From February 2000 to August 2008, The Gutsy Group provided $131, 250 to fund the St. Vincent’s Hospital Immunology Centre Mouse Model. This project centred on a mouse model that mimicked human ulcerative colitis.
The research was carried out under the direction of Professor Tony d’Apice, Professor of Immunology at St. Vincent’s Hospital. The Professor’s main research was humanising mice and pigs so animal kidneys may be successfully transplanted into humans in the future. Mice were inserted with the human gene 1-2 fucosyltransferase in the course of different research. Unexpectedly, and through serendipity, these mice developed colitis. As a result, this event enabled extensive research into the mechanism of the colitis to be performed on this animal model over the next nine years.
This research was conducted by four research fellows, Dr Ashley Miller, Dr Steven Brown, Dr Greg Moore and Dr Mark Lust, all of whom were awarded PhDs for their research. Three of the researchers received gold medals for this research into gastroenterology. Through this research it was demonstrated that these mice had abnormal thymus glands with consequent major effects on the immune system, a world first.
In the transgenic Mouse Model of Ulcerative Colitis (hFUT1), the human gene for Alpha 1-2 fucosyltransferase, inserted into the normal DNA of the mouse, produced spontaneous colitis that was similar to the human disease, ulcerative colitis. The mice developed severe diarrhoea, wasting and early death.
As a result of extensive research with the model, it was found that this genetic manipulation changed the type and shape of the sugar molecules that protruded from the surface of many cells, including lymphocytes, which are the major cells that control immunity. It was found that this abnormality caused:
This is the first time that an animal model of colitis had been developed due to a thymic abnormality.
It was found that the colitis in this model could be reversed by irradiating the mice and transplanting normal immune system using bone marrow from a normal mouse. Furthermore, if the abnormal mice were bred in a germ-free environment (have no bacteria in the gut), they did not develop colitis.
Finally, many experiments were performed to detect coagulation abnormalities, but no significant defects were identified.
Further information can be found in the articles published in the Inflammatory Disease Journal:
Brown, S.J., Miller A.M., Cowan P.J., Slavin J, Connell W.R.,. Moore G.T., Bell S., Elliott P.R., Desmond P.V., d’Apice A.J., Altered Immune System Glycosylation Causes Colitis in Alpha1,2-fucosyltransferase Transgenic Mice, Inflammatory Bowel Disease 2004 Sep; 10(5):546-56.
Moore, G.T., Brown, S.J., Winterhalter A.C., Lust M., Salvaris E.J., Selan C., Nandurkar H.H, Desmond P.V., Cowan P.J., d’Apice A.J., Glycosylation Changes in hFUT1 Transgenic Mice Increase TCR Signaling and Apoptosis Resulting in Thymocyte Maturation Arrest, Mol. Immunology 2008 Apr; 45(8):52401-2410
In 2005 and 2006 The Gutsy Group provided funding of $20,000 to the Health Economics Group at The University of Melbourne. The analysis was carried out by Stephen Colgan, research fellow with the Health Economics Group Programme Evaluation Unit, under the tutelage of Associate Professor Rob Carter. This research was undertaken to assess the financial burden of inflammatory bowel disease in Australia, to highlight the future impact of IBD, and to assist in the raising of funds.
The final report on the cost of inflammatory bowel disease was tabled in March, 2006. The report was the first comprehensive assessment of the costs of IBD in Australia and the most complete economic assessment of the burden of the disease. Some of the key findings were:
Please contact us if you would like to obtain a copy of the report.
In 2007 and 2008, in conjunction with the Bennelong Foundation, The Gutsy Group contributed $70,000 to a study undertaken by research fellow, Dr Jarrad Wilson from the Department of Gastroenterology at St. Vincent’s Hospital, Melbourne. The funding was used to produce the first prospective population-based Australian incidence and study of inflammatory bowel disease.
As a result of this research, Dr Jarrad Wilson was awarded the gold medal in 2008 by the Gastroenterological Society of Australia for the best clinical research for a junior investigator.
The report is titled High Incidence of Inflammatory Bowel Disease in Australia: A Prospective Population-Based Australian Incidence Study.
