, is restricted to the small intestine and results in fistulas, and one subtype of ulcerative colitis begins in childhood. By predicting the course of the disease in different groups of people, these markers will help doctors tailor treatments to the exact type of disease a patient has.
Many markers are actually antibodies, which are proteins produced by specialized immune cells after they come into contact with an antigen -- a substance that stimulates an immune response. The presence of antibodies is a sign that the immune system is reacting to a real or imagined invader. In IBD, that immune reaction becomes abnormal and excessive.
New studies have linked specific biomarkers to particular subtypes of IBD, including the following: - Anti-flagellin antibody (CBir1) is found in a higher proportion of people with disease in the small intestine complicated by fistulas, perforations, and other serious problems.
- Anti-saccharomyces cerevisiae antibody (ASCA) may be indicative of small-bowel Crohn's disease in children.
- A blood test showing an immune response to various bacterial species may predict more rapid disease progress in children.
- Calprotectin, a calcium-binding protein measured in the stool, may predict IBD relapse.
- High levels of C-reactive protein (CRP) are predictive of patients' response to biologic therapies (e.g., infliximab (Remicade®).
Some of these markers are clinically available. Some doctors are already using them as an adjunct for diagnosis and to measure disease activity and response to treatment.
With this growing arsenal of biomarkers, physicians will be able to diagnose IBD subtypes with far greater accuracy and predict their patients' response to specific kinds of treatments. That means they may be able to bring a person's disease under control more quickly and move away from the trial-and-error approach when it comes to prescribing the best medication.
Anti-OmpC -- the antibody to a specific protein on the outer membrane of a bacterium called Escherichia coli (E. coli) -- has recently been identified as another significant biomarker. New data show that anti-OmpC levels are high among members of families that have a history of both Crohn's and colitis. Researchers speculate, then, that ulcerative colitis in these "mixed" families may be a different disease from that found in colitis-only families.
Genetic MarkersNew studies continue to illuminate the relationship between genotype and phenotype: in other words, between genetic makeup and particular disease characteristics. Most of the newer data are non-confirmatory, either ruling out the role of a genetic abnormality in IBD or calling for additional studies to confirm tentative findings.
Several links between mutated genes and disease complications have been established. One, the NOD2 (also known as CARD15) gene mutation, was identified in 1998 as linked to the presence of Crohn's disease. Now, NOD2 turns out to be relevant for patients with ulcerative colitis in that it may predict chronic pouchitis -- inflammation of the internal pouch created after surgical removal of the colon.
Several other genes may also be markers for disease subtypes, although scientists have not yet confirmed their overall role in increasing a person's susceptibility to IBD: - The CARD8 gene, when found together with high levels of OmpC, may predict more aggressive Crohn's disease including intestinal perforation as a possible complication.
- Mutations of OCTN1 and OCTN2 are associated with Crohn's disease complicated by perianal fistulas.
Mutations in the OCTN1, OCTN2, and Dlg5 genes may turn out to be linked to a patient's overall susceptibility to IBD, but none of these genes has yet been confirmed as such. Mind-Body ConnectionAnother recent study has named three major predictors of relapse: - high levels of C-reactive protein;
- fistulizing disease; and
- a high biopsychosocial index number.
This last factor measures a patient's perceived level of stress and the way that person deals with it. The study's authors found that people with low stress who face things directly tend to do well. For those living under high stress, however, it may pay to stick one's head in the sand. In other words, a little avoidance can be a good thing when the going gets tough. Behavior modification, therefore, may be an effective treatment strategy that can teach patients to cope better with high levels of stress.
Probing ProbioticsProbiotics are "good" bacteria that improve intestinal microbial balance. Found in dairy products such as yogurt and available in supplement form, probiotics are sometimes taken to alleviate antibiotic-induced diarrhea. Recently, they have become the focus of formal research, widely recognized for their potential as treatments for Crohn's and colitis.
A group of researchers recently engineered a probiotic bacterium that produces IL-10, a protein that calms inflammation. Just as there are new treatments for blocking TNF-alpha, a protein that aggravates inflammation, scientists are developing other drugs capable of increasing a person's levels of IL-10 in order to calm out-of-control inflammation. Experts say the study lays the groundwork for larger-scale clinical trials of probiotic bacteria, which are being planned for the near future.
Bone Marrow TransplantationYet another novel study has recently found that when mice engineered to develop Crohn's disease underwent bone marrow transplantation from healthy mice, their disease improved markedly. The study has breathed new life into this line of investigation and earned recognition for excellence at Digestive Disease Week 2005, the largest international meeting of physicians, researchers, and academics in gastroenterology, hepatology, endoscopy, and gastrointestinal surgery, held in Chicago this past May.
Up in Smoke?It is a well-known fact that smoking reduces a person's risk of developing ulcerative colitis. A recent study has isolated the carbon monoxide (CO) in cigarette smoke as a likely component in a unique anti-inflammatory pathway, or series of biochemical reactions that reduce inflammation. Researchers found that CO was indeed effective in warding off colitis in experimental mice. Although the substance is toxic in large quantities, researchers believe that understanding this pathway could help us learn why smoking, a health threat in most contexts, is a "good guy" when it comes to preventing colitis. In time, CO itself may prove to be an actual treatment for IBD, although it must be noted that nobody is advocating smoking as a treatment for IBD. Also, it has been known for years that smoking worsens Crohn's disease.
ConclusionFor most of us, the science behind IBD can seem like a sandstorm of possibilities. Will the real IBD culprits be found? Is it all about a few needles hiding in a huge haystack? The answers to these questions are yes and no respectively, today's researchers say. The culprits will be found, and not in some impossibly huge haystack.
Scientists are homing in on the genes, microbes, proteins, and pathways governing the development of IBD. CCFA will continue to report on these many-sided efforts to solve the IBD puzzle. |
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