Publications by authors named "Elena F Verdu"

122 Publications

Correction to: Probiotics for Celiac Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Am J Gastroenterol 2021 Jul 9. Epub 2021 Jul 9.

Department of Medicine, Farncombe Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.

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http://dx.doi.org/10.14309/ajg.0000000000001371DOI Listing
July 2021

Increased Bacterial Proteolytic Activity Detected Before Diagnosis of Ulcerative Colitis.

Inflamm Bowel Dis 2021 Jun 14. Epub 2021 Jun 14.

From the Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada.

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http://dx.doi.org/10.1093/ibd/izab144DOI Listing
June 2021

Risk perception and knowledge of COVID-19 in patients with celiac disease.

World J Gastroenterol 2021 Mar;27(12):1213-1225

Department of Medicine, Farncombe Family Digestive Research Institute, McMaster University, Hamilton L8S4K1, ON, Canada.

Background: We recently demonstrated that the odds of contracting coronavirus disease 2019 (COVID-19) in patients with celiac disease (CeD) is similar to that of the general population. However, how patients with CeD perceive their COVID-19 risk may differ from their actual risk.

Aim: To investigate risk perceptions of contracting COVID-19 in patients with CeD and determine the factors that may influence their perception.

Methods: We distributed a survey throughout 10 countries between March and June 2020 and collected data on demographics, diet, COVID-19 testing, and risk perceptions of COVID-19 in patients with CeD. Participants were recruited through various celiac associations, clinic visits, and social media. Risk perception was assessed by asking individuals whether they believe patients with CeD are at an increased risk of contracting COVID-19 when compared to the general population. Logistic regression was used to determine the influencing factors associated with COVID-19 risk perception, such as age, sex, adherence to a gluten-free diet (GFD), and comorbidities such as cardiac conditions, respiratory conditions, and diabetes. Data was presented as adjusted odds ratios (aORs).

Results: A total of 10737 participants with CeD completed the survey. From them, 6019 (56.1%) patients with CeD perceived they were at a higher risk or were unsure if they were at a higher risk of contracting COVID-19 compared to the non-CeD population. A greater proportion of patients with CeD perceived an increased risk of contracting COVID-19 when compared to infections in general due to their CeD (56.1% 26.7%, < 0.0001). Consequently, 34.8% reported taking extra COVID-19 precautions as a result of their CeD. Members of celiac associations were less likely to perceive an increased risk of COVID-19 when compared to non-members (49.5% 57.4%, < 0.0001). Older age (aOR: 0.99; 95%CI: 0.99 to 0.99, < 0.001), male sex (aOR: 0.84; 95%CI: 0.76 to 0.93, = 0.001), and strict adherence to a GFD (aOR: 0.89; 95%CI: 0.82 to 0.96, = 0.007) were associated with a lower perception of COVID-19 risk and the presence of comorbidities was associated with a higher perception of COVID-19 risk (aOR: 1.38; 95%CI: 1.22 to 1.54, < 0.001).

Conclusion: Overall, high levels of risk perceptions, such as those found in patients with CeD, may increase an individual's pandemic-related stress and contribute to negative mental health consequences. Therefore, it is encouraged that public health officials maintain consistent communication with the public and healthcare providers with the celiac community. Future studies specifically evaluating mental health in CeD could help determine the consequences of increased risk perceptions in this population.
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http://dx.doi.org/10.3748/wjg.v27.i12.1213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006100PMC
March 2021

A Riddle, Wrapped in a Mystery, Inside an Enigma: Another Key to Wheat Sensitivity?

Am J Gastroenterol 2021 05;116(5):943-945

Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada.

Abstract: Nonceliac gluten sensitivity, or the more preferred term, nonceliac wheat sensitivity (NCWS), is a heterogenous condition that is diagnosed purely on the basis of symptoms and without an understanding of disease mechanisms and triggers. Biomarkers to identify patients and implementation of dietary treatment in a personalized manner are needed. Mansueto et al. identified a population of NCWS patients with associated autoimmune markers and immune activation. The presence of these markers could be used, in combination with other serological tests, to help develop better diagnostic strategies for NCWS.
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http://dx.doi.org/10.14309/ajg.0000000000001241DOI Listing
May 2021

Epithelial production of elastase is increased in inflammatory bowel disease and causes mucosal inflammation.

Mucosal Immunol 2021 05 5;14(3):667-678. Epub 2021 Mar 5.

IRSD, Université de Toulouse, INSERM, INRAe, ENVT, UPS, Toulouse, France.

Imbalance between proteases and their inhibitors plays a crucial role in the development of Inflammatory Bowel Diseases (IBD). Increased elastolytic activity is observed in the colon of patients suffering from IBD. Here, we aimed at identifying the players involved in elastolytic hyperactivity associated with IBD and their contribution to the disease. We revealed that epithelial cells are a major source of elastolytic activity in healthy human colonic tissues and this activity is greatly increased in IBD patients, both in diseased and distant sites of inflammation. This study identified a previously unrevealed production of elastase 2A (ELA2A) by colonic epithelial cells, which was enhanced in IBD patients. We demonstrated that ELA2A hyperactivity is sufficient to lead to a leaky epithelial barrier. Epithelial ELA2A hyperactivity also modified the cytokine gene expression profile with an increase of pro-inflammatory cytokine transcripts, while reducing the expression of pro-resolving and repair factor genes. ELA2A thus appears as a novel actor produced by intestinal epithelial cells, which can drive inflammation and loss of barrier function, two essentials pathophysiological hallmarks of IBD. Targeting ELA2A hyperactivity should thus be considered as a potential target for IBD treatment.
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http://dx.doi.org/10.1038/s41385-021-00375-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075934PMC
May 2021

Gluten-induced RNA methylation changes regulate intestinal inflammation via allele-specific translation in epithelial cells.

