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Chierico, F.D.;  Rapini, N.;  Deodati, A.;  Matteoli, M.C.;  Cianfarani, S.;  Putignani, L. Type 1 Diabetes and Gut Microbiota. Encyclopedia. Available online: (accessed on 15 April 2024).
Chierico FD,  Rapini N,  Deodati A,  Matteoli MC,  Cianfarani S,  Putignani L. Type 1 Diabetes and Gut Microbiota. Encyclopedia. Available at: Accessed April 15, 2024.
Chierico, Federica Del, Novella Rapini, Annalisa Deodati, Maria Cristina Matteoli, Stefano Cianfarani, Lorenza Putignani. "Type 1 Diabetes and Gut Microbiota" Encyclopedia, (accessed April 15, 2024).
Chierico, F.D.,  Rapini, N.,  Deodati, A.,  Matteoli, M.C.,  Cianfarani, S., & Putignani, L. (2022, December 06). Type 1 Diabetes and Gut Microbiota. In Encyclopedia.
Chierico, Federica Del, et al. "Type 1 Diabetes and Gut Microbiota." Encyclopedia. Web. 06 December, 2022.
Type 1 Diabetes and Gut Microbiota

Type 1 diabetes (T1D) is a multifactorial autoimmune disease driven by T-cells against the insulin-producing islet β-cells, resulting in a marked loss of β-cell mass and function. A dysbiotic gut microbial profile has been associated with T1D patients. Moreover, new evidence propose that perturbation in gut microbiota may influence the T1D onset and progression. One of the prominent features in clinically silent phase before the onset of T1D is the presence of a microbiota characterized by low numbers of commensals butyrate producers, thus negatively influencing the gut permeability. The loss of gut permeability leads to the translocation of microbes and microbial metabolites and could lead to the activation of immune cells. Moreover, microbiota-based therapies to slow down disease progression or reverse T1D have shown promising results.

type 1 diabetes (T1D) insulin resistance gut microbiome dysbiosis

1. Introduction

Type 1 diabetes (T1D) is a multifactorial autoimmune disease characterized by T-cell-mediated destruction of insulin-producing β-cells of the pancreas. T1D is the most commonly diagnosed diabetes in children and adolescents (under 20 years of age) and causes ≥85% of all diabetes cases in these age groups worldwide [1]. Across the globe, it is evaluated that 1,110,100 people aged 0–19 years have T1D, with 128,900 newly diagnosed cases each year [2].
The condition is characterized by the body’s complete inability to produce insulin, an essential anabolic hormone that helps the body’s cells use glucose for energy. Importantly, insulin facilitates entry of glucose to muscle and adipose cells, induces the store of glucose as glycogen in liver and the synthesis of fatty acids, stimulates the uptake of amino acids, impedes the breakdown of fat in adipose tissue, and promotes the uptake of potassium into cells [3]. T1D is clinically characterized by the primary appearance of islet autoantibodies (AAbs). The AAbs are islet cell cytoplasmic antibodies (ICA), antibodies to insulin (IAA), to glutamic acid decarboxylase (GAD), insulinoma-associated 2 antibodies, or protein tyrosine phosphatase antibodies (IA-2) and zinc transporter8 antibodies (ZnT8) [4]. The natural history of T1D presents a “pre-stage 1” in which individuals carrying T1D susceptibility alleles have not yet developed islet AAbs. The development of two or more islet antibodies defines the “stage 1”, which can progress to “stage 2”, when dysglycemia appears, and then progresses to symptomatic diabetes (stage 3) [5]. The decline in β-cell number starts years before the symptoms of hyperglycaemia become evident. Moreover, a direct correlation exists between the number of detectable antibodies and their higher titers to the increased risk of developing T1D [3].
Recently, the development of T1D can be attributed to the intervention by genetic, epigenetic, and environmental factors. One such key identified environmental factor is gastrointestinal microbiota which comprises 100 trillion cells in the human gut, 10 times the number of human cells [6]. Since the gut microbiota plays a fundamental role in the revelation of framework and function of the host immune system, any changes in diet, overuse of antibiotics, or gastrointestinal tract infections can lead to substantial shifts in the composition of the individual microbiome over extensive periods. These shifts, which result in the disruption of the normal gut microbiota called the dysbiosis, lead to conditions such as autoimmune and inflammatory disorders [7][8]. Recent studies using high-end sequencing technologies have shown a significant difference in the intestinal microbial profile between T1D patients and healthy controls, suggesting correlation between T1D development and gut microbiota profile [9]. Moreover, new evidence proposes that perturbation in gut microbiota may be involved in the pathophysiology of T1D, and gut dysbiosis resulting in immunological deregulation and gut leakiness as the plausible pathogenic mechanisms in the onset of T1D [10]. Despite the latest findings, the explicit role of microbiota that mediates T1D is under investigation.

