University Professor, Department of Medicine
Associate Dean, Research

Email: scollins@mcmaster.ca

Year of appointment: 1981

Research Areas

Immune modulation of enteric nerve and muscle function

Focus

Functional Gastrointestinal Disorders (FGD) are chronic abdominal symptom-complexes that occur in the absence of any discernible structural abnormality; they are disorders of GI function. They are accompanied by psychiatric co-morbidity in up 60% of patients, prompting the suspicion that they are “psychosomatic disorders”.  We have challenged this perception by investigating the role of infection and inflammation in these disorders. Our research has provided proof of concept that the mucosal immune system modulates function in the intestinal sensory-motor apparatus and promoted the hypothesis that low grade inflammation plays a pathophysiological role in at least a subset of patients with FGD.

We developed a murine model of long-term gut dysfunction following transient enteric infection and showed that this was maintained by low grade inflammation. Translating this, we followed patients in UK and in Walkerton, Ont., with acute gastroenteritis and established that up to 30% develop FGD. Two questions then emerged: what factors maintain the low-grade inflammation in these disorders, and what is the basis for the psychiatric co-morbidity seen in up to 60% of patients with FGD?  The relationship between low grade inflammation in the gut and psychiatric co-morbidity is currently unknown and we propose that gut dysfunction and behavioral abnormalities are due to a disturbance of the intestinal microbiota (dysbiosis). Our work now focuses on the effect of the intestinal microbiota on host function, with emphasis on the gastrointestinal tract and brain and underlying neuro-immune mechanisms. In our current work, we build on our recent observations in murine models showing that experimental disruption of the intestinal microbiota produces changes not only in gut function and low grade inflammation, but also in behavior. We continue our work on residents of Walkerton which involves phenotyping and genotyping those with post-infective IBS, and will be embarking on a study correlating GI symptoms and behavior with profiles of resident bacteria in Walkerton residents. Our aim is to understand how resident microbes not only maintain health but also and to understand how perturbation of this ecosystem contributes to the expression of disease within and outside the gastrointestinal tract.

Methologies

We have a large germ-free (gnotobiotic) facility which is critical for this work, as well as an enteric microbiological facility that includes anaerobic culture, 16S rDNA-based RT-PCR, qPCR, denaturing gradient gel electrophoresis (DGGE). We also have access to CFI funded Roche 454 DNA sequencer. We have technology for in situ hybridization of brain tissue, for performing tests of several behaviors, and for the comprehensive evaluation of gut function in vivo and in vitro, including motility, pain perception and mucosal barrier function.

Funding

Project 1

Title: The immunomodulation of gastrointestinal motility

CIHR, 2004-09

Background: Gut motility and pain perception are altered in conditions associated with inflammation or immune activation.

Objectives: To determine the mechanisms underlying altered neuro-muscular function in murine models of functional and inflammatory bowel disorders.

Significance: A better understanding of mechanisms underlying altered motility and sensory function will lead to improved treatments of diarrhea and abdominal pain in inflammatory bowel disorders

Project 2

Title: Effects of probiotics on intestinal neuromuscular function

Nestle Foundation, 2001–09

Background: The colon contains huge numbers of commensal organisms that are important for its health and normal function.

Objectives: To examine the ability of commensal bacteria to modulate gut motility and to develop a rational approach to the use of probiotics in disorders of the GI tract. Significance: Probiotics may be useful in treating functional disorders of the gastrointestinal tract.