Gut 2021 Feb 1. Epub 2021 Feb 1.

Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV-EHU), Leioa, Spain

Objectives: Coeliac disease (CD) is a complex autoimmune disorder that develops in genetically susceptible individuals. Dietary gluten triggers an immune response for which the only available treatment so far is a strict, lifelong gluten free diet. Human leucocyte antigen (HLA) genes and several non-HLA regions have been associated with the genetic susceptibility to CD, but their role in the pathogenesis of the disease is still essentially unknown, making it complicated to develop much needed non-dietary treatments. Here, we describe the functional involvement of a CD-associated single-nucleotide polymorphism (SNP) located in the 5'UTR of in the inflammatory environment characteristic of the coeliac intestinal epithelium.

Design: The function of the CD-associated SNP was investigated using an intestinal cell line heterozygous for the SNP, N6-methyladenosine (mA)-related knock-out and HLA-DQ2 mice, and human samples from patients with CD.

Results: Individuals harbouring the risk allele had higher mA methylation in the 5'UTR of RNA, rendering greater XPO1 protein amounts that led to downstream nuclear factor kappa B (NFkB) activity and subsequent inflammation. Furthermore, gluten exposure increased overall mA methylation in humans as well as in in vitro and in vivo models.

Conclusion: We identify a novel mA-XPO1-NFkB pathway that is activated in CD patients. The findings will prompt the development of new therapeutic approaches directed at mA proteins and XPO1, a target under evaluation for the treatment of intestinal disorders.
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http://dx.doi.org/10.1136/gutjnl-2020-322566DOI Listing
February 2021

Reply.

Gastroenterology 2021 May 20;160(6):2207-2208. Epub 2021 Jan 20.

Farncombe Family Digestive Health Research Institute, McMaster University Medical Center, Hamilton Health Sciences, Hamilton, Canada.

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http://dx.doi.org/10.1053/j.gastro.2021.01.205DOI Listing
May 2021

Reply.

Clin Gastroenterol Hepatol 2021 Jul 24;19(7):1511. Epub 2020 Dec 24.

Farncombe Family Digestive Health Research Institute, McMaster University Medical Center, Hamilton Health Sciences, Hamilton, Ontario, Canada.

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http://dx.doi.org/10.1016/j.cgh.2020.12.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759344PMC
July 2021

Novel Fecal Biomarkers That Precede Clinical Diagnosis of Ulcerative Colitis.

Gastroenterology 2021 Apr 10;160(5):1532-1545. Epub 2020 Dec 10.

Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada. Electronic address:

Background & Aims: Altered gut microbiota composition and function have been associated with inflammatory bowel diseases, including ulcerative colitis (UC), but the causality and mechanisms remain unknown.

Methods: We applied 16S ribosomal RNA gene sequencing, shotgun metagenomic sequencing, in vitro functional assays, and gnotobiotic colonizations to define the microbial composition and function in fecal samples obtained from a cohort of healthy individuals at risk for inflammatory bowel diseases (pre-UC) who later developed UC (post-UC) and matched healthy control individuals (HCs).

Results: Microbiota composition of post-UC samples was different from HC and pre-UC samples; however, functional analysis showed increased fecal proteolytic and elastase activity before UC onset. Metagenomics identified more than 22,000 gene families that were significantly different between HC, pre-UC, and post-UC samples. Of these, 237 related to proteases and peptidases, suggesting a bacterial component to the pre-UC proteolytic signature. Elastase activity inversely correlated with the relative abundance of Adlercreutzia and other potentially beneficial taxa and directly correlated with known proteolytic taxa, such as Bacteroides vulgatus. High elastase activity was confirmed in Bacteroides isolates from fecal samples. The bacterial contribution and functional significance of the proteolytic signature were investigated in germ-free adult mice and in dams colonized with HC, pre-UC, or post-UC microbiota. Mice colonized with or born from pre-UC-colonized dams developed higher fecal proteolytic activity and an inflammatory immune tone compared with HC-colonized mice.

Conclusions: We have identified increased fecal proteolytic activity that precedes the clinical diagnosis of UC and associates with gut microbiota changes. This proteolytic signature may constitute a noninvasive biomarker of inflammation to monitor at-risk populations that can be targeted therapeutically with antiproteases.
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http://dx.doi.org/10.1053/j.gastro.2020.12.004DOI Listing
April 2021

Aryl hydrocarbon receptor ligand production by the gut microbiota is decreased in celiac disease leading to intestinal inflammation.

Sci Transl Med 2020 10;12(566)

Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Metabolism of tryptophan by the gut microbiota into derivatives that activate the aryl hydrocarbon receptor (AhR) contributes to intestinal homeostasis. Many chronic inflammatory conditions, including celiac disease involving a loss of tolerance to dietary gluten, are influenced by cues from the gut microbiota. We investigated whether AhR ligand production by the gut microbiota could influence gluten immunopathology in nonobese diabetic (NOD) mice expressing DQ8, a celiac disease susceptibility gene. NOD/DQ8 mice, exposed or not exposed to gluten, were subjected to three interventions directed at enhancing AhR pathway activation. These included a high-tryptophan diet, gavage with that produces AhR ligands or treatment with an AhR agonist. We investigated intestinal permeability, gut microbiota composition determined by 16 rRNA gene sequencing, AhR pathway activation in intestinal contents, and small intestinal pathology and inflammatory markers. In NOD/DQ8 mice, a high-tryptophan diet modulated gut microbiota composition and enhanced AhR ligand production. AhR pathway activation by an enriched tryptophan diet, treatment with the AhR ligand producer , or pharmacological stimulation using 6-formylindolo (3,2-b) carbazole (Ficz) decreased immunopathology in NOD/DQ8 mice exposed to gluten. We then determined AhR ligand production by the fecal microbiota and AhR activation in patients with active celiac disease compared to nonceliac control individuals. Patients with active celiac disease demonstrated reduced AhR ligand production and lower intestinal AhR pathway activation. These results highlight gut microbiota-dependent modulation of the AhR pathway in celiac disease and suggest a new therapeutic strategy for treating this disorder.
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http://dx.doi.org/10.1126/scitranslmed.aba0624DOI Listing
October 2020

The Risk of Contracting COVID-19 Is Not Increased in Patients With Celiac Disease.

