Publications by authors named "Alberto Caminero"

30 Publications

  • Page 1 of 1

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

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

Current and emerging therapies for coeliac disease.

Nat Rev Gastroenterol Hepatol 2021 03 20;18(3):181-195. Epub 2020 Nov 20.

Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Coeliac disease is a common enteropathy that occurs in genetically susceptible individuals in response to the ingestion of gluten proteins present in wheat, rye and barley. Currently, the only available treatment for the condition is a strict, life-long gluten-free diet that, despite being safe and often effective, is associated with several challenges. Due to the high cost, particularly restrictive nature and perception of decreased quality of life associated with the diet, some patients are continuously exposed to gluten, which prevents an adequate disease control. Moreover, a subgroup of patients does not respond to the diet adequately, and healing of the small-bowel mucosa can be incomplete. Thus, there is a need for alternative treatment forms. The increasingly understood pathogenetic process of coeliac disease has enabled the identification of various targets for future therapies. Multiple investigational therapies ranging from tolerogenic to immunological approaches are in the pipeline, and several drug candidates have entered phase II/III clinical trials. This Review gives a broad overview of the different investigative treatment modalities for coeliac disease and summarizes the latest advances in this field.
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http://dx.doi.org/10.1038/s41575-020-00378-1DOI Listing
March 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

Host immune interactions in chronic inflammatory gastrointestinal conditions.

Curr Opin Gastroenterol 2020 11;36(6):479-484

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

Purpose Of Review: We performed a literature review of the latest studies on the interactions between the host immune system and microbes in chronic intestinal inflammatory conditions.

Recent Findings: The mechanisms leading to celiac disease (CeD) and inflammatory bowel disease (IBD), the most common chronic inflammatory gastrointestinal conditions, are complex. The intestinal homeostasis depends on the interactions between the microbiota, the intestinal mucosa and the host immune system. Failure to achieve or maintain equilibrium between a host and its microbiota has the potential to induce chronic conditions with an underlying inflammatory component. Mechanisms by which intestinal microbes trigger inflammation include the alteration of intestinal permeability, activation of the host immune system and digestion of dietary antigens with a consequent repercussion on tolerance to food. Therefore, therapies modulating gut microbiota, including diet, antibiotics, probiotics and faecal transplantation have a potential in CeD and IBD. Probiotics are effective to treat pouchitis and faecal transplant for ulcerative colitis, but the evidence is less clear in Crohn's disease or CeD.

Summary: Diverse regulatory mechanisms cooperate to maintain intestinal homeostasis, and a breakdown in these pathways may precipitate inflammation. The role of microbiota inducing immune dysfunction and inflammation supports the therapeutic rationale of manipulating microbiota to treat chronic inflammatory conditions.
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http://dx.doi.org/10.1097/MOG.0000000000000673DOI Listing
November 2020

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

The neuroimmunological toll of nutrient absorption.

Allergy 2020 09 13;75(9):2415-2417. Epub 2020 Jul 13.

Department of Immunology & Oncology, Centro Nacional de Biotecnología (CNB)-CSIC, Madrid, Spain.

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http://dx.doi.org/10.1111/all.14458DOI Listing
September 2020

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

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

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

Mechanisms by which gut microorganisms influence food sensitivities.

Nat Rev Gastroenterol Hepatol 2019 01;16(1):7-18

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

Finely tuned mechanisms enable the gastrointestinal tract to break down dietary components into nutrients without mounting, in the majority of cases, a dysregulated immune or functional host response. However, adverse reactions to food have been steadily increasing, and evidence suggests that this process is environmental. Adverse food reactions can be divided according to their underlying pathophysiology into food intolerances, when, for instance, there is deficiency of a host enzyme required to digest the food component, and food sensitivities, when immune mechanisms are involved. In this Review, we discuss the clinical and experimental evidence for enteric infections and/or alterations in the gut microbiota in inciting food sensitivity. We focus on mechanisms by which microorganisms might provide direct pro-inflammatory signals to the host promoting breakdown of oral tolerance to food antigens or indirect pathways that involve the metabolism of protein antigens and other dietary components by gut microorganisms. Better understanding of these mechanisms will help in the development of preventive and therapeutic strategies for food sensitivities.
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http://dx.doi.org/10.1038/s41575-018-0064-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767923PMC
January 2019

Gluten-degrading bacteria are present in the human small intestine of healthy volunteers and celiac patients.

