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1.
Gastroenterology ; 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32416141

RESUMO

BACKGROUND & AIMS: There is controversy over the association between celiac disease and inflammatory bowel diseases (IBD). We performed a systematic review and meta-analysis to assess evidence for an association between celiac disease 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 celiac disease in patients with IBD, and IBD in patients with celiac disease, 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 celiac disease in patients with IBD vs controls (relative risk [RR], 3.96; 95% CI, 2.23-7.02) and increased risk of IBD in patients with celiac disease 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 celiac disease 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 celiac disease and increased risk of celiac disease in patients with IBD, compared with other patient populations. High-quality prospective cohort studies are needed to assess the risk of celiac disease-specific and IBD-specific biomarkers in patients with IBD and celiac disease.

2.
Front Immunol ; 11: 155, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32117293

RESUMO

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.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32217152

RESUMO

BACKGROUND & AIMS: It is not clear how often patients who are on gluten-free diets (GFDs) for treatment celiac disease are still 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 following 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 years; interquartile range, 5-12 years) 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 ELISA 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). Numbers 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 are still frequently exposed to gluten. Assays to detect GIP in stool and urine might be used to assist dietitians in assessment of GFD compliance.

4.
Neuropsychobiology ; 79(1): 5-12, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30928978

RESUMO

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.

6.
mBio ; 10(6)2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848276

RESUMO

The Gram-negative marine bacterium Vibrio parahaemolyticus is a common cause of infectious gastroenteritis due to the ingestion of contaminated seafood. Most virulent V. parahaemolyticus 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 V. parahaemolyticus-associated gastroenteritis. Germfree mice were infected with a pathogenic clinical isolate of V. parahaemolyticus, 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 V. parahaemolyticus strain lacking the T3SS1 (POR2) also developed severe pathology, similar to that seen with RIMD. In contrast, the ΔT3SS2 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 (POR2ΔvopC), 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 ΔT3SS2 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 V. parahaemolyticus IMPORTANCE Vibrio parahaemolyticus 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 V. parahaemolyticus 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 V. parahaemolyticus 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 in vivo infection.


Assuntos
Gastroenterite/microbiologia , Sistemas de Secreção Tipo III , Vibrioses/microbiologia , Vibrio parahaemolyticus/fisiologia , Fatores de Virulência/genética , Animais , Antibacterianos/farmacologia , Morte Celular , Proliferação de Células , Modelos Animais de Doenças , Farmacorresistência Bacteriana , Gastroenterite/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Camundongos , Estreptomicina/farmacologia , Vibrio parahaemolyticus/efeitos dos fármacos , Virulência
7.
Gastroenterol. hepatol. (Ed. impr.) ; 42(7): 449-457, ago.-sept. 2019. ilus, graf
Artigo em Inglês | IBECS | ID: ibc-183840

RESUMO

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


El trigo es un cereal frecuente en la dieta occidental y una importante fuente de proteínas y fibra. Sin embargo, algunas personas presentan reacciones adversas a una dieta con trigo. La más conocida es la enfermedad celíaca, que se manifiesta después del consumo de gluten por parte de individuos con predisposición genética. Otras enfermedades relacionadas con el trigo no están tan bien definidas por lo que respecta al diagnóstico, el desencadenante específico y las vías subyacentes. A pesar de ello, la incidencia general de trastornos relacionados con el trigo ha aumentado en las últimas décadas, y se ha sugerido el papel de factores microbianos. Varios estudios han descrito cambios de la microbiota intestinal en pacientes celíacos frente a individuos sanos, pero hay menos información sobre otros trastornos relacionados con el trigo. En este artículo tratamos la importancia de la microbiota intestinal en el metabolismo de las proteínas del trigo y el desarrollo de trastornos inflamatorios o funcionales. El conocimiento de estas interacciones abrirá nuevas vías para el desarrollo terapéutico con bacterias con una capacidad óptima de degradación de las proteínas del trigo


Assuntos
Humanos , Triticum/metabolismo , Hipersensibilidade a Trigo/complicações , Doença Celíaca/complicações , Doença Celíaca/enzimologia , Doença Celíaca/metabolismo , Microbioma Gastrointestinal
8.
Gastroenterol Hepatol ; 42(7): 449-457, 2019.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31262542

RESUMO

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.


Assuntos
Microbioma Gastrointestinal , Proteínas de Plantas/metabolismo , Triticum , Imunidade Adaptativa , Bactérias/metabolismo , Doença Celíaca/dietoterapia , Doença Celíaca/metabolismo , Doença Celíaca/microbiologia , Dieta Livre de Glúten , Hipersensibilidade Alimentar/dietoterapia , Hipersensibilidade Alimentar/microbiologia , Hipersensibilidade Alimentar/prevenção & controle , Glutens/efeitos adversos , Humanos , Imunidade Inata , Proteínas de Plantas/imunologia , Linfócitos T/imunologia , Triticum/efeitos adversos , Triticum/imunologia , Inibidores da Tripsina/efeitos adversos , Inibidores da Tripsina/metabolismo , Aglutininas do Germe de Trigo/efeitos adversos , Aglutininas do Germe de Trigo/metabolismo
9.
Neurogastroenterol Motil ; 31(10): e13675, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31290223

RESUMO

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.

