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INTRODUCTION AND OBJECTIVES: Microbial translocation contributes to cirrhosis progression and complications. This study aims to investigate whether molecules related to intestinal permeability or microbial translocation can serve as prognostic biomarkers in patients with decompensated cirrhosis. MATERIALS AND METHODS: We prospectively evaluated hospitalized patients with decompensated cirrhosis for liver function, complications during hospitalization, in-hospital mortality, composite outcomes of in-hospital mortality and complications, 12-month mortality, and survival rates. Blood samples were collected upon admission, and 1,3 beta-d-glucan, zonulin, calprotectin, and lipopolysaccharide-binding protein were measured using commercial kits. RESULTS: Ninety-one patients with decompensated cirrhosis were enrolled. The mean age was 58 ± 12 years; 57% were male. The three main cirrhosis etiologies were hepatitis C (35%), alcohol (25%), and non-alcoholic steatohepatitis (17%). In terms of liver function, 52% were Child C, and 68% had model for end-stage liver disease ≥15. The in-hospital and one-year mortality rates were 31% and 57%, respectively. Child-Pugh, 1,3 beta-glucan, and model for end-stage liver disease were positively correlated; zonulin was associated with complications during hospitalization (acute kidney injury) and composite outcomes, and calprotectin was associated with all outcomes except 12-month mortality. CONCLUSIONS: Serum calprotectin and zonulin levels emerge as noninvasive prognostic biomarkers for potentially unfavorable outcomes in patients with decompensated cirrhosis.
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Inflammatory bowel diseases (IBD) are chronic conditions arising from an intricate interplay of genetics and environmental factors, and are associated with gut dysbiosis, inflammation, and gut permeability. In this study, we investigated whether the inflammatory potential of the diet is associated with the gut microbiota profile, inflammation, and permeability in forty patients with IBD in clinical remission. The dietary inflammatory index (DII) score was used to assess the inflammatory potential of the diet. The fecal microbiota profile was analyzed using 16SrRNA (V3-V4) gene sequencing, while fecal zonulin and calprotectin levels were measured with enzyme-linked immunosorbent assays. We found a positive correlation between the DII score and elevated calprotectin levels (Rho = 0.498; p = 0.001), but not with zonulin levels. Although α- and ß-diversity did not significantly differ across DII quartiles, the most pro-inflammatory diet group exhibited a higher fecal abundance of Veillonella rogosae (p = 0.026). In addition, the abundance of some specific bacteria sequences showed an exponential behavior across DII quartiles and a correlation with calprotectin or zonulin levels (p ≤ 0.050). This included a positive correlation between sq702. Veillonella rogosae and fecal calprotectin levels (Rho = 0.419, p = 0.007). DII, calprotectin, and zonulin levels were identified as significant predictors of 6-month disease relapse (p ≤ 0.050). Our findings suggest a potential relationship of a pro-inflammatory diet intake with Veillonella rogosae and calprotectin levels in IBD patients in clinical remission, which may contribute to disease relapse.
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Doenças Inflamatórias Intestinais , Humanos , Biomarcadores , Inflamação , Fezes/microbiologia , Doença Crônica , Dieta , Recidiva , Complexo Antígeno L1 LeucocitárioRESUMO
OBJECTIVE: To investigate why certain at-risk individuals develop celiac disease (CD), we examined the association of proton pump inhibitors (PPI), histamine-2 receptor antagonists (H2RAs), and antibiotic prescriptions in the first 6 months of life with an early childhood diagnosis of CD. STUDY DESIGN: A retrospective cohort study was performed using the Military Healthcare System database. Children with a birth record from October 1, 2001, to September 30, 2013, were identified. Outpatient prescription records were queried for antibiotic, PPI, and H2RA prescriptions in the first 6 months of life. Cox proportional hazards regression was used to calculate the hazard ratio (HR) of developing CD based on medication exposure. International Classification of Diseases, Ninth Revision, Clinical Modification codes identified children with an outpatient visit for CD. RESULTS: There were 968â524 children who met the inclusion criteria with 1704 cases of CD in this group. The median follow-up for the cohort was approximately 4.5 years. PPIs (HR, 2.23; 95% CI, 1.76-2.83), H2RAs (HR, 1.94; 95% CI, 1.67-2.26), and antibiotics (HR, 1.14; 95% CI, 1.02-1.28) were all associated with an increased hazard of CD. CONCLUSIONS: There is an increased risk of developing CD if antibiotics, PPIs and H2RAs are prescribed in the first 6 months of life. Our study highlights modifiable factors, such as medication stewardship, that may change the childhood risk of CD.
