In contrast to the metabolic syndrome and T2 DM, type 1 diabetes is an autoimmune disease caused by a cellular-mediated autoimmune destruction of the β-cells of the pancreas (T cells). The destruction of the β-cells of the pancreas leads to a consequent insulin deficiency. This form of diabetes accounts for 5–10% of those with diabetes and the patients are typically younger and leaner [ 62 ].

However, with the use of insulin therapy and as a result of the global obesity “epidemic”, approximately 50% of patients with T1 DM are currently obese or overweight [ 63 ]. That said, some of the pathomechanisms related to overnutrition that have already been described may also account for some T1 DM patients. This part of the review will lay the focus on the specific “autoimmune” aspects of the disorder and the possible impact of the gut microbiota.

The observation of a rapidly rising incidence of T1 DM (and other autoimmune diseases) in the last decades is suggestive of environmental factors contributing to the disorder and cannot be explained by the identified genetic risk variants. The substantial increase of antibiotics usage in medicine and in agriculture over the past 50 years may be such a factor [ 64 ]. Other factors may be nutrition, natural birth vs. caesarean section, hygiene status etc. [ 64 ]. As stated in the previous chapters about the metabolic syndrome and T2 DM, we will initially focus on a possible altered gut microbiota composition in T1 DM. It needs to be emphasized that these findings demonstrate microbial changes and that further functional studies are needed to prove causality between these kinds of changes and β-cell autoimmunity, which will be described later.

3.1. The Role and Composition of Gut Microbiota with Special Regard of Diabetes Mellitus Type 1

lactobacillus strains also reduced diabetes in NOD mice [ Lactobacillus and Bifidobacterium in a control population of BB-DR (bio-bred diabetes resistant) rats. In murine models, associations between gut microbiome composition and type 1 diabetes or anti-islet cell autoimmunity have already been reported. The scientist’s favourite pet for the study of T1 DM is the non-obese diabetic (NOD) mouse. Their diabetes has several features comparable to human T1 DM such as immunopathogenesis, genetic susceptibility and responsiveness to environmental factors [ 65 ]. In these mouse models, it had already been demonstrated that the probiotic treatment of NOD mice prevented the onset of T1 DM [ 66 ] and a low-fat diet together withstrains also reduced diabetes in NOD mice [ 67 ]. Antibiotics are able to prevent the onset of T1 DM in rats that are prone to diabetes (BB-DP rats) [ 68 ]. Furthermore, the incidence of diabetes in NOD mice is increasing in a germ-free environment [ 69 ]. As for the microbial composition in the gut of BB-DP rats, Roesch et al. [ 70 ] reported a higher abundance ofandin a control population of BB-DR (bio-bred diabetes resistant) rats.

Bacteroidetes increased continuingly in between the three sampling points, whereas they decreased in the controls. The Firmicutes expressed an inverse pattern. Clostridiae increased in the T1 DM children, but decreased in the controls. Although the case number was low, a striking finding was the increase of the Bacteroidetes in line with the children developing autoimmune pathology. One of the first studies in humans with T1 DM was conducted by Giongo et al. [ 71 ]. The authors investigated stool samples from four Finnish children who all developed autoimmunity and T1 DM over time and four histocompatibility leukocyte antigen (HLA)-DQ and age-matched children served as controls. The samples were collected at three different points in time, the first about 120 days, the last about 600 days after birth. At the phylum level, theincreased continuingly in between the three sampling points, whereas they decreased in the controls. Theexpressed an inverse pattern.increased in the T1 DM children, but decreased in the controls. Although the case number was low, a striking finding was the increase of thein line with the children developing autoimmune pathology.

n = 18) with autoantibody-negative children matched for age, sex, early feeding history and HLA-DR risk genotype. The major finding of this analysis was that the Bacteroidetes phylum, the Bacteroidaceae family and the Bacteroides genus were more common in autoantibody-positive children than in autoantibody-negative peers. Roseburia faecis was more abundant in autoantibody-negative than autoantibody-positive children whereas Clostridium perfringens were more abundant in children with β-cell autoimmunity than in those without. The Bacteroides genus was associated with autoantibody positivity. The children with a higher number of autoantibodies had lower numbers of short-chain fatty acid producers than the control children. The authors speculate that the correlation of certain bacterial findings with the number of positive autoantibodies could indicate a role of dysbiosis as a regulator of β-cell autoimmunity in the progression of the autoimmune process towards clinical disease. De Goffau et al. [ 72 ] compared the intestinal microbiota composition in children with at least two diabetes-associated autoantibodies (= 18) with autoantibody-negative children matched for age, sex, early feeding history and HLA-DR risk genotype. The major finding of this analysis was that thephylum, thefamily and thegenus were more common in autoantibody-positive children than in autoantibody-negative peers.was more abundant in autoantibody-negative than autoantibody-positive children whereaswere more abundant in children with β-cell autoimmunity than in those without. Thegenus was associated with autoantibody positivity. The children with a higher number of autoantibodies had lower numbers of short-chain fatty acid producers than the control children. The authors speculate that the correlation of certain bacterial findings with the number of positive autoantibodies could indicate a role of dysbiosis as a regulator of β-cell autoimmunity in the progression of the autoimmune process towards clinical disease.

