The incidence of type 1 diabetes (T1D) has been progressively rising over the past several decades due to complex environmental changes . Factors proposed to contribute to this rise include diet, antibiotic use, infection, vitamin D levels, toxin and chemical exposure, birth weight and birth delivery route . Many of these are intimately linked to the function and composition of the gut microbiota, leading to the hypothesis that disturbances in the gut microbiota are associated with T1D pathogenesis. In this review, we discuss recent advances in understanding the role of the gut microbiota in islet autoimmunity mechanistic insights as to how the microbiota and islet immune response may be connected.
MICROBIAL DYSBIOSIS IN TYPE 1 DIABETES
Early studies suggested an increased abundance of members of the Bacteroides genus and decreased microbial diversity in at-risk individuals with islet-autoantibodies (IAb+) and those with T1D and hinted that these differences may be linked to reduced metabolism of short-chain fatty acids (SCFAs) [3–7]. However, the majority of these studies were underpowered, involved individuals from a single location and relied on single time-point 16S rRNA gene amplicon sequencing to estimate community composition. Unsurprisingly, these limitations led to discordant findings regarding specific taxa which might contribute to autoimmunity. Recently, findings from longitudinal stool samples from ‘The Environmental Determinants of Diabetes in the Young’ (TEDDY) study overcame these limitations and have provided a more robust understanding of the temporal development of the gut microbiota in T1D [8▪▪,9▪▪]. These studies used both amplicon sequencing (n = 12 005) and shotgun metagenome (n = 10 867) sequencing to explore community composition and functional potential of the bacteria in stool samples from 903 children at increased risk of developing T1D. TEDDY individuals were accrued from six sites in the USA and Europe. Comparison of abundance data from the amplicon sequencing of IAb+ children and controls (n = 316 pairs) found higher levels of Erysipelotrichaceae in those with IAbs. Sixteen genera significantly differed between children who developed T1D from controls (n = 96 pairs). These included higher levels of Lactococcus, Streptococcus and Akkermansia in control individuals. In the metagenomic arm of the TEDDY study, 415 controls, 267 IAb+ and 101 T1D individuals were analyzed [9▪▪]. Taxonomic differences revealed modest effects including higher Streptococcus thermophilus, Lactococcus lactis, Lactobacillus rhamnosus and Bifidobacterium dentium in controls. S. thermophilus and L. lactis are common in dairy products and B. dentium was shown to be sensitive to perturbation by antibiotics. The taxonomic differences identified in the amplicon vs. metagenomics only partly overlapped, perhaps due to bias introduced by the respective methodologies including slightly different approaches to the data cleaning or reflecting the marginal significance of the changes. Although these studies represent the largest and most rigorous of their kind, it should be noted that most of the findings regarding T1D were of modest effect size, and restricted to predominantly white populations with early-onset disease. In addition, some stool samples were shipped at ambient temperature which may have distorted the observed bacterial populations . Furthermore, the analysis of IAb+ children in TEDDY combined individuals that were both single and multiple antibody positive, which represent distinct risk profiles [11,12]. Therefore, assessment of the microbiota in only high-risk multiple antibody-positive individuals and longitudinally across the transition between stages of prediabetes in larger cohorts is still needed.
FUNCTIONAL DYSBIOSIS IMPLICATES ALTERED SHORT-CHAIN FATTY ACID PRODUCTION IN TYPE 1 DIABETES
It is possible that while there may be a high degree of taxonomic variability in the gut microbiota, common functional features may be associated with T1D. Previous studies in humans, nonobese diabetic (NOD) mice, and virus-induced rat models of T1D have supported a decrease in microbial production of SCFA as contributing to disease risk [4,5,13,14]. SCFAs such as butyrate, acetate and propionate have many reported beneficial properties for the host including promoting mucous production, antimicrobial peptide production and promoting colonic regulatory T cells (Tregs) . Analysis of functional potential using metagenomics on 783 TEDDY individuals indicated that the metagenome of control children had more genes involved in fermentation and SCFA synthesis compared with T1D individuals [9▪▪]. de Groot et al. found decreased abundance of butyrate producers in the stool of long-standing T1D individuals (n = 53) relative to healthy controls (n = 50). Aberrant SCFA production was supported by decreased levels of acetate and propionate in the blood, although SCFA levels in the stool did not differ between groups, and by a decreased ratio of the butyryl-CoA : acetate-CoA transferase gene. Together these new data support that reduced SCFA synthesis is associated with T1D and future clinical studies could be aimed at promoting SCFA delivery to the gut.