Res Microbiol 2017 Sep 16;168(7):673-684. Epub 2017 May 16.

Área de Microbiología, Facultad de Biología y Ciencias Ambientales, Universidad de León, 24071 León, Spain; Instituto de Biología Molecular, Genómica y Proteómica (INBIOMIC), Universidad de León, 24071 León, Spain. Electronic address:

Gluten is the only known environmental factor that triggers celiac disease. Several studies have described an imbalance between the intestinal microbiota of different individuals based on diagnoses. Moreover, recent studies have suggested that human bacteria may play an important role in gluten hydrolysis. However, there has been no research focusing on the small intestine. This study aimed to characterize the adult small intestine microbiota possibly implicated in gluten hydrolysis. Duodenal biopsies from different diagnosed individuals were cultured in a gluten-containing medium, and the grown microbiota was analyzed by culture dependent/independent methods. Results showed that gluten-degrading bacteria can be found in the human small intestine. Indeed, 114 bacterial strains belonging to 32 species were isolated; 85 strains were able to grow in a medium containing gluten as the sole nitrogen source, 31 strains showed extracellular proteolytic activity against gluten protein and 27 strains showed peptidolytic activity towards the 33 mer peptide, an immunogenic peptide for celiac disease patients. We found that there are no differences based on the diagnosis, but each individual has its own population of gluten-hydrolyzing bacteria. These bacteria or their gluten-degrading enzymes could help to improve the quality of life of celiac disease patients'.
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http://dx.doi.org/10.1016/j.resmic.2017.04.008DOI Listing
September 2017

How infection can incite sensitivity to food.

Science 2017 04;356(6333):29-30

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

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http://dx.doi.org/10.1126/science.aan1500DOI Listing
April 2017

Duodenal Bacteria From Patients With Celiac Disease and Healthy Subjects Distinctly Affect Gluten Breakdown and Immunogenicity.

Gastroenterology 2016 10 30;151(4):670-83. Epub 2016 Jun 30.

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

Background & Aims: Partially degraded gluten peptides from cereals trigger celiac disease (CD), an autoimmune enteropathy occurring in genetically susceptible persons. Susceptibility genes are necessary but not sufficient to induce CD, and additional environmental factors related to unfavorable alterations in the microbiota have been proposed. We investigated gluten metabolism by opportunistic pathogens and commensal duodenal bacteria and characterized the capacity of the produced peptides to activate gluten-specific T-cells from CD patients.

Methods: We colonized germ-free C57BL/6 mice with bacteria isolated from the small intestine of CD patients or healthy controls, selected for their in vitro gluten-degrading capacity. After gluten gavage, gliadin amount and proteolytic activities were measured in intestinal contents. Peptides produced by bacteria used in mouse colonizations from the immunogenic 33-mer gluten peptide were characterized by liquid chromatography tandem mass spectrometry and their immunogenic potential was evaluated using peripheral blood mononuclear cells from celiac patients after receiving a 3-day gluten challenge.

Results: Bacterial colonizations produced distinct gluten-degradation patterns in the mouse small intestine. Pseudomonas aeruginosa, an opportunistic pathogen from CD patients, exhibited elastase activity and produced peptides that better translocated the mouse intestinal barrier. P aeruginosa-modified gluten peptides activated gluten-specific T-cells from CD patients. In contrast, Lactobacillus spp. from the duodenum of non-CD controls degraded gluten peptides produced by human and P aeruginosa proteases, reducing their immunogenicity.