2. T1D Risk Factors

From a genetic standpoint, more than 50 gene loci have been implicated in T1D risk, most of which act on the immune system. By far, the strongest risk has been attributed to genes encoding human leukocyte antigen (HLA) genes [11]. Almost 90% of the patients were tested to carry the high-risk haplotypes DR4-DQ8 (DR4-DQA1*03:01-DQB1*03:02) or DR3-DRQ2 (DRB1*03:01-DQA1*05:01-DQB1*02:01) [12][13]. Several other immune-related genes have also been described in the pathogenesis of T1D [14][15]. Large-scale genome-wide association studies have identified multiple single nucleotide polymorphisms linked to T1D, many of them belonging to pathways involved in inflammation, immunity, and apoptosis [16]. Notably, there is often an overlap among T1D and other autoimmune and inflammatory traits loci. Some of these genes include CTLA 4, a down-regulator of the CD8+ T-cell response; KIR genes, a family of cell-surface receptors found on natural killer cells that regulate their function; interleukin (IL) genes such as IL-4 and IL-13, which are immunomodulatory cytokines; IL2RA, interleukin-2 receptor subunit alpha, which is involved in Treg function [13][17].
Surprisingly, 90% of T1D cases have no first-degree relatives, and the pairwise concordance rate from homozygotic twins is described to be only 27% [18]. Furthermore, only 10–15% of the individuals with genetic risk ultimately develop T1D. This clearly indicates that the role of environmental triggers in the pathophysiology of T1D is much more significant than the one imputable to genetics. Moreover, the fact that T1D incidence has increased by several folds in the last 30 years, and the tendency of migrants to acquire the same risk of T1D as the population in their new area of residence, reinforces the hypothesis of the impact of environmental factors [19][20][21].
Numerous research findings describe a positive role of diet, lifestyle, gut microbiota, infections, and psychological stress in driving auto-immunity or β-cell dysfunction towards T1D development [21][22]. Among these, diet during early infancy could be an important factor. Breastfeeding is said to have a protective role, whereas the introduction of cow’s milk or cereals/gluten in early infancy could have an adverse role by inducing interferon (INF)-γ secretion and β-cell stress [22]. However, there are no conclusive human studies to prove this. Moreover, a protective role has been attributed to Vitamin D. As a modulator of inflammation, Vitamin D has a protective effect on IL-1-Th1-mediated damage of β-cells by inhibition of macrophage activation, abolition of CD4+ expression, inhibition of IL-2 and IFN γ, and reduction of the expression of major histocompatibility complex class II molecules [23]. Similarly, intake of omega-3 fatty is said to have a protective role in T1D inflammation [21].
In addition to these, certain viral infections, mainly enteroviruses (EVs), which enter through the intestine, have shown a strong positive correlation to T1D development [22]. One type of EV, the Coxsackievirus B, is known to replicate in islet β-cells and increase endoplasmic reticulum stress by disrupting the unfolded protein response pathway [24]. Finally, the gut microbiome composition has been observed to be different in healthy versus TID cases in both human and animal models.

3. Role of Gut Microbiota in T1D Pathophysiology

A complex correlation between intestinal microbiota, immune system, and gut permeability has already been identified, although not completely unraveled [25]. The gut permeability is modulated by the gut barrier which comprises gut microbiota, mucus, enterocytes, tight junction (TJ) proteins, and the innate and adaptive immune cells forming the gut-associated lymphoid tissue [26]. The disassembly of TJ and the disruption of the integrity of the intestinal barrier can lead the intestinal permeability and the passage of microbial antigens and products or the microorganisms themselves. The TJ of the gut barrier is regulated by the expression of TJ proteins comprising claudin-2, occludin, cingulin, and zonula occludens (ZO) proteins. Some studies have demonstrated that the intestinal permeability depends on the increased levels of zonulin, whose production is influenced by bacterial colonization [27][28]. It is also understood that zonulin reversibly regulates intestinal permeability by modulating TJ [29][30][31]. Interestingly, before the onset of clinically evident T1D, high serum zonulin levels are present [32]. Moreover, in T1D patients, an increase of gut paracellular permeability has been detected [32][33][34][35][36] (Figure 1).
Figure 1. Increasing gut paracellular permeability in T1D patients. The alteration of tight junction (TJ) proteins leads to the increase of intestinal permeability, providing access to the lamina propria environment for foreign agents (e.g., bacteria and bacterial and diet products). The accumulation of these bacteria and molecules can trigger inflammation pathways, causing intestinal inflammation. The activated and expanded T-cells in the gut-associated lymphoid tissue (GALT) could travel via mesenteric and pancreatic lymph nodes to the pancreas and induce T1D. Created with
Interestingly, the increase of small intestinal permeability has also found in subjects at risk of developing T1D, confirming the hypothesis that alterations in intestinal mucosa barrier might be correlated to an autoimmune process that promotes disease onset [34][37]. Moreover, children with multiple islet autoantibodies (≥2 IA) who progressed to T1D presented a higher intestinal permeability compared those who did not progress, suggesting an involvement of intestinal permeability in the pathogenesis of T1D [38].
Many gut commensals play a role in modulating the permeability of the intestinal barrier [39]. A hypothesis is based on the evidence that some gut bacteria express GAD and produce gamma-aminobutyric acid. The GAD released from bacteria as a consequence of gut bacterial destruction (e.g., through viral- or antibiotic-mediated mechanisms) may act as an antigen to activate submucosal T-cells, causing miseducation of the host immune system and leading to the development of T1D [40][41].
Bioinformatics data confirmed that some of the microbes can carry peptide sequences similar to insulin, potentially triggering auto-immunity [42]. Interestingly, T-cell clones against preproinsulin peptides have shown high cross-reactivity to the peptides of Bacteroides and Clostridium species [43]. In a NOD mouse model, a peptide produced by Parabacteroides distasonis with homology to β-chain of insulin has been identified [44]. This peptide can be recognized by T-cells, cross-stimulating an immune response to this chain of insulin [44].
Lastly, by the gnotobiotic zebrafish model, it has been also demonstrated that the normal expansion of the pancreatic β-cell population during early larval development requires the intestinal microbiota by the activity of a bacterial protein termed β-cell expansion factor A (BefA), produced by gut microbes [45]. These findings shed light on a possible a role of the gut microbiota in early pancreatic β-cell development and suggest a link between fecal microbiota composition in childhood and an increase in diabetes risk.

