Causes and Risks for IBD // The Manitoba IBD Risk Factor Study
In 2002, thanks to funding support from the Crohn’s and Colitis Foundation of Canada, we recruited nearly 500 adults under age 50 with IBD and almost 500 adults who were generally healthy and did not have IBD, to learn about possible factors that might have increased the risk of developing IBD.
We had two main questions in this study:
What are the risk factors associated with developing IBD?
Can we uncover possible causes of IBD?
What did we do?
Everyone in the study answered questions about lifestyle and dietary habits, particularly during childhood.
Everyone provided blood samples so we could study genetic markers (using DNA) and circulating blood markers (using serum).
A smaller group, including those with IBD and those without the disease, had colonoscopies so that we could collect biopsies (tissue samples) directly from the bowel.
What did we find?
1. Risk Factors for IBD
2. Infections as a cause of IBD?
1. Risk Factors for IBD
The survey information suggested several protective factors that may help decrease the risk of developing Crohn’s disease. These included: growing up on a farm; having unpasteurized milk as the main type of milk as a child; having a pet cat before the age of 5; growing up in a large family. While these may sound surprising, the findings somewhat support the “hygiene hypothesis”. This refers to the possibility that growing up in a crowded, less clean environment is actually protective against getting a chronic immune disease like Crohn’ disease.
Why would this be? It is thought that if young children are exposed to infections and gut bugs, even if they do not get sick from these infections or bugs, it ‘exercises’ their immune system and helps it to develop in a healthier way.
The survey information also suggested several factors that may increase the risk of developing IBD. These included: being Jewish; having a relative with IBD; ever having smoked; living with a smoker. Our findings confirmed those of other studies, which had also found an increased risk of developing IBD among smokers, individuals of Jewish background, and in families where someone already has IBD; our study highlighted that second hand smoke exposure can also increase the risk.
Bernstein CN, Rawsthorne P, Cheang M, Blanchard JF. A population-based case control study of potential risk factors for IBD. American Journal of Gastroenterology 2006; 101: 993-1002.
2. Infections as a cause of IBD?
We partnered with other researchers and completed several studies examining the bowel tissue and blood gathered from the IBD and healthy participants, to try and figure out if certain kinds of infections might cause IBD.
Together with researchers at Stanford University in California, we were the first to report on the normal human gut microbiome. The human gut microbiome refers to the bacteria or ‘gut bugs’ that normally reside within the bowel. All humans have millions of bugs of different varieties in their bowels that help keep the bowels working properly.
Eckburg P, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson K, Relman DA. Diversity of the human intestinal microbial flora. Science 2005; 308:1635-1638.
Together with researchers from McMaster University in Hamilton, Ontario, we searched for the presence of Helicobacter pylori, the bug that is known to cause stomach ulcers. We found that some people with ulcerative colitis had DNA for this bug in their bowel, and that none of the non-IBD participants had this bug, so we initially thought it might provide a clue to a cause of IBD. Since this study, however, others have not found Helicobacter pylori to be important for people with ulcerative colitis, even in a subset.
Streutker C, Bernstein CN, Chan VL, Riddell RH, Croitoru K. PCR analysis for species-specific Ribosomal DNA detects Helicobacter species DNA in intestinal tissues from patients with inflammatory bowel disease. Journal of Clinical Microbiology 2004; 42: 660-664.
Together with researchers at Agriculture Manitoba, we looked for the presence of a gut bug called Mycobacterium avium paratuberculosis. This bug causes a disease in cattle called Johne’s disease that is very much like human Crohn’s disease. We did not find that any tissues from persons with Crohn’s disease or from the study’s healthy participants contained any DNA for this bug.
Bernstein CN, Nayar G, Hamel A, Blanchard JF. A pursuit of animal borne infections in the mucosa of subjects with inflammatory bowel disease and population-based controls. Journal of Clinical Microbiology 2003; 41:4986-90.
In related studies, together with researchers at the University of Wisconsin, we tested the blood of the IBD and healthy (non-IBD) participants to determine if the blood contained antibodies to Mycobacterium avium paratuberculosis. We did not find that persons with Crohn’s disease were any more likely to have developed antibodies to fight this infection than healthy individuals, so we concluded that it was unlikely that this gut bug is important in IBD.
Bernstein CN, Blanchard JF, Rawsthorne P, Collins MT. A population-based case control study of seroprevalence of Mycobacterium paratuberculosis in patients with Crohn's disease and ulcerative colitis. Journal of Clinical Microbiology 2004; 42:1129-1135.
Bernstein CN, Wang MH, Sargent M, Brant SR, Collins MT. Testing the interaction between NOD-2 status and serological response to Mycobacterium paratuberculosis in IBD. Journal of Clinical Microbiology 2007; 45: 968-71.
Together with researchers in the Faculty of Agriculture, University of Manitoba, we explored whether there were any gut bugs unique to IBD. We found a special type of Escherichia coli (E coli) that was especially common in Crohn’s disease. The E coli had properties of an adherent invasive E coli; this technical description refers to how the E coli interacts within its environment in the gut. What was exciting about this finding is that other labs in other countries were also discovering a similar E coli associated with Crohn’s disease, which confirmed we were on to something important. In a related study we analyzed tissue from a tissue bank of newly diagnosed patients established by the Crohn’s and Colitis Foundation of Canada, and we found an increased presence of this E coli in those tissues, suggesting that this bug is present early on in the disease process. Hence, it remains a possibility that this bug is a trigger for Crohn’s disease.
Kotlowski R, Bernstein CN, Sepehri S, Krause DO. High prevalence of Escherichia coli belonging to the B2+D phylogenetic group in inflammatory bowel disease. Gut 2007; 56: 669-75.
Sepehri S, Kotlowski R, Bernstein CN, Krause DO. Microbial diversity of inflamed and non-inflamed gut biopsy tissues in inflammatory bowel disease. Inflammatory Bowel Diseases 2007:13: 675-683.
Sepehri S, Kotlowski R, Bernstein CN, Krause DO. Phylogenetic analysis of inflammatory bowel disease associated Escherichia coli and the fimH virulence determinant. Inflammatory Bowel Diseases 2009; 15:1737-45.
Krause DO, Dowd SE, Little AC, Bernstein CN. Complete genome sequence of adherent invasive Escherichia coli UM146 isolated from ileal Crohn’s disease biopsy tissue. Journal of Bacteriology 2010; 193(2):583.
Sepehri S, Khafipour E, Bernstein CN, Coombes BK, Pilar AV, Karmali M, Ziebell K, Krause DO. Characterization of Escherichia coli isolated from gut biopsies of newly diagnosed patients with inflammatory bowel disease. Inflammatory Bowel Diseases 2011: 17: 1451-63.
We examined whether rubella (German measles) might contribute to the development of IBD. This question was triggered by two observations: (1) rising rates of Crohn’s disease among boys and young men compared to girls and young women; and (2) that until the 1980s, only girls were vaccinated against rubella and boys were not. We measured antibody responses to three viruses, measles, mumps and rubella, in persons with IBD compared to healthy individuals without IBD. We found that the healthy individuals were more likely to have antibodies to rubella (meaning they were exposed to rubella) than individuals with IBD, suggesting that the presence of the rubella may have been protective against developing IBD.
Bernstein CN, Rawsthorne P, Blanchard JF. A population-based case control study of measles, mumps and rubella and inflammatory bowel disease. Inflammatory Bowel Diseases 2007;13:759-762.