Conclusions: Small intestinal bacteria exhibit distinct gluten metabolic patterns in vivo, increasing or reducing gluten peptide immunogenicity. This microbe-gluten-host interaction may modulate autoimmune risk in genetically susceptible persons and may underlie the reported association of dysbiosis and CD.
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http://dx.doi.org/10.1053/j.gastro.2016.06.041DOI Listing
October 2016

Novel perspectives on therapeutic modulation of the gut microbiota.

Therap Adv Gastroenterol 2016 Jul 4;9(4):580-93. Epub 2016 Apr 4.

Farncombe Family Digestive Health Research Institute, McMaster University, 1280 Main Street West, Hamilton, ON, Canada L8S 4L8.

The gut microbiota contributes to the maintenance of health and, when disrupted, may drive gastrointestinal and extragastrointestinal disease. This can occur through direct pathways such as interaction with the epithelial barrier and mucosal immune system or indirectly via production of metabolites. There is no current curative therapy for chronic inflammatory conditions such as inflammatory bowel disease, which are complex multifactorial disorders involving genetic predisposition, and environmental triggers. Therapies are directed to suppress inflammation rather than the driver, and these approaches are not devoid of adverse effects. Therefore, there is great interest in modulation of the gut microbiota to provide protection from disease. Interventions that modulate the microbiota include diet, probiotics and more recently the emergence of experimental therapies such as fecal microbiota transplant or phage therapy. Emerging data indicate that certain bacteria can induce protective immune responses and enhance intestinal barrier function, which could be potential therapeutic targets. However, mechanistic links and specific therapeutic recommendations are still lacking. Here we provide a pathophysiological overview of potential therapeutic applications of the gut microbiota.
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http://dx.doi.org/10.1177/1756283X16637819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913331PMC
July 2016

Age-related differences in celiac disease: Specific characteristics of adult presentation.

World J Gastrointest Pharmacol Ther 2015 Nov;6(4):207-12

Santiago Vivas, Institute of Biomedicine (IBIOMED), University of León, 24008 León, Spain.

Celiac disease may appear both in early childhood and in elderly subjects. Current knowledge of the disease has revealed some differences associated to the age of presentation. Furthermore, monitoring and prognosis of celiac subjects can vary depending on the pediatric or adult stage. The main objective of this review is to provide guidance for the adult diagnostic and follow-up processes, which must be tailored specifically for adults and be different from pediatric patients.
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http://dx.doi.org/10.4292/wjgpt.v6.i4.207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635160PMC
November 2015

Differences in gluten metabolism among healthy volunteers, coeliac disease patients and first-degree relatives.

Br J Nutr 2015 Oct;114(8):1157-67

1Instituto de Biología Molecular,Genómica y Proteómica (INBIOMIC),Campus de Vegazana,Universidad de León,León 24071,Spain.

Coeliac disease (CD) is an immune-mediated enteropathy resulting from exposure to gluten in genetically predisposed individuals. Gluten proteins are partially digested by human proteases generating immunogenic peptides that cause inflammation in patients carrying HLA-DQ2 and DQ8 genes. Although intestinal dysbiosis has been associated with patients with CD, bacterial metabolism of gluten has not been studied in depth thus far. The aim of this study was to analyse the metabolic activity of intestinal bacteria associated with gluten intake in healthy individuals, CD patients and first-degree relatives of CD patients. Faecal samples belonging to twenty-two untreated CD patients, twenty treated CD patients, sixteen healthy volunteers on normal diet, eleven healthy volunteers on gluten-free diet (GFD), seventy-one relatives of CD patients on normal diet and sixty-nine relatives on GFD were tested for several proteolytic activities, cultivable bacteria involved in gluten metabolism, SCFA and the amount of gluten in faeces. We detected faecal peptidasic activity against the gluten-derived peptide 33-mer. CD patients showed differences in faecal glutenasic activity (FGA), faecal tryptic activity (FTA), SCFA and faecal gluten content with respect to healthy volunteers. Alterations in specific bacterial groups metabolising gluten such as Clostridium or Lactobacillus were reported in CD patients. Relatives showed similar parameters to CD patients (SCFA) and healthy volunteers (FTA and FGA). Our data support the fact that commensal microbial activity is an important factor in the metabolism of gluten proteins and that this activity is altered in CD patients.
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http://dx.doi.org/10.1017/S0007114515002767DOI Listing
October 2015

Pharmacological approaches in celiac disease.

