Two putative glutamate decarboxylases of Streptococcus pneumoniae as possible antigens for the production of anti-GAD65 antibodies leading to type 1 diabetes mellitus / Dos supuestas glutamato descarboxilasas de Streptococcus pneumoniae como posibles antígenos para la producción de anticuerpos anti-GAD65 que conducen a la diabetes mellitus tipo 1

Type 1 diabetes mellitus (T1DM) has been increasing in prevalence in the last decades and has become a global burden. Autoantibodies against human glutamate decarboxylase (GAD65) are among the first to be detected at the onset of T1DM. Diverse viruses have been proposed to be involved in the triggering of T1DM because of molecular mimicry, i.e., similarity between parts of some viral proteins and one or more epitopes of GAD65. However, the possibility that bacterial proteins might also be responsible for GAD65 mimicry has been seldom investigated. To date, many genomes of Streptococcus pneumoniae (the pneumococcus), a prominent human pathogen particularly prevalent among children and the elderly, have been sequenced. A dataset of more than 9000 pneumococcal genomes was mined and two different (albeit related) genes (gadA and gadB), presumably encoding two glutamate decarboxylases similar to GAD65, were found. The various gadASpn alleles were present only in serotype 3 pneumococci belonging to the global lineage GPSC83, although some homologs have also been discovered in two subspecies of Streptococcus constellatus (pharyngis and viborgensis), an isolate of the group B streptococci, and several strains of Lactobacillus delbrueckii. Besides, gadBSpn alleles are present in > 10% of the isolates in our dataset and represent 16 GPSCs with 123 sequence types and 20 different serotypes. Sequence analyses indicated that gadA- and gadB-like genes have been mobilized among different bacteria either by prophage(s) or by integrative and conjugative element(s), respectively. Substantial similarities appear to exist between the putative pneumococcal glutamate decarboxylases and well-known epitopes of GAD65. In this sense, the use of broader pneumococcal conjugate vaccines such as PCV20 would prevent the majority of serotypes expressing those genes that might potentially contribute to T1DM.(AU)

Paeoniflorin protects NOD mice from T1D through regulating gut microbiota and TLR4 mediated myD88/TRIF pathway.

This study aimed to explore the effect of PF in regulating the progression of T1D through regulating gut microbiota and inhibiting TLR4-myD88/TRIF pathway. T1D mouse models were established and received PF treatment through intraperitoneal injection. The glucose, sugar tolerance, the incidence of T1D and H&E staining were detected to verify the effect of PF on T1D. Meanwhile, the changes of gut microbiota and the permeability of intestines in mice were also measured. On parallel, the number and function of immune cells were detected by Flow Cytometry. The expressions of ZO-1, ZO-2 and TLR4-myD88/TRIF pathway related proteins were detected by western blotting. Mice received PF treatment had decreased incidence of T1D and inflammatory infiltration in islet tissues compared with those received PBS treatment. In addition to that, PF treated mice had increased Sutterella species and decreased intestinal permeability, in which the decreased ratio of Th1/Th17 and increased Treg cells were also identified. The expression of TLR4-myD88/TRIF pathway was also suppressed in response to PF treatment. Moreover, further treatment with TLR4 agonist, LPS, could reverse the effect of PF on T1D mice. PF can suppress the TLR4 mediated myD88/TRIF pathway to change the distribution of gut microbiota, so as to protect NOD mice from T1D.

Alterations of oral microbiota and impact on the gut microbiome in type 1 diabetes mellitus revealed by integrated multi-omic analyses.

BACKGROUND: Alterations to the gut microbiome have been linked to multiple chronic diseases. However, the drivers of such changes remain largely unknown. The oral cavity acts as a major route of exposure to exogenous factors including pathogens, and processes therein may affect the communities in the subsequent compartments of the gastrointestinal tract. Here, we perform strain-resolved, integrated meta-genomic, transcriptomic, and proteomic analyses of paired saliva and stool samples collected from 35 individuals from eight families with multiple cases of type 1 diabetes mellitus (T1DM). RESULTS: We identified distinct oral microbiota mostly reflecting competition between streptococcal species. More specifically, we found a decreased abundance of the commensal Streptococcus salivarius in the oral cavity of T1DM individuals, which is linked to its apparent competition with the pathobiont Streptococcus mutans. The decrease in S. salivarius in the oral cavity was also associated with its decrease in the gut as well as higher abundances in facultative anaerobes including Enterobacteria. In addition, we found evidence of gut inflammation in T1DM as reflected in the expression profiles of the Enterobacteria as well as in the human gut proteome. Finally, we were able to follow transmitted strain-variants from the oral cavity to the gut at the individual omic levels, highlighting not only the transfer, but also the activity of the transmitted taxa along the gastrointestinal tract. CONCLUSIONS: Alterations of the oral microbiome in the context of T1DM impact the microbial communities in the lower gut, in particular through the reduction of "mouth-to-gut" transfer of Streptococcus salivarius. Our results indicate that the observed oral-cavity-driven gut microbiome changes may contribute towards the inflammatory processes involved in T1DM. Through the integration of multi-omic analyses, we resolve strain-variant "mouth-to-gut" transfer in a disease context. Video Abstract.