HOST–MICROBIOTA INTERACTIONS IN TYPE 1 DIABETES
A demonstration that dysbiosis of the microbiota in T1D is linked to changes in the intestinal barrier function, the gut immune response or inflammation in the pancreas has been challenging. We utilized fecal metaproteomics to interrogate the relationship between microbial dysbiosis and host proteins derived from the gut and pancreas of healthy controls and IAb- relatives (n = 51) compared with IAb+ (N = 17) and recent-onset T1D (n = 33) individuals [17▪]. Multivariate analysis found highly significant differences were present in both the human and microbial derived proteomes of T1D compared with controls with IAb+ individuals presenting an intermediate phenotype. Host proteins (galectin-3 and fibrillin-1) potentially associated with inflammation were upregulated in new-onset cases. The pancreatic enzymes CELA3A and CUZD1 were decreased in T1D and the IAb+ group, suggesting a deterioration of the exocrine pancreas precedes clinical diagnosis. IgA and CLCA1 (a constituent of the mucin layer), were significantly lower in the IAb+ cases. Integration of the metaproteomics with microbial abundance data revealed that microbial taxa enriched in healthy individuals correlated with proteins involved in maintaining the mucus barrier, microvilli adhesion and exocrine pancreas function. Although current metaproteomics techniques can only identify a fraction of the microbial proteins present, this approach may allow a better understanding of host–microbiota interactions. Validation in additional cohorts, preferably longitudinal, is required to better understand these findings.
IDENTIFICATION OF DISEASE PROTECTIVE TAXA: LESSONS FROM ANIMAL MODELS
The NOD mouse model of T1D spontaneously develops autoimmune diabetes with a highly variable onset which has been exploited to study associations between gut microbial taxa and disease risk. Hu et al. observed higher alpha-diversity in the gut microbiota of disease-free NOD mice compared with mice that later progressed to disease. Taxonomic changes were driven by an increase in members of Firmicutes and a decrease in Bacteroidetes in mice that developed disease. Significant associations between the gut but not the oral or vaginal microbiota were found with diabetes development, reinforcing the importance of the gut in T1D. Hänninen et al.[19▪▪] compared the faecal microbiota of high and low-disease incidence NOD colonies. Similar to Hu et al., they observed higher alpha-diversity and a higher Bacteroidetes to Firmicutes ratio in the mice with reduced disease progression. Significantly, while they were able to significantly increase community diversity by cohousing mice from the high and low-incidence colonies, not all taxa were effectively transferred and disease incidence was not altered. Remarkably, introduction of one of the ‘missing’ taxa, Akkermansia muciniphila, significantly delayed disease onset which was accompanied by increased mucous production, reduced crypt length and decreased serum lipopolysaccharide. This was consistent with the described function of A. muciniphila as a mucin degrader and stimulator of mucin production leading to improved gut barrier function . Introduction of A. muciniphila resulted in altered abundance of other taxa suggesting that a single species may drive changes in the wider community structure by altering the nutritional and inflammatory landscape of the gut.
ORIGINS OF DYSBIOSIS IN TYPE 1 DIABETES
The composition of the gut microbiota is determined by environmental, genetic and stochastic influences . Understanding the origin of microbial dysbiosis in T1D is crucial to enable effective targeting of the microbiota as a therapeutic approach.
If genetic susceptibility to T1D contributes to shaping the gut microbiota, then this may pose a barrier to introduction of a ‘healthy’ microbiota. In accordance with this, passive transfer of microbiota by cohousing susceptible NOD mice with disease resistant C57BL/6 mice led to only modest shifts in the microbial composition and did not alter disease incidence . This suggests that the NOD gut environment is inhospitable to certain taxa and that genetic background may bias towards a NOD-associated community composition. Supporting this, we found that six independent NOD colonies had a more similar gut microbiota to each other than to genetically disparate C57BL/6 colonies [23▪]. We tested whether T1D susceptibility contributed to shaping the gut microbiota by using congenic NOD mice that carry protective alleles of T1D susceptibility loci, namely the major histocompatibility complex (MHC), Idd3 (IL2) and the Idd5 (Ctla4, Acadl and Slc11a1) [24–26]. Idd3 and Idd5 protective alleles improve Treg function and immune tolerance [27,28]. NOD mice carrying both Idd3 and Idd5 protective alleles had a highly disparate microbiota composition to control NOD mice, including increased A. muciniphila abundance [23▪]. This was accompanied by increased mucous production and decreased immune infiltration within the lamina propria. In contrast, variation in the MHC resulted in only minor alterations in the gut microbiota. Silverman et al. examined NOD mice carrying a disease protective MHC-II Eα16 gene and found an increase in alpha diversity and compositional changes (albeit modest) in the NOD-Eα16 mice compared with control littermates. Significant disease protection was transferrable to offspring from Eα16 mothers but not fathers supporting that these changes were functionally meaningful. These data argue that T1D genetic susceptibility contributes to shaping the gut microbiota and that even modest changes in the microbial composition may have profound effects on disease progression.
Although host genetics contributes to sculpting the gut ecosystem, external players are thought to contribute far more potently to community variation . Major factors that influence the development of the gut microbiota in young children include the mother's microbiota, infant diet and acute events that can perturb the microbiota such as infection and antibiotics. The mother's microbiota is in turn shaped by many life events resulting in intergenerational effects. Currently, the most robust evidence supports infant diet, particularly age of exposure to solid foods and probiotic use as contributing to T1D risk [31–34]. Although, it should be noted that these behaviours have strong associations with sociodemographic factors, making it difficult to unravel the true causative events .
