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Kassam Z.,McMaster University | Lee C.H.,McMaster University | Lee C.H.,Hamilton Regional Laboratory Medicine Program | Yuan Y.,McMaster University | And 3 more authors.
American Journal of Gastroenterology | Year: 2013

OBJECTIVES: The clinical and economic burden of Clostridium difficile infection (CDI) is significant. Recurrent CDI management has emerged as a major challenge with suboptimal response to standard therapy. Fecal microbiota transplantation (FMT) has been used as a treatment to reconstitute the normal microbial homeostasis and break the cycle of antibiotic agents that may further disrupt the microbiome. Given the lack of randomized-controlled trials (RCTs) and limitations in previous systematic reviews, we aimed to conduct a systematic review with robust methods to determine the efficacy and safety profile of FMT in CDI.METHODS: An electronic search was conducted using MEDLINE (1946-March 2012), EMBASE (1974-March 2012) and Cochrane Central Register of Controlled Trials (2012). The search strategy was not limited by language. Abstract data were excluded and only completed studies that underwent the full, rigorous peer-review process were included. Studies that used FMT via any delivery modality for laboratory or endoscopically proven CDI with clinical resolution as primary outcome were included. A sample size of 10 or more patients was a further criterion. Elements of the Centre for Reviews and Dissemination checklist and the National Institute of Clinical Excellence quality assessment for case series checklist were employed to determine study quality. Eligibility assessment and data extraction were performed by two independent researchers. Both unweighted pooled resolution rates (UPR) and weighted pooled resolution rates (WPR) were calculated with corresponding 95% confidence intervals (CI) for overall studies, as well as predefined subgroups.RESULTS: Eleven studies with a total of 273 CDI patients treated with FMT were identified; no RCTs were found as none have been published. Two-hundred and forty-five out of 273 patients experienced clinical resolution (UPR 89.7%; WPR 89.1% (95% CI 84 to 93%)). There was no statistically significant heterogeneity between studies (Cochran Q test P=0.13, I 2 =33.7%). A priori subgroup analysis suggested that lower gastrointestinal FMT delivery (UPR 91.4%; WPR 91.2% (95% CI 86 to 95%)) led to a trend towards higher clinical resolution rates than the upper gastrointestinal route (UPR 82.3%; WPR 80.6% (95% CI 69-90%)) (proportion difference of WPR was 10.6% (95% CI-0.6 to 22%)). No difference in clinical outcomes was detected between anonymous vs. patient selected donors. There were no reported adverse events associated with FMT and follow-up was variable from weeks to years.CONCLUSIONS: FMT holds considerable promise as a therapy for recurrent CDI but well-designed, RCTs and long-term follow-up registries are still required. These are needed to identify the right patient, efficacy and safety profile of FMT before this approach can be widely advocated. © 2013 by the American College of Gastroenterology.


News Article | March 2, 2017
Site: www.biosciencetechnology.com

Research from McMaster University has found that bacteria in the gut impacts both intestinal and behavioral symptoms in patients suffering from irritable bowel syndrome (IBS), a finding which could lead to new microbiota-directed treatments. The new study, published today in Science Translational Medicine, was led by researchers from the Farncombe Family Digestive Health Research Institute at McMaster, Drs. Premysl Bercik and Stephen Collins, in collaboration with researchers from the University of Waterloo. IBS is the most common gastrointestinal disorder in the world. It affects the large intestine and patients suffer from abdominal pain and altered bowel habits like diarrhea and constipation, which are often accompanied by chronic anxiety or depression. Current treatments aimed at improving symptoms have limited efficacy because the underlying causes are unknown. The goal of the study was to explore whether fecal microbiota from human IBS patients with diarrhea has the ability to influence gut and brain function in recipient mice. Using fecal transplants, researchers transferred microbiota from IBS patients with or without anxiety into germ-free mice. The mice went on to develop changes both in intestinal function and behavior reminiscent of the donor IBS patients, compared to mice that were transplanted with microbiota from healthy individuals. The researchers found that aspects of the illness that were impacted through fecal transplants included gastrointestinal transit (the time it takes for food to leave the stomach and travel through the intestine); intestinal barrier dysfunction; low grade inflammation; and anxiety-like behavior. "This is a landmark study because it moves the field beyond a simple association, and towards evidence that changes in the microbiota impact both intestinal and behavioral responses in IBS," said Giada De Palma, the study's first author and research associate with the Farncombe Family Digestive Health Research Institute. "Our findings provide the basis for developing therapies aimed at the intestinal microbiota, and for finding biomarkers for the diagnosis of IBS," said Premysl Bercik, the study's lead author and Associate Professor of Medicine at McMaster University. The authors conclude that their findings raise the possibility that "microbiota-directed therapies, including pre- or probiotic treatment, may be beneficial in treating not only intestinal symptoms but also components of the behavioral manifestations of IBS." Interestingly, the authors noted that since the study showed that microbiota in the gut can influence the brain, it "adds to evidence suggesting that the intestinal microbiota may play some role in the spectrum of brain disorders ranging from mood or anxiety to other problems that may include autism, Parkinson's disease and multiple sclerosis." However, they added that further work is required to better define the relationship in these conditions.