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Antibacterianos , Doença Celíaca , Criança , Humanos , Lactente , Pré-Escolar , Estudos Retrospectivos , Antibacterianos/efeitos adversos , Inibidores da Bomba de Prótons/efeitos adversos , Antagonistas dos Receptores H2 da Histamina/efeitos adversos , Fatores de RiscoRESUMO
Zonulin has previously been related to intestinal permeability in various inflammatory diseases, and more recently to the physiopathology of severe COVID-19 infections. We analysed serum samples from a previous study of a Peruvian cohort of hospitalised COVID-19 patients, for the quantification of zonulin by sandwich ELISA. Comparisons with clinical data, haematological and biochemical parameters and cytokine/chemokine levels were made. We found higher baseline zonulin levels in deceased patients, and zonulin was associated with fatal outcome in multivariable analyses, even after adjustment for age, gender, and obesity. There were also positive correlations between zonulin, creatinine, D-dimer values and prothrombin time, while inverse correlations were found for Sa/FiO2 ratio and CCL5 (RANTES). Further longitudinal studies are recommended to analyse the variation of zonulin levels over time as well as their relationship with long-COVID.
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COVID-19 , Haptoglobinas , Precursores de Proteínas , Biomarcadores , COVID-19/mortalidade , Quimiocina CCL5 , Creatinina , Humanos , Permeabilidade , Peru/epidemiologia , Síndrome de COVID-19 Pós-AgudaRESUMO
ABSTRACT Background: Inflammatory bowel disease (IBD) comprises the spectrum between Crohn's disease (CD) and ulcerative colitis (UC), a condition whose prevalence in countries such as Brazil has increased significantly in recent years. Changes in the intestinal epithelial barrier function and, consequently, an increase in intestinal permeability, have been suggested as important factors in the pathogenesis of different autoimmune conditions, including IBD. Therefore, there is a need for a practical tool to assess gut barrier integrity in these patients. Objective: To study factors associated with serum zonulin levels, a marker of intestinal permeability, in patients with IBD. Methods: This was a cross-sectional observational study that included 117 patients with IBD and 32 healthy controls. Disease activity was assessed by the Simple Clinical Colitis Activity Index (SCCAI) in UC and by the Harvey-Bradshaw Index (HBI) in CD subjects. Zonulin levels were measured by ELISA and inflammatory cytokines by Cytometric Bead Array, using commercially available kits. Results: The mean age of IBD patients was 44.0±15.9 years, 66.7% were female, 57 subjects were diagnosed with CD and 60 with UC. At evaluation, clinical remission was observed in 56.7% of CD patients and in 59.2% of UC subjects. No differences were observed in zonulin levels when comparing IBD patients with the control group (95.28 ng/mL vs 96.61 ng/mL, P=0.573) and when comparing patients with CD to those with UC (79.68 ng/mL vs 106.10 ng/mL, P=0.887). Among IBD group, zonulin concentrations were higher among females, correlated positively with body mass index (BMI) and age; and negatively with hemoglobin and hematocrit. In patients with UC, zonulin correlated negatively with hemoglobin, hematocrit, and albumin; and positively with BMI and SCCAI. Among CD patients, zonulin was positively correlated with age and BMI, but not with HBI. No correlations were observed between zonulin and circulating cytokines in IBD patients. Conclusion: In this cohort mostly comprised of patients in clinical remission, serum zonulin levels were not higher in patients with IBD than healthy controls, and correlated with variables not linked to baseline disease, such as sex, age and BMI. However, zonulin correlated with clinical and laboratory parameters of disease severity and activity among subjects with UC, but not among patients with CD. These findings indicate a potential role for zonulin as a biomarker in IBD, particularly in UC.
RESUMO Contexto: A doença inflamatória intestinal (DII) compreende o espectro entre a doença de Crohn (DC) e a colite ulcerativa, condição esta cuja prevalência em países como o Brasil vem aumentando significativamente nos últimos anos. Alterações na função da barreira epitelial intestinal e, consequentemente, um aumento da permeabilidade intestinal, têm sido sugeridos como fatores importantes envolvidos na patogênese de diferentes condições autoimunes, dentre elas, a DII. Desta forma, existe a necessidade de uma ferramenta prática para avaliar a integridade da barreira epitelial intestinal nestes pacientes. Objetivo: Estudar os fatores associados com os níveis séricos de zonulina, um marcador da permeabilidade intestinal, em pacientes com DII. Métodos: Estudo observacional transversal que incluiu 117 pacientes com DII e 32 indivíduos que compuseram o grupo controle. A atividade da doença foi avaliada pelo Simple Cliniical Colitis Activity Index (SCCAI) na colite ulcerativa e pelo índice de Harvey-Bradshaw (IHB) em pacientes com DC. Os níveis de zonulina foram quantificados por ELISA e os níveis das citocinas inflamatórias pelo Cytometric Bead Array, utilizando kits comercialmente disponíveis. Resultados: A média de idade dos pacientes com DII foi de 44,0±15,9 anos, 66,7% eram do sexo feminino, 57 pacientes eram portadores de DC e 60 pacientes eram portadores de colite ulcerativa. No momento da avaliação clínico-laboratorial, 56,7% dos pacientes com DC encontravam-se em remissão clínica e, dentre os pacientes com colite ulcerativa, 59,2% deles assim se encontravam. Não foram observadas diferenças nos níveis séricos de zonulina entre pacientes com DII e grupo controle (95,28 ng/mL vs 96,61 ng/mL; P=0,573), assim como entre pacientes com DC e pacientes com colite ulcerativa (79,68 ng/mL vs 106,10 ng/mL, P=0,887). Dentre os pacientes com DII, as concentrações de zonulina foram mais elevadas no sexo feminino e correlacionaram-se positivamente com o índice de massa corporal (IMC) e com a idade, correlacionando-se negativamente com os níveis de hemoglobina e hematócrito. Nos pacientes com colite ulcerativa, as concentrações de zonulina correlacionaram-se negativamente com os parâmetros hemoglobina, hematócrito e albumina e, positivamente, com o IMC e com o SCCAI. Dentre os pacientes com DC, a zonulina sérica correlacionou-se positivamente com a idade e com o IMC, mas não com o IHB. Não foram observadas correlações entre os níveis de zonulina e as citocinas circulantes nos pacientes com DII. Conclusão: Nesta coorte constituída majoritariamente por pacientes em remissão clínica, os níveis séricos de zonulina não se mostraram aumentados em pacientes com DII em relação a indivíduos controles e correlacionaram-se com variáveis não relacionadas à doença de base, como com o sexo, com a idade e com o IMC. No entanto, os níveis séricos de zonulina correlacionaram-se com parâmetros clínicos e laboratoriais de gravidade e atividade da doença dentre os pacientes com colite ulcerativa, mas não dentre os pacientes com DC. Estes achados indicam um potencial papel da zonulina sérica como um biomarcador na DII, principalmente na colite ulcerativa.
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[This corrects the article DOI: 10.3389/fcimb.2022.1000291.].
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Resumen En los últimos meses, se ha comunicado globalmente, un aumento de casos de hepatitis de etiología no precisada. La población más afectada son los niños bajo los 5 años, pero con un rango etario hasta los 16 años. Clínicamente, se presentan con una hepatitis colestásica con pródromos de síntomas digestivos (deposiciones alteradas, náuseas y vómitos) y en que en el estudio etiológico pareciera haber una asociación directa o indirecta con infección por adenovirus. En general, la evolución es benigna, pero cerca de 13% ha requerido ingreso a unidad de cuidados intensivos y 10%, trasplante hepático. Las hipótesis sobre su etiología son varias, la mayoría relacionadas con algún agente infeccioso, ya sea como gatillante o actor principal. No se ha evidenciado hasta ahora la presencia de algún tóxico común ni la inmunización contra SARS-CoV-2 como causa de enfermedad. Se presenta una revisión sobre los datos disponibles a la fecha y posibles hipótesis de la etiopatogenia.
Abstract In recent months there has been an increase in cases reports of hepatitis of unknown origin. The most affected population are children under 5 years of age, but it has been described in adolescents up to 16 years of age. The clinical presentation consists of cholestatic hepatitis with a prodrome of diarrhea, nausea, and vomiting. Prognosis is generally benign but, on average, 13% of patients have required admission to an intensive care unit and 10% a liver transplant. Etiological studies have associated this entity to adenoviral infections, but hypotheses include other infectious agents, either as a triggering factor or as its main etiology, toxins, and even immunizations against SARS-CoV-2. In the following review we present the data available to date regarding the different pathogenesis theories.
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A western diet and increased intestinal permeability may contribute to systemic inflammation and the development of cardio-metabolic alterations. The aim of this study was to assess the relationship between diet, biomarkers of intestinal permeability, and chronic low-grade inflammation on the cardiometabolic profile. A cross-sectional study was carried out in 238 young subjects aged 18-29 years, divided into two groups: with <3 cardiometabolic risk factors (CRF) and ≥3 risk factors. Anthropometric parameters, biochemical profile, and serum levels of zonulin, lipopolysaccharide (LPS), and high-sensitivity C-reactive protein (hs-CRP) were measured, and the macronutrient intake was evaluated. Interaction models showed elevated glucose levels in the presence of high biomarker levels: zonulin ≥51.6 ng/mL plus LPS ≥ 1.35 EU/mL (ß = 1.1, p = 0.006), and LPS ≥1.35 EU/mL plus hs-CRP ≥ 4.3 mg/L (ß = 1.2, p = 0.007). In addition, triglyceride levels increased in the presence of LPS ≥ 1.35 EU/mL and hs-CRP ≥ 4.3 mg/L (ß = 3.9, p = 0.01). Despite having increased biomarker levels, a higher consumption of water (≥2100 mL), polyunsaturated fatty acids (≥6.0 g), or fiber (≥30 g) decreased triglyceride (ß = -9.6, p = 0.03), total cholesterol (ß = -5.1, p = 0.01), and LDL-C levels (ß = -7.7, p = 0.01). These findings suggest that the increased consumption of water, PUFA and fiber may improve lipid profile in subjects with intestinal permeability dysfunction or low-grade systemic inflammation.
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Proteína C-Reativa/metabolismo , Fatores de Risco Cardiometabólico , Dieta , Lipopolissacarídeos/sangue , Precursores de Proteínas/sangue , Adolescente , Adulto , Feminino , Haptoglobinas , Humanos , Inflamação/sangue , Inflamação/metabolismo , Masculino , Adulto JovemRESUMO
BACKGROUND: Increased intestinal permeability may be associated with certain disorders, such as obesity and small intestine bacterial overgrowth (SIBO). OBJECTIVE: This study aimed to investigate intestinal permeability and SIBO in excess weight adolescents. METHODS: This cross-sectional study included 67 adolescents with excess weight and 66 normal weight adolescents. Excess weight was defined as a body mass index for age (BMI/age) > +1 SD, which includes having excess body weight and obesity. SIBO was diagnosed by a breath test after the ingestion of lactulose according to the production of hydrogen and methane. Zonulin (haptoglobin) was considered an indicator of intestinal permeability. RESULTS: Adolescents with excess weight had a higher height/age Z-score (median [25th; 75th percentile]: +0.6 [-0.4; +1.0]) than those in the normal weight group (-0.1 [-0.6; +0.7]; P = .014). Zonulin (mg/mL) in the excess weight (2.3 [1.5; 3.8]) adolescents was higher than that in the normal weight (1.6 [1.0; 2.2]) adolescents (P < .001). SIBO was diagnosed in 23.3% (31/133) of the adolescents. The adolescents with SIBO had a lower (P < .05) BMI/age (+0.6 [-0.6; +1.9]) and height/age (-0.3 [-0.7; +0.3]) than the adolescents without SIBO (+1.3 [+0.1; +2.6] and +0.2 [-0.5; +1.0], respectively). No association was found between zonulin and SIBO. CONCLUSION: Excess weight is associated with increased intestinal permeability. No relationship was found between SIBO and intestinal permeability; however, SIBO was related to lower BMI and height for age Z-scores.
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Intestino Delgado , Lactulose , Sobrepeso/microbiologia , Obesidade Infantil/microbiologia , Adolescente , Síndrome da Alça Cega , Testes Respiratórios , Estudos de Casos e Controles , Estudos Transversais , Humanos , Intestino Delgado/microbiologia , PermeabilidadeRESUMO
OBJECTIVE: To evaluate the serum levels of zonulin, which regulates tight junctions between enterocytes and is a physiological modulator controlling intestinal permeability, in patients with autism spectrum disorders (ASDs). STUDY DESIGN: Serum zonulin levels were determined in 32 patients with ASD and 33 healthy controls using an enzyme-linked immunosorbent assay. The severity of ASD symptoms was assessed with the Childhood Autism Rating Scale. RESULTS: Serum zonulin levels were significantly higher in the patients with ASD (122.3 ± 98.46 ng/mL) compared with the healthy controls (41.89 ± 45.83 ng/mL). There was a positive correlation between zonulin levels and Childhood Autism Rating Scale score when all subjects were assessed (r = 0.523; P < .001). CONCLUSIONS: This study suggests that zonulin, which regulates intestinal permeability, plays a role in the development of symptoms of ASD.
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Transtorno Autístico/sangue , Toxina da Cólera/sangue , Mucosa Intestinal/metabolismo , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Feminino , Haptoglobinas , Humanos , Masculino , Permeabilidade , Precursores de ProteínasRESUMO
OBJECTIVE: To test the hypothesis that feeding and antibiotic exposures affect intestinal barrier maturation in preterm infants, we serially measured intestinal permeability (IP) biomarkers in infants <33 weeks gestation (gestational age [GA]) during the first 2 weeks of life. STUDY DESIGN: Eligible infants <33 weeks GA were enrolled within 4 days of birth in a prospective study of IP biomarkers (NCT01756040). Study participants received the nonmetabolized sugars lactulose/rhamnose enterally on study days 1, 8, and 15 and lactulose/rhamnose were measured in urine by high-performance liquid chromatography. Serum zonulin and fecal alpha-1-anti-trypsin, 2 other IP markers, were measured by semiquantitative Western blot and ELISA, respectively. RESULTS: In a cohort of 43 subjects, the lactulose/rhamnose ratio was increased on day 1 and decreased over 2 weeks, but remained higher in infants born at ≤28 weeks of gestation compared with IP in infants born at >28 weeks of gestation. Exclusive breastmilk feeding was associated with more rapid maturation in intestinal barrier function. A cluster analysis of 35 subjects who had urine samples from all time points revealed 3 IP patterns (cluster 1, normal maturation: n = 20 [57%]); cluster 2, decreased IP during the first week and subsequent substantial increase: n = 5 [14%]); and cluster 3, delayed maturation: n = 10 [29%]). There were trends toward more prolonged antibiotic exposure (P = .092) and delayed initiation of feeding ≥4 days (P = .064) in infants with abnormal IP patterns. CONCLUSIONS: Intestinal barrier maturation in preterm infants is GA and postnatal age dependent, and is influenced by feeding with a maturational effect of breastmilk feeding and possibly by antibiotic exposures. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01756040.