2008-13 CIHR – Team Grant on mucosal immunity

2004-9 ORDCF Grant for the Study of Chronic GI Diseases

Selected Publications

• Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology 2009; 136(6): 2003-14. PDF
• Ghia JE, Blennerhassett P, Deng Y, Verdu EF, Khan WI, Collins SM. Reactivation of inflammatory bowel disease in a mouse model of depression. Gastroenterology 2009; 136(7): 2280-2288. PDF
• Bercik P, Verdú EF, Foster JA, Lu J, Scharringa A, Kean I, Wang L, Blennerhassett P, Collins SM. Role of gut-brain axis in persistent abnormal feeding behavior in mice following eradication of Helicobacter pylori infection. Am J Physiol Regul Integr Comp Physiol 2009; 296(3): 587-94. PDF
• Zhu Q, Thomson CW, Rosenthal KL, McDermott MR, Collins SM, Gauldie J. Immunization with adenovirus at the large intestinal mucosa as an effective vaccination strategy against sexually transmitted viral infection. Mucosal Immunol 2008; 1(1): 78-88. PDF
• Verdu EF, Bercik P, Huang XX, Lu J, Al-Mutawaly N, Sakai H, Tompkins TA, Croitoru K, Tsuchida E, Perdue M, Collins SM. The role of luminal factors in the recovery of gastric function and behavioral changes after chronic Helicobacter pylori infection. Am J Physiol Gastrointest Liver Physiol 2008; 295(4): 664-70. PDF
• Ghia JE, Blennerhassett P, Collins SM. Impaired parasympathetic function increases susceptibility to inflammatory bowel disease in a mouse model of depression. J Clin Invest 2008; 118(6): 2209-18. PDF
• Spaziani R, Bayati A, Redmond K, Bajaj H, Mazzadi S, Bienenstock J, Collins SM, Kamath MV. Vagal dysfunction in irritable bowel syndrome assessed by rectal distension and baroreceptor sensitivity. Neurogastroenterol Motil 2008; 20(4): 336-42. PDF
• Collins SM. Translating symptoms into mechanisms: functional GI disorders. Adv Physiol Educ 2007; 31(4): 329-31. PDF
• Piche T, Vanbiervliet G, Pipau FG, Dainese R, Hébuterne X, Rampal P, Collins SM. Low risk of irritable bowel syndrome after Clostridium difficile infection. Can J Gastroenterol 2007; 21(11): 727-31. PDF
• Ganguli SC, Kamath MV, Redmond K, Chen Y, Irvine EJ, Collins SM, Tougas G. A comparison of autonomic function in patients with inflammatory bowel disease and in healthy controls. Neurogastroenterol Motil 2007; 19(12): 961-7. PDF
• Ghia JE, Blennerhassett P, El-Sharkawy RT, Collins SM. The protective effect of the vagus nerve in a murine model of chronic relapsing colitis. Am J Physiol Gastrointest Liver Physiol 2007; 293(4): 711-8. PDF
• Ghia JE, Blennerhassett P, Collins SM. Vagus nerve integrity and experimental colitis. Am J Physiol Gastrointest Liver Physiol 2007; 293(3): 560-7. PDF
• Paré P, Bridges R, Champion MC, Ganguli SC, Gray JR, Irvine EJ, Plourde V, Poitras P, Turnbull GK, Moayyedi P, Flook N, Collins SM. Recommendations on chronic constipation (including constipation associated with irritable bowel syndrome) treatment. Can J Gastroenterol 2007; 21(SB): 3-22. PDF
• Zhu Q, Thomson CW, Zhang G, Stämpfli M, McDermott MR, Collins SM, Gauldie J. Eosinophilia is induced in the colon of Th2-sensitized mice upon exposure to locally expressed antigen. Am J Physiol Gastrointest Liver Physiol 2007; 293(1): 383-90. PDF
• Akiho H, Khan WI, Al-Kaabi A, Blennerhassett P, Deng Y, Collins SM. Cytokine modulation of muscarinic receptors in the murine intestine. Am J Physiol Gastrointest Liver Physiol 2007; 293(1): 250-5. PDF