News Article | March 1, 2017
Site: www.eurekalert.org

Hamilton, ON (March 1, 2017) - Research from McMaster University has found that bacteria in the gut impacts both intestinal and behavioural symptoms in patients suffering from irritable bowel syndrome (IBS), a finding which could lead to new microbiota-directed treatments. The new study, published today in Science Translational Medicine, was led by researchers from the Farncombe Family Digestive Health Research Institute at McMaster, Drs. Premysl Bercik and Stephen Collins, in collaboration with researchers from the University of Waterloo. IBS is the most common gastrointestinal disorder in the world. It affects the large intestine and patients suffer from abdominal pain and altered bowel habits like diarrhea and constipation, which are often accompanied by chronic anxiety or depression. Current treatments aimed at improving symptoms have limited efficacy because the underlying causes are unknown. The goal of the study was to explore whether fecal microbiota from human IBS patients with diarrhea has the ability to influence gut and brain function in recipient mice. Using fecal transplants, researchers transferred microbiota from IBS patients with or without anxiety into germ-free mice. The mice went on to develop changes both in intestinal function and behavior reminiscent of the donor IBS patients, compared to mice that were transplanted with microbiota from healthy individuals. The researchers found that aspects of the illness that were impacted through fecal transplants included gastrointestinal transit (the time it takes for food to leave the stomach and travel through the intestine); intestinal barrier dysfunction; low grade inflammation; and anxiety-like behaviour. "This is a landmark study because it moves the field beyond a simple association, and towards evidence that changes in the microbiota impact both intestinal and behavioral responses in IBS," said Giada De Palma, the study's first author and research associate with the Farncombe Family Digestive Health Research Institute. "Our findings provide the basis for developing therapies aimed at the intestinal microbiota, and for finding biomarkers for the diagnosis of IBS," said Premysl Bercik, the study's lead author and Associate Professor of Medicine at McMaster University. The authors conclude that their findings raise the possibility that "microbiota-directed therapies, including pre- or probiotic treatment, may be beneficial in treating not only intestinal symptoms but also components of the behavioural manifestations of IBS." Interestingly, the authors noted that since the study showed that microbiota in the gut can influence the brain, it "adds to evidence suggesting that the intestinal microbiota may play some role in the spectrum of brain disorders ranging from mood or anxiety to other problems that may include autism, Parkinson's disease and multiple sclerosis." However, they added that further work is required to better define the relationship in these conditions. This study was supported by grants from CIHR and Nestle Switzerland.


Ford A.C.,Farncombe Family Digestive Health Research Institute | Thabane M.,Farncombe Family Digestive Health Research Institute | Collins S.M.,Farncombe Family Digestive Health Research Institute | Moayyedi P.,Farncombe Family Digestive Health Research Institute | And 3 more authors.
Gastroenterology | Year: 2010

Background & Aims: Symptoms of dyspepsia may occur following an episode of acute gastroenteritis, but data are conflicting. We assessed prevalence of uninvestigated dyspepsia in a cohort of individuals, some of whom were exposed to bacterial dysentery in May 2000, as well as risk factors for dyspepsia in exposed individuals. Methods: This was a cohort study conducted in the town of Walkerton, Ontario, Canada. Involved individuals were recruited into the Walkerton Health Study between 2002 and 2003 and were attending for annual assessment in 2008. Exposed individuals were subdivided into those with self-reported gastroenteritis, with acute illness unconfirmed by health records, and those with clinically confirmed gastroenteritis, with substantiation of acute illness by health record review. Presence of dyspepsia at 8 years, according to a broad definition (any symptom referable to the upper gastrointestinal tract), and the Rome II criteria, was compared between exposed and nonexposed individuals. Results: Of 2597 subjects eligible, 1088 (41.9%) provided data for analysis, and 706 (64.9%) had reported acute gastroenteritis. Multivariate odd ratios for dyspepsia at 8 years in exposed individuals using a broad definition and the Rome II definition were 2.09 (95% confidence interval: 1.58-2.78) and 2.30 (95% confidence interval: 1.63-3.26), respectively. Prevalence of dyspepsia was higher in females; smokers; those with premorbid irritable bowel syndrome, anxiety, or depression; and those reporting >7 days of diarrhea or abdominal cramps during the acute illness. Conclusions: Symptoms of dyspepsia 8 years after an outbreak of acute gastroenteritis were significantly more prevalent in exposed compared with nonexposed individuals. © 2010 AGA Institute.


