Finding Causes and Triggers

Dr. Simon Hirota | University of Calgary
Research: Finding targets to block intestinal fibrosis in IBD
Date: 2017-2020
Amount: $375,000

Crohn’s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) that are characterized by chronic inflammation in specific regions of the gastrointestinal tract, leading to extensive tissue damage and alterations in overall gut function. While some patients with IBD can be managed by existing therapies, a significant number of patients with CD and UC become unresponsive to drugs, and manifest with severe disease complications often requiring surgical intervention.

Fibrosis represents a frequent complication of both CD and UC. The most severe phenotype, in which fibrosis leads to intestinal obstruction, occurs in 30-50% of CD patients within 10 years of disease onset, with 50-60% of patients requiring surgery within 20 years of diagnosis. While underappreciated in UC patients, fibrosis also leads to bowel wall stiffening in this subtype of IBD, an effect that manifests clinically in the form of colonic dysmotility and incontinence.

Dr. Hirota is trying to understand how the pregnane X receptor (PXR), a sensor for chemicals of bacterial and environmental origin, regulates key pathways/mechanisms thought to contribute to intestinal fibrosis. Mutations in the PXR gene are associated with IBD, but its role in fibrosis has not been studied. In the long-term, Dr. Hirota seeks to implicate the PXR as a viable target for treating intestinal fibrosis in the context of chronic inflammation.

Dr. Yasmin Nasser | University of Calgary
Research: The role of the microbiome in chronic and visceral somatic pain in IBD
Date: 2017-2018
Amount: $50,000

Inflammatory bowel diseases are chronic, debilitating illnesses. At present, the goal of treatment in IBD is complete healing of intestinal inflammation. However, despite achieving this target, over twenty percent of IBD patients continue to experience chronic abdominal pain, which is a distressing and devastating symptom.

Previous research has shown evidence of increased expression of the transient receptor potential vanilloid-1 receptor (TRPV1) in IBD patients with complete intestinal healing; TRPV1 is a key nerve receptor involved in abdominal pain sensation. There is early evidence that disruptions in gut microbes can also change TRPV1 on pain-sensing nerves.

Therefore, the goal of Dr. Nasser’s research is to study the role of gut microbes in the development of chronic pain in IBD and the interaction between gut microbes and TRPV1 on pain-sensing nerve by treating an animal model of IBD with chronic pain with antibiotics.

Her research may have a broad impact on the health of patients suffering from IBD as it will give us greater understanding into the role of gut microbes in pain sensation. This may in turn lead to new strategies, such as the use of targeted antibiotics against specific gut bacteria, and/or the use of pro- or pre-biotics to treat pain in IBD.

Dr. Brian Coombes | McMaster University
Co-investigators: Dr. Jonathan Schertzer
Research: Drug and diet-induced changes in Crohn's-associated microbes
Date: 2017-2020
Amount: $375,000

Canada has a disproportionately high rate of Crohn’s disease among developed countries, with growing incidence especially among an adolescent population.

Knowledge of etiologic routes to Crohn’s disease remains incomplete, however a large body of evidence supports microbes in our gut as active participants in the disease process. For example, inflammation in Crohn’s disease causes expansion of adherent-invasive Escherichia coli (AIEC) bacteria that have pathogen-like characteristics as verified using culture and molecular methods.

In previous work, Dr. Coombes developed the first chronic colonization model using human biopsy-isolates of AIEC, allowing him to characterize AIEC-induced inflammation and fibrosis over long periods of time in the host. Leveraging these findings, he is now studying how AIEC persists in the inflamed gut and making novel connections between Crohn's disease risk factors that impact upon how AIEC behaves in the host.

Dr. Coombes and his team believe that a quantitative understanding of how Crohn’s disease risk factors interact, through the use of robust pre-clinical models, will lead to the development of targeted interventions to prevent disease in at-risk individuals.

Dr. Humberto Jijon | University of Calgary
Co-investigator: Dr. Paul Beck
Research: Development of IgA-SEQ to analyze the human and murine microbiome during colitis
Date: 2017-2018
Amount: $50,000

Inflammatory bowel disease is a chronic inflammatory condition of the gut believed to occur in genetically predisposed individuals who are exposed to unknown environmental triggers. In terms of environmental triggers, the microbes that reside in the intestine referred to as the microbiota are likely the most important.

The microbiota of each individual is a unique collection of hundreds of different bacterial, viral and fungal species. It seems most likely that individuals with IBD lose tolerance to specific members of their microbiota and thus the microbial perpetuating factors in IBD will vary from individual to individual.

Although scientists can look at patterns within the microbiota, it has proven extremely difficult to identify which specific bacterial species drive disease in patients with IBD, likely because different species drive disease in different individuals. Recently however, a group in Yale published a method could allow scientists to use the immune response in IBD to help identify the culprit bacteria that drive inflammation in different individuals.

Humans produce antibodies when exposed to bacteria, and these antibodies specifically bind to the surface of these bacteria. Bacteria which exist in a healthy relationship with the host immune system (commensals) may become lightly coated with antibody, whereas bacteria which have lost this relationship and cause inflammation will trigger a strong immune response and ultimately become coated with a greater amount of stronger antibody.

In the gut, the primary antibody produced is called IgA, thus looking for bacteria coated with high levels of IgA potentially allows the separation of colitis-causing bacteria (IgA-high) from other innocent bystander bacteria (IgA-low). Once you have separated these bacteria from the rest of the microbiota, the next step is to identify which bacterial species make up this IgA-high group using DNA sequence technologies. This is the process which Dr. Jijon and his team will begin.