Endesfelder et al. [ 73 ] sought to determine whether differences are present in the early composition of the gut microbiome in children who developed anti-islet cell autoimmunity. They investigated the microbiome of 298 stool samples prospectively taken up to age 3 from 22 case children who produced anti-islet cell autoantibodies and 22 matched control children who remained islet cell autoantibody-negative in the follow-up. Contrastingly, in this much larger cohort, and after correction for multiple testing, there were no individual bacterial genera that showed significantly different abundances between anti-islet cell autoantibody-positive and anti-islet cell autoantibody-negative children. The microbiome changed markedly during the first year of life, and this was further affected by breast-feeding, food introduction, and birth delivery mode. As possible reasons for the discrepancy with the two previously reported Finnish studies, the authors discuss the differences in sample sizes, the different study design reported by de Goffau et al. [ 72 ], and/or possible geographical differences between the German and Finnish children.

In a cohort of 33 infants genetically predisposed to T1 DM, a marked drop in alpha-diversity (the Chao1 alpha-diversity is a measure of the number of distinct microbes in a community) was observed in the T1 DM progressors in the time window between seroconversion and T1 DM diagnosis, accompanied by spikes in inflammation-favouring organisms, gene functions, and serum and stool metabolites. This means that an increased amount of potentially pathogenic bacterial species was detected at that time [ 74 ].

However, in the most recent study of de Groot et al. [ 75 ], 53 T1 DM patients with a disease duration between 5–16 years (mean 9 years), were compared with 52 healthy controls. In this first observational study in subjects with long-standing T1 DM, the authors reported that the faecal analysis showed decreased butyrate-producing species in T1 DM and fewer butyryl-CoA transferase genes. Furthermore, plasma levels of acetate and propionate were lower in T1 DM, with similar faecal SCFA.

Since the composition of gut microbiota may be different in different geographical regions, different nutritional habits, etc., 15 T1 DM Chinese children (vs. 15 controls) were also examined and the authors reported an imbalance of the faecal microbiota composition, too [ 76 ].

A novel approach concerning gut microbiota composition in gut microbiota was reported by Pellegrini et al. [ 77 ]. The authors made an attempt to clarify whether changes in the gut microbiota may rather reflect a common “autoimmune milieu” (in other words, a composition of the gut microbiota predisposing for the development and/or the chronification of autoimmune diseases) or if changes are specific between different autoimmune disorders. In another novel approach, the authors did not only evaluate the inflammatory profile, and the microbiome, but also their correlation on the same duodenal biopsies of patients with T1 DM compared with healthy control subjects and patients with celiac disease (CD). The study included 19 individuals with already diagnosed T1 DM, mean age 34 years, mean diabetes duration 20 years, 16 healthy control individuals, mean age 38 years and 19 individuals with CD (untreated) diagnosed at the time of biopsy, mean age 5 years. In measuring the expression of 91 genes related to inflammation (cytokines, chemokine receptors and chemokines) in the gut mucosa, 13 genes were significantly more expressed in patients with CD compared to control subjects. Four genes were more expressed both in patients with CD and in patients with T1 DM compared to control subjects. Ten genes were significantly more expressed in patients with T1 DM but not in patients with CD compared to control subjects. As for the leucocytes infiltrating the duodenal gut mucosa, lymphocytes (CD3-positive cells) in the lamina propria were present in all the groups, their percentage was significantly higher in patients with CD compared with control subjects and patients with T1 DM. The analysis of neutrophil infiltration resulted in a low percentage of positive cells in all biopsies without any significant difference among the three groups.

The composition of bacterial populations was measured using ultra-deep pyrosequencing. The mean bacterial diversity, as estimated by the Chao1 index from the equalized data sets, was not different among the groups, although significant differences in the phyla distribution were observed. The patients with T1 DM showed a reduction in the percentage of Proteobacteria and an increase in Firmicutes. The phylum of Bacteroidetes showed a trend to reduction in patients with T1 DM and patients with CD compared with control subjects. Also, the ratio of Firmicutes / Bacteroidetes was significantly increased in T1 DM and the CD group. In conclusion, the authors report that the duodenal mucosa in T1 DM shows a peculiar signature of inflammation and a specific microbiome composition. Furthermore, the authors discovered an association between some analysed inflammatory markers and specific taxa. The findings in comparison with the CD group suggest that some changes are specific between different autoimmune disorders.

Summarizing, the results of studies addressing the gut microbiota composition in T1 DM are sometimes conflicting with a trend towards altered composition. The meaning of this and possible autoimmune pathomechanisms are addressed in the following chapter: