The GI Society is currently focused on learning more about what patients are going through and is funding a number of surveys to learn the true patient experience. Some examples of these studies are listed below.
Inflammatory bowel disease (IBD) is an umbrella term that primarily refers to Crohn’s disease and ulcerative colitis. These diseases are characterized by inflammation in the digestive tract. In ulcerative colitis, this inflammation is limited to the inner mucosa of the colon. In Crohn’s disease, inflammation can occur in any part of the digestive tract and through the entire thickness of the gut wall. IBD can cause frequent diarrhea, abdominal pain, rectal bleeding, fever, malnutrition, and many other symptoms, and often leads to a decreased quality of life. Canada has among the highest prevalence of IBD in the world at 0.7% of the population. While new medications and treatments do become available, there are still some gaps in treatment options and disease knowledge, from the patient perspective. The Gastrointestinal Society hosted a survey on its English and French websites from July 6 to September 4, 2018, asking patients about their views on the unmet need in IBD. We had 432 qualified respondents.
Between the spring and autumn of 2016, we hosted a survey on our English (www.badgut.org) and French (www.mauxdeventre.org) websites to help understand how Clostridium difficile infection (CDI) affects people. To qualify, survey participants had to confirm that they were either an individual who had experienced CDI or a caregiver of someone with CDI. We had 167 respondents.
During early 2016, we hosted a survey on our English & French websites to help understand the way that irritable bowel syndrome (IBS) affects patients living with this condition. To qualify, survey participants had to confirm that they were either an individual diagnosed with IBS or the parent of an individual diagnosed with IBS. We had 2,961 respondents: 2,505 in English and 456 in French.
During the first part of 2015, we hosted a survey on our English & French websites to help understand inflammatory bowel disease (IBD) patients’ opinions and outlooks regarding biosimilars (previously known as subsequent entry biologics/SEBs). To qualify, survey participants had to confirm that they were either a person with IBD or a caregiver of a person with IBD. We had 423 respondents, 317 in English; 106 in French, but not everyone answered each question, as they were not mandatory.
Canadian Society of Intestinal Research
Please Note: we have suspended the CSIR granting program until further notice. The Canadian Society of Intestinal Research has awarded grants to a number of clinical and basic research projects on various digestive disease and disorder topics since 1980 to researchers at the University of British Columbia and its teaching hospitals.
- Clinical research involves studies on patients, usually testing a new drug or new technique.
- Basic research does not involve patients directly and may include studies on cells, biochemical reactions, and metabolic reactions. Basic research is aimed at understanding the pathogenesis and pathophysiology of a condition. Pathogenesis refers to the primary cause of the disease and pathophysiology refers to understanding the disease process once it is established.
Support for research also involves training people in all aspects of research. CSIR has awarded grants for doctors to travel to other parts of the world to study and train under the direction of highly specialized skilled personnel in the field of gastroenterology.
The following are outlines from the projects which we have most recently awarded funds.
Exploiting the Surface Display Property of Caulobacter Crescentus as an Investigative Tool for Inflammatory Bowel Disease.
Considerable interest exists in the use of functional foods for the treatment of a variety of human ailments. Some of these comprise harmless bacteria present in certain dietary products such as yoghurt, and others are non-pathogenic strains of bacteria normally resident in our intestines. There is evidence that these agents can alter the course of gastrointestinal disorders, including aspects of inflammatory bowel diseases.
At a research level, these microorganisms can be modified so that they express ‘inflammation dampening’ molecules. When tested in animal models of inflammation, they are highly effective in reducing inflammation at a number of different levels. This opens up a promising avenue for investigating similar, more refined/efficacious approaches for human diseases.
The major aim of this research proposal is to engineer a harmless organism, which is unrelated to those in routine use, to express one of these inflammation-modulating molecules. Performing subsequent assays prior to animal work, will allow verification of its efficacy. If successful in the animal model, this could eventually lead to novel treatments for IBD, which affects about 0.5% of the Canadian population.
The Role of Probiotics and Curcumin in Colitis-associated Carcinogenesis.
Dr. Salh’s laboratory is interested in colitis-associated colon cancer, a condition that is difficult to diagnose and treat. Doctors currently manage this disease using periodic screening colonoscopy, starting about ten years after an ulcerative colitis diagnosis, and by performing random biopsies of bowel tissue during these procedures. This screening method is not perfect, as the specific tissue biopsied during the colonoscopy might not contain cancer cells while an area not biopsied could contain disease, which might then go untreated.
Additionally, there are few therapeutic options, other than complete surgical removal of the colon, since the cancer disease process may occur at multiple sites throughout the colon.
These issues point to the need for an improved understanding of this disease at various levels. Dr. Salh hopes to address some of these in this pilot study. In depth examinations are performed on mice, where repeated rounds of inflammation have induced colon cancer. In doing so, the lab hopes to discover novel genetic markers, and to see which of these might be modifiable by the use of probiotics and curcumin. The eventual aim will be to see if the same markers might help in human disease.
Dissecting Chemotherapy Resistance in Colorectal Cancer using a Genome-wide Approach.
See 2003 grant below for details about this study.
Dissecting Chemotherapy Resistance in Colorectal Cancer using a Genome-wide Approach.
Colorectal cancer is the third most common cancer, with an estimated 17,600 new cases and 6,500 deaths in Canada in 2002. Recent statistics also indicate that 1 in 15 Canadians will develop colorectal cancer and 1 in 35 will die of this disease in their lifetime. Significant progress has been made over the years to improve our understanding of the biology involved in the development of colorectal cancer. As a result of this, early cancer detection has contributed to the overall decline in incidence and mortality associated with this disease in the last two decades. But despite this positive trend, the overall five-year survival of patients diagnosed with colorectal cancer remains at 62%. The worst outcome occurs in patients with advanced tumours, where the 5-year survival rate is merely 9%. Early cancer detection and resection provides the best chance of cure. Unfortunately, many patients still present with advanced tumours that require chemo-and/or radiation therapy for disease control. These treatment modalities are only effective in decreasing mortality by 30%.We know that one of the reasons for this poor therapeutic response is due to a phenomenon known as chemotherapy resistance. This phenomenon allows tumours to escape the effects of therapy, thereby permitting the continued survival of cancel cells. This ultimately leads to disease progression and death. Recent studies have shown that many of the genetic changes that occur either during the formation of the tumour or following exposure to chemotherapy can contribute to this phenomenon of chemotherapy resistance.
The goal of this study is to identify those genes that allow tumours to survive despite treatment. We propose using a powerful technology, the DNA microarray system, to identify the genetic profile of colorectal tumours resistant to therapeutic agents. The proposed project will simultaneously probe over 12,000 genes in the human genome and quickly identify potential genes involved in chemotherapy resistance. Initial results indicate that this approach can help us identify novel therapeutic targets. This study will not only further our understanding of the mechanisms involved in therapeutic resistance, but will allow us to develop therapeutic interventions to circumvent this phenomenon. The ultimate goal is to improve the survival outcome of patients living with advanced colorectal cancer.
The Role of the Integrin-Linked Kinase in Intestinal Inflammation.
See 2002 grant below for further details about this study.
Colon Cancer Screening: What are we doing? Is it cost saving?
See 2002 grant below for details about this study.
The role of the integrin-linked kinase in intestinal inflammation.
Inflammatory bowel disease is thought to be due to a chronic unchecked inflammation, occurring on a genetically predetermined background, initiated by the migration of microorganisms, or their products, across an intestinal barrier that is abnormally ‘leaky’. This sets up a response, which leads to ulceration and weakness of the intestinal lining that is commonly observed. The mechanism of this damage is believed to be multifactorial but is dependent upon aberrant activation of white cells (neutrophils, lymphocytes, and macrophages), endothelial cells and even the epithelial cells. The mechanisms involved in epithelial cell damage by injurious agents (inflammatory cell products/chemicals such as TNK, reactive oxygen, and nitrogen species) have been partially addressed in previous applications with a number of interesting observations. The most important among these being that oxidant-induced cell death was effected by a type of protein kinase, known as Jun N-terminal kinase (MCBRC, 2000). Other work in the laboratory indicates that another protein, kinase p38 Hog, is involved in the production of important inflammatory mediators known as chemokines which act as mediators for amplification of the immune response. This effect occurred without an effect on the transcription factor NF Kappa B (J Leukoc Biol, submitted).
Using funds from previous awards we were able to complete work on an animal model to investigate the influence of curcumin on the inflammatory response in the intestine. The manuscript arising from this work is undergoing revision for the American Journal of Physiology. A European group has published an accelerated report indicating that p38 MAPK inhibitors may work in human IBD (Gastroenterology, 2002), in some cases even where anti-TNF therapy had failed. This clearly highlights the importance of selectively targeting protein kinases as a novel strategy. This year we have chosen another protein kinase called integrin-linked kinase (ILK). We have shown a role for this kinase in colonic polyposis (Oncogene, 2001) and cancer (Int J Cancer, submitted). Now we wish to explore its role in the pro-inflammatory response of intestinal epithelial cells. Recent work indicated that it may influence NF Kappa B activation and that it can modulate nitric oxide production.
Colon Cancer Screening: What are we doing? Is it cost-saving?
Colon cancer affects approximately 15,000 Canadians each year with over 50% dying from the disorder. If the disease is detected early, a cure is much more likely. Colon cancer screening refers to the assessment of asymptomatic patients for the presence of colon caner. The ideal screening test is inexpensive, accurate, easy to perform, and accepted by the general population. There are several ways in which a physician can screen for colon cancer. These involve radiological (barium enema), stool tests (to evaluate for blood), and endoscopic (where a flexible tube directly visualizes the colon).
Over the past decade, colonoscopy has been suggested by leading authorities as the best way to evaluate and screen for colon cancer. Colonoscopy involves the use of a colonoscope to directly visualize the colon in a sedated patient. Lesions such as polyps can be removed (or at least sampled) at the time of the procedure. Cost analyses have demonstrated that the most cost-effective way to screen the general population in the United States is via colonoscopy.
There are no data regarding the use or costs of colonoscopy screening for colon cancer in Canada. Although it is practiced widely through our hospital systems, it is unclear how it is being practiced. We are initiating a 3-phase project for the evaluation of colon screening by colonoscopy in British Columbia. The first phase is simply a questionnaire to determine who is being evaluated and how often. This will be conducted at 3 different hospitals and will give us information from over 2,000 patients who are undergoing colonoscopy. We will be able to determine exactly how colonoscopy is being used in British Columbia for screening purposes.
The second phase of the project is to determine the exact costs of colonoscopy and other aspects of colon cancer evaluation and treatment. Costs for procedures in British Columbia are often difficult to determine and our intentions are to determine the costs, not only for colonoscopy, but also for other models of colon cancer screening and for the treatment of each phase of colon cancer therapy. Obtaining all of these costs is time consuming and research nurse support as well as epidemiological support is required.
Once we have determined all of these different costs, we will enter the third phase of this project. This will involve the use of decision analysis (modeling) to determine which methods for colon cancer screening are the most effective and economical. To do this a chart is constructed with all the different methods of screening and all the possible outcomes accounted for in graphic formulation. The probabilities and attendant costs are then applied to each arm of the flow chart. The resulting costs and outcomes are calculated by multiplying the probabilities of each arm with the costs. This will determine not only the best possible outcomes, but also the most economical outcomes.
Through this study we hope to determine which patients are being screened by colonoscopy (and how often), how expensive endoscopic procedures are and ultimately, the most cost-effective method to screen patients. This information is desperately required not only for the day-to-day care of patients, but also for assessment of national policies and recommendations for the screening of colon cancer.
Modulation of murine colitis by protein kinase inhibitors
See 2000 grant below for details about this study.
Bile duct epithelial cell injury in C. Rodentium induced murine colitis: A model for primary sclerosing cholangitis in IBD
Primary sclerosing cholangitis (PSC) is a disease in which the bile duct – the tube that carries bile from the liver to the intestine – becomes inflamed, scarred, and irreversibly obstructs. PSC represents the most common liver complication in patients with inflammatory bowel disease (IBD), most often in ulcerative colitis but also in Crohn’s colitis, and it portends a dismal prognosis in symptomatic patients. There is no effective medical treatment for PAC. Liver transplantation is the only available curative therapy.
