{"id":20,"date":"2015-10-20T16:16:26","date_gmt":"2015-10-20T16:16:26","guid":{"rendered":"https:\/\/lab.research.sickkids.ca\/sherman\/?page_id=20"},"modified":"2019-05-27T18:43:35","modified_gmt":"2019-05-27T18:43:35","slug":"research","status":"publish","type":"page","link":"https:\/\/lab.research.sickkids.ca\/sherman\/research\/","title":{"rendered":"Research"},"content":{"rendered":"

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The purpose of our research is to discover novel methods to prevent and treat intestinal injury in humans and enhance the quality-of-life and health of Canadians<\/strong><\/span><\/h3>\n

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Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) describe a wide range of digestive disorders characterized by inflammation of the gastrointestinal tract, abdominal pain and diarrhea, which can be caused by a variety of factors including host genetics and infections with pathogenic bacteria. \u00a0Our laboratory strives to better understand host-microbe interactions in the gut in the setting of disease.\u00a0 We investigate the mechanisms by which intestinal pathogens, such as enterohemorrhagic Escherichia coli<\/em> and adherent-invasive E. coli<\/em> from patients with Crohn’s disease affect epithelial cell models and relevant animal models of disease.\u00a0 \u00a0Our research has led to the discovery of various treatment strategies (probiotics, prebiotics, and micronutrients) which alleviate or prevent disease outcome.\u00a0 We are well-known for our work with probiotics and have been fortunate to see our findings progress to prospective, randomized clinical trials.<\/p>\n

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Gut microbiome in health and disease: \u00a0<\/b>The gut microbiome is a carefully balanced, complex collection of\u00a0100 trillion\u00a0beneficial and \u00a0potentially pathogenic bacteria that play a major role in maintaining health and well-being.\u00a0 Dysbiosis (bacterial imbalance) can cause increased populations of harmful bacteria, thereby leading to disease. Our laboratory is interested in how \u201cgood\u201d and \u201cbad\u201d bacteria interact with the host to either cause disease or promote health. Beneficial microbes perform many useful functions for their host, such as fermenting unutilized substrates, repressing the colonization and growth of harmful\/pathogenic bacteria, and producing needed vitamins for the host. Using models of IBD, IBS, and various molecular-based methods, we are able to\u00a0monitor the alterations in gut microflora community structure and their functions.<\/p>\n

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Host\u00a0responses to <\/b>enteropathogenic<\/b> Escherichia coli <\/i><\/b>(EPEC)<\/b>,<\/i><\/b>\u00a0 enterohemorrhagic <\/b>E. coli<\/i><\/b> (EHEC) and adherent-invasive <\/b>E. coli<\/i><\/b> (AIEC) infection:<\/b>\u00a0 Enteric pathogens such as EPEC, EHEC and AIEC ((a bacterium\u00a0 isolated from the terminal ileum of patients with Crohn\u2019s disease) are the leading cause of diarrhea and are implicated in the pathogenesis of inflammatory diseases such as Crohn\u2019s disease.\u00a0 Using established relevant epithelial cell lines, we are able to study how these bacteria interact with the host to challenge innate and adaptive immunity and cause changes in cellular responses. We assess how these pathogens cause cytoskeletal rearrangements, disrupt barrier function, activate signal transduction pathways, and affect membrane trafficking, proliferation and apoptosis.<\/p>\n

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<\/b>Cellular responses to infection:<\/strong> One of the hallmarks of active intestinal inflammation is the mucosal infiltration of neutrophils. \u00a0These granulomatous cells are \u2018first responders\u2019 and are well-equipped with an array of anti-microbial and proteolytic enzymes to combat infection.\u00a0 More recently, neutrophils have been shown to cast out DNA-rich web-like strands (termed neutrophil extracellular traps; NETs) to capture, contain and kill bacteria.\u00a0 The intestinal tract is subject to intense microbial burden. Thus, our\u00a0studies also focus on the capacity of commensal\/probiotic bacteria (those that maintain and support intestinal health) and pathogenic bacteria (those implicated in intestinal disease) to induce NETs, during health and disease.<\/p>\n

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Animal models of human disease:<\/b> Using relevant in vivo <\/i>models of IBD, IBS,\u00a0and early-life stress we are able to delineate how Citrobacter<\/i> rodentium<\/i> (a murine-specific enteric bacterial pathogen) affects biological mechanisms.\u00a0 Our whole system models enable us to study dose-response, efficacy and specificity of the therapeutics used, and define disease progression, immunological responses, \u00a0physiological changes. \u00a0We are also able to utilize specific molecular techniques to study shifts in microbial populations during\u00a0infection and treatment.<\/p>\n

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Therapeutic strategies for alleviating the onset and progression <\/b>of disease<\/b>: <\/b>Using complimentary\u00a0in vitro<\/i> and in vivo<\/i> models, we investigate the mechanisms by which probiotics (beneficial bacteria that, when ingested in sufficient amounts, provide health benefits to the host), prebiotics (non-digestible food ingredients that promote the growth of beneficial gut bacteria), and dietary constituents (vitamins and fatty acids) influence the onset and progression of intestinal injury and mucosal inflammation.<\/p>\n

Our published results demonstrate that:<\/p>\n

    \n
  1. enteric pathogens subvert host responses, modulate inflammatory responses, modify gene expression, alter the microbiome, and disrupt epithelial cell microvilli,<\/li>\n
  2. non-traditional therapeutics such as probiotics, prebiotics and micronutrients prevent pathogen-induced responses and reduce disease outcome, and<\/li>\n
  3. probiotics prevent death in neonates infected with a murine pathogen in a time-, dose-, and species specific manner.<\/li>\n<\/ol>\n

    <\/h3>\n

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