[ 9 Mejía-León M.E.

Petrosino J.F.

Ajami N.J.

Domínguez-Bello M.G.

de la Barca A.M. Fecal microbiota imbalance in Mexican children with type 1 diabetes. Mejía-León ME et al. 2014 7–18 Children with T1D at diagnosis (n = 8) and after 2 years of insulin treatment (n = 13) vs. healthy controls (n = 8); Mexico At diagnosis, T1D patients had high levels of Bacteroides, whereas controls had Prevotella dominance. After 2 years of insulin treatment, cases resembled the controls.

[ 10 Kemppainen K.M.

Ardissone A.N.

Davis-Richardson A.G.

Fagen J.R.

Gano K.A.

et al. Early childhood gut microbiomes show strong geographic differences among subjects at high risk for type 1 diabetes. Kemppainen KM et al. 2015 0–2 Seronegative young children with high risk HLA genotype (n = 15 from each site); Finland, Sweden, Germany, and USA Bacterial diversity differed by geographical location. Children from Finland and Colorado had lower bacterial diversity, and children from Sweden and Washington state had Bifidobacterium dominance.

[ 11 Soyucen E.

Gulcan A.

Aktuglu-Zeybek A.C.

Onal H.

Kiykim E.

Aydin A. Differences in the gut microbiota of healthy children and those with type 1 diabetes. Soyucen E et al. 2014 6–15 Children with newly diagnosed T1D (n = 35) and healthy controls (n = 35); Turkey Compared to controls, Bifidobacterium colonization was lower in patients with T1D. Candida albicans and Enterobacteriaceae (other than Echerichia coli) were increased in controls.

[ 12 Kostic A.D.

Gevers D.

Siljander H.

Vatanen T.

Hyötyläinen T.

Hämäläinen A.M.

et al. The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Kostic AD et al. 2015 0–3 Young children with islet autoimmunity (n = 11) and healthy controls (n = 22). All have HLA-conferred risk for T1D; Finland and Estonia Drop in alpha-diversity between seroconversion and T1D diagnosis, accompanied with an increase in proinflammatory organisms, changes in gene functions, and serum and stool metabolites. Microbial relationships were shared across most subjects. Strain compositions were highly variable between individuals, but stable within individuals throughout infancy. Metabolic composition and