Villani A.,McGill University | Lemire M.,Ontario Cancer Institute | Thabane M.,Farncombe Family Digestive Health Research Institute | Belisle A.,McGill University | And 8 more authors.
Gastroenterology | Year: 2010

Background & Aims: Acute gastroenteritis is the strongest risk factor for irritable bowel syndrome (IBS). In May 2000, >2300 residents of Walkerton, Ontario, developed gastroenteritis from microbial contamination of the municipal water supply; a longitudinal study found that >36.2% of these developed IBS. We used this cohort to study genetic susceptibility to post-infectious (PI)-IBS. Methods: We screened 79 functional variants of genes with products involved in serotoninergic pathways, intestinal epithelial barrier function, and innate immunity and performed fine mapping in regions of interest. We compared data from Walkerton residents who developed gastroenteritis and reported PI-IBS 2 to 3 years after the outbreak (n = 228, cases) with data from residents who developed gastroenteritis but did not develop PI-IBS (n = 581, controls). Results: Four variants were associated with PI-IBS, although the association was not significant after correction for the total number of single nucleotide polymorphisms. Two were located in TLR9, which encodes a pattern recognition receptor (rs352139, P545P; P = .0059 and rs5743836, -T1237C; P = .0250; r2 < 0.14); 1 was in CDH1, which encodes a tight junction protein (rs16260, -C160A; P = .0352); and 1 was in IL6, which encodes a cytokine (rs1800795, -G174C; P = .0420). Denser mapping of these 3 regions revealed 1 novel association in IL6 (rs2069861; P = .0069) and 14 associations that could be accounted for by linkage disequilibrium with the 4 original variants. The TLR9, IL6, and CDH1 variants all persisted as independent risk factors for PI-IBS when controlling for previously identified clinical risk factors. Conclusion: This is the first descriptive study to assess potential genetic determinants of PI-IBS. Genes that encode proteins involved in epithelial cell barrier function and the innate immune response to enteric bacteria are associated with development of IBS following acute gastroenteritis. © 2010 AGA Institute.


Shajib M.S.,Farncombe Family Digestive Health Research Institute | Shajib M.S.,McMaster University | Khan W.I.,Farncombe Family Digestive Health Research Institute | Khan W.I.,McMaster University | Khan W.I.,Hamilton Health Sciences
Acta Physiologica | Year: 2015

Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter and hormone that contributes to the regulation of various physiological functions by its actions in the central nervous system (CNS) and in the respective organ systems. Peripheral 5-HT is predominantly produced by enterochromaffin (EC) cells of the gastrointestinal (GI) tract. These gut-resident cells produce much more 5-HT than all neuronal and other sources combined, establishing EC cells as the main source of this biogenic amine in the human body. Peripheral 5-HT is also a potent immune modulator and affects various immune cells through its receptors and via the recently identified process of serotonylation. Alterations in 5-HT signalling have been described in inflammatory conditions of the gut, such as inflammatory bowel disease. The association between 5-HT and inflammation, however, is not limited to the gut, as changes in 5-HT levels have also been reported in patients with allergic airway inflammation and rheumatoid arthritis. Based on searches for terms such as '5-HT', 'EC cell', 'immune cells' and 'inflammation' in pubmed.gov as well as by utilizing pertinent reviews, the current review aims to provide an update on the role of 5-HT in biological functions with a particular focus on immune activation and inflammation. © 2015 Scandinavian Physiological Society.


Oberc A.,McMaster University | Oberc A.,Michael G Degroote Institute For Infectious Disease Research | Coombes B.K.,McMaster University | Coombes B.K.,Michael G Degroote Institute For Infectious Disease Research | Coombes B.K.,Farncombe Family Digestive Health Research Institute
Frontiers in Immunology | Year: 2015

Crohn's disease (CD) is an immune-mediated intestinal illness that significantly compromises health in many developed countries. Although definitive causes remain elusive, the required contribution of microbes in the progression of disease has become an accepted concept. Known CD risk factors, such as antibiotic use and acute infectious gastroenteritis, may impact the gut. This concept is now being explored with a view toward understanding the beneficial and unfavorable microbes that may be altered in numbers during such external insults. A comprehensive understanding of the microbial component to CD could be useful clinically as future therapies may focus on preventing risk exposures on susceptible individuals, eliminating harmful microbes, or restoring a protective gut microbiome. Here, we examine how acute infectious gastroenteritis and antibiotic exposure may impact the gut microbiota in the context of inflammation in CD. © 2015 Oberc and Coombes.