Systematically assessing microbiome-disease associations identifies drivers of inconsistency in metagenomic research.

Evaluating the relationship between the human gut microbiome and disease requires computing reliable statistical associations. Here, using millions of different association modeling strategies, we evaluated the consistency-or robustness-of microbiome-based disease indicators for 6 prevalent and well-studied phenotypes (across 15 public cohorts and 2,343 individuals). We were able to discriminate between analytically robust versus nonrobust results. In many cases, different models yielded contradictory associations for the same taxon-disease pairing, some showing positive correlations and others negative. When querying a subset of 581 microbe-disease associations that have been previously reported in the literature, 1 out of 3 taxa demonstrated substantial inconsistency in association sign. Notably, >90% of published findings for type 1 diabetes (T1D) and type 2 diabetes (T2D) were particularly nonrobust in this regard. We additionally quantified how potential confounders-sequencing depth, glucose levels, cholesterol, and body mass index, for example-influenced associations, analyzing how these variables affect the ostensible correlation between Faecalibacterium prausnitzii abundance and a healthy gut. Overall, we propose our approach as a method to maximize confidence when prioritizing findings that emerge from microbiome association studies.

Similarities between bacterial GAD and human GAD65: Implications in gut mediated autoimmune type 1 diabetes.

A variety of islet autoantibodies (AAbs) can predict and possibly dictate eventual type 1 diabetes (T1D) diagnosis. Upwards of 75% of those with T1D are positive for AAbs against glutamic acid decarboxylase (GAD65 or GAD), a producer of gamma-aminobutyric acid (GABA) in human pancreatic beta cells. Interestingly, bacterial populations within the human gut also express GAD and produce GABA. Evidence suggests that dysbiosis of the microbiome may correlate with T1D pathogenesis and physiology. Therefore, autoimmune linkages between the gut microbiome and islets susceptible to autoimmune attack need to be further elucidated. Utilizing in silico analyses, we show that 25 GAD sequences from human gut bacterial sources show sequence and motif similarities to human beta cell GAD65. Our motif analyses determined that most gut GAD sequences contain the pyroxical dependent decarboxylase (PDD) domain of human GAD65, which is important for its enzymatic activity. Additionally, we showed overlap with known human GAD65 T cell receptor epitopes, which may implicate the immune destruction of beta cells. Thus, we propose a physiological hypothesis in which changes in the gut microbiome in those with T1D result in a release of bacterial GAD, thus causing miseducation of the host immune system. Due to the notable similarities we found between human and bacterial GAD, these deputized immune cells may then target human beta cells leading to the development of T1D.

Microbial Signatures in The Rodent Eyes With Retinal Dysfunction and Diabetic Retinopathy.

Purpose: The gut microbiome has been linked to disease pathogenesis through their interaction in metabolic, endocrine, and immune functions. The goal of this study was to determine whether the gut and plasma microbiota could transfer microbes to the retina in type 1 diabetic mice with retinopathy. Methods: We analyzed the fecal, plasma, whole globe, and retina microbiome in Akita mice and compared with age-matched wild-type (WT) mice using 16S rRNA sequencing and metatranscriptomic analysis. To eliminate the contribution of the ocular surface and plasma microbiome, mice were perfused with sterile saline solution, the whole globes were extracted, and the neural retina was removed under sterile conditions for retinal microbiome. Results: Our microbiome analysis revealed that Akita mice demonstrated a distinct pattern of microbes within each source: feces, plasma, whole globes, and retina. WT mice and Akita mice experienced transient bacteremia in the plasma and retina. Bacteria were identified in the retina of the Akita mice, specifically Corynebacterium, Pseudomonas, Lactobacillus, Staphylococcus, Enterococcus, and Bacillus. Significantly increased levels of peptidoglycan (0.036 ± 0.001 vs. 0.023 ± 0.002; P < 0.002) and TLR2 (3.47 ± 0.15 vs. 1.99 ± 0.07; P < 0.0001) were observed in the retina of Akita mice compared to WT. Increased IBA+ cells in the retina, reduced a- and b-waves on electroretinography, and increased acellular capillary formation demonstrated the presence of retinopathy in the Akita cohort compared to WT mice. Conclusions: Together, our findings suggest that transient bacteremia exists in the plasma and retina of both cohorts. The bacteria found in Akita mice are distinct from WT mice and may contribute to development of retinal inflammation and barrier dysfunction in retinopathy.

