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      Intestinal Dysbiosis in Autoimmune Diabetes Is Correlated With Poor Glycemic Control and Increased Interleukin-6: A Pilot Study

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          Abstract

          Intestinal dysbiosis associated with immunological deregulation, leaky gut, bacterial translocation, and systemic inflammation has been associated with autoimmune diseases, such as type 1 diabetes (T1D). The aim of this study was to investigate the intestinal dysbiosis in T1D patients and correlate these results with clinical parameters and cytokines. The present study was approved by the Barretos Cancer Hospital (Process number 903/2014), and all participants have signed the informed consent in accordance with the Declaration of Helsinki, and answered a questionnaire about dietary habits. Stool samples were used for bacterial 16S sequencing by MiSeq Illumina platform. IL-2, IL-4, IL-6, IL-10, IL-17A, TNF, and IFN-γ plasma concentrations were determined by cytometric bead arrays. The Pearson’s chi-square, Mann–Whitney and Spearman correlation were used for statistical analyses. Alpha and beta diversities were conducted by using an annotated observed taxonomic units table. This study included 20 patients and 28 controls, and we found significant differences ( P < 0.05) among consumption of vegetables, proteins, milk and derivatives, spicy food, and canned food when we compare patients and controls. We detected intestinal dysbiosis in T1D patients when we performed the beta diversity analysis ( P = 0.01). The prevalent species found in patients’ stool were the Gram-negatives Bacteroides vulgatus, Bacteroides rodentium, Prevotella copri, and Bacteroides xylanisolvens. The inflammatory interleukin-6 was significantly increased ( P = 0.017) in patients’ plasma. Furthermore, we showed correlation among patients with poor glycemic control, represented by high levels of HbA1 C percentages and Bacteroidetes, Lactobacillales, and Bacteroides dorei relative abundances. We concluded that there are different gut microbiota profiles between T1D patients and healthy controls. The prevalent Gram-negative species in T1D patients could be involved in the leaky gut, bacterial translocation, and poor glycemic control. However, additional studies, with larger cohorts, are required to determine a “signature” of the intestinal microbiota in T1D patients in the Brazilian population.

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          The Immune Response to Prevotella Bacteria in Chronic Inflammatory Disease.

          The microbiota plays a central role in human health and disease by shaping immune development, immune responses, metabolism, and protecting from invading pathogens. Technical advances that allow comprehensive characterization of microbial communities by genetic sequencing have sparked the hunt for disease modulating bacteria. Emerging studies in humans have linked increased abundance of Prevotella species at mucosal sites to localized and systemic disease, including periodontitis, bacterial vaginosis, rheumatoid arthritis, metabolic disorders, and low-grade systemic inflammation. Intriguingly, Prevotella abundance is reduced within the lung microbiota of asthma and COPD. Increased Prevotella abundance is associated with augmented Th17-mediated mucosal inflammation, which is in line with the marked capacity of Prevotella in driving Th17 immune responses in vitro. Studies indicate, that Prevotella predominantly activate TLR2 leading to production of Th17-polarizing cytokines by antigen presenting cells, including IL-23 and IL-1. Furthermore, Prevotella stimulate epithelial cells to produce IL-8, IL-6 and CCL20, which can promote mucosal Th17 immune responses and neutrophil recruitment. Prevotella-mediated mucosal inflammation leads to systemic dissemination of inflammatory mediators, bacteria, and bacterial products, which in turn may affect systemic disease outcomes. Studies in mice support a causal role of Prevotella as colonization experiments promote clinical and inflammatory features of human disease. When compared to strict commensal bacteria, Prevotella exhibit increased inflammatory properties as demonstrated by augmented release of inflammatory mediators from immune cells and various stromal cells. These findings indicate that some Prevotella strains may be clinically important pathobionts that can participate in human disease by promoting chronic inflammation. This article is protected by copyright. All rights reserved.
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            The role of the intestinal microbiota in type 1 diabetes mellitus.

            Type 1 diabetes mellitus (T1DM) is a chronic immune-mediated disease with a subclinical prodromal period, characterized by selective loss of insulin-producing-β cells in the pancreatic islets of genetically susceptible individuals. The incidence of T1DM has increased several fold in most developed countries since World War II, in conjunction with other immune-mediated diseases. Rapid environmental changes and modern lifestyles are probably the driving factors that underlie this increase. These effects might be mediated by changes in the human microbiota, particularly the intestinal microbiota. Research on the gut microbiome of individuals at risk of developing T1DM and in patients with established disease is still in its infancy, but initial findings indicate that the intestinal microbiome of individuals with prediabetes or diabetes mellitus is different to that of healthy individuals. The gut microbiota in individuals with preclinical T1DM is characterized by Bacteroidetes dominating at the phylum level, a dearth of butyrate-producing bacteria, reduced bacterial and functional diversity and low community stability. However, these changes seem to emerge after the appearance of autoantibodies that are predictive of T1DM, which suggests that the intestinal microbiota might be involved in the progression from β-cell autoimmunity to clinical disease rather than in the initiation of the disease process.
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              Increased intestinal permeability precedes clinical onset of type 1 diabetes.

