Mucosal immunology, immuno-physiology and host defense in the context of intestinal infection/inflammation.
Mucosal injury and inflammation in the gastrointestinal (GI) tract is associated with activation of immune system and alteration in the intestinal physiology which includes changes in motility, mucus production and neuro-endocrine function. Using the model of enteric nematode infection my research involves studies to elucidate the immunological basis of altered intestinal physiology and pathophysiology specifically the roles T cell subsets, cytokines, and chemokines in regulation of intestinal goblet and enteroendocrine cells biology, and intestinal muscle function in the context of GI infection/inflammation in relation to host defense. In addition, my research also includes investigations on immunological strategies to modulate intestinal inflammation in experimental colitis model.
Cell culture, immunohistochemistry, immunofluorescence, lymphocyte proliferation study, ELISA, western blotting, physiological studies on muscle, laser capture micro-dissection and RT-PCR.
Title: Endrocrinological regulation of gut inflammation by serotonin.
Funding Source: Crohn’s and Colitis Foundation of Canada (CCFC)
Program Name: Grant in Aid of Research
Background: The inflammatory bowel diseases (IBDs) are chronic, recurrent intestinal inflammatory disorders of complex pathogenesis. Mucosal changes in IBD are characterized by ulcerative lesions accompanied by a prominent infiltrate of immune cells, and alteration in serotonin producing enteroendocrine cells. However, it is not clear whether the change in enterochromaffin cell function is a cause of inflammation or an effect of inflammation.
Objective: To elucidate the role of serotonin in immune activation and regulation of gut inflammation using model of experimental colitis.
Significance: This research will provide novel information on the role of serotonin in immune signaling in the context of gut inflammation. Understanding the role of serotonin in immune activation and intestinal pathology may ultimately lead to improved therapeutic strategies to combat gut inflammatory disorders.
Title: Immuno-endocrine interaction in gut: role in inflammation and host defense
Funding Source: Canadian Institutes of Health Research (CIHR)
Program Name: Operating-Institute of Infection & Immunity Priority Announcement
Background: Gut contains the largest endocrine organ in the body. Utilizing an enteric infection-induced mouse model of gut inflammation recently we have shown an important immuno-endocrine axis in the gut, where secretory products from CD4+ T cells interact with enteroendocrine cells or their precursors to enhance serotonin production in the gut. However, the mechanisms regulating enteroendocrine cell function and serotonin production in the gut, and the precise role of serotonin in gut inflammation and host defense is still not clear.
Objective: To investigate the mechanisms by which immune mediators regulate enteroendocrine cell biology, and the role of serotonin in regulation of gut inflammation, and in host defense.
Significance: This research will provide us novel information on immuno-endocrine interaction in gut in enteric infection and inflammation. In addition to enhancing our understanding of enteroendocrine cell biology this study will provide new information on the role of serotonin in intestinal pathology and host defense.
Title: Immune-mediated alteration of enterochromaffin cell function and serotonin production in the context of intestinal pathophysiology and host defense.
Funding Source: Canadian Institutes of Health Research (CIHR)
Program Name: Operating Grant
Background: The most well characterized subset of enteroendocrine cells is enterochromaffin (EC) cells, which synthesize and release serotonin in the gut. Serotonin contributes to GI physiology (motility and secretion etc.) and is considered to be important in maintaining intestinal homeostasis. Serotonin has been implicated in a number of gut disorders including IBD, functional disorders like irritable bowel syndrome, and in a number of enteric infections. Objectives: To elucidate the immunological control of EC cell function in gut and to explore the role of EC cells in intestinal pathophysiology and host defense using the model of enteric parasite infection. Significance: This study will provide important data pertinent to understanding immuno-endocrine axis in gut in the context of host defense, and will give new information on this often overlooked cell in relation to intestinal homeostasis.