McPhee J.B.,McMaster University | Small C.L.,McMaster University | Reid-Yu S.A.,McMaster University | Brannon J.R.,McGill University | And 3 more authors.
Infection and Immunity | Year: 2014

Host defense peptides secreted by colonocytes and Paneth cells play a key role in innate host defenses in the gut. In Crohn's disease, the burden of tissue-associated Escherichia coli commonly increases at epithelial surfaces where host defense peptides concentrate, suggesting that this bacterial population might actively resist this mechanism of bacterial killing. Adherent-invasive E. coli (AIEC) is associated with Crohn's disease; however, the colonization determinants of AIEC in the inflamed gut are undefined. Here, we establish that host defense peptide resistance contributes to host colonization by Crohn's-associated AIEC. We identified a plasmid-encoded genomic island (called PI-6) in AIEC strain NRG857c that confers high-level resistance to α-helical cationic peptides and α-and β-defensins. Deletion of PI-6 sensitized strain NRG857c to these host defense molecules, reduced its competitive fitness in a mouse model of infection, and attenuated its ability to induce cecal pathology. This phenotype is due to two genes in PI-6, arlA, which encodes a Mig-14 family protein implicated in defensin resistance, and arlC, an OmpT family outer membrane protease. Implicit in these findings are new bacterial targets whose inhibition might limit AIEC burden and disease in the gut. © 2014, American Society for Microbiology.


News Article | August 24, 2016
Site: www.chromatographytechniques.com

About 40 percent of the population have a genetic disposition to celiac disease, but only about one percent develop the autoimmune condition when exposed to gluten, and this could be promoted by the type of bacteria present in the gut. Researchers at McMaster University have found that gluten, a common protein in the Western diet that is not well digested by the gut enzymes, could be metabolized by bacteria. The scientists of the Farncombe Family Digestive Health Research Institute at McMaster University discovered that mice that harbored in their gut the opportunistic bacteria Pseudomonas aeruginosa (Psa) isolated from celiac patients, metabolized gluten differently than mice treated with Lactobacillus, often used as probiotics. More interestingly, when the chemistry of gluten metabolism by Psa and Lactobacillus were analyzed, the researchers found that Psa produced gluten sequences that stimulated inflammation in celiac patients, while Lactobacillus was able to detoxify gluten. The paper, published online in the international medical journal Gastroenterology, was funded by a grant from the Canadian Institutes for Health Research and involved researchers in Canada, Australia and Germany. "So the type of bacteria that we have in our gut contributes to the digestion of gluten, and the way this digestion is performed could increase or decrease the chances of developing celiac disease in a person with genetic risk," said Elena Verdu, senior author of the study and an associate professor of medicine for the Michael G. DeGroote School of Medicine at McMaster. "Celiac disease is caused by gluten in genetically predisposed people, but bacteria in our gut could tip the balance in some people between developing the disease or staying healthy." Celiac disease is the inflammatory reaction triggered by eating gluten, which is a group of proteins found in wheat, rye and barley, and which leads to destruction of the gut lining. The number of people who suffer from celiac disease has been steadily increasing in the past decade, and some researchers feel it may be blamed on environmental factors. "We may be closer to understanding the way gut bacteria and opportunistic pathogens such as Psa could affect celiac disease risk. This will help us develop strategies to prevent these disorders, but more research is needed," said Verdu.


McClemens J.,Farncombe Family Digestive Health Research Institute
Clinical and vaccine immunology : CVI | Year: 2013

Enteric parasite infections around the world are a huge economic burden and decrease the quality of life for many people. The use of beneficial bacteria has attracted attention for their potential therapeutic applications in various diseases. However, the effects of beneficial bacteria in enteric parasitic infections remain largely unexplored. We investigated the effects of ingestion of Lactobacillus rhamnosus (JB-1) in a model of enteric nematode (Trichuris muris) infection. C57BL/6 (resistant to infection), AKR (susceptible to infection), interleukin 10 (IL-10) knockout (KO), and mucin Muc2 KO mice were infected with T. muris and treated orally with probiotic JB-1 or medium. The mice were sacrificed on various days postinfection to examine goblet cells, epithelial cell proliferation, cytokines, and worm burdens. Treatment with JB-1 significantly enhanced worm expulsion in resistant C57BL/6 mice, and this was associated with increases in IL-10 levels, goblet cell numbers, and epithelial cell proliferation. Beneficial effects of JB-1 were absent in IL-10 KO and resistant mice treated with γ-irradiated bacteria. Live JB-1 treatment also expedited worm expulsion in Muc2 KO mice and, more importantly, in AKR mice (susceptible to infection). Injection of IL-10 directly into the colonic tissue of uninfected mice induced goblet cell hyperplasia. These findings demonstrate that JB-1 modulates goblet cell biology and promotes parasite expulsion via an IL-10-mediated pathway and provide novel insights into probiotic effects on innate defense in nematode infection.

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