Clin Gastroenterol Hepatol 2021 02 12;19(2):391-393. Epub 2020 Oct 12.

Farncombe Family Digestive Health Research Institute, McMaster University Medical Center, Hamilton Health Sciences, Hamilton, Ontario, Canada. Electronic address:

The World Health Organization declared coronavirus disease-2019 (COVID-19) a global pandemic in March 2020. Since then, there are more than 34 million cases of COVID-19 leading to more than 1 million deaths worldwide. Numerous studies suggest that celiac disease (CeD), a chronic immune-mediated gastrointestinal condition triggered by gluten, is associated with an increased risk of respiratory infections. However, how it relates to the risk of COVID-19 is unknown. To address this gap, we conducted a cross-sectional study to evaluate whether patients with self-reported CeD are at an increased risk of contracting COVID-19.
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http://dx.doi.org/10.1016/j.cgh.2020.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548761PMC
February 2021

Saccharomyces boulardii CNCM I-745 modulates the microbiota-gut-brain axis in a humanized mouse model of Irritable Bowel Syndrome.

Neurogastroenterol Motil 2021 03 21;33(3):e13985. Epub 2020 Sep 21.

Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.

Background: Gnotobiotic mice colonized with microbiota from patients with irritable bowel syndrome (IBS) and comorbid anxiety (IBS+A) display gut dysfunction and anxiety-like behavior compared to mice colonized with microbiota from healthy volunteers. Using this model, we tested the therapeutic potential of the probiotic yeast Saccharomyces boulardii strain CNCM I-745 (S. bou) and investigated underlying mechanisms.

Methods: Germ-free Swiss Webster mice were colonized with fecal microbiota from an IBS+A patient or a healthy control (HC). Three weeks later, mice were gavaged daily with S. boulardii or placebo for two weeks. Anxiety-like behavior (light preference and step-down tests), gastrointestinal transit, and permeability were assessed. After sacrifice, samples were taken for gene expression by NanoString and qRT-PCR, microbiota 16S rRNA profiling, and indole quantification.

Key Results: Mice colonized with IBS+A microbiota developed faster gastrointestinal transit and anxiety-like behavior (longer step-down latency) compared to mice with HC microbiota. S. bou administration normalized gastrointestinal transit and anxiety-like behavior in mice with IBS+A microbiota. Step-down latency correlated with colonic Trpv1 expression and was associated with altered microbiota profile and increased Indole-3-acetic acid (IAA) levels.

Conclusions & Inferences: Treatment with S. bou improves gastrointestinal motility and anxiety-like behavior in mice with IBS+A microbiota. Putative mechanisms include effects on pain pathways, direct modulation of the microbiota, and indole production by commensal bacteria.
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http://dx.doi.org/10.1111/nmo.13985DOI Listing
March 2021

Gluten-Free Diet Reduces Symptoms, Particularly Diarrhea, in Patients With Irritable Bowel Syndrome and Antigliadin IgG.

Clin Gastroenterol Hepatol 2020 Aug 19. Epub 2020 Aug 19.

Department of Medicine, Farncombe Institute, McMaster University, Hamilton, Ontario, Canada. Electronic address:

Background & Aims: Many patients with irritable bowel syndrome (IBS) perceive that their symptoms are triggered by wheat-containing foods. We assessed symptoms and gastrointestinal transit before and after a gluten-free diet (GFD) in unselected patients with IBS and investigated biomarkers associated with symptoms.

Methods: We performed a prospective study of 50 patients with IBS (ROME III, all subtypes), with and without serologic reactivity to gluten (antigliadin IgG and IgA), and 25 healthy subjects (controls) at a university hospital in Hamilton, Ontario, Canada, between 2012 and 2016. Gastrointestinal transit, gut symptoms, anxiety, depression, somatization, dietary habits, and microbiota composition were studied before and after 4 weeks of a GFD. HLA-DQ2/DQ8 status was determined. GFD compliance was assessed by a dietitian and by measuring gluten peptides in stool.

Results: There was no difference in symptoms among patients at baseline, but after the GFD, patients with antigliadin IgG and IgA reported less diarrhea than patients without these antibodies (P = .03). Compared with baseline, IBS symptoms improved in 18 of 24 patients (75%) with antigliadin IgG and IgA and in 8 of 21 patients (38%) without the antibodies. Although constipation, diarrhea, and abdominal pain were reduced in patients with antigliadin IgG and IgA, only pain decreased in patients without these antibodies. Gastrointestinal transit normalized in a higher proportion of patients with antigliadin IgG and IgA. Anxiety, depression, somatization, and well-being increased in both groups. The presence of antigliadin IgG was associated with overall reductions in symptoms (adjusted odds ratio compared with patients without this antibody, 128.9; 95% CI, 1.16-1427.8; P = .04). Symptoms were reduced even in patients with antigliadin IgG and IgA who reduced gluten intake but were not strictly compliant with the GFD. In controls, a GFD had no effect on gastrointestinal symptoms or gut function.

Conclusions: Antigliadin IgG can be used as a biomarker to identify patients with IBS who might have reductions in symptoms, particularly diarrhea, on a GFD. Larger studies are needed to validate these findings. ClinicalTrials.gov: NCT03492333.
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http://dx.doi.org/10.1016/j.cgh.2020.08.040DOI Listing
August 2020

Probiotics for Celiac Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Am J Gastroenterol 2020 10;115(10):1584-1595

Department of Medicine, Farncombe Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.

Introduction: Many patients with celiac disease (CD) experience persistent symptoms despite adhering to the gluten-free diet. Different studies have assessed the use of probiotics as an adjuvant treatment for CD. We performed a systematic review and meta-analysis to evaluate the efficacy of probiotics in improving gastrointestinal (GI) symptoms and quality of life (QOL) in patients with CD.

Methods: We searched EMBASE, MEDLINE, CINAHL, Web of Science, CENTRAL, and DARE databases up to February 2019 for randomized controlled trials (RCTs) evaluating probiotics compared with placebo for treating CD. We collected data on GI symptoms, QOL, adverse events, serum tumor necrosis factor-α, intestinal permeability, and microbiota composition.

Results: We screened 2,831 records and found that 7 articles describing 6 RCTs (n = 5,279 participants) were eligible for quantitative analysis. Probiotics improved GI symptoms when assessed by the GI Symptoms Rating Scale (mean difference symptom reduction: 228.7%; 95% confidence interval [CI] 243.96-213.52; P = 0.0002). There was no difference in GI symptoms after probiotics when different questionnaires were pooled. The levels of Bifidobacteria increased after probiotics (mean difference: 0.85 log colony-forming units (CFU) per gram; 95% CI 0.38-1.32 log CFU per gram; P = 0.0003). There were insufficient data on tumor necrosis factor-a levels or QOL for probiotics compared with placebo. No difference in adverse events was observed between probiotics and placebo. The overall certainty of the evidence ranged from very low to low.

Discussion: Probiotics may improve GI symptoms in patients with CD. High-quality clinical trials are needed to improve the certainty in the evidence (see Visual abstract, Supplementary Digital Content 2, http://links.lww.com/AJG/B595).
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http://dx.doi.org/10.14309/ajg.0000000000000749DOI Listing
October 2020

Association Between Inflammatory Bowel Diseases and Celiac Disease: A Systematic Review and Meta-Analysis.

Gastroenterology 2020 09 13;159(3):884-903.e31. Epub 2020 May 13.

Department of Medicine, Farncombe Family Digestive Research Institute, McMaster University, Hamilton, Ontario, Canada. Electronic address:

Background & Aims: There is controversy over the association between celiac disease (CeD) and inflammatory bowel diseases (IBD). We performed a systematic review and meta-analysis to assess evidence for an association between CeD and IBD.

Methods: We searched databases including MEDLINE, EMBASE, CENTRAL, Web of Science, CINAHL, DARE, and SIGLE through June 25, 2019 for studies assessing the risk of CeD in patients with IBD, and IBD in patients with CeD, compared with controls of any type. We used the Newcastle-Ottawa Scale to evaluate the risk of bias and GRADE to assess the certainty of the evidence.

Results: We identified 9791 studies and included 65 studies in our analysis. Moderate certainty evidence found an increased risk of CeD in patients with IBD vs controls (risk ratio [RR] 3.96; 95% confidence interval [CI] 2.23-7.02) and increased risk of IBD in patients with CeD vs controls (RR 9.88; 95% CI 4.03-24.21). There was low-certainty evidence for the risk of anti-Saccharomyces antibodies, a serologic marker of IBD, in patients with CeD vs controls (RR 6.22; 95% CI 2.44-15.84). There was low-certainty evidence for no difference in risk of HLA-DQ2 or DQ8 in patients with IBD vs controls (RR 1.04; 95% CI 0.42-2.56), and very low-certainty evidence for an increased risk of anti-tissue transglutaminase in patients with IBD vs controls (RR 1.52; 95% CI 0.52-4.40). Patients with IBD had a slight decrease in risk of anti-endomysial antibodies vs controls (RR 0.70; 95% CI 0.18-2.74), but these results are uncertain.

Conclusions: In a systematic review and meta-analysis, we found an increased risk of IBD in patients with CeD and increased risk of CeD in patients with IBD, compared with other patient populations. High-quality prospective cohort studies are needed to assess the risk of CeD-specific and IBD-specific biomarkers in patients with IBD and CeD.
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http://dx.doi.org/10.1053/j.gastro.2020.05.016DOI Listing
September 2020

Real-World Gluten Exposure in Patients With Celiac Disease on Gluten-Free Diets, Determined From Gliadin Immunogenic Peptides in Urine and Fecal Samples.

Clin Gastroenterol Hepatol 2021 03 23;19(3):484-491.e1. Epub 2020 Mar 23.

Dr. C. Bonorino Udaondo Gastroenterology Hospital, Buenos Aires, Argentina; Research Institutes of Health, Universidad del Salvador, Buenos Aires, Argentina. Electronic address:

Background & Aims: It is not clear how often patients who are on gluten-free diets (GFDs) for treatment of celiac disease still are exposed to gluten. We studied levels of gluten immunogenic peptides (GIP) in fecal and urine samples, collected over 4 weeks, from patients with celiac disease on a long-term GFD.

Methods: We performed a prospective study of 53 adults with celiac disease who had been on a GFD for more than 2 years (median duration, 8 y; interquartile range, 5-12 y) in Argentina. At baseline, symptoms were assessed by the celiac symptom index questionnaire. Patients collected stool each Friday and Saturday and urine samples each Sunday for 4 weeks. We used a commercial enzyme-linked immunosorbent assay to measure GIP in stool and point-of-care tests to measure GIP in urine samples.

