**3. The immunity-diet-microbiota interplay in type 1 diabetes**

The microbiota modulates the immune response of the host even before birth as suggested by the fact that the intrauterine environment is not completely sterile. Indeed, there is evidence that the placenta harbours a low-abundance commensal microbiota similar to the oral microbiota [22]. Thus, the foetus is exposed to antigens against which it has to develop immunological tolerance. Following birth, diet represents the crucial factor guiding microbiota composition as well as immunity. Dietary antigens correlated with T1D are modulated by feeding regimens (breast milk vs infant formula) and the introduction of solid foods (particularly of wheat). While infant formula has been historically associated with T1D, breast milk has beneficial immunomodulatory effects in the neonatal gut. Within this line of thought, studies in mice showed that sIgA transferred passively in breast milk promotes gut homeostasis and prevents bacterial translocation [23].

Studies in Finnish and American children revealed that fat and protein intake from milk products promote a risk of advanced β-cell autoimmunity and consequently progression to T1D [24]. Patients with T1D and latent autoimmune diabetes of adults were shown to have elevated titres of anti-β-casein antibodies. Several bovine β-casein variants have a Pro-Gly-Pro-Ile-Pro motif in their sequence, which is also present in the glucose transporter GLUT2. Hence, a plausible explanation for pancreatic damage is a cross reactivity of the immune system initially targeted against the dietary antigen in milk.

T1D is similar in terms of its genetic HLA-associated risk with celiac disease and T1D children have an altered T-cell reactivity against wheat antigens in the gut [25]. Consequently, diets high in gluten are considered an important culprit for microbiota changes and T1D development [26]. Thus, introduction of gluten-containing foods between 3 and 7 months of age can significantly decrease the risk of T1D autoimmunity [27].

*johnsonii N6.2* delayed diabetes development via regulation of gut integrity, specifically by

The Intricate Relationship between Diabetes, Diet and the Gut Microbiota

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MyD88 is an adapter protein downstream of multiple toll-like receptors involved in sensing of microorganisms. The knock out of this protein in the NOD mouse was shown to protect against diabetes. Importantly, heterozygous MyD88KO/+ NOD mice, which normally develop disease, are protected from diabetes when colonized from birth with the intestinal microbiota of a MyD88-KO NOD donor mouse [36]. Thus, disease progression in the NOD mouse is partially determined by an exacerbated innate immune response to commensal microbiota, and changes in the composition of the microbiota may diminish this response and counteract disease.

Considerable effort has been made in the last years in order to provide more information regarding the composition of the diabetogenic microbiota in humans. As expected, the pattern of bacterial abundance is distinct between different studies due to variations caused by ethnicity, geography and age. Despite these variations, all studies have shown *Bacteroides* as a main driver for T1D-associated dysbiosis. Indeed, there is a direct relation between the abundance of *Bacteroides* and T1D-associated autoantibodies [37, 38]. However, another study found no difference in *Bacteroides* levels when analysing children with anti-islet cell autoim-

Dysbiosis was linked to autoimmunity and subsequent progression to T1D. Importantly, the appearance of β-cell autoimmunity precedes the onset of hyperglycemia for over 15 years [40]. Therefore, targeting the microbiota could potentially postpone T1D development in chil-

Recently, Kostic et al. highlighted specific features of the T1D microbiome [38]. The study investigated 33 infants from Finland and Estonia who were genetically predisposed to diabetes and observed a relative 25% reduction in alpha-diversity in T1D patients compared to non-converters and seroconverters (positive for at least two of the autoantibodies analysed including insulin autoantibodies, islet cell antibodies, islet antigen-2 antibodies and glutamic acid carboxylase antibodies). Microbiota shifts were evident in T1D children but not in the seroconverters without disease. T1D subjects were shown to harbour an enrichment of "pathobionts that is of commensal bacteria able to become pathogens such as Rikenellaceae, *Blautia* and the *Ruminococcus* and *Streptococcus* genera." Furthermore, the authors observed a depletion of bacteria such as *Lachnospiraceae* and *Veillonellaceae*, which are commonly under

A healthy gut microbiota is enriched with butyrate producers (i.e., *Faecalibacterium*) which determine elevated production of mucin and increased tight junction assembly which all determine an elevated epithelial integrity (**Figure 1**). A niche with high mucin production favours the enrichment of mucin degrading bacteria such as *Akkermansia muciniphila.* T1D subjects were reported to be colonized by lower levels of butyrate producing microorganisms such as *Roseburia* and *Faecalibacterium* and of mucin degrading bacteria such as *Akkermansia* and *Prevotella* [37, 41, 42]. In addition, the Bacteroidete: Firmicutes ratio was proposed as an early marker for autoimmune diseases since a higher level of Bacteroidetes was evident in

increasing the tight junction protein claudin-1 [35].

munity versus healthy controls [39].

dren with β-cell autoimmunity.

abundant in inflammatory conditions (**Figure 1**).

children who developed T1D [43].

Gluten is a well-known trigger for celiac disease and recently for T1D due to its effects on gut permeability. As a consequence of the impaired gut barrier, gliadin peptides move across the epithelium into the lamina propria where they are detected by dendritic cells. Dendritic cells recognize gliadin peptides and migrate to other sites including the pancreatic lymph nodes where they activate autoreactive T cells [27].