The Role of the Gut Microbiota in the Pathogenesis of Diabetes.

Diabetes mellitus is a significant clinical and therapeutic problem because it can lead to serious long-term complications. Its pathogenesis is not fully understood, but there are indications that dysbiosis can play a role in the development of diabetes, or that it appears during the course of the disease. Changes in microbiota composition are observed in both type 1 diabetes (T1D) and type 2 diabetes (T2D) patients. These modifications are associated with pro-inflammation, increased intestinal permeability, endotoxemia, impaired ß-cell function and development of insulin resistance. This review summarizes the role of the gut microbiota in healthy individuals and the changes in bacterial composition that can be associated with T1D or T2D. It also presents new developments in diabetes therapy based on influencing the gut microbiota as a promising method to alter the course of diabetes. Moreover, it highlights the lacking data and suggests future directions needed to prove the causal relationship between dysbiosis and diabetes, both T1D and T2D.

Administration of Human Derived Upper gut Commensal Prevotella histicola delays the onset of type 1 diabetes in NOD mice.

BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease that is increasing in prevalence worldwide. One of the contributing factors to the pathogenesis of T1D is the composition of the intestinal microbiota, as has been demonstrated. in T1D patients, with some studies demonstrating a deficiency in their levels of Prevotella. We have isolated a strain of Prevotella histicola from a duodenal biopsy that has anti-inflammatory properties, and in addition, alters the development of autoimmune diseases in mouse models. Therefore, our hypothesis is that the oral administration of P. histicola might delay the development of T1D in the non-obese diabetic (NOD) mice. To assess this, we used the following materials and methods. Female NOD mice (ages 5-8 weeks) were administered every other day P. histicola that was cultured in-house. Blood glucose levels were measured every other week. Mice were sacrificed at various time points for histopathological analysis of the pancreas. Modulation of immune response by the commensal was tested by analyzing regulatory T-cells and NKp46+ cells using flow cytometry and intestinal cytokine mRNA transcript levels using quantitative RT-PCR. For microbial composition, 16 s rRNA gene analysis was conducted on stool samples collected at various time points. RESULTS: Administration of P. histicola in NOD mice delayed the onset of T1D. Beta diversity in the fecal microbiomes demonstrated that the microbial composition of the mice administered P. histicola was different from those that were not treated. Treatment with P. histicola led to a significant increase in regulatory T cells with a concomitant decrease in NKp46+ cells in the pancreatic lymph nodes as compared to the untreated group after 5 weeks of treatment. CONCLUSIONS: These observations suggest that P. histicola treatment delayed onset of diabetes by increasing the levels of regulatory T cells in the pancreatic lymph nodes. This preliminary work supports the rationale that enteral exposure to a non pathogenic commensal P. histicola be tested as a future therapy for T1D.

The Gut Microbiome of Adults With Type 1 Diabetes and Its Association With the Host Glycemic Control.