Results: Overall, 159 of 420 stool and urine samples (37.9%) were positive for GIP; 88.7% of patients had at least 1 fecal or urine sample that was positive for GIP (median, 3 excretions). On weekends (urine samples), 69.8% of patients excreted GIP at least once, compared with 62.3% during weekdays (stool). The number of patients with a sample that was positive for GIP increased over the 4-week study period (urine samples in week 1 vs week 4: P < .05). Patients with symptoms had more weeks in which GIP was detected in stool than patients without symptoms (P < .05). The number of samples that were positive for GIP correlated with titers of deamidated gliadin peptide IgA in patients' blood samples, but not with levels of tissue transglutaminase.

Conclusions: Patients with celiac disease on a long-term GFD still frequently are exposed to gluten. Assays to detect GIP in stool and urine might be used to assist dietitians in assessment of GFD compliance.
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http://dx.doi.org/10.1016/j.cgh.2020.03.038DOI Listing
March 2021

Microbial Regulation of Enteric Eosinophils and Its Impact on Tissue Remodeling and Th2 Immunity.

Front Immunol 2020 13;11:155. Epub 2020 Feb 13.

Department of Pathology & Molecular Medicine, McMaster Immunology Research Centre (MIRC), McMaster University, Hamilton, ON, Canada.

Eosinophils have emerged as multifaceted cells that contribute to tissue homeostasis. However, the impact of the microbiota on their frequency and function at mucosal sites remains unclear. Here, we investigated the role of the microbiota in the regulation of enteric eosinophils. We found that small intestinal (SI) eosinophilia was significantly greater in germ-free (GF) mice compared to specific pathogen free (SPF) controls. This was associated with changes in the production of enteric signals that regulate eosinophil attraction and survival, and was fully reversed by complex colonization. Additionally, SI eosinophils of GF mice exhibited more cytoplasmic protrusions and less granule content than SPF controls. Lastly, we generated a novel strain of eosinophil-deficient GF mice. These mice displayed intestinal fibrosis and were less prone to allergic sensitization as compared to GF controls. Overall, our study demonstrates that commensal microbes regulate intestinal eosinophil frequency and function, which impacts tissue repair and allergic sensitization to food antigens. These data support a critical interplay between the commensal microbiota and intestinal eosinophils in shaping homeostatic, innate, and adaptive immune processes in health and disease.
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http://dx.doi.org/10.3389/fimmu.2020.00155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033414PMC
March 2021

Effects of Antibiotic Pretreatment of an Ulcerative Colitis-Derived Fecal Microbial Community on the Integration of Therapeutic Bacteria .

mSystems 2020 Jan 28;5(1). Epub 2020 Jan 28.

Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada.

Fecal microbiota transplantation (FMT) is a proposedly useful strategy for the treatment of gastrointestinal (GI) disorders through remediation of the patient gut microbiota. However, its therapeutic success has been variable, necessitating research to uncover mechanisms that improve patient response. Antibiotic pretreatment has been proposed as one method to enhance the success rate by increasing niche availability for introduced species. Several limitations hinder exploring this hypothesis in clinical studies, such as deleterious side effects and the development of antimicrobial resistance in patients. Thus, the purpose of this study was to evaluate the use of an , bioreactor-based, colonic ecosystem model as a form of preclinical testing by determining how pretreatment with the antibiotic rifaximin influenced engraftment of bacterial strains sourced from a healthy donor into an ulcerative colitis-derived defined microbial community. Distinct species integrated under the pretreated and untreated conditions, with the relative rifaximin resistance of the microbial strains being an important influencer. However, both conditions resulted in the integration of taxa from clusters IV and XIVa, a concomitant reduction of , and similar decreases in metabolites associated with poor health status. Our results agree with the findings of similar research in the clinic by others, which observed no difference in primary patient outcomes whether or not patients were given rifaximin prior to FMT. We therefore conclude that our model is useful for screening for antibiotics that could improve efficacy of FMT when used as a pretreatment. Patients with gastrointestinal disorders often exhibit derangements in their gut microbiota, which can exacerbate their symptoms. Replenishing these ecosystems with beneficial bacteria through fecal microbiota transplantation is thus a proposedly useful therapeutic; however, clinical success has varied, necessitating research into strategies to improve outcomes. Antibiotic pretreatment has been suggested as one such approach, but concerns over harmful side effects have hindered testing this hypothesis clinically. Here, we evaluate the use of bioreactors supporting defined microbial communities derived from human fecal samples as models of the colonic microbiota in determining the effectiveness of antibiotic pretreatment. We found that relative antimicrobial resistance was a key determinant of successful microbial engraftment with rifaximin (broad-spectrum antibiotic) pretreatment, despite careful timing of the application of the therapeutic agents, resulting in distinct species profiles from those of the control but with similar overall outcomes. Our model had results comparable to the clinical findings and thus can be used to screen for useful antibiotics.
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http://dx.doi.org/10.1128/mSystems.00404-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989129PMC
January 2020

The enemy within the gut: bacterial pathogens in celiac autoimmunity.

Nat Struct Mol Biol 2020 01;27(1):5-7

Institute of Translation Immunology, University Medical Center, Mainz, Germany.

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http://dx.doi.org/10.1038/s41594-019-0360-5DOI Listing
January 2020

A Novel Mouse Model of Enteric Vibrio parahaemolyticus Infection Reveals that the Type III Secretion System 2 Effector VopC Plays a Key Role in Tissue Invasion and Gastroenteritis.

mBio 2019 12 17;10(6). Epub 2019 Dec 17.

Division of Gastroenterology, Hepatology and Nutrition, BC Children's Hospital Research Institute and the University of British Columbia, Vancouver, Canada

The Gram-negative marine bacterium is a common cause of infectious gastroenteritis due to the ingestion of contaminated seafood. Most virulent strains encode two type III secretion systems (T3SS1 and T3SS2); however, the roles they and their translocated effectors play in causing intestinal disease remain unclear. While studies have identified T3SS1 effectors as responsible for killing epithelial cells in culture, the T3SS2 effectors caused massive epithelial cell disruption in a rabbit ileal loop model. Additional models are thus needed to clarify the pathogen-host interactions that drive -associated gastroenteritis. Germfree mice were infected with a pathogenic clinical isolate of , RIMD2210633 (RIMD). The pathogen was found to adhere to as well as invade the cecal mucosa, accompanied by severe inflammation and dramatic mucosal damage, including widespread sloughing of infected epithelial cells. Mice infected with a strain lacking the T3SS1 (POR2) also developed severe pathology, similar to that seen with RIMD. In contrast, the strain (POR3) appeared unable to invade the intestinal mucosa or cause any mucosal pathology. Confirming a role for TS332 effectors, a strain expressing the T3SS2 but lacking VopC (POR2), a T3SS2 effector implicated in epithelial cell invasion in culture, was strongly attenuated in invading the intestinal mucosa and in causing gastroenteritis, although infection with this mutant resulted in more pathology than the strain. We thus present an experimental system that enables further characterization of T3SS effectors as well as the corresponding host inflammatory response involved in the gastroenteritis caused by invasive causes severe gastroenteritis following consumption of contaminated seafood. Global warming has allowed this pathogen to spread worldwide, contributing to recent outbreaks. Clinical isolates are known to harbor an array of virulence factors, including T3SS1 and T3SS2; however, the precise role these systems play in intestinal disease remains unclear. There is an urgent need to improve our understanding of how infects hosts and causes disease. We present a novel mouse model for this facultative intracellular pathogen and observe that the T3SS2 is essential to pathogenicity. Moreover, we show that the T3SS2 effector VopC, previously shown to be a Rac and Cdc42 deamidase that facilitates bacterial uptake by nonphagocytic cells, also plays a key role in the ability of to invade the intestinal mucosa and cause gastroenteritis. This experimental model thus provides a valuable tool for future elucidation of virulence mechanisms used by this facultative intracellular pathogen during infection.
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http://dx.doi.org/10.1128/mBio.02608-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918077PMC
December 2019

Active thrombin produced by the intestinal epithelium controls mucosal biofilms.

Nat Commun 2019 07 19;10(1):3224. Epub 2019 Jul 19.

IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, U1220, CHU Purpan, CS60039, 31024, Toulouse, France.

Proteolytic homeostasis is important at mucosal surfaces, but its actors and their precise role in physiology are poorly understood. Here we report that healthy human and mouse colon epithelia are a major source of active thrombin. We show that mucosal thrombin is directly regulated by the presence of commensal microbiota. Specific inhibition of luminal thrombin activity causes macroscopic and microscopic damage as well as transcriptomic alterations of genes involved in host-microbiota interactions. Further, luminal thrombin inhibition impairs the spatial segregation of microbiota biofilms, allowing bacteria to invade the mucus layer and to translocate across the epithelium. Thrombin cleaves the biofilm matrix of reconstituted mucosa-associated human microbiota. Our results indicate that thrombin constrains biofilms at the intestinal mucosa. Further work is needed to test whether thrombin plays similar roles in other mucosal surfaces, given that lung, bladder and skin epithelia also express thrombin.
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http://dx.doi.org/10.1038/s41467-019-11140-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642099PMC
July 2019

The impact of dietary fermentable carbohydrates on a postinflammatory model of irritable bowel syndrome.

Neurogastroenterol Motil 2019 10 9;31(10):e13675. Epub 2019 Jul 9.

Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada.

Background: A low fermentable carbohydrate (FODMAP) diet is used in quiescent inflammatory bowel disease when irritable bowel syndrome-like symptoms occur. There is concern that the diet could exacerbate inflammation by modifying microbiota and short-chain fatty acid (SCFA) production. We examined the effect of altering dietary FODMAP content on inflammation in preclinical inflammatory models.

Methods: C57BL/6 mice were given 3% dextran sodium sulfate (DSS) in drinking water for 5 days and recovered for 3 weeks (postinflammatory, n = 12), or 5 days (positive-control, n = 12). Following recovery, DSS-treated or control mice (negative-control, n = 12) were randomized to 2-week low- (0.51 g/100 g total FODMAP) or high-FODMAP (4.10 g) diets. Diets mimicked human consumption containing fructose, sorbitol, galacto-oligosaccharide, and fructan. Colons were assessed for myeloperoxidase (MPO) activity and histological damage. Supernatants were generated for perforated patch-clamp recordings and cytokine measurement. Cecum contents were analyzed for microbiota, SCFA, and branched-chain fatty acids (BCFA). Data were analyzed by two-way ANOVA with Bonferroni.

Key Results: Inflammatory markers were higher in the positive-control compared with negative-control and postinflammatory groups, but no differences occurred between the two diets within each treatment (MPO P > .99, histological scores P > .99, cytokines P > .05), or the perforated patch-clamp recordings (P > .05). Microbiota clustered mainly based on DSS exposure. No difference in SCFA content occurred. Higher total BCFA occurred with the low-FODMAP diet in positive-control (P < .01) and postinflammatory groups (P < .01).

Conclusions And Inferences: In this preclinical study, reducing dietary FODMAPs did not exacerbate nor mitigate inflammation. Microbiota profile changes were largely driven by inflammation rather than diet. Low FODMAP intake caused a shift toward proteolytic fermentation following inflammation.
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http://dx.doi.org/10.1111/nmo.13675DOI Listing
October 2019

Metabolism of wheat proteins by intestinal microbes: Implications for wheat related disorders.

Gastroenterol Hepatol 2019 Aug - Sep;42(7):449-457. Epub 2019 Jun 28.

Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.

Wheat is a common cereal in the Western diet and an important source of protein as well as fiber. However, some individuals develop adverse reactions to a wheat-containing diet. The best characterized is celiac disease which develops after intake of gluten in individuals with genetic predisposition. Other wheat-related conditions are less well defined in terms of diagnosis, specific trigger and underlying pathways. Despite this, the overall prevalence of wheat-related disorders has increased in the last decades and the role of microbial factors has been suggested. Several studies have described an altered intestinal microbiota in celiac patients compared to healthy subjects, but less information is available regarding other wheat-related disorders. Here, we discuss the importance of the intestinal microbiota in the metabolism of wheat proteins and the development of inflammatory or functional conditions. Understanding these interactions will open new directions for therapeutic development using bacteria with optimal wheat protein degrading capacity.
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http://dx.doi.org/10.1016/j.gastrohep.2019.04.001DOI Listing
January 2020

Celiac disease: should we care about microbes?

Am J Physiol Gastrointest Liver Physiol 2019 08 12;317(2):G161-G170. Epub 2019 Jun 12.

Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.

The prevalence of celiac disease (CeD) has increased in the last decades, suggesting a role for environmental factors in addition to gluten. Several cohort studies have shown that different gastrointestinal infections increase CeD risk. However, the mechanisms by which microbes participate in CeD have remained elusive. Recently, with the use of animal models, both viral and bacterial opportunistic pathogens were shown to induce immune activation relevant for CeD. The hypothesis that viral and/or bacterial infections can contribute to immune activation and breakdown of tolerance toward gluten in genetically susceptible individuals is therefore reinforced. Here, we discuss the evidence regarding the role of microbes in promoting CeD and the specific pathways triggered by microbes that could participate in CeD pathogenesis. Understanding these pathways will allow us to develop optimal microbiota-modulating strategies to help prevent CeD.
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http://dx.doi.org/10.1152/ajpgi.00099.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734371PMC
August 2019

Evolving Paradigms in the Diagnosis of Adult Patients With Celiac Disease.

Am J Gastroenterol 2019 06;114(6):854-857

Farncombe Family Digestive Health Research Institute, McMaster University Health Sciences Centre, Hamilton, Ontario, Canada.

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http://dx.doi.org/10.14309/ajg.0000000000000279DOI Listing
June 2019

Investigation of the Gut Microbiome in Patients with Schizophrenia and Clozapine-Induced Weight Gain: Protocol and Clinical Characteristics of First Patient Cohorts.

Neuropsychobiology 2020 29;79(1):5-12. Epub 2019 Mar 29.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada,

Background: Emerging evidence suggests an important role of the human gut microbiome in psychiatry and neurodevelopmental disorders. An increasing body of literature based on animal studies has reported that the gut microbiome influences brain development and behavior by interacting with the gut-brain axis. Furthermore, as the gut microbiome has an important role in metabolism and is known to interact with pharmaceuticals, recent evidence suggests a role for the microbiome in antipsychotic-induced metabolic side effects in animals and humans.

Purpose: Here we present the protocol for a two-phase study investigating the gut microbiome in healthy controls and in patients with schizophrenia treated with antipsychotics.

Methods: Phase I of our study involves humans exclusively. We recruit 25 patients who are chronically treated with clozapine and compare them with 25 healthy controls matched for age, sex, BMI, and smoking status. A second cohort consists of 25 patients newly starting on clozapine, and a third cohort includes 25 antipsychotic-naive patients. The patients in the second cohort and third cohort are prospectively assessed for up to 6 and 12 weeks, respectively. Phase II of this study will incorporate microbiota humanized mouse models to examine the influence of human fecal transplant on metabolic parameters and the gut-brain axis. Progress and Future Directions: We are underway with the first participants enrolled in all phase I treatment cohorts. This study will contribute to elucidating the role of the gut microbiome in schizophrenia and metabolic side effects. In addition, its results may help to explore potential therapeutic targets for antipsychotic-induced metabolic side effects.
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http://dx.doi.org/10.1159/000494696DOI Listing
November 2020

Gluten immunogenic peptide excretion detects dietary transgressions in treated celiac disease patients.

World J Gastroenterol 2019 Mar;25(11):1409-1420

Research Institutes, Universidad del Salvador, Buenos Aires 1050, Argentina.

Background: Life-long removal of gluten from the diet is currently the only way to manage celiac disease (CeD). Until now, no objective test has proven useful to objectively detect ingested gluten in clinical practice. Recently, tests that determine consumption of gluten by assessing excretion of gluten immunogenic peptides (GIP) in stool and urine have been developed. Their utility, in comparison with conventional dietary and analytical follow-up strategies, has not been fully established.

Aim: To assess the performance of enzyme-linked immunosorbent assay (ELISA) and point-of-care tests (PoCTs) for GIP excretion in CeD patients on gluten-free diet (GFD).

Methods: We conducted an observational, prospective, cross-sectional study in patients following a GFD for at least two years. Using the Gastrointestinal Symptom Rating Scale questionnaire, patients were classified at enrollment as asymptomatic or symptomatic. Gluten consumption was assessed twice by 3-d dietary recall and GIP excretion (by ELISA in stool and PoCTs (commercial kits for stool and urine) in two consecutive samples. These samples and dietary reports were obtained 10 day apart one from the other. Patients were encouraged to follow their usual GFD during the study period.

