*5.1.2 Analytical results*

Dysbiosis is shaped by host-related individual factors and early-life exposure to certain microorganisms, and its alterations undergo extensive changes with the change in diet. The permeability of the intestinal barrier plays an important role in the initiation and evolution of autoimmune conflict, aside from the background of genetic predisposition. The intercellular tight junctions control the permeability of the epithelium, allowing the absorption of nutrients, but preventing the passage of various environmental antigens (i.e., food, bacterial, viral, and fungal). Dysbiosis decreases intestinal permeability and facilitates the translocation of bacterial antigens [52].

Microbiota derangements have been implicated in the evolution of both T1DM and T2DM [71]. Dysbiosis occurs very early in subjects with a genetic predisposition for T1DM, probably since the neonatal period [51]. It is unknown whether the genetic predisposition to T1DM shapes the microbiota of high-risk individuals or whether the microbiota is the cause or effect of the disease [71].

As stated above, the human microbiota stabilizes during the first 3 years of life, while three parallel phenomena occur—(i) development of the immune system, (ii) maturation of the microbiota, and (iii) seroconversion to T1DM-associated autoantibodies. The possible conditioning of the two (i.e., seroconversion and T1DM occurrence) events is unknown. In a longitudinal study, Kostic et al. showed a decrease in the bacterial diversity of the microbiota that occurs before the development of the clinical disease in children positive for anti-insulin antibodies [70]. The *Clostridium*, *Veillonella Bacteroides* increase in abundance, while *Lactobacillus*, *Bifidobacterium*, *Prevotella* genera decrease compared to healthy subjects, suggesting the correlation between microbiota disturbance and T1DM [18, 19]. Different authors reported other changes associated with T1DM. Increases of *Bacteroidetes* (Gram-negative) and decreases of *Prevotella* and *Firmicutes* (Gram-positive producing SCFA) observed in children with T1DM when compared to healthy subjects suggest an increased intestinal barrier permeability and decreased SCFA production [70]. The microbiota of children with T1DM is unstable and has a smaller population of butyrate-producing bacteria, which correlates with an increased barrier permeability. Healthy children have higher levels of *Lactobacillus rhamnosus* and *Bifidobacterium dentium*, while the group of *Streptococcus mitis/oralis/pneumoniae* is abundant in subjects with T1DM.

Furthermore, the microbiota changes evolve with disease progression [65].

The fungal microbiome of the human population is evaluated in 267 species, with the most commonly represented by g. *Candida*, *Saccharomyces*, *Penicillium*, and *Aspergillus*. The individual mycobiome rarely contains more than one genus, but this panel is enough to influence the entire composition of the microbiota population, either directly by interactions with bacterial cells or indirectly by immune modulation. In patients with type 1 diabetes and those with inflammatory bowel disease, there was an overgrowth of *Candida* [70].

Despite the abundance of experimental and clinical results suggesting a bidirectional relationship between dysbiosis and T1DM onset and progress, there are questions that still need an answer—(i) is their relationship causal or simultaneous? and (ii) the condition of causality is that the change of one variable leads to the change of another repeatedly and generally? [65].