OBJECTIVE: Previous studies have demonstrated an association between gut microbiota composition and type 1 diabetes (T1D) pathogenesis. However, little is known about the composition and function of the gut microbiome in adults with longstanding T1D or its association with host glycemic control. RESEARCH DESIGN AND METHODS: We performed a metagenomic analysis of the gut microbiome obtained from fecal samples of 74 adults with T1D, 14.6 ± 9.6 years following diagnosis, and compared their microbial composition and function to 296 age-matched healthy control subjects (1:4 ratio). We further analyzed the association between microbial taxa and indices of glycemic control derived from continuous glucose monitoring measurements and blood tests and constructed a prediction model that solely takes microbiome features as input to evaluate the discriminative power of microbial composition for distinguishing individuals with T1D from control subjects. RESULTS: Adults with T1D had a distinct microbial signature that separated them from control subjects when using prediction algorithms on held-out subjects (area under the receiver operating characteristic curve = 0.89 ± 0.03). Linear discriminant analysis showed several bacterial species with significantly higher scores in T1D, including Prevotella copri and Eubacterium siraeum, and species with higher scores in control subjects, including Firmicutes bacterium and Faecalibacterium prausnitzii (P < 0.05, false discovery rate corrected for all). On the functional level, several metabolic pathways were significantly lower in adults with T1D. Several bacterial taxa and metabolic pathways were associated with the host's glycemic control. CONCLUSIONS: We identified a distinct gut microbial signature in adults with longstanding T1D and associations between microbial taxa, metabolic pathways, and glycemic control indices. Additional mechanistic studies are needed to identify the role of these bacteria for potential therapeutic strategies.

Gut mucosa alterations and loss of segmented filamentous bacteria in type 1 diabetes are associated with inflammation rather than hyperglycaemia.

OBJECTIVE: Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of pancreatic ß-cells producing insulin. Both T1D patients and animal models exhibit gut microbiota and mucosa alterations, although the exact cause for these remains poorly understood. We investigated the production of key cytokines controlling gut integrity, the abundance of segmented filamentous bacteria (SFB) involved in the production of these cytokines, and the respective role of autoimmune inflammation and hyperglycaemia. DESIGN: We used several mouse models of autoimmune T1D as well as mice rendered hyperglycaemic without inflammation to study gut mucosa and microbiota dysbiosis. We analysed cytokine expression in immune cells, epithelial cell function, SFB abundance and microbiota composition by 16S sequencing. We assessed the role of anti-tumour necrosis factor α on gut mucosa inflammation and T1D onset. RESULTS: We show in models of autoimmune T1D a conserved loss of interleukin (IL)-17A, IL-22 and IL-23A in gut mucosa. Intestinal epithelial cell function was altered and gut integrity was impaired. These defects were associated with dysbiosis including progressive loss of SFB. Transfer of diabetogenic T-cells recapitulated these gut alterations, whereas induction of hyperglycaemia with no inflammation failed to do so. Moreover, anti-inflammatory treatment restored gut mucosa and immune cell function and dampened diabetes incidence. CONCLUSION: Our results demonstrate that gut mucosa alterations and dysbiosis in T1D are primarily linked to inflammation rather than hyperglycaemia. Anti-inflammatory treatment preserves gut homeostasis and protective commensal flora reducing T1D incidence.

Microbiology of periodontal disease in adolescents with Type 1 diabetes.

BACKGROUND AND AIMS: Diabetes and periodontal disease are chronic disorders with complex interplay. Periodontal microbiota may play a major role in the development of periodontal disease (PD). The study was framed to identify oral microorganisms and assess oral biofilm in children & adolescents with T1DM and PD. METHODS: In this cross-sectional study we recruited a total of 60 subjects aged 10-18 years (in 3 groups of 20 each). Group 1: Diabetes with periodontal disease (DMPD), Group 2: Diabetes without periodontal disease (DM), Group 3: Periodontal disease without Diabetes (PD).Gingival plaque samples were collected and processed for culture based microbial identification and biofilm assay. RESULTS: The microbial diversity in the DMPD group was higher. Staphylococcus warneri was the only organism specifically isolated from DMPD group. Staphylococcus vitulinus, Streptococcus sanguinis, Pseudomonas aeruginosa, was commonly isolated from both DMPD and PD group especially higher incidence in DMPD group (P ≤ 0.001).There was a strong positive correlation between poor glycaemic control and biofilm formation in both Groups 1 & 2 (DMPD and DM) patients (Spearman's Rho: 0.868, P < 0.001). CONCLUSION: Children & adolescents with T1DM with worse glycaemic control, associated with higher abundance of biofilm formation and greater microbial diversity, especially in those with T1DM with PD.

Virus Infection Is an Instigator of Intestinal Dysbiosis Leading to Type 1 Diabetes.