• Vallance BA, Radojevic N, Hogaboam CM, Deng Y, Gauldie J, Collins SM. IL-4 gene transfer to the small bowel serosa leads to intestinal inflammation and smooth muscle hyperresponsiveness. Am J Physiol Gastrointest Liver Physiol 2007; 292(1): 385-94. PDF
• Ghia JE, Blennerhassett P, Kumar-Ondiveeran H, Verdu EF, Collins SM. The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology 2006; 131(4): 1122-30. PDF
• Verma-Gandhu M, Verdu EF, Bercik P, Blennerhassett PA, Al-Mutawaly N, Ghia JE, Collins SM. Visceral pain perception is determined by the duration of colitis and associated neuropeptide expression in the mouse. Gut 2007; 56(3): 358-64. PDF
• Verma-Gandhu M, Verdu EF, Cohen-Lyons D, Collins SM. Lymphocyte-mediated regulation of beta-endorphin in the myenteric plexus. Am J Physiol Gastrointest Liver Physiol 2007; 292(1): 344-8. PDF
• Martin FP, Verdu EF, Wang Y, Dumas ME, Yap IK, Cloarec O, Bergonzelli GE, Corthesy-Theulaz I, Kochhar S, Holmes E, Lindon JC, Collins SM, Nicholson JK. Transgenomic metabolic interactions in a mouse disease model: interactions of Trichinella spiralis infection with dietary Lactobacillus paracasei supplementation. J Proteome Res 2006; 5(9): 2185-93. PDF
• Marshall JK, Thabane M, Garg AX, Clark WF, Salvadori M, Collins SM; Walkerton Health Study Investigators. Incidence and epidemiology of irritable bowel syndrome after a large waterborne outbreak of bacterial dysentery. Gastroenterology 2006; 131(2): 445-50. PDF
• Borgaonkar MR, Ford DC, Marshall JK, Churchill E, Collins SM. The incidence of irritable bowel syndrome among community subjects with previous acute enteric infection. Dig dis Sci 2006; 51(5): 1026-32. PDF
• Khan WI, Motomura Y, Wang H, El-Sharkawy RT, Verdu EF, Verma-Gandhu M, Rollins BJ, Collins SM. Critical role of MCP-1 in the pathogenesis of experimental colitis in the context of immune and enterochromaffin cells. Am J Physiol Gastrointest Liver Physiol 2006; 291(5): 803-11. PDF
• Varghese AK, Verdú EF, Bercik P, Khan WI, Blennerhassett PA, Szechtman H, Collins SM. Antidepressants attenuate increased susceptibility to colitis in a murine model of depression. Gastroenterology 2006; 130(6): 1743-53. PDF
• Verma-Gandhu M, Bercik P, Motomura Y, Verdu EF, Khan WI, Blennerhassett PA, Wang L, El-Sharkawy RT, Collins SM. CD4+ T-cell modulation of visceral nociception in mice. Gastroenterology 2006; 130(6): 1721-8. PDF
• Khan WI, Collins SM. Gut motor function: immunological control in enteric infection and inflammation. Clin Exp Immunol 2006; 143(3): 389-97. PDF
• Collins SM. Complex system approaches: could they enhance the relevance of clinical research? Phys Ther 2005; 85(12): 1393-4. PDF
• Motomura Y, Khan WI, El-Sharkawy RT, Verma-Gandhu M, Verdu EF, Gauldie J, Collins SM. Induction of a fibrogenic response in mouse colon by overexpression of monocyte chemoattractant protein 1. Gut 2006; 55(5): 662-70. PDF
• Collins SM. Dysregulation of peripheral cytokine production in irritable bowel syndrome. Am J Gastroenterol 2005; 100(11): 2517-8. PDF
• Verdu EF, Collins SM. Irritable bowel syndrome and probiotics: from rationale to clinical use. Curr Opin Gastroenterol 2005; 21(6): 697-701. PDF