The research was carried out in Greater Geelong, Victoria. The risk population was 259,000, and all 274 general practitioners and specialists working in this area were contacted every two months to identify all new cases occurring in one year. The results were:
In 2010, through the generous support of the Tattersalls George Adams Foundation,The Gutsy Group, Inc. committed $80,000 to a clinical study into the prevention of Crohn’s disease after surgery. The research project was titled The Post-Operative Crohn’s Endoscopic Recurrence (POCER) Study. This project was led by Professor Michael Kamm and Dr Peter de Cruz from St. Vincent’s Hospital, Melbourne
This project was chosen as it represented a novel approach to a common problem and was the first study of its type. It had the potential to enhance both the clinical and basic science knowledge base regarding the prevention of Crohn’s after surgery. This project was jointly funded with the NMHRC which separately donated $392,000 to the project.
The project’s results had the potential to affect clinical practice in the near future. The basic science component of exploring the microbiological reasons why Crohn’s disease may reoccur after an operation has never been studied. The results would also potentially illuminate the underlying mechanisms in the intestinal immune system responsible for causing Crohn’s disease. The study involved over 20 teaching hospitals in Australia and New Zealand over three years.
The IBD research projects funded for Professor Jane Andrews and her team at The Royal Adelaide Hospital focuses on a topic that has gained much publicity recently. FMT is an evidence-based strategy for treating a particular form of infectious colitis known as Clostridium Difficile. Whether it is effective for the treatment of IBD is still unknown.
Professor Andrews’ team is conducting a randomised-controlled trial of FMT in patients who are acutely unwell with ulcerative colitis. To date, 50 patients have been recruited in the study, and results will hopefully be available next year.
As well as looking at the effect of FMT in recipients (patients) the study is looking closely at the characteristics of the donor stool that make it more likely for a patient to respond. Emerging data suggests that not all donor stool is equal!
Gutsy Group funding was also helpful in the study team successfully obtaining National Health and Medical Research Council (NHMRC) funding to conduct associated research into the microbiota (gut bacteria) in ulcerative colitis patients. There has been great recent interest in FMT amongst patients and the media, but well-designed studies such as this one, are required to confirm its validity, or otherwise, as an effective treatment for IBD.
The successful applicant for 2012/13 was from the University of Queensland and the research group of Professor Timothy Florin. This study is investigating the role of a newer immunomodulator, thioguanine, in managing Inflammatory Bowel Disease (IBD), and incorporates both basic science and clinical aspects. The scientific committee felt this study could bring exciting results at a national and international level and has the most potential for improving the quality of life of patients living with IBD. The Gutsy Group, Inc. has committed $150,000 over three years and looks forward to updating our supporters as results come to hand.
Principal Investigator – Professor Rupert Leong
The University of Sydney, Concord Clinical School
Inflammatory bowel disease (IBD) is a chronic disabling gastrointestinal condition thought to be caused by disturbances in the interaction between our immune system and the microorganisms in our gastrointestinal tract. Current therapies for IBD are expensive and rely on suppressing the immune system which is associated with significant side effects, increased risk of infections and certain cancers. Even if initially effective, subsequent loss of response to these therapies is common.
Faecal microbial transplantation (FMT) is the infusion of faecal material (and associated microorganisms) derived from a healthy individual (donor) to a diseased individual. It aims to correct the imbalance in the recipient’s gut microbiome by replacing it with microbiota from healthy donors. FMT is a promising non-immunosuppressive, non-pharmacological treatment for ulcerative colitis (UC) with studies showing that FMT delivered by colonoscopy followed by regular enema therapy will lead to improvement in active UC. Ongoing therapy with FMT may have the ability to maintain remission in UC, however FMT delivered through colonoscopy or regular enema therapy is not practical in the long term.
FMT in an oral capsule form is the ideal form of therapy and may revolutionise the treatment of UC. We have commenced a controlled trial assessing orally administered FMT given by capsules to treat ulcerative colitis both as an induction therapy as well a maintenance treatment. We believe findings from this trial will advance the field of microbial based treatments in IBD
C.Keung Lay
Intestinal fibrosis is an over-accumulation of scar tissue within the wall of the bowel which impairs bowel function. This occurs in over 70% of patients with inflammatory bowel disease (IBD) leading to intestinal narrowing (strictures), blockages, and fistulas (abnormal connections between the bowel and other structures). While there are many treatments targeting inflammation in IBD, there are none for fibrosis. Yet complications from fibrosis are the main reason that IBD patients require hospitalisation and surgery.
