New Understanding Brings Hope
From left to right: Emma Darbinian and Emilia Liana Falcone
Work from the laboratory of Dr. Emilia Liana Falcone, Director of the Microbiome and Mucosal Defenses Research Unit at the Montreal Clinical Research Institute (IRCM), recently published in the prestigious scientific journal Blood, brings a valuable advance in our understanding of inflammatory bowel disease as well as promising avenues of treatment for this debilitating condition.
Dr. Emilia Liana Falcone's laboratory has long studied chronic granulomatous disease (CGD), a genetically acquired immune deficiency that makes affected patients who are more susceptible to certain infections and inflammation. In fact, over 50% of these individuals suffer from inflammatory bowel disease.
The Falcone laboratory is the first to demonstrate the importance of the gut microbiota in CGD. In this new study, which is first-authored by PhD candidate Emma Darbinian, the team has demonstrated that the immune response to the disrupted microbiota in CGD varies according to the genetic mutation and disease-causing protein involved.
More specifically, the most common form of CGD, caused by a gp91phox protein deficiency, leads to an activation of the NLRP3 inflammasome at the intestinal barrier when the microbiota is disrupted; The second more common form of CGD, caused by a p47phox protein deficiency, leads to an increased production of oxygen reagents at the intestinal barrier.
The importance of this discovery
These findings highlight the fact that treatment for inflammatory bowel disease in the context of CGD may need to be personalized and tailored according to the mutation and protein affected.
In addition, the research team discovered a new therapeutic target (the NLRP3 inflammasome) for the most common form of CGD (caused by gp91phox deficiency). Work on the role of an NLRP3 inflammasome inhibitor in gp91phox-deficient CGD mice is ongoing.
More broadly, this work is advancing our understanding of the pathogenesis of inflammatory bowel diseases in general.
Acknowledgements
Dr. Falcone and Emma Darbinian would like to thank the co-authors and collaborators in the USA / NIH: Dr. Steve Holland, Dr. Thomas Leto, Dr. Agnes Donko, Dr. Yu Han, Dr. Prabha Chandrasekaran.
The Falcone laboratory is supported by a Tier 2 Canada Research Chair (CRC2) on the role of the microbiome in innate errors of immunity and post-infectious conditions, the Canadian Institutes of Health Research (CIHR) and the Fonds de recherche du Québec (FRQ) Clinical Research Scholars - Junior 1.
The work was also supported by the Intramural Research Program of the NIH (NIAID Transition Program in Clinical Research Award), the John R. Evans Leaders Fund of the Canada Foundation for Innovation (CFI), the Research Chair of the J-Louis Lévesque Foundation, the Mirella and Lino Saputo Foundation, the IRCM Foundation.
Special thanks to members of the IRCM imaging, histology, molecular biology, bioinformatics and animal core facilities.