10.
Nat Commun ; 10(1): 3224, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324782

RESUMO

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.


Assuntos
Bactérias/metabolismo , Biofilmes , Microbioma Gastrointestinal/fisiologia , Mucosa Intestinal/microbiologia , Trombina/metabolismo , Animais , Linhagem Celular , Colo/microbiologia , Neoplasias do Colo/microbiologia , Epitélio/microbiologia , Homeostase , Humanos , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Pele , Trombina/genética , Bexiga Urinária
11.
Am J Physiol Gastrointest Liver Physiol ; 317(2): G161-G170, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31188640

RESUMO

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.

13.
Nat Commun ; 10(1): 1198, 2019 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-30867416

RESUMO

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.


Assuntos
Proteínas de Bactérias/metabolismo , Doença Celíaca/imunologia , Proteínas na Dieta/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Metaloendopeptidases/metabolismo , Receptor PAR-2/imunologia , Adulto , Idoso , Animais , Antígenos/imunologia , Antígenos/metabolismo , Proteínas de Bactérias/genética , Biópsia , Estudos de Casos e Controles , Doença Celíaca/diagnóstico por imagem , Doença Celíaca/microbiologia , Doença Celíaca/patologia , Estudos de Coortes , Colonoscopia , Proteínas na Dieta/metabolismo , Modelos Animais de Doenças , Duodeno/imunologia , Duodeno/metabolismo , Duodeno/microbiologia , Duodeno/patologia , Feminino , Microbioma Gastrointestinal/imunologia , Vida Livre de Germes , Glutens/imunologia , Glutens/metabolismo , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Antígenos HLA-DQ/metabolismo , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Metaloendopeptidases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Pessoa de Meia-Idade , Proteólise , Pseudomonas aeruginosa/imunologia , Pseudomonas aeruginosa/metabolismo , Receptor PAR-2/metabolismo , Regulação para Cima , Adulto Jovem
14.
World J Gastroenterol ; 25(11): 1409-1420, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30918433

RESUMO

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 (Cohen´s kappa: 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.


Assuntos
Doença Celíaca/dietoterapia , Dieta Livre de Glúten , Glutens/análise , Cooperação do Paciente , Peptídeos/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Assintomáticas , Doença Celíaca/diagnóstico , Doença Celíaca/imunologia , Doença Celíaca/urina , Estudos Transversais , Autoavaliação Diagnóstica , Ensaio de Imunoadsorção Enzimática , Fezes/química , Feminino , Glutens/química , Glutens/imunologia , Glutens/metabolismo , Humanos , Eliminação Intestinal , Masculino , Pessoa de Meia-Idade , Peptídeos/química , Peptídeos/imunologia , Peptídeos/metabolismo , Testes Imediatos , Estudos Prospectivos , Inquéritos e Questionários
15.
Gastroenterology ; 156(8): 2266-2280, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30802444

RESUMO

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.


Assuntos
Doença Celíaca/imunologia , Dieta Livre de Glúten/métodos , Gliadina/efeitos adversos , Lactobacillus/imunologia , Triticum/efeitos adversos , Amilases/antagonistas & inibidores , Animais , Doença Celíaca/dietoterapia , Doença Celíaca/fisiopatologia , Modelos Animais de Doenças , Microbioma Gastrointestinal/imunologia , Gliadina/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Lactobacillus/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Valores de Referência , Sensibilidade e Especificidade , Triticum/imunologia , Inibidores da Tripsina/imunologia , Inibidores da Tripsina/farmacologia
16.
Nat Rev Dis Primers ; 5(1): 3, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30631077

RESUMO

Coeliac disease is an immune-mediated enteropathy against dietary gluten present in wheat, rye and barley and is one of the most common lifelong food-related disorders worldwide. Coeliac disease is also considered to be a systemic disorder characterized by a variable combination of gluten-related signs and symptoms and disease-specific antibodies in addition to enteropathy. The ingestion of gluten leads to the generation of harmful gluten peptides, which, in predisposed individuals, can induce adaptive and innate immune responses. The clinical presentation is extremely variable; patients may have severe gastrointestinal symptoms and malabsorption, extraintestinal symptoms or have no symptoms at all. Owing to the multifaceted clinical presentation, diagnosis remains a challenge and coeliac disease is heavily underdiagnosed. The diagnosis of coeliac disease is achieved by combining coeliac disease serology and small intestinal mucosal histology during a gluten-containing diet. Currently, the only effective treatment for coeliac disease is a lifelong strict gluten-free diet; however, the diet is restrictive and gluten is difficult to avoid. Optimizing diagnosis and care in coeliac disease requires continuous research and education of both patients and health-care professionals.