Title: Helminth Antigen Based Novel Strategy to Ameliorate Colonic Inflammation in Experimental Model of Colitis
Funding source: Crohn’s and Colitis Foundation of Canada (CCFC)
Program name: Innovation in IBD Research Grant
Background: The causes of IBD are unknown but epidemiological works suggest that environmental factors are important in the pathogenesis of the IBD which is associated with dysregulation of mucosal immune system. IBD is common in developed countries and is rare in countries where helminth infections are common. It has been hypothesized that environmental factor like helminth infection may have significant influence on the development of IBD by modulating immune responses and have led to the development of the “hygiene hypothesis” of IBD, that is, that IBD occurs more commonly in societies where the prevalence of chronic enteric infestation is low.
Objective: To develop helminth antigen or purified protein based strategy to achieve beneficial effect in colonic inflammation.
Significance: This research will not only ultimately lead to a novel strategy in treating IBD but will also provide valuable information on the mechanisms involved in intestinal inflammatory disorders.
- Yabut, JM, Crane, JD, Green, AE, Keating, DJ, Khan, WI, Steinberg, GR et al.. Emerging Roles for Serotonin in Regulating Metabolism: New Implications for an Ancient Molecule. Endocr. Rev. 2019; :. doi: 10.1210/er.2018-00283. PubMed PMID:30901029 .
- Haq, S, Grondin, J, Banskota, S, Khan, WI. Autophagy: roles in intestinal mucosal homeostasis and inflammation. J. Biomed. Sci. 2019;26 (1):19. doi: 10.1186/s12929-019-0512-2. PubMed PMID:30764829 PubMed Central PMC6375151.
- Kwon, YH, Wang, H, Denou, E, Ghia, JE, Rossi, L, Fontes, ME et al.. Modulation of Gut Microbiota Composition by Serotonin Signaling Influences Intestinal Immune Response and Susceptibility to Colitis. Cell Mol Gastroenterol Hepatol. 2019; :. doi: 10.1016/j.jcmgh.2019.01.004. PubMed PMID:30716420 .
- Vincent, AD, Wang, XY, Parsons, SP, Khan, WI, Huizinga, JD. Abnormal absorptive colonic motor activity in germ-free mice is rectified by butyrate, an effect possibly mediated by mucosal serotonin. Am. J. Physiol. Gastrointest. Liver Physiol. 2018;315 (5):G896-G907. doi: 10.1152/ajpgi.00237.2017. PubMed PMID:30095295 .
- Banskota, S, Ghia, JE, Khan, WI. Serotonin in the gut: Blessing or a curse. Biochimie. 2018; :. doi: 10.1016/j.biochi.2018.06.008. PubMed PMID:29909048 .
- Libertucci, J, Dutta, U, Kaur, S, Jury, J, Rossi, L, Fontes, ME et al.. Inflammation-related differences in mucosa-associated microbiota and intestinal barrier function in colonic Crohn's disease. Am. J. Physiol. Gastrointest. Liver Physiol. 2018;315 (3):G420-G431. doi: 10.1152/ajpgi.00411.2017. PubMed PMID:29848021 .
- Cloutier, N, Allaeys, I, Marcoux, G, Machlus, KR, Mailhot, B, Zufferey, A et al.. Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration. Proc. Natl. Acad. Sci. U.S.A. 2018;115 (7):E1550-E1559. doi: 10.1073/pnas.1720553115. PubMed PMID:29386381 PubMed Central PMC5816207.
- Saeed, S, Bonnefond, A, Tamanini, F, Mirza, MU, Manzoor, J, Janjua, QM et al.. Loss-of-function mutations in ADCY3 cause monogenic severe obesity. Nat. Genet. 2018;50 (2):175-179. doi: 10.1038/s41588-017-0023-6. PubMed PMID:29311637 .
- Kittanakom, S, Shajib, MS, Garvie, K, Turner, J, Brooks, D, Odeh, S et al.. Comparison of Fecal Calprotectin Methods for Predicting Relapse of Pediatric Inflammatory Bowel Disease. Can J Gastroenterol Hepatol. 2017;2017 :1450970. doi: 10.1155/2017/1450970. PubMed PMID:28491862 PubMed Central PMC5410371.
- Shajib, MS, Baranov, A, Khan, WI. Diverse Effects of Gut-Derived Serotonin in Intestinal Inflammation. ACS Chem Neurosci. 2017;8 (5):920-931. doi: 10.1021/acschemneuro.6b00414. PubMed PMID:28288510 .