4. Gut Microbiota Dysbiosis in T1D

The gut microbiota dysbiosis in T1D patients has already been described [46][47]. The “TEDDY study” showed the higher abundance of Bifidobacterium spp. and the lower abundance of Streptococcus thermophilus and Lactococcus lactis in children before the seroconversion or the onset of T1D with respect to healthy subjects [48].
The increase of Bacteroides abundance in T1D patients and subjects a risk to develop T1D compared to aged-matched healthy controls has been reported in different studies [46][49][50].
The alteration in microbiota composition seems to be present only in T1D progressors and not in children at risk who did not develop the disease. This evidence came from a Finnish study in which a reduction in microbiota richness was detected in children who develop T1D prior to diagnosis but after seroconversion [51]. Moreover, the seroconversion has been positively correlated with the increase of lipopolysaccharides biosynthesis in Bacteroides genome and sulfate reduction in Anaerostipes genome [52].
The enhanced activity of Bacteroides and a down-regulation of functions associated with Bifidobacterium in T1D patients were confirmed by a metaproteomic study on pediatric patients at T1D onset. The reduced activity of Bifidobacterium was highlighted in patients with low insulin need, suggesting the presence of a transient condition of the gut microbiota composition and functions related to a very early stage of the disease (Levi Mortera Stefano at al., “Functional and taxonomic traits of the gut microbiota in type 1 diabetes children at the onset: a metaproteomic study”. Submitted to International Journal of Molecular Sciences Manuscript ID: ijms-2032220, 30 October 2022).
In an Italian cohort of T1D patients, a high abundance of Bifidobacterium stercoris, Bacteroides intestinalis, Bacteroides cellulosilyticus, and Bacteroides fragilis was found [53]. An abundance of Bacteroides dorei and Bacteroides vulgatus was described in a cohort of Finnish children at high risk to develop T1D [54].
A study based on the integration of metagenomic and metabolomics approaches on T1D patients at onset, their siblings, and healthy subjects, revealed the increase in Clostridiales and Dorea and the decrease in Dialister and Akkermansia in T1D patients and their siblings, showing a specific profile of gut microbiota linked to familiar environment. Moreover, T1D patients were characterized by higher levels of isobutyrate, malonate, Clostridium, Enterobacteriaceae, Clostridiales, and Bacteroidales. Patients with higher anti-GAD levels showed low abundances of Roseburia, Faecalibacterium, and Alistipes, and those with normal blood pH and low serum HbA1c levels showed high levels of purine and pyrimidine intermediates. These results shed light on specific gut microbial and metabolic profiles predictive of T1D progression and severity [55].
Moreover, changes in the gut microbiota composition of T1D patients have been associated with glycemic control and disease-related complications, suggesting that the gut microbiota may also be involved in the development of diabetes-associated complications [56].
Moreover, in autoantibody-positive children, an increased abundance of Bacteroides and a low abundance of butyrate-producing species were found [47]. A negative correlation between butyrate-producers, the intestinal permeability, and the risk of developing T1D has also been reported [47][57][58][59]. However, even in the late phase of prediabetes, a low numbers of butyrate producers were found, suggesting the role of microbiota as a regulator of β-cell autoimmunity in the progression of the disease [10][47]

5. Conclusion

Although T1D was earlier regarded to have genetic roots, compelling evidences state a strong role of Gut microbiota in disease onset and progression. Thus, the correction of dysbiosis by microbial-based therapies could help in promoting immune tolerance at onset, and improve gut permeability decreasing inflammation during the disease progression.


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