Curr Opin Pharmacol 2015 Dec 27;25:7-12. Epub 2015 Sep 27.

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

Celiac disease is an autoimmune enteropathy triggered by the ingestion of gluten, characterized by immune responses toward gluten constituents and the autoantigen transglutaminase 2. The only current treatment available for celiac disease is a gluten-free diet, however there are a plethora of therapies in development for the treatment of celiac disease (e.g. vaccine), management of symptoms while consuming gluten (e.g. Necator americanus) or adjuvant therapies in conjunction with the gluten-free diet (e.g. larazotide acetate). Current approaches in development target barrier function, immune responses, detoxifying gluten or sequestering gluten. Developing therapies include those targeting environmental factors, such as the microbiota or proteases.
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http://dx.doi.org/10.1016/j.coph.2015.09.002DOI Listing
December 2015

Diversity of the cultivable human gut microbiome involved in gluten metabolism: isolation of microorganisms with potential interest for coeliac disease.

FEMS Microbiol Ecol 2014 May 3;88(2):309-19. Epub 2014 Mar 3.

Instituto de Biología Molecular, Genómica y Proteómica (INBIOMIC), Universidad de León, León, Spain.

Gluten, a common component in the human diet, is capable of triggering coeliac disease pathogenesis in genetically predisposed individuals. Although the function of human digestive proteases in gluten proteins is quite well known, the role of intestinal microbiota in the metabolism of proteins is frequently underestimated. The aim of this study was the isolation and characterisation of the human gut bacteria involved in the metabolism of gluten proteins. Twenty-two human faecal samples were cultured with gluten as the principal nitrogen source, and 144 strains belonging to 35 bacterial species that may be involved in gluten metabolism in the human gut were isolated. Interestingly, 94 strains were able to metabolise gluten, 61 strains showed an extracellular proteolytic activity against gluten proteins, and several strains showed a peptidasic activity towards the 33-mer peptide, an immunogenic peptide in patients with coeliac disease. Most of the strains were classified within the phyla Firmicutes and Actinobacteria, mainly from the genera Lactobacillus, Streptococcus, Staphylococcus, Clostridium and Bifidobacterium. In conclusion, the human intestine exhibits a large variety of bacteria capable of utilising gluten proteins and peptides as nutrients. These bacteria could have an important role in gluten metabolism and could offer promising new treatment modalities for coeliac disease.
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http://dx.doi.org/10.1111/1574-6941.12295DOI Listing
May 2014

Coeliac disease screening in first-degree relatives on the basis of biopsy and genetic risk.

Eur J Gastroenterol Hepatol 2014 Mar;26(3):263-7

aGastroenterology Unit bPathology Department cPaediatric Department, University Hospital of León, Altos de Nava s/n dInstitute of Molecular Biology (INBIOMIC) eMicrobiology Department fInstitute of Biomedicine (IBIOMED), University of León, León, Spain.

Background: Serological markers of coeliac disease (CD) lack diagnostic value to identify mild histopathological lesions mainly in adults at risk of CD.

Aims: The aim of this study was to evaluate the usefulness of human leukocyte antigen (HLA)-DQ2/8 genotyping, followed by duodenal biopsy for the detection of CD in adult first-degree relatives (FDRs) of patients with CD.

Materials And Methods: Ninety-two adult DQ2/8 positive FDRs were consecutively included. A duodenal biopsy was offered irrespective of the serology result or associated symptoms. The clinical features, associated autoimmune diseases and biochemical parameters were recorded.