In order to find treatments for intestinal fibrosis, we need to improve our understanding of the disease as well as realistic models to test new therapies. To accomplish this in our research, we are using a powerful microscopy technique called biospectroscopy, which uses infra-red laser energies to excite chemical bonds present in intestinal tissue, producing a unique chemical signature. From this we can accurately identify the components of a Crohn’s stricture and identify an energy “fingerprint” of fibrosis. Then we can predict which patients are at risk for intestinal fibrosis, as well as potential targets for drug treatments. Excitingly, these microscopes can rapidly produce results in minutes at the time of colonoscopy.
Using this information, we will create a human model of intestinal fibrosis in Crohn’s disease by growing “mini-guts” (organoids) from intestinal biopsies taken during colonoscopy. These “mini-guts” represent the patients Crohn’s disease state as they are grown from their own intestinal stem cells. The environment of these “mini-guts” will be altered to simulate fibrosis so we can then use this model to test drug and stem cell therapies that may improve fibrosis.
This research is highly important to the field of IBD with benefits of earlier detection of fibrosis in Crohn’s disease, improved clinical outcomes and reduction in health care costs. Furthermore, results of our research may discover new targets for fibrosis and new drug therapies which can progress directly to human trials without the need for animal studies.
Associate Professor Mireille Hanna Lahoud and Dr Jakob Begun
2nd year of Gutsy Group funding of proposed 3 year project ($100,000 funded to date).
The immune system’s role is to protect the body from harmful infections. Specialised cells within the body, called antigen presenting cells, monitor for signs of infection, and activate the immune system accordingly. This enables the immune system to induce a tightly regulated immune response to eliminate infected cells, but also minimise harm to the body. However, in some circumstances, the immune system can respond inappropriately to non-threatening factors (e.g. normal self-cells or commensal bacteria that are naturally present within the body) resulting in auto-inflammatory diseases. IBD, including Crohn’s disease, are chronic auto-inflammatory diseases affecting the gut. Patients require life-long therapies, with many requiring surgery. The researchers have identified a protein receptor that is expressed on the surface of antigen presenting cells and can regulate autoinflammatory responses to protect against IBD. The research aims to understand how this modulator controls inflammation and to develop strategies to target this protein and dampen gastrointestinal inflammation in IBD patients. CURRENT RESEARCH PROJECTS Pregnancy In Crohn’s and Colitis: Observations, Levels and Outcomes: The PICCOLO Study. Dr Emma Flanagan and Associate Professor Sally Bell 1st year of proposed 3 year project funded by direct donor ($50,000), Jim Carroll, The Trustee of The Donald Ratcliffe and Phyllis Macleod Trust. IBD commonly affects women when they are in their childbearing years. Most IBD medications are safe in pregnancy, and the greatest driver of poor pregnancy outcomes in patients with IBD is active disease, which can increase rates of miscarriage and preterm birth. However, women with IBD can have poor knowledge about the adverse impact of active IBD on pregnancy, and conversely, on the safety of maintenance IBD medication during pregnancy. The PICCOLO study is the first study designed to evaluate the effect of a single, individualized patient education consultation as an intervention for improving pregnancy-related knowledge and outcomes in women with IBD. The study is for female patients with IBD aged 18-45 who are pregnant or have an active pregnancy wish. In participants who are pregnant during the study period, serial assessments of disease activity will be conducted as well as monitoring of drug levels during pregnancy and after delivery (ie: for mothers and babies). Disease activity during pregnancy will be safely assessed to ensure inflammation is controlled and that both women and babies are given the best opportunities for a successful pregnancy and delivery.
Dr Emma Flanagan and Associate Professor Sally Bell
1st year of proposed 3 year project funded by direct donor ($50,000), Jim Carroll, The Trustee of The Donald Ratcliffe and Phyllis Macleod Trust.
IBD commonly affects women when they are in their childbearing years. Most IBD medications are safe in pregnancy, and the greatest driver of poor pregnancy outcomes in patients with IBD is active disease, which can increase rates of miscarriage and preterm birth. However, women with IBD can have poor knowledge about the adverse impact of active IBD on pregnancy, and conversely, on the safety of maintenance IBD medication during pregnancy. The PICCOLO study is the first study designed to evaluate the effect of a single, individualized patient education consultation as an intervention for improving pregnancy-related knowledge and outcomes in women with IBD. The study is for female patients with IBD aged 18-45 who are pregnant or have an active pregnancy wish. In participants who are pregnant during the study period, serial assessments of disease activity will be conducted as well as monitoring of drug levels during pregnancy and after delivery (ie: for mothers and babies). Disease activity during pregnancy will be safely assessed to ensure inflammation is controlled and that both women and babies are given the best opportunities for a successful pregnancy and delivery.