Results: Forty-four patients were enrolled, of which 19 (43.2%) were symptomatic despite being on a GFD. Overall, 83 sets of stool and/or urine samples were collected. Eleven out of 44 patients (25.0%) had at least one positive GIP test. The occurrence of at least one positive test was 32% in asymptomatic patients compared with 15.8% in symptomatic patients. GIP was concordant with dietary reports in 65.9% of cases (: 0.317). PoCT detected dietary indiscretions. Both ELISA and PoCT in stool were concordant (concomitantly positive or negative) in 67 out of 74 (90.5%) samples. Excretion of GIP was detected in 7 (8.4%) stool and/or urine samples from patients considered to be strictly compliant with the GFD by dietary reports.

Conclusion: GIP detects dietary transgressions in patients on long-term GFD, irrespective of the presence of symptoms. PoCT for GIP detection constitutes a simple home-based method for self-assessment of dietary indiscretions.
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http://dx.doi.org/10.3748/wjg.v25.i11.1409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429344PMC
March 2019

Duodenal bacterial proteolytic activity determines sensitivity to dietary antigen through protease-activated receptor-2.

Nat Commun 2019 03 13;10(1):1198. Epub 2019 Mar 13.

Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, L8S 4K1, ON, Canada.

Microbe-host interactions are generally homeostatic, but when dysfunctional, they can incite food sensitivities and chronic diseases. Celiac disease (CeD) is a food sensitivity characterized by a breakdown of oral tolerance to gluten proteins in genetically predisposed individuals, although the underlying mechanisms are incompletely understood. Here we show that duodenal biopsies from patients with active CeD have increased proteolytic activity against gluten substrates that correlates with increased Proteobacteria abundance, including Pseudomonas. Using Pseudomonas aeruginosa producing elastase as a model, we show gluten-independent, PAR-2 mediated upregulation of inflammatory pathways in C57BL/6 mice without villus blunting. In mice expressing CeD risk genes, P. aeruginosa elastase synergizes with gluten to induce more severe inflammation that is associated with moderate villus blunting. These results demonstrate that proteases expressed by opportunistic pathogens impact host immune responses that are relevant to the development of food sensitivities, independently of the trigger antigen.
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http://dx.doi.org/10.1038/s41467-019-09037-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416356PMC
March 2019

Non-celiac gluten or wheat sensitivity: It's complicated!

Neurogastroenterol Motil 2018 08;30(8):e13392

Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.

In the last 30 years, non-celiac gluten sensitivity (NCGS) has emerged as an intriguing and controversial topic in gastroenterology. The diagnosis of NCGS/NCWS requires a symptomatic reaction to gluten, or wheat-containing food, and remission of symptoms with gluten or wheat challenge, in patients in whom celiac disease and wheat allergy have been excluded. There have been several randomized clinical trials (RCT) addressing this issue which have produced controversial results. In this issue of Neurogastroenterology and Motility, a double-blind placebo-controlled randomized trial in patients with suspected NCGS on GFD, did not reproduce symptoms after gluten intake compared to placebo. This mini-review addresses outstanding issues related to the diagnosis of NCGS/NCWS as well as areas of interest for future studies that could explain, in part, the controversy in this area.
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http://dx.doi.org/10.1111/nmo.13392DOI Listing
August 2018

Lactobacilli Degrade Wheat Amylase Trypsin Inhibitors to Reduce Intestinal Dysfunction Induced by Immunogenic Wheat Proteins.

Gastroenterology 2019 06 22;156(8):2266-2280. Epub 2019 Feb 22.

Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada. Electronic address:

Background & Aims: Wheat-related disorders, a spectrum of conditions induced by the ingestion of gluten-containing cereals, have been increasing in prevalence. Patients with celiac disease have gluten-specific immune responses, but the contribution of non-gluten proteins to symptoms in patients with celiac disease or other wheat-related disorders is controversial.

Methods: C57BL/6 (control), Myd88, Ticam1, and Il15 mice were placed on diets that lacked wheat or gluten, with or without wheat amylase trypsin inhibitors (ATIs), for 1 week. Small intestine tissues were collected and intestinal intraepithelial lymphocytes (IELs) were measured; we also investigated gut permeability and intestinal transit. Control mice fed ATIs for 1 week were gavaged daily with Lactobacillus strains that had high or low ATI-degrading capacity. Nonobese diabetic/DQ8 mice were sensitized to gluten and fed an ATI diet, a gluten-containing diet or a diet with ATIs and gluten for 2 weeks. Mice were also treated with Lactobacillus strains that had high or low ATI-degrading capacity. Intestinal tissues were collected and IELs, gene expression, gut permeability and intestinal microbiota profiles were measured.

Results: In intestinal tissues from control mice, ATIs induced an innate immune response by activation of Toll-like receptor 4 signaling to MD2 and CD14, and caused barrier dysfunction in the absence of mucosal damage. Administration of ATIs to gluten-sensitized mice expressing HLA-DQ8 increased intestinal inflammation in response to gluten in the diet. We found ATIs to be degraded by Lactobacillus, which reduced the inflammatory effects of ATIs.

Conclusions: ATIs mediate wheat-induced intestinal dysfunction in wild-type mice and exacerbate inflammation to gluten in susceptible mice. Microbiome-modulating strategies, such as administration of bacteria with ATI-degrading capacity, may be effective in patients with wheat-sensitive disorders.
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http://dx.doi.org/10.1053/j.gastro.2019.02.028DOI Listing
June 2019
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