Results: Sixty-seven FDRs (mean age 34 years) underwent a duodenal biopsy. Histopathological alterations were found in 32 (48%) and showed the following stages: 12 Marsh I (18%), one Marsh II (1.5%), four Marsh IIIA (6%), five Marsh IIIB (7.5%) and 10 Marsh IIIC (15%). Positive serological markers were present in 17/67 (25%), with only one showing Marsh I and the remainder presenting some degree of duodenal atrophy (Marsh III). In addition, 33/67 (54%) had gastrointestinal symptoms, with dyspepsia being the most prevalent. The distribution of symptoms, anaemia and autoimmune disease was independent of the duodenal histopathological stage. Serology-based screening would diagnose 50% of the cases showing any degree of CD spectrum and miss 6% of the cases with mucosal atrophy.

Conclusion: Adult FDRs of patients with CD can benefit from a screening strategy on the basis of HLA-DQ genotyping, followed by a duodenal biopsy. Gastrointestinal symptoms and lymphocytic enteritis are common findings that may benefit from a gluten-free diet.
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http://dx.doi.org/10.1097/MEG.0000000000000020DOI Listing
March 2014

Differences in faecal bacteria populations and faecal bacteria metabolism in healthy adults and celiac disease patients.

Biochimie 2012 Aug 20;94(8):1724-9. Epub 2012 Apr 20.

Área de Microbiología, Universidad de León, 24071 León, Spain.

Unlabelled: Differences in the intestinal microbiota between children and adults with celiac disease (CD) have been reported; however, differences between healthy adults and adults with CD have not been clearly demonstrated. The aim of this study was to evaluate the differences in the intestinal microbiota between adults with CD and healthy individuals. Microbial communities in faecal samples were evaluated by PCR-denaturing gradient gel electrophoresis (DGGE) and gas-liquid chromatography of short chain fatty acids (SCFAs). The study group included 10 untreated CD patients, 11 treated CD patients and 11 healthy adults (in normal gluten diet and in GFD). UPGMA clustered the dominant microbial communities of healthy individuals together and separated them from the dominant microbial communities of the untreated CD patients. Most of the dominant microbial communities of the treated CD patients clustered together with those of healthy adults. The treated CD patients showed a reduction in the diversity of Lactobacillus and Bifidobacterium species. The presence of Bifidobacterium bifidum was significantly higher in untreated CD patients than healthy adults. There was a significant difference between untreated CD patients and healthy adults, as well as between treated CD patients and healthy adults, regarding acetic acid, propionic acid, butyric acid, and total SCFAs.

In Conclusion: healthy adults have a different faecal microbiota from that of untreated CD patients. A portion of the treated CD patients displayed a restored "normal" microbiota. The treated CD patients significantly reduce the Lactobacillus and Bifidobacterium diversity. Healthy adults have a different faecal SCFAs content from that of CD patients.
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http://dx.doi.org/10.1016/j.biochi.2012.03.025DOI Listing
August 2012

Monitoring of gluten-free diet compliance in celiac patients by assessment of gliadin 33-mer equivalent epitopes in feces.

Am J Clin Nutr 2012 Mar 18;95(3):670-7. Epub 2012 Jan 18.

Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain.

Background: Certain immunotoxic peptides from gluten are resistant to gastrointestinal digestion and can interact with celiac-patient factors to trigger an immunologic response. A gluten-free diet (GFD) is the only effective treatment for celiac disease (CD), and its compliance should be monitored to avoid cumulative damage. However, practical methods to monitor diet compliance and to detect the origin of an outbreak of celiac clinical symptoms are not available.

Objective: We assessed the capacity to determine the gluten ingestion and monitor GFD compliance in celiac patients by the detection of gluten and gliadin 33-mer equivalent peptidic epitopes (33EPs) in human feces.

Design: Fecal samples were obtained from healthy subjects, celiac patients, and subjects with other intestinal pathologies with different diet conditions. Gluten and 33EPs were analyzed by using immunochromatography and competitive ELISA with a highly sensitive antigliadin 33-mer monoclonal antibody.

Results: The resistance of a significant part of 33EPs to gastrointestinal digestion was shown in vitro and in vivo. We were able to detect gluten peptides in feces of healthy individuals after consumption of a normal gluten-containing diet, after consumption of a GFD combined with controlled ingestion of a fixed amount of gluten, and after ingestion of <100 mg gluten/d. These methods also allowed us to detect GFD infringement in CD patients.

