Finding Causes and Triggers
A common question asked by patients and their caregivers is "What causes Crohn's disease and ulcerative colitis?". Unfortunately, the causes and triggers of these chronic diseases remain unknown.
With the support of grants from Crohn's and Colitis Canada, the researchers noted below are moving us closer to discovering the factors that lead to the onset of these diseases by researching environmental triggers, genetic markers, and more.
2018 Grant Recipients
Dr. Christophe Altier | University of Calgary
Research: Targeting spinal microglia in IBD pain
Persistent abdominal pain is a common challenge for people living with IBD. While treatments are available, researchers still do not fully understand the underlying factors that contribute to the onset of persistent pain.
Through prior research, Dr. Altier discovered that spinals cells, known as microglia, communicate with cells in the gastrointestinal tract. Building on this discovery, Dr. Altier will research the make-up of this cellular communication in order to provide a more comprehensive understanding of the onset of persistent abdominal pain, and identify opportunities for new forms of treatment.
Dr. Wallace MacNaughton | University of Calgary
Research: Novel peptides to enhance mucosal healing
Evidence shows that the lining of the intestine in people with IBD does not repair itself as effectively as it does in healthy people, and researchers do not know why. This lining is an important barrier and, when compromised, causes inflammation and significant pain and discomfort for people living with IBD.
Dr. MacNaughton and his team will use novel approaches to better understand the healing process. With this information, they will develop new therapies or adjuncts to current therapies to keep people living with IBD in remission.
2017 Grant Recipients
Dr. Simon Hirota | University of Calgary
Research: Finding targets to block intestinal fibrosis in IBD
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 the chronic and visceral somatic pain in IBD
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
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
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.
2016 Grant Recipients
Dr. Claude Asselin | Université Sherbrooke
Research: Histone deacetylases: epigenetic regulators of intestinal epithelial homeostasis
Our body responds to the environment which can make us more or less susceptible to disease. The environment can cause a gene to turn “on” or “off” through epigenetic changes.
Dr. Asselin is studying how certain proteins control genetic and epigenetic information in the gut cells leading to IBD.
Dr. Elena Verdu | McMaster University
Research: The role of Microbial Proteases in Colitis
Dr. Verdu will be investigating the impact that bacteria collected from UC patients has on germ-free mice in order to better understand how the certain bacteria may lead to gut leakiness or chronic inflammation seen in IBD.
Dr. Mark Silverberg | Mount Sinai Hospital
Research: Studying patients who have undergone pouch surgery to look at changes in the intestinal microbiome to determine the role they play in inflammation
The digestive tract is home to hundreds of trillions of microorganisms, which generally exist with the host in a mutually beneficial relationship. Yet changes in the number and types of bacteria has been implicated in numerous conditions, including inflammatory bowel disease (IBD) (including ulcerative colitis (UC)) which affects over 200,000 Canadians. However, relatively little is known about how changes in this bacterial community may contribute towards disease susceptibility.
For this study, we therefore make use of a human model of IBD, the ileal pouch-anal anastomosis (IPAA) following surgery for severe UC, to evaluate how the composition of the intestinal microbiome changes over time, and how these changes may result in the development of intestinal inflammation.
In previous studies we have demonstrated there are differences in the content of the microbial community of the inflamed pouch compared to tissue which is healthy. However, it is difficult to determine whether the observed changes played a role in disease development or were the result of the disease process. As such, we have designed a study, which aims to follow patients over time, both prior to and following the development of inflammation, to observe both normal changes in the pouch tissue following surgery, and those which may actually predict or contribute towards disease development.
The information generated by this study will provide a greater understanding of factors which are causative in disease development, and will have the potential to lead to therapies which decrease the frequency of pouch inflammation and IBD occurrence in general.
2015 Grant Recipients
Dr. Stephen Girardin | University of Toronto
Co-investigators: Dr. Katrina Gee, Dr. David Reed, and Dr. Alan Lomax
Research: NOD2 Genetic mutation in IBD
Dr. Girardin will study the impact of the most common genetic mutation in IBD, NOD2, on the function of the small intestine, using a unique animal model and also organoids (“mini-guts” derived from human gut cells).
To learn about the completed research projects that we have supported, click here.