In addition to genetic predisposition, environmental determinants contribute to a complex etiology leading to onset of type 1 diabetes (T1D). Multiple studies have established the gut as an important site for immune modulation that can directly impact development of autoreactive cell populations against pancreatic self-antigens. Significant efforts have been made to unravel how changes in the microbiome function as a contributor to autoimmune responses and can serve as a biomarker for diabetes development. Large-scale longitudinal studies reveal that common environmental exposures precede diabetes pathology. Virus infections, particularly those associated with the gut, have been prominently identified as risk factors for T1D development. Evidence suggests recent-onset T1D patients experience pre-existing subclinical enteropathy and dysbiosis leading up to development of diabetes. The start of these dysbiotic events coincide with detection of virus infections. Thus viral infection may be a contributing driver for microbiome dysbiosis and disruption of intestinal homeostasis prior to T1D onset. Ultimately, understanding the cross-talk between viral infection, the microbiome, and the immune system is key for the development of preventative measures against T1D.

Type 1 diabetes in pregnancy is associated with distinct changes in the composition and function of the gut microbiome.

BACKGROUND: The gut microbiome changes in response to a range of environmental conditions, life events and disease states. Pregnancy is a natural life event that involves major physiological adaptation yet studies of the microbiome in pregnancy are limited and their findings inconsistent. Pregnancy with type 1 diabetes (T1D) is associated with increased maternal and fetal risks but the gut microbiome in this context has not been characterized. By whole metagenome sequencing (WMS), we defined the taxonomic composition and function of the gut bacterial microbiome across 70 pregnancies, 36 in women with T1D. RESULTS: Women with and without T1D exhibited compositional and functional changes in the gut microbiome across pregnancy. Profiles in women with T1D were distinct, with an increase in bacteria that produce lipopolysaccharides and a decrease in those that produce short-chain fatty acids, especially in the third trimester. In addition, women with T1D had elevated concentrations of fecal calprotectin, a marker of intestinal inflammation, and serum intestinal fatty acid-binding protein (I-FABP), a marker of intestinal epithelial damage. CONCLUSIONS: Women with T1D exhibit a shift towards a more pro-inflammatory gut microbiome during pregnancy, associated with evidence of intestinal inflammation. These changes could contribute to the increased risk of pregnancy complications in women with T1D and are potentially modifiable by dietary means. Video abstract.

Controls of Hyperglycemia Improves Dysregulated Microbiota in Diabetic Mice.

BACKGROUND: Type 1 diabetes (T1DM) is a chronic autoimmune disease characterized by T-cell-mediated destruction of insulin-producing beta cells. Evidence shows that patients with T1DM and mice used in specific diabetic models both exhibit changes in their intestinal microbiota and dysregulated microbiota contributes to the pathogenesis of T1DM. Islet transplantation (Tx) is poised to play an important role in the treatment of T1DM. However, whether treatment of T1DM with islet Tx can rescue dysregulated microbiota remains unclear. METHODS: In this study, we induced diabetic C57BL/6 mice with streptozotocin. Then treatment with either insulin administration, or homogenic or allogenic islet Tx was performed to the diabetic mice. Total DNA was isolated from fecal pellets and high-throughput 16S rRNA sequencing was used to investigate intestinal microbiota composition. RESULTS: The overall microbial diversity was comparable between control (nonstreptozotocin treated) and diabetic mice. Our results showed the ratio of the Bacteroidetes: Firmicutes between nondiabetic and diabetic mice was significant different. Treatment with islet Tx or insulin partially corrects the dysregulated bacterial composition. At the genus level, Bacteroides, Odoribacter, and Alistipes were associated with the progression and treatment efficacy of the disease, which may be used as a biomarker to predict curative effect of treatment for patients with T1DM. CONCLUSIONS: Collectively, our results indicate that diabetic mice show changed microbiota composition and that treatment with insulin and islet Tx can partially correct the dysregulated microbiota.

IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice.

Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of insulin-producing ß cells. BDC2.5 T cells in BDC2.5 CD4+ T cell receptor transgenic Non-Obese Diabetic (NOD) mice (BDC2.5+ NOD mice) can abruptly invade the pancreatic islets resulting in severe insulitis that progresses rapidly but rarely leads to spontaneous diabetes. This prevention of diabetes is mediated by T regulatory (Treg) cells in these mice. In this study, we investigated the role of interleukin 10 (IL-10) in the inhibition of diabetes in BDC2.5+ NOD mice by generating Il-10-deficient BDC2.5+ NOD mice (BDC2.5+Il-10-/- NOD mice). Our results showed that BDC2.5+Il-10-/- NOD mice displayed robust and accelerated diabetes development. Il-10 deficiency in BDC2.5+ NOD mice promoted the generation of neutrophils in the bone marrow and increased the proportions of neutrophils in the periphery (blood, spleen, and islets), accompanied by altered intestinal immunity and gut microbiota composition. In vitro studies showed that the gut microbiota from BDC2.5+Il-10-/- NOD mice can expand neutrophil populations. Moreover, in vivo studies demonstrated that the depletion of endogenous gut microbiota by antibiotic treatment decreased the proportion of neutrophils. Although Il-10 deficiency in BDC2.5+ NOD mice had no obvious effects on the proportion and function of Treg cells, it affected the immune response and activation of CD4+ T cells. Moreover, the pathogenicity of CD4+ T cells was much increased, and this significantly accelerated the development of diabetes when these CD4+ T cells were transferred into immune-deficient NOD mice. Our study provides novel insights into the role of IL-10 in the modulation of neutrophils and CD4+ T cells in BDC2.5+ NOD mice, and suggests important crosstalk between gut microbiota and neutrophils in type 1 diabetes development.

Alcohol as friend or foe in autoimmune diseases: a role for gut microbiome?

Alcohol is well known for promoting systemic inflammation and aggravating multiple chronic health conditions. Thus, alcohol may also be expected to serve as a risk factor in autoimmune diseases. However, emerging data from human and animal studies suggest that alcohol may in fact be protective in autoimmune diseases. These studies point toward alcohol's complex dose-dependent relationship in autoimmune diseases as well as potential modulation by duration and type of alcohol consumption, cultural background and sex. In this review, we will explore alcohol's pro- and anti-inflammatory properties in human and animal autoimmune diseases, including autoimmune diabetes, thyroid disease, systemic lupus erythematosus, rheumatoid arthritis, experimental autoimmune encephalomyelitis and multiple sclerosis. We will also discuss potential mechanisms of alcohol's anti-inflammatory effects mediated by the gut microbiome.

Impact of type 1 diabetes on the composition and functional potential of gut microbiome in children and adolescents: possible mechanisms, current knowledge, and challenges.

Diabetes prevalence and incidence among youth have been increasing globally. Type 1 Diabetes (T1D) in children or adolescents accounts for 5-10% of all diagnosed cases of diabetes. Emerging evidence indicates that genetic factors, especially genes in the human leukocyte antigen region, are not the only factors involved in the predisposition of an individual to T1D. The pathogenesis and development of T1D is driven by both genetic predisposition and environmental factors. Studies indicate that gut microbiota is one of the potential environmental influencers involved in the pathophysiology of TID. Gut microbiota mediates the development of diabetes by altering intestinal permeability, modifying intestinal immunity, and molecular mimicry. The gut microbial diversity, taxonomic profile, and functional potential of gut microbes are significantly altered in individuals with T1D as compared to healthy individuals. However, studies are still needed to identify the specific microbes and microbial metabolites that are involved in the development and pathogenesis of T1D. This will help the development of microbiome-based therapeutic strategies for the prevention and treatment of T1D. The present review article highlights the following: (i) the current knowledge and knowledge gaps in understanding the association between T1D and gut microbiome specifically focusing on the composition and functional potential of gut microbiome in children and adolescents, (ii) the possible mechanisms involved in gut microbiome-mediated T1D pathogenesis, and (iii) challenges and future direction in this field.Abbreviations: B/F ratio: Bacteroidetes to Firmicutes ratio; F/B ratio: Firmicutes to Bacteroidetes ratio; FDR: First-degree relatives; GPR: G protein-coupled receptors; HLA: human leucocyte antigen; IL: interleukin; IFN- γ: interferon-γ; KEGG: Kyoto Encyclopedia of Genes and Genomes; LPS: lipopolysaccharide; mTOR: mammalian target of rapamycin; PICRUSt: Phylogenetic Investigation of Communities by Reconstruction of Unobserved States; SCFA: short chain fatty acids; T1D: Type 1 diabetes; T2D: Type 2 diabetes; TJ: tight junction; Tregs: regulatory T cells.

Intestinal Microbiota in Common Chronic Inflammatory Disorders Affecting Children.

