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Jacobson Lab

Inflammatory Bowel Disease (IBD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract that affects approximately 200,000 individuals in Canada, with 20-25% diagnosed in childhood or adolescence. Epidemiologic studies suggest increasing incidence and changing disease phenotype in the Western world. The underlying etiology remains elusive since there are a variety of putative pathogenetic mechanisms and variable time intervals between exposure to a putative trigger and onset of clinical disease. It is presently hypothesized that IBD develops in genetically susceptible individuals as a result of an abnormal immune response to intestinal microflora. Genetic susceptibility might be expressed as altered function of the intestinal epithelial barrier or a defective/dysregulated immune system. Our work in the laboratory is focusing on the role of the epithelial barrier in intestinal inflammatory disease and potential modifiers including diet (probiotics, polyunsaturated fatty acids), enteric pathogens and enteric neuropeptides.

In our clinical studies we have demonstrated that the South Asian pediatric population of BC has amongst the highest incidence of IBD in pediatrics. We also recently demonstrated a 3.6-fold increase in incidence of IBD in children referred to BC Children’s Hospital between 1991 and 2004.

Further studies will examine the role of early dietary experience and epithelial barrier dysfunction in the etiopathogenesis of IBD in this population.

Current Research Projects:

Diet and IBD
Our research program focuses on the effects of maternal dietary fat on the developing intestine and on its structure and function in the offspring. In the past 50 years, the Western diet has shown a dramatic increase in consumption of omega-6 fatty acids from polyunsaturated vegetable oils, largely at the expense of saturated animal fats and tropical oils. This change has resulted in a marked increase in the dietary ratio of omega-6 to omega-3 fatty acids. The biochemical and physiological consequences of this shift in dietary fat consumption are still unclear.
Recent research supports the association between these changes in dietary fat intake and intestinal function in humans. Epidemiologic studies suggest that these dietary changes may be linked to the increased frequency of allergic and inflammatory conditions observed in the human population over the last 50-75 years.
Thus, our objective is to elucidate whether the early dietary fatty acid supply, at a time when the intestinal morphology is still developing, influences intestinal epithelial structure and permeability—i.e., alters the primary protective barrier in the intact organism and increases the propensity for the later development of intestinal dysfunction.

Enteric Infections and IBD
Food and water-borne diseases are a major cause of mortality worldwide. Currently, water-borne diseases cause approximately 6 million deaths worldwide each year; this problem is most serious in developing countries where almost 90 per cent of diseases result from a lack of clean water. However, in Canada our source water is often contaminated also, which poses a major environmental and health issue. In fact, hundreds of communities endure boil-water advisories every year and in B.C. alone, an estimated 300-400 communities are on boil-water advisories at any given time.
Escherichia coli (E. coli) is a prominent bacterial infection transmitted via tainted food and water supplies that cause gastrointestinal (GI) disease. There were 1,038 cases of pathogenic E.coli infections in Canada in 2004 alone (most up to date record; Health Canada). Current research indicates that even transient pathogenic E. coli infections can trigger serious health problems months or years after the initial infection- there is a higher incidence of IBD, Crohn's disease (CD) and ulcerative colitis (UC) post-infection, suggesting that protecting against infection is important to maintaining health.
The goal of our studies is to understand how these bacteria weaken the epithelial barrier and identify protective treatments to shield against the bacterial toxins. Given the number of reported outbreaks of disease each year, and the long-term health complications, there is an urgent need to develop therapeutics that will protect the GI epithelial barrier from bacteria.

The Enteric Nervous System and IBD
Our research program focuses on understanding intestinal epithelial barrier function and neuro-epithelial regulatory mechanisms in health and disease. In our studies, we investigate the role of Vasoactive Intestinal Peptide (VIP) in the in vivo and in vitro regulation of pathogen mediated alteration in intestinal barrier function. In addition, we are examining whether alterations in barrier integrity observed in enteric infection parallel those observed in pediatric patients with IBD.
Our studies a in Citrobacter rodentium (C. rodentium) mouse model of colitis demonstrated that mucosal VIP was increased prior to colonic colonization, suggesting a possible protective role for VIP in enteric infection. Similarly, in pediatric patients with IBD, we have observed an increase in mucosal VIP in inflamed colonic tissues. These data suggest that VIP, or more a stable synthetic analogue, has the potential to become a novel therapeutic tool in the management of IBD patients, by enhancing barrier homeostasis and abrogating and/or preventing inflammatory disease.

Images

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Schematic representation of bacterial-induced disruption of the GI epithelial barrier. Weakening of this barrier allows transfer of macromolecules across the paracellular junction, initiating a localized immune response. Our preliminary data reveals VIP enhances the epithelial barrier, stregthening the paracellular junctions.

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Citrobacter rodentium (green) attaches to the epithelial cells lining the murine colon and disrupts proteins involved in barrier formation (red). Cell nuclei (blue).