• Verdú EF, Bercik P, Verma-Gandhu M, Huang XX, Blennerhassett P, Jackson W, Mao Y, Wang L, Rochat F, Collins SM. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut 2006; 55(2): 182-90. PDF
• Akiho H, Deng Y, Blennerhassett P, Kanbayashi H, Collins SM. Mechanisms underlying the maintenance of muscle hypercontractility in a model of postinfective gut dysfunction. Gastroenterology 2005; 129(1): 131-41. PDF
• Bercik P, Verdu EF, Collins SM. Is irritable bowel syndrome a low-grade inflammatory bowel disease? Gastroenterol Clin North Am 2005; 34(2): 235-45. PDF
• Vallance BA, Gunawan MI, Hewlett B, Bercik P, Van Kampen C, Galeazzi F, Sime PJ, Gauldie J, Collins SM. TGF-beta1 gene transfer to the mouse colon leads to intestinal fibrosis. Am J Physiol Gastrointest Liver Physiol 2005; 289(1): 116-28. PDF
• Khan WI, Collins SM. Immune-mediated alteration in gut physiology and its role in host defence in nematode infection. Parasite Immunol 2004; 26(8-9): 319-26. PDF
• Marshall JK, Thabane M, Garg AX, Clark W, Meddings J, Collins SM; WEL Investigators. Intestinal permeability in patients with irritable bowel syndrome after a waterborne outbreak of acute gastroenteritis in Walkerton, Ontario. Aliment Pharmacol Ther 2004; 20(11-12): 1317-22. PDF
• Van Kampen C, Gauldie J, Collins SM. Proinflammatory properties of IL-4 in the intestinal microenvironment. Am J Physiol Gastrointest Liver Physiol 2005; 288(1): 111-7. PDF
• Akiho H, Lovato P, Deng Y, Ceponis PJ, Blennerhassett P, Collins SM. Interleukin-4- and -13-induced hypercontractility of human intestinal muscle cells-implication for motility changes in Crohn's disease. Am J Physiol Gastrointest Liver Physiol 2005; 288(4): 609-15. PDF
• Verdú EF, Bercík P, Bergonzelli GE, Huang XX, Blennerhasset P, Rochat F, Fiaux M, Mansourian R, Corthésy-Theulaz I, Collins SM. Lactobacillus paracasei normalizes muscle hypercontractility in a murine model of postinfective gut dysfunction. Gastroenterology 2004; 127(3): 826-37. PDF
• Khan WI, Motomura Y, Blennerhassett PA, Kanbayashi H, Varghese AK, El-Sharkawy RT, Gauldie J, Collins SM. sruption of CD40-CD40 ligand pathway inhibits the development of intestinal muscle hypercontractility and protective immunity in nematode infection. Am J Physiol Gastrointest Liver Physiol 2005; 288(1): 15-22. PDF
• Motomura Y, Kanbayashi H, Khan WI, Deng Y, Blennerhassett PA, Margetts PJ, Gauldie J, Egashira K, Collins SM. The gene transfer of soluble VEGF type I receptor (Flt-1) attenuates peritoneal fibrosis formation in mice but not soluble TGF-beta type II receptor gene transfer. Am J Physiol Gastrointest Liver Physiol 2005; 288(1): 143-50. PDF
• Collins SM, Barbara G. East meets West: infection, nerves, and mast cells in the irritable bowel syndrome. Gut 2004; 53(8): 1068-9. PDF
• Bercík P, Wang L, Verdú EF, Mao YK, Blennerhassett P, Khan WI, Kean I, Tougas G, Collins SM. Visceral hyperalgesia and intestinal dysmotility in a mouse model of postinfective gut dysfunction. Gastroenterology 2004; 127(1): 179-87. PDF
• Vallance BA, Dijkstra G, Qiu B, Van der Waaij LA, Van Goor H, Jansen PL, Mashimo H, Collins SM. Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity. Am J Physiol Gastrointest Liver Physiol 2004; 287(4): 865-74. PDF
• Verdu EF, Collins SM. Microbial-gut interactions in health and disease. Irritable bowel syndrome. Best Pract Res Clin Gastroenterol 2004; 18(2): 315-21. PDF