              Recent observations have shown subclinical intestinal abnormalities in human type 1 diabetes. Whether these are related to the pathogenetic process or secondary to the diabetes remains to be clarified. The aim of this study was to investigate this issue by examining intestinal permeability to sugars in subjects at different stages of type 1 diabetes: preclinical, new-onset and long-term established disease. Eighty-one subjects with islet autoimmunity (18 preclinical, 28 new-onset and 35 long-term type 1 diabetes) and 40 healthy control subjects were investigated by a lactulose-mannitol test, consisting of oral administration of the two sugars and measurement of their urinary excretion. All groups of subjects with islet autoimmunity showed an increase in intestinal permeability (p < or = 0.009 vs controls) to the disaccharide lactulose, indicative of a damaged barrier, but a similar permeability to the monosaccharide mannitol (NS vs controls), indicative of an integral surface mucosa; consequently there was an increase in the lactulose:mannitol excretion ratio (p < or = 0.025 vs controls). These findings indicate the presence of a subclinical enteropathy associated with type 1 diabetes that is already detectable before clinical onset of the disease, and suggest that the small intestine is an organ participating in the pathogenetic process of type 1 diabetes.
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                Author and article information

                Contributors
                URI : https://frontiersin.org/people/u/472737
                URI : https://frontiersin.org/people/u/472748
                URI : https://frontiersin.org/people/u/472907
                URI : https://frontiersin.org/people/u/472746
                URI : https://frontiersin.org/people/u/458403
                URI : https://frontiersin.org/people/u/446692
                URI : https://frontiersin.org/people/u/471377
                URI : https://frontiersin.org/people/u/432033
                URI : https://frontiersin.org/people/u/443158
                URI : https://frontiersin.org/people/u/102972
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                25 July 2018
                2018
                : 9
                : 1689
                Affiliations
                [1] 1Microbiome Study Group, School of Health Sciences Dr. Paulo Prata (FACISB) , Barretos, Brazil
                [2] 2QGene-Solutions and Logistics in Health , Sao Carlos, Brazil
                [3] 3Board of Health from Barretos , Barretos, Brazil
                [4] 4Department of Technology, School of Agricultural and Veterinarian Sciences, São Paulo State University (UNESP) , Jaboticabal, Sao Paulo, Brazil
                [5] 5DNA Consult Genetics and Biotechnology , Sao Carlos, Brazil
                [6] 6Biotechnology Department, Sao Carlos Federal University, UFSCAR , Sao Carlos, Brazil
                [7] 7Barretos Cancer Hospital (HCB) , Barretos, Brazil
                [8] 8Institute of Biosciences, Humanities and Exact Sciences (IBILCE), São Paulo State University (UNESP) , Sao Jose do Rio Preto, Sao Paulo, Brazil
                Author notes

                Edited by: Juarez Antonio Simões Quaresma, Instituto Evandro Chagas, Brazil

                Reviewed by: Maryam Dadar, Razi Vaccine and Serum Research Institute, Iran; Lidia Santarpia, Università degli Studi di Napoli Federico II, Italy; Alexander Nikolaevich Orekhov, Institute for Atherosclerosis Research, Russia

                *Correspondence: Gislane Lelis Vilela de Oliveira, glelisvilela@ 123456gmail.com

                Specialty section: This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2018.01689
                6068285
                30090100
                07d5e745-9400-4689-900b-f9fa827a5e11
                Copyright © 2018 Higuchi, Rodrigues, Gonzaga, Paiolo, Stefanutto, Omori, Pinheiro, Brisotti, Matheucci, Mariano and de Oliveira.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 06 April 2018
                : 10 July 2018
                Page count
                Figures: 7, Tables: 2, Equations: 0, References: 50, Pages: 12, Words: 6132
                Funding
                Funded by: Fundação de Amparo à Pesquisa do Estado de São Paulo 10.13039/501100001807
                Award ID: 2016/50204-0
                Categories
                Immunology
                Original Research

                Immunology
                type 1 diabetes,dietary habits,intestinal dysbiosis,inflammatory cytokines,interleukin-6,glycemic control

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