ObjectiveType 1 diabetes (T1D) is characterised by islet autoimmunity and beta cell destruction. A gut microbiota–immunological interplay is involved in the pathophysiology of T1D. We studied microbiota-mediated effects on disease progression in patients with type 1 diabetes using faecal microbiota transplantation (FMT).DesignPatients with recent-onset (<6 weeks) T1D (18–30 years of age) were randomised into two groups to receive three autologous or allogenic (healthy donor) FMTs over a period of 4 months. Our primary endpoint was preservation of stimulated C peptide release assessed by mixed-meal tests during 12 months. Secondary outcome parameters were changes in glycaemic control, fasting plasma metabolites, T cell autoimmunity, small intestinal gene expression profile and intestinal microbiota composition.ResultsStimulated C peptide levels were significantly preserved in the autologous FMT group (n=10 subjects) compared with healthy donor FMT group (n=10 subjects) at 12 months. Small intestinal Prevotella was inversely related to residual beta cell function (r=−0.55, p=0.02), whereas plasma metabolites 1-arachidonoyl-GPC and 1-myristoyl-2-arachidonoyl-GPC levels linearly correlated with residual beta cell preservation (rho=0.56, p=0.01 and rho=0.46, p=0.042, respectively). Finally, baseline CD4 +CXCR3+T cell counts, levels of small intestinal Desulfovibrio piger and CCL22 and CCL5 gene expression in duodenal biopsies predicted preserved beta cell function following FMT irrespective of donor characteristics.ConclusionFMT halts decline in endogenous insulin production in recently diagnosed patients with T1D in 12 months after disease onset. Several microbiota-derived plasma metabolites and bacterial strains were linked to preserved residual beta cell function. This study provides insight into the role of the intestinal gut microbiome in T1D.Trial registration numberNTR3697.

This study shows that duodenal mucosa in T1D presents disease-specific abnormalities in the inflammatory profile and microbiota. Understanding the mechanisms underlying these features is critical to disentangle the complex pathogenesis of T1D and to gain new perspectives for future therapies targeting the intestine.

Chemokines and their receptors have been associated with or implicated in the pathogenesis of type 1 diabetes (T1D), but the identification of a single specific chemokine/receptor pathway that may constitute a suitable target for the development of therapeutic interventions is still lacking. Here, we used multiple low-dose (MLD) streptozotocin (STZ) injections and the NOD mouse model to investigate the potency of CXCR1/2 inhibition to prevent inflammation- and autoimmunity-mediated damage of pancreatic islets. Reparixin and ladarixin, noncompetitive allosteric inhibitors, were used to pharmacologically blockade CXCR1/2. Transient blockade of said receptors was effective in preventing inflammation-mediated damage in MLD-STZ and in preventing and reversing diabetes in NOD mice. Blockade of CXCR1/2 was associated with inhibition of insulitis and modification of leukocytes distribution in blood, spleen, bone marrow, and lymph nodes. Among leukocytes, CXCR2+ myeloid cells were the most decreased subpopulations. Together these results identify CXCR1/2 chemokine receptors as “master regulators” of diabetes pathogenesis. The demonstration that this strategy may be successful in preserving residual β-cells holds the potential to make a significant change in the approach to management of human T1D.

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In patients with type 1 diabetes (T1D), pancreatic β cells are destroyed by a selective autoimmune attack and their replacement with functional insulin-producing cells is the only possible cure for this disease. The field of islet transplantation has evolved significantly from the breakthrough of the Edmonton Protocol in 2000, since significant advances in islet isolation and engraftment, together with improved immunosuppressive strategies, have been reported. The main limitations, however, remain the insufficient supply of human tissue and the need for lifelong immunosuppression therapy. Great effort is then invested in finding innovative sources of insulin-producing β cells. One old alternative with new recent perspectives is the use of non-human donor cells, in particular porcine β cells. Also the field of preexisting β cell expansion has advanced, with the development of new human β cell lines. Yet, large-scale production of human insulin-producing cells from stem cells is the most recent and promising alternative. In particular, the optimization of in vitro strategies to differentiate human embryonic stem cells into mature insulin-secreting β cells has made considerable progress and recently led to the first clinical trial of stem cell treatment for T1D. Finally, the discovery that it is possible to derive human induced pluripotent stem cells from somatic cells has raised the possibility that a sufficient amount of patient-specific β cells can be derived from patients through cell reprogramming and differentiation, suggesting that in the future there might be a cell therapy without immunosuppression.

We detected a specific hiPSCs microRNAs signature during differentiation into insulin-producing cells and demonstrated that differentially expressed microRNAs target several genes involved in pancreas organogenesis.

In patients with PER rhinitis and intermittent asthma, MFNS improves the QoL and the burden of respiratory symptoms. Treating rhinitis may affect the asthma-related QoL.

These data overall suggest that human iPSCs have the potential to generate insulin-producing cells and that these differentiated cells can engraft and secrete insulin in vivo.