• Mawe GM, Collins SM, Shea-Donohue T. Changes in enteric neural circuitry and smooth muscle in the inflamed and infected gut. Neurogastroenterol Motil 2004; 16(S1): 133-6. PDF
• Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, Pasquinelli G, Morselli-Labate AM, Grady EF, Bunnett NW, Collins SM, Corinaldesi R. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126(3): 693-702. PDF
• Barbara G, De Giorgio R, Stanghellini V, Corinaldesi R, Cremon C, Gerard N, Gerard C, Grady EF, Bunnett NW, Blennerhassett PA, Collins SM. Neutral endopeptidase (EC 3.4.24.11) downregulates the onset of intestinal inflammation in the nematode infected mouse. Gut 2003; 52(10): 1457-64. PDF
• Dunlop SP, Jenkins D, Neal KR, Naesdal J, Borgaonker M, Collins SM, Spiller RC. Randomized, double-blind, placebo-controlled trial of prednisolone in post-infectious irritable bowel syndrome. Aliment Pharmacol Ther 2003; 18(1): 77-84. PDF
• Khan WI, Richard M, Akiho H, Blennerhasset PA, Humphreys NE, Grencis RK, Van Snick J, Collins SM. Modulation of intestinal muscle contraction by interleukin-9 (IL-9) or IL-9 neutralization: correlation with worm expulsion in murine nematode infections. Infect Immun 2003; 71(5): 2430-8. PDF
• Gwee KA, Collins SM, Read NW, Rajnakova A, Deng Y, Graham JC, McKendrick MW, Moochhala SM. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut 2003; 52(4): 523-6. PDF
• Collins SM, McHugh K, Croitoru K, Howorth M. The establishment of a national tissue bank for inflammatory bowel disease research in Canada. Can J Gastroenterol 2003; 17(2): 107-9. PDF
• Khan WI, Blennerhasset PA, Varghese AK, Chowdhury SK, Omsted P, Deng Y, Collins SM. Intestinal nematode infection ameliorates experimental colitis in mice. Infect Immun 2002; 70(11): 5931-7. PDF
• Bercík P, De Giorgio R, Blennerhassett P, Verdú EF, Barbara G, Collins SM. Immune-mediated neural dysfunction in a murine model of chronic Helicobacter pylori infection. Gastroenterology 2002; 123(4): 1205-15. PDF
• Piche T, Collins SM, Rampal P. [Role of enteric infections and inflammation in functional bowel disorders] Gastroenterol Clin Biol 2002; 26(6-7): 624-9. PDF
• Verdú EF, Deng Y, Bercik P, Collins SM. Modulatory effects of estrogen in two murine models of experimental colitis. Am J Physiol Gastrointest Liver Physiol 2002; 283(1): 27-36. PDF
• Collins SM. A case for an immunological basis for irritable bowel syndrome. Gastroenterology 2002; 122(7): 2078-80. PDF
• Mayer EA, Collins SM. Evolving pathophysiologic models of functional gastrointestinal disorders. Gastroenterology 2002; 122(7): 2032-48. PDF
• Wang XY, Berezin I, Mikkelsen HB, Der T, Bercik P, Collins SM, Huizinga JD. Pathology of interstitial cells of Cajal in relation to inflammation revealed by ultrastructure but not immunohistochemistry. Am J Pathol 2002; 160(4): 1529-40. PDF
• Akiho H, Blennerhassett P, Deng Y, Collins SM. Role of IL-4, IL-13, and STAT6 in inflammation-induced hypercontractility of murine smooth muscle cells. Am J Physiol Gastrointest Liver Physiol 2002; 282(2): 226-32. PDF
• De Giorgio R, Barbara G, Blennerhassett P, Wang L, Stanghellini V, Corinaldesi R, Collins SM, Tougas G. Intestinal inflammation and activation of sensory nerve pathways: a functional and morphological study in the nematode infected rat. Gut 2001; 49(6): 822-7. PDF