Assuntos
Doença Celíaca/dietoterapia , Doença Celíaca/diagnóstico , Doença Celíaca/fisiopatologia , Dieta Livre de Glúten/métodos , Humanos , Mucosa Intestinal/anormalidades , Mucosa Intestinal/patologia , Poaceae/efeitos adversos , Qualidade de Vida/psicologia , Fatores de Risco , Triticum/efeitos adversos
17.
Biomaterials ; 194: 195-214, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30612006

RESUMO

In recent years, the advent of intestinal organoid culture systems has revolutionized in vitro studies of the small intestine epithelium. Intestinal organoids are derived from self-organizing and self-renewing intestinal stem cells and closely recapitulate the native intestinal epithelium. They therefore represent a more physiologically-relevant in vitro model than conventional cell cultures for studying intestinal development, biology and pathophysiology. Moreover, they represent a promising and unprecedented new tool in the realm of regenerative and personalized medicine. In this review, we outline the current approaches to develop intestinal organoids and describe the strategies used to induce complexity, multicellularity and modularity in organoid culture systems; this knowledge will contribute to improved biomimicry of the organoid culture system. We focus on co-culture systems and explore the convergence of organoid technology and engineering principals. Finally, we describe applications of intestinal organoids in various fields.

18.
Cell Chem Biol ; 26(1): 17-26.e13, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30482680

RESUMO

Clostridium difficile causes increasing numbers of life-threatening intestinal infections. Symptoms associated with C. difficile infection (CDI) are mediated by secreted protein toxins, whose virulence is modulated by intracellular auto-proteolysis following allosteric activation of their protease domains by inositol hexakisphosphate (IP6). Here, we explore the possibility of inactivating the C. difficile toxin B (TcdB) by triggering its auto-proteolysis in the gut lumen prior to cell uptake using gain-of-function small molecules. We anticipated that high calcium concentrations typically found in the gut would strongly chelate IP6, precluding it from pre-emptively inducing toxin auto-proteolysis if administered exogenously. We therefore designed IP6 analogs with reduced susceptibility to complexation by calcium, which maintained allosteric activity at physiological calcium concentrations. We found that oral administration of IP6 analogs attenuated inflammation and promoted survival in mouse models of CDI. Our data provide impetus to further develop small-molecule allosteric triggers of toxin auto-proteolysis as a therapeutic strategy.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Toxinas Bacterianas/antagonistas & inibidores , Infecções por Clostridium/tratamento farmacológico , Clostridium difficile/efeitos dos fármacos , Inflamação/tratamento farmacológico , Ácido Fítico/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Proteínas de Bactérias/metabolismo , Toxinas Bacterianas/metabolismo , Infecções por Clostridium/metabolismo , Modelos Animais de Doenças , Inflamação/metabolismo , Camundongos , Ácido Fítico/administração & dosagem , Ácido Fítico/química , Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/química
19.
Nat Rev Gastroenterol Hepatol ; 16(1): 7-18, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30214038

RESUMO

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.


Assuntos
Hipersensibilidade Alimentar/etiologia , Microbioma Gastrointestinal/imunologia , Animais , Doença Celíaca/etiologia , Doença Celíaca/imunologia , Hipersensibilidade Alimentar/imunologia , Humanos , Lactobacillus/imunologia
20.
Sci Rep ; 8(1): 14184, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-30242285

RESUMO

The intestinal barrier encompasses structural, permeability and immune aspects of the gut mucosa that, when disrupted, may contribute to chronic inflammation. Although gnotobiotic studies have demonstrated the effects of microbiota on mucosal and systemic immunity, as well as intestinal barrier architecture and innate immune characteristics, its impact on barrier function remains unclear. We compared germ-free and conventional mice, as well as mice colonized with human fecal microbiota that were followed for 21 days post-colonization. Colonic barrier structure was investigated by immunohistochemistry, molecular and electron microscopy techniques. Permeability was assessed in colon tissue by Ussing chambers, and by serum LPS and MDP detection using TLR4- and NOD2-NFκB reporter assays. Microbiota profile was determined by Illumina 16S rRNA gene sequencing. Low dose dextran sodium sulfate was administered to assess microbiota-induced barrier changes on resistance to colonic injury. Permeability to paracellular probes and mucus layer structure resembled that of conventional mice by day 7 post-colonization, coinciding with reduced claudin-1 expression and transient IL-18 production by intestinal epithelial cells. These post-colonization adaptations were associated with decreased systemic bacterial antigen exposure and reduced susceptibility to intestinal injury. In conclusion, commensal colonization promotes physiological barrier structural and functional adaptations that contribute to intestinal homeostasis.


Assuntos
Colo/microbiologia , Colo/fisiologia , Microbioma Gastrointestinal/fisiologia , Homeostase/fisiologia , Microbiota/fisiologia , Animais , Colo/efeitos dos fármacos , Sulfato de Dextrana/farmacologia , Fezes , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Vida Livre de Germes/efeitos dos fármacos , Vida Livre de Germes/fisiologia , Homeostase/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/fisiopatologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/fisiologia , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Intestinos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microbiota/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , RNA Ribossômico 16S/metabolismo
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