Conclusions: Gluten-derived peptides could be sensitively detected in human feces in positive correlation with the amount of gluten intake. These techniques may serve to show GFD compliance or infringement and be used in clinical research in strategies to eliminate gluten immunotoxic peptides during digestion. This trial was registered at clinicaltrials.gov as NCT01478867.
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http://dx.doi.org/10.3945/ajcn.111.026708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278243PMC
March 2012

Differences of small intestinal bacteria populations in adults and children with/without celiac disease: effect of age, gluten diet, and disease.

Inflamm Bowel Dis 2012 Apr 8;18(4):649-56. Epub 2011 Aug 8.

Área de Microbiología, Facultad de Biología y Ciencias Ambientales, Universidad de León, León, Spain.

Background: Scientific evidence has revealed microecological changes in the intestinal tract of celiac infants. The objective of this work is the study of bacterial differences in the upper small intestine in both adults (healthy, untreated celiac disease [CD], and CD treated with a gluten-free diet) and children (healthy and untreated CD).

Methods: Intestinal bacterial communities were identified by 16S rRNA gene sequencing of DNA extracted from duodenal biopsies.

Results: Analysis of the sequences from adults and children showed that this niche was colonized by bacteria affiliated mainly with three phyla: Firmicutes, Proteobacteria, and Bacteroidetes. In total, 89 different genera were identified in adults and 46 in children. Bacterial richness was significantly lower in the children than in the adults. A global principal component analysis of the bacterial communities of both healthy and untreated CD patient groups (including both children and adults) revealed a strong effect of age in principal component 1--clustering all adults and children separately--and a possible effect of the disease in adults with untreated patients clustering separately.

Conclusions: There are bacterial differences in the upper small intestine between untreated children CD patients and untreated CD adults due to age. There are bacterial differences in the upper small bacteria microbiota between treated and untreated CD adults due to treatment with a gluten-free diet.
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http://dx.doi.org/10.1002/ibd.21830DOI Listing
April 2012

A gluten metabolism study in healthy individuals shows the presence of faecal glutenasic activity.

Eur J Nutr 2012 Apr 14;51(3):293-9. Epub 2011 Jun 14.

Área de Microbiología, Universidad de León, 24071, León, Spain.

Purpose: To study the gluten metabolism in healthy individuals and its effect over the intestinal microbial activity.

Methods: The faeces of eleven healthy subjects were analysed under 4 diet regimens: their normal gluten diet, a strict gluten-free diet (GFD), a GFD with a supplemental intake of 9 g gluten/day and a GFD with a supplemental intake of 30 g gluten/day. Gluten content, faecal tryptic activity (FTA), short-chain fatty acids (SCFAs) and faecal glutenasic activity (FGA) were analysed in faecal samples.

Results: Faecal gluten contents, FTA, SCFAs and FGA varied significantly with different levels of gluten intake in the diet. When high gluten doses (30 g/day) were administered in the diet, SCFA concentrations (70.5 mmoles/kg faeces) were significantly different from those from the GFD period (33.8 mmoles/kg faeces) of the experiment. However, the FTA showed significant differences between the GFD (34 units) and the normal gluten-containing diet (60 units) and also between the GFD and the GFD + 30 g of gluten/day (67 units). When gluten was present in the diet, gluten was detected in the faeces, showing that at least a portion of the gluten ingested is eliminated in the large intestine, providing a substrate for intestinal microbial proteases. We have also shown the presence of faecal glutenasic activity that increased proportionally with the gluten intake in the diet, showing an enzymatic activity of 993 units in DSG, 2,063 units in DSG + 9 g and 6,090 units in DSG + 30 g.

Conclusions: The activity of the intestinal microbiota is modified by gluten intake in the diet. The incorporation of gluten in the diet increases the activity of a gluten proteolytic activity in the faeces.
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http://dx.doi.org/10.1007/s00394-011-0214-3DOI Listing
April 2012
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