Precisely what factors are responsible for the development or progression of PSC are unknown. However several observations support the theory that PSC is an immunologically mediated bile duct disease that develops in genetically susceptible individuals. The close relationship between PSC and IBD (50%-75% of patients with PSC have IBD) suggest a common cause involving immune factors.
Our laboratory has had a longstanding interest in studying immune mechanisms of bile duct injury. Recently, in collaboration with Dr. Jacobson, we found a bile duct inflammatory injury in a standard mouse model of colitis, similar to PSC in IBD patients with colitis. Further preliminary studies have shown that the bile duct injury is mediated by immune cells.
This proposal aims to further characterize the mechanism of bile duct injury in this experimental mouse model of colitis. I will determine the type of immune cells that mediate the bile duct lesion. I will examine the bile duct cell factors which may influence the development of the injury. Finally I will define how immune cells derived from mice with colitis mediate the bile duct injury.
The results of these studies will elucidate some of the immune factors that cause bile duct injury in this experimental mouse model of colitis. The data will help us understand how PSC develops and progresses in IBD patients. Furthermore, characterization of the bile duct injury in this model will allow for the development and testing of novel treatment strategies, which may have a profound impact in the clinical management of PSC in patients with IBD.
Modulation of murine colitis by protein kinase inhibitors
Inflammatory bowel disease is thought to be due to a chronic inflammation, occurring on a genetically predetermined background, initiated by the migration of microorganisms, or their products, across an intestinal barrier that is abnormally ‘leaky’. This sets up a response that leads to ulceration and weakness of the intestinal lining that is commonly observed. The mechanism of this damage is believed to be multifactorial but is dependent upon activation of white cells (neutrophils, lymphocytes and macrophages), endothelial cells and even the epithelial cells. The mechanisms involved in epithelial cell damage by injurious agents (inflammatory cell products/chemicals such as TNF, reactive oxygen and nitrogen species) have been partially addressed in the previous applications with a number of interesting observations. The most important being that oxidant-induced cell death was effected by a type of protein kinase known as jun N-terminal kinase (JNK). Secondly we observed that nitric oxide induced cell death in Caco2 cells occurred in a biphasic concentration dependent manner, but was independent of MAPK activation. New work ongoing in the laboratory indicates that another protein kinase p38 Hog is involved in the production of important inflammatory mediators known as chemokines, which act as mediators for amplification of the immune response.
The purpose of the current investigation is to extrapolate the findings we have obtained in cell culture conditions to an animal model. More specifically, we will examine the role of inhibitors of specific protein kinases (MAPK/SAPK: mitogen-activated/stress-activated protein kinases) in ameliorating intestinal damage in achemically induced model of colitis. This model has been widely used and validated by the intestinal disease Research Groups in Calgary and MacMaster.
The long-term goal would be to prevent intestinal damage by using traditional (5-ASA) as well as potentially novel (Protein kinase inhibitor) compounds.
Enteric nervous system responses to inflammation in pediatric IBD
Ulcerative colitis and Crohn’s disease are inflammatory bowel diseases (IBD) of unknown etiology that are characterised by frequent remissions and exacerbations of the intestinal inflammatory process. The recurrent nature of the intestinal inflammatory process with release of potentially toxic mediators of inflammation leads to damage of nerves both within and remote from the bowel. Studies in adult patients with IBD and in animal models of inflammation have revealed structural and functional changes in nerves both within and remote from the bowel. Furthermore, the inflammation may alter the nerve structure such that specific components of the nerves within the bowel become direct targets for attack by immune cells. In addition, studies have revealed that the nerves themselves may influence the function of immune cells. Therefore, this widespread disruption in neural integrity likely leads to an alteration in a bi-directional communication between the nervous system and immune system. This altered interaction may then influence the course and activity of the intestinal inflammatory process. Furthermore, the nerve changes may predispose to changes in muscle contraction of the bowel (motility) and secretion of fluid by the bowel leading to crampy abdominal pain and diarrhea.
