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Waliul I. Khan, MBBS, PhD, FRCPath

Professor, Department of Pathology & Molecular Medicine

Email: khanwal@mcmaster.ca 

Mucosal immunology, immuno-physiology and host defense in the context of intestinal infection/inflammation.

Focus

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.

Methodologies

Cell culture, immunohistochemistry, immunofluorescence, lymphocyte proliferation study, ELISA, western blotting, physiological studies on muscle, laser capture micro-dissection and RT-PCR. 

Project 1

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.

Project 2

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.

Project 3

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.

Project 4

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.

  1. Shajib, MS, Baranov, A, Khan, WI. Diverse effects of gut-derived serotonin in intestinal inflammation. ACS Chem Neurosci. 2017; :. doi: 10.1021/acschemneuro.6b00414. PubMed PMID:28288510 .
  2. Cavallari, JF, Denou, E, Foley, KP, Khan, WI, Schertzer, JD. Different Th17 immunity in gut, liver, and adipose tissues during obesity: the role of diet, genetics, and microbes. Gut Microbes. 2016;7 (1):82-9. doi: 10.1080/19490976.2015.1127481. PubMed PMID:26939856 PubMed Central PMC4856458.
  3. Ikhtaire, S, Shajib, MS, Reinisch, W, Khan, WI. Fecal calprotectin: its scope and utility in the management of inflammatory bowel disease. J. Gastroenterol. 2016;51 (5):434-46. doi: 10.1007/s00535-016-1182-4. PubMed PMID:26897740 .
  4. Wang, H, Kim, JJ, Denou, E, Gallagher, A, Thornton, DJ, Shajib, MS et al.. New Role of Nod Proteins in Regulation of Intestinal Goblet Cell Response in the Context of Innate Host Defense in an Enteric Parasite Infection. Infect. Immun. 2015;84 (1):275-85. doi: 10.1128/IAI.01187-15. PubMed PMID:26527214 PubMed Central PMC4694016.
  5. Raman, K, Wang, H, Troncone, MJ, Khan, WI, Pare, G, Terry, J et al.. Overlap Chronic Placental Inflammation Is Associated with a Unique Gene Expression Pattern. PLoS ONE. 2015;10 (7):e0133738. doi: 10.1371/journal.pone.0133738. PubMed PMID:26207633 PubMed Central PMC4514672.
  6. Kim, JJ, Wang, H, Terc, JD, Zambrowicz, B, Yang, QM, Khan, WI et al.. Blocking peripheral serotonin synthesis by telotristat etiprate (LX1032/LX1606) reduces severity of both chemical- and infection-induced intestinal inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 2015;309 (6):G455-65. doi: 10.1152/ajpgi.00299.2014. PubMed PMID:26206858 .
  7. Denou, E, Lolmède, K, Garidou, L, Pomie, C, Chabo, C, Lau, TC et al.. Defective NOD2 peptidoglycan sensing promotes diet-induced inflammation, dysbiosis, and insulin resistance. EMBO Mol Med. 2015;7 (3):259-74. doi: 10.15252/emmm.201404169. PubMed PMID:25666722 PubMed Central PMC4364944.
  8. Kim, JJ, Khan, WI. 5-HT7 receptor signaling: improved therapeutic strategy in gut disorders. Front Behav Neurosci. 2014;8 :396. doi: 10.3389/fnbeh.2014.00396. PubMed PMID:25565996 PubMed Central PMC4263172.
  9. Crane, JD, Palanivel, R, Mottillo, EP, Bujak, AL, Wang, H, Ford, RJ et al.. Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis. Nat. Med. 2015;21 (2):166-72. doi: 10.1038/nm.3766. PubMed PMID:25485911 .
  10. Shajib, MS, Khan, WI. The role of serotonin and its receptors in activation of immune responses and inflammation. Acta Physiol (Oxf). 2015;213 (3):561-74. doi: 10.1111/apha.12430. PubMed PMID:25439045 .
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