• Collins SM, Piche T, Rampal P. The putative role of inflammation in the irritable bowel syndrome. Gut 2001; 49(6): 743-5. PDF
• Collins SM. Peripheral mechanisms of symptom generation in irritable bowel syndrome. Can J Gastroenterol 2001; 15(SB): 14-6. PDF
• Galeazzi F, Lovato P, Blennerhassett PA, Haapala EM, Vallance BA, Collins SM. Neural change in Trichinella-infected mice is MHC II independent and involves M-CSF-derived macrophages. Am J Physiol Gastrointest Liver Physiol 2001; 281(1): 151-8. PDF
• Khan WI, Blennerhassett PA, Deng Y, Gauldie J, Vallance BA, Collins SM. IL-12 gene transfer alters gut physiology and host immunity in nematode-infected mice. Am J Physiol Gastrointest Liver Physiol 2001; 281(1): 102-10. PDF
• Barbara G, De Giorgio R, Deng Y, Vallance B, Blennerhassett P, Collins SM. Role of immunologic factors and cyclooxygenase 2 in persistent postinfective enteric muscle dysfunction in mice. Gastroenterology 2001; 120(7): 1729-36. PDF
• Rühl A, Franzke S, Collins SM, Stremmel W. Interleukin-6 expression and regulation in rat enteric glial cells. Am J Physiol Gastrointest Liver Physiol 2001; 280(6): 1163-71. PDF
• Vallance BA, Blennerhassett PA, Huizinga JD, Collins SM. Mast cell-independent impairment of host defense and muscle contraction in T. spiralis-infected W/W(V) mice. Am J Physiol Gastrointest Liver Physiol 2001; 280(4): 640-8. PDF
• Collins SM. Stress and the Gastrointestinal Tract IV. Modulation of intestinal inflammation by stress: basic mechanisms and clinical relevance. Am J Physiol Gastrointest Liver Physiol 2001; 280(3): 315-8. PDF
• Khan WI, Vallance BA, Blennerhassett PA, Deng Y, Verdu EF, Matthaei KI, Collins SM. Critical role for signal transducer and activator of transcription factor 6 in mediating intestinal muscle hypercontractility and worm expulsion in Trichinella spiralis-infected mice. Infect Immun 2001; 69(2): 838-44. PDF
• Huizinga JD, Berezin I, Sircar K, Hewlett B, Donnelly G, Bercik P, Ross C, Algoufi T, Fitzgerald P, Der T, Riddell RH, Collins SM, Jacobson K. Development of interstitial cells of Cajal in a full-term infant without an enteric nervous system. Gastroenterology 2001; 120(2): 561-7. PDF
• Khan WI, Blennerhasset P, Ma C, Matthaei KI, Collins SM. Stat6 dependent goblet cell hyperplasia during intestinal nematode infection. Parasite Immunol 2001; 23(1): 39-42. PDF
• Der T, Bercik P, Donnelly G, Jackson T, Berezin I, Collins SM, Huizinga JD. Interstitial cells of cajal and inflammation-induced motor dysfunction in the mouse small intestine. Gastroenterology 2000; 119(6): 1590-9. PDF
• Vallance BA, Matthaei KI, Sanovic S, Young IG, Collins SM. Interleukin-5 deficient mice exhibit impaired host defence against challenge Trichinella spiralis infections. Parasite Immunol 2000; 22(10): 487-92. PDF
• Barbara G, Xing Z, Hogaboam CM, Gauldie J, Collins SM. Interleukin 10 gene transfer prevents experimental colitis in rats. Gut 2000; 46(3): 344-9. PDF
• Galeazzi F, Haapala EM, van Rooijen N, Vallance BA, Collins SM. Inflammation-induced impairment of enteric nerve function in nematode-infected mice is macrophage dependent. Am J Physiol Gastrointest Liver Physiol 2000; 278(2): 259-65. PDF

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