To date very little work has been done looking at the nervous system within the bowel in pediatric IBD. We feel that examining the nervous system in children with IBD to determine whether similar neural responses to intestinal inflammation do occur as compared to those described in adult patients with IBD is important. This study will better help us understand whether age and duration of the disease are important determinant of the observed neural responses. Moreover, we believe that this study will give us further insight into neuroimmune interactions and will likely lead to new avenues of therapeutic intervention.
Mitogen-activated protein kinases in IBD
Inflammatory bowel disease is thought to be due to a chronic inflammation initiated by the migration of microorganisms, or their products, across an intestinal barrier that is abnormally leaky. This sets up a response that leads to ulceration and weakness of the intestinal lining that is commonly observed. The mechanism of this damage is believed to be multifactorial but is dependent upon activation of white cells (neutrophils, lymphocytes and macrophages) that are typically implicated in the pathophysiology of these diseases. The mechanisms involved in epithelial cell damage by injurious agents (inflammatory cell products/chemicals such as TNF, reactive oxygen and nitrogen species) have not been addressed. One probable contender, nitric oxide is an important molecule produced by inflammatory cells that has cell damaging and protective properties. Inflammatory bowel disease (IBD) patients are know to produce highly elevated amounts of this when compared to population of patients without IBD. The significance of this is currently unknown.
The purpose of the current investigation will be to examine the role of protein (MAPK/SAPK: mitogen-activated/stress-activated protein kinases) and lipid signalling (PI 3-kinase: phosphatidylinositol 3-kinase) pathways on the survival of intestinal cell lines in response to bacterial products, as well as nitric oxide, when applied to the apical and basolateral surface of intestinal cells. Additionally, the influence of both standard anti-IBD compounds (such as 5-ASA) as well as inhibitors of defined protein kinase pathways will be used to assess their relative effects upon cell damage/survival. The information will be useful for defining critical survival molecules operating in the intestine. The long-term goal would be to prevent intestinal damage by using traditional as well as potentially novel compounds.
Regulation of signal transduction in IBD
The purpose of this research proposal is to increase our understanding of the biochemical pathways that regulate inflammatory responses in the intestine. Crohn’s disease and ulcerative colitis are both associated with excessive and persistent inflammatory responses, although the factor(s) that trigger the inflammation remains unknown. A cure for inflammatory bowel disease (IBD) will probably not emerge until these causal factors are identified. In the meantime, the treatment of IBD is largely directed at measures to control or modify aberrant inflammatory responses.
The experiments that are proposed will examine that role of intracellular signaling pathways that are implicated in intestinal inflammation. Sphingomyelin is a complex fatty substance that is one of the building blocks of most cell membranes. It can be broken down by an enzyme called sphingomyelinase to components including ceramide, and several of these components have been shown to regulate cell growth as well as to change the production of pro-inflammatory molecules by white blood cells. Phosphatidic acid (PA) is an acidic fatty molecule that is involved in the transmission of signals from the outside to the inside of cells. This messenger is formed by the action of an enzyme called phospholipase D (PLD). Contrary to ceramides, PA is a potent mitogenic agent that can induce cell proliferation. The principal applicant is an expert in the analysis of components of the sphingomyelinase and PLD pathways, and the co-applicant is a gastroenterologist with experience in the analysis of inflammatory mediators such leukotrienes, prostaglandins, and PAF, all of which are know to be involved in IBD. The applicants will use cultured cells to determine how the PLD and sphingomyelinase pathways can regulate the production of inflammatory mediators, and will test a number of compounds that inhibit or counteract the effects of ceramides during inflammation. As well, they will examine if 5-ASA, a drug that is widely used in treatment of IBD, acts in part through the PLD and sphingomyelinase pathways to exert its anti-inflammatory effects. It is important to emphasize that in recent work funded by the Canadian Society of Intestinal Research, the applicants have found that a compound used for blocking PAF receptor activation is in fact a potent inhibitor of PLD activity. This compound can now be used in further studies for determining the mechanisms of action of drugs acting through the stimulation of PLD activity.