The incidence and prevalence rate of chronic inflammatory disorders is on the rise in the pediatric population. Recent research indicates the crucial role of interactions between the altered intestinal microbiome and the immune system in the pathogenesis of several chronic inflammatory disorders in children, such as inflammatory bowel disease (IBD) and autoimmune diseases, such as type 1 diabetes mellitus (T1DM) and celiac disease (CeD). Here, we review recent knowledge concerning the pathogenic mechanisms underlying these disorders, and summarize the facts suggesting that the initiation and progression of IBD, T1DM, and CeD can be partially attributed to disturbances in the patterns of composition and abundance of the gut microbiota. The standard available therapies for chronic inflammatory disorders in children largely aim to treat symptoms. Although constant efforts are being made to maximize the quality of life for children in the long-term, sustained improvements are still difficult to achieve. Additional challenges are the changing physiology associated with growth and development of children, a population that is particularly susceptible to medication-related adverse effects. In this review, we explore new promising therapeutic approaches aimed at modulation of either gut microbiota or the activity of the immune system to induce a long-lasting remission of chronic inflammatory disorders. Recent preclinical studies and clinical trials have evaluated new approaches, for instance the adoptive transfer of immune cells, with genetically engineered regulatory T cells expressing antigen-specific chimeric antigen receptors. These approaches have revolutionized cancer treatments and have the potential for the protection of high-risk children from developing autoimmune diseases and effective management of inflammatory disorders. The review also focuses on the findings of studies that indicate that the responses to a variety of immunotherapies can be enhanced by strategic manipulation of gut microbiota, thus emphasizing on the importance of proper interaction between the gut microbiota and immune system for sustained health benefits and improvement of the quality of life of pediatric patients.

Inflammasomes and Type 1 Diabetes.

Microbiota have been identified as an important modulator of susceptibility in the development of Type 1 diabetes in both animal models and humans. Collectively these studies highlight the association of the microbiota composition with genetic risk, islet autoantibody development and modulation of the immune responses. However, the signaling pathways involved in mediating these changes are less well investigated, particularly in humans. Importantly, understanding the activation of signaling pathways in response to microbial stimulation is vital to enable further development of immunotherapeutics, which may enable enhanced tolerance to the microbiota or prevent the initiation of the autoimmune process. One such signaling pathway that has been poorly studied in the context of Type 1 diabetes is the role of the inflammasomes, which are multiprotein complexes that can initiate immune responses following detection of their microbial ligands. In this review, we discuss the roles of the inflammasomes in modulating Type 1 diabetes susceptibility, from genetic associations to the priming and activation of the inflammasomes. In addition, we also summarize the available inhibitors for therapeutically targeting the inflammasomes, which may be of future use in Type 1 diabetes.

Bifidobacterium reduction is associated with high blood pressure in children with type 1 diabetes mellitus.

Children with Type 1 diabetes mellitus (T1DM) have an elevated risk of abnormal blood pressure (BP) measurements and patterns. Both hypertension and T1DM are well-known risk factors for cardiovascular disease and kidney failure. The human microbiome has been linked to both diabetes and hypertension, but the relationship between the gut microbiome and BP in children with T1DM is not well-understood. In this cross-sectional study, we examined the relationship between resting office BP and gut microbiota composition, diversity, and richness in children with T1DM and healthy controls. We recruited 29 pediatric subjects and divided them into three groups: healthy controls (HC, n = 5), T1DM with normal BP (T1DM-Normo, n = 17), and T1DM with elevated BP (T1DM-HBP, n = 7). We measured the BP, dietary and clinical parameters for each subject. We collected fecal samples to perform the 16s rDNA sequencing and to measure the short-chain fatty acids (SCFAs) level. The microbiome downstream analysis included the relative abundance of microbiota, alpha and beta diversity, microbial markers using Linear Discriminant effect size analysis (LEfSe), potential gut microbial metabolic pathways using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) and metabolic pathways validation using Statistical Inference of Associations between Microbial Communities And host phenotype (SIAMCAT) machine learning toolbox. Our study results showed that T1DM-HBP group had distinct gut microbial composition (at multiple taxonomic levels) and reduced diversity (richness and abundance) compared with T1DM-Normo and HC groups. Children with T1DM-HBP showed a significant reduction of Bifidobacterium levels (especially B. adolescentis, B. bifidum, and B. longum) compared to the T1DM-Normo group. We also observed unique gut-microbial metabolic pathways, such as elevated lipopolysaccharide synthesis and glutathione metabolism in children with T1DM-HBP compared to T1DM-Normo children. We can conclude that the reduction in the abundance of genus Bifidobacterium could play a significant role in elevating the BP in pediatric T1DM subjects. More studies are needed to corroborate our findings and further explore the potential contributing mechanisms we describe.