The increasing use of antibiotics has led to close scrutiny of their role in T1D. A single course of the macrolide antibiotic tylosin-tartrate administered during early life to NOD pups was able to accelerate T1D incidence in male mice, which are usually relatively protected [36▪]. A short antibiotic exposure was sufficient to induce long-term remodelling of the gut microbiota, including increased abundance of several pathobionts. These antibiotic mediated changes were sex-specific and linked to an altered functional potential of the metagenome and gene expression changes in the host gut including in immune-response pathways. This suggests that the early-life period may be a sensitive time for disruption of pathways leading to autoimmunity and sex should be considered in future analyses of the impact of antibiotics. It is of note that long-term treatment with another low-dose antibiotic (penicillin) did not accelerate disease . In human studies, the most recent large-scale cohorts have not found associations with early-life antibiotic exposure and increased islet autoimmunity [38,39]. Therefore, other early-life factors may have greater importance in structuring the gut microbiota in human populations.
MANIPULATING THE MICROBIOTA THROUGH PROBIOTICS
Early probiotic supplementation initiated during the first month of life has been linked to decreased risk of progression to islet autoimmunity in the TEDDY study . Significantly, protection was only seen in children with a high-risk human leukocyte antigen (HLA) DR3/4 genotype. The probiotics used varied but mainly contained mixtures of Lactobacillus and Bifidobacterium species. Recent analysis of the microbiome development in the TEDDY cohort found that infant probiotic exposure was a significant covariate associated with microbiome variance across a range of ages, at least at the genus level [8▪▪]. In a clinical trial conducted in Finland, a probiotic containing L. rhamnosus, Bifidobacterium breve and Propionibacterium freudenreichii was given to pregnant mothers and their infants from birth in a protocol designed to investigate protection from allergy . In this cohort (n = 1223), 14 children progressed to T1D and 25 became IAb+ during the 13-year follow-up but no effect of probiotics was seen. Although this study was not powered to investigate T1D, it suggests that this combination of probiotics may not be protective. Potentially, stratification by HLA genotype may be required to see a beneficial effect from probiotics. HLA risk genotype has been reported to impact development of commensal-specific antibodies providing a possible mechanism for the influence of HLA on the microbiota [41▪▪]. In NOD mice, administration of a probiotic bacteria Clostridium butyricum resulted in highly significant disease protection . This was accompanied by increases in gut-homing Tregs in the mesenteric and pancreatic lymph nodes as well as in microbial genes involved in butyrate production. Hence, a wider range of probiotic species may need to be tested in human clinical trials for their ability to modulate the microbiota composition and prevent T1D.
IMMUNOTHERAPY ALTERS THE INTESTINAL IMMUNE RESPONSE TO THE MICROBIOTA
The composition of the gut microbiota is modulated by two-way interactions with the intestinal immune system. Reductions in the proportion of Tregs and increased inflammatory cytokines have been described in the small intestine of T1D individuals [43,44]. Therefore, immunotherapies that modulate the innate or adaptive immune system may change the intestinal immune response and the composition of the gut microbiota. To verify this, we used low-dose IL-2 therapy, which robustly expands Tregs and protects NOD mice from T1D . IL-2 treatment expanded Tregs within the intestine, increased goblet cell mucous production and reduced intestinal immune infiltration as well as altering the gut microbiota composition [23▪]. Likewise, inhibiting innate immune activation either with IL-1R blockade or a histone deacetylase inhibitor in a rat model of T1D also induced potent alterations in the gut microbiota . Modulation of the gut microbiota by immunotherapy may be a surrogate marker of response to therapy, without contributing itself to disease protection. Yu et al.[47▪▪] investigated this using tolerogenic anti-CD3 therapy. They showed that anti-CD3 expands IL-10 producing type 1 regulatory T (Tr1) cells in the small intestine. These intestinal Tr1 cells were able to suppress T1D development in a disease transfer model and the Tr1 cells were able to migrate from the colon to the pancreas. These data support that induction of immune regulation within the gut is able to limit the autoimmune response within the pancreas.
Evidence is now solidifying around a functional dysbiosis with a reduced potential to produce SCFAs linked to T1D. Future work to more precisely identify health-associated taxa, their functional potential and methods to promote colonization of these strains into the gut is needed. Methods to deliver SCFA to the gut are of key interest for new therapies. Such microbiome targeted therapies may be combined with immunotherapies for maximum benefit. Many other questions remain of interest including the role of intestinal viruses in this interplay. Altogether, current evidence validates that the gut microbiota plays an important role in the pathogenesis of T1D.
Financial support and sponsorship
E.E.H.-W. is funded by a Juvenile Diabetes Research Foundation (JDRF) career development fellowship, JDRF grants 3-SRA-2019-730-S-B, 2-SRA-2019-703-M-B and Children's Hospital Foundation grant WIS0202018. This research was carried out at the Translational Research Institute, Woolloongabba, QLD 4102, Australia. The Translational Research Institute is supported by a grant from the Australian Government.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
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