The results of the work will increase our understanding of inflammation in the intestine, and could lead directly to the discovery of new drugs and treatment strategies for IBD.
Note: This project did not proceed due to lack of qualified subjects.
A controlled trial of hyperbaric oxygen for perineal Crohn’s Disease
Crohn’s disease is a chronic inflammatory condition primarily affecting the intestinal tract. It can often involve the area around the anus (the perineum) causing scarring of the anus and rectum, fissures in the skin around the anus, abscesses in the tissues around the anus, and tracts (fistulae) between the rectum or anus and the skin near the anus. These are notoriously difficult to heal since their location ensures a constant flow of fecal material causing irritation and infection. Many therapies have been tried but none are consistently effective. Antibiotics are the most widely used therapy, but immune suppressing agents may be of use.
Hyperbaric oxygen is 100% oxygen delivered at two to three times the normal atmospheric pressure in a small pressurized chamber. Its use is well established in helping to heal wounds in diabetics with poor circulation and in radiation burns where circulation is impaired. It increases oxygen delivery to the tissues by dissolving more oxygen in the watery portion of the blood. It may be useful in treating Crohn’s disease since there is scarring and inflammation that impairs blood flow and the oxygen delivery necessary for healing.
This project, to treat 20 patients with perineal Crohn’s disease on a trial basis, is partially funded by the British Columbia Medical Services Plan.
Regulation of signal transduction in IBD
Crohn’s disease and ulcerative colitis are both associated with excessive and persistent inflammatory responses, although the factor(s) that “trigger” the inflammation remains unknown. A cure for inflammatory bowel disease (IBD) will probably not emerge until these causal factors are identified. In the meantime, the treatment of IBD is largely directed at measures to control or modify aberrant inflammatory responses. The purpose of this research is to increase our understanding of the biochemical pathways that regulate inflammatory responses in the intestine. The focus of this study is to examine the role of a recently discovered intracellular signalling pathway in intestinal inflammation.
Modulation of inflammatory cytokines in patients with IBD.
Dr. Krystal’s research team at the Terry Fox Laboratory developed strategies to measure the level of inflammatory cytokines released into medium from intact intestinal biopsies. The levels of these cytokines secreted by biopsies, taken from inflamed and non-inflamed areas, of the gut of children with IBD were examined in a pilot study. Also tested were identical biopsies in the presence and absence of various anti-inflammatory agents.
The goal of Dr. Krystal’s current investigation is to expand his studies using adult biopsies. The level of cytokines in both IBD patients and normal individuals will be examined. Patients will be classified on the basis of cytokine levels, to determine if this is of diagnostic and/or prognostic value. Various anti-inflammatory medications will then be assessed to see which inhibits the secretion of these inflammatory cytokines most effectively.
Measles virus & Crohn’s disease.
The association between the measles virus RNA and antigen expression, in intestinal Crohn’s disease in children, is being explored in this study by identifying the type and location of infected cells.
Immunogenetics and role of endothelins in Crohn’s disease.
This was a study to address fundamental unanswered questions in Crohn’s disease. Current knowledge in immunology was applied and an attempt was made to identify a genetic marker for Crohn’s disease. This study also to provided experimental evidence regarding the hypotheses that a discreet agent in the environment is important as the cause of Crohn’s disease. A further goal was to analyze the immunologic responses in Crohn’s disease in greater depths to provide new treatment strategies.
T-cell receptor heterogenity and genetic markers in Crohn’s disease.
The immediate goal of this study was to develop specific immunotherapy directed against the cells or agents that play important roles in causation of IBD, thus circumventing the disadvantages and side effects of the older therapeutic drugs. This research was designed to add to our fundamental understanding of IBD.
Autoreactive T lymphocytes and cytokine production in IBD determined by antigen-induced secretion of gamma interferon.
Patients in this research were reviewed on a longer term basis than previously studied, measuring their T suppressor lymphocytes on a regular basis. The goal of this study was to possibly determine whether there is a direct cause of connection between change in the level of T suppressor lymphocytes and a relapse of Crohn’s disease. This study also examined the correlation of smoking and Crohn’s relapse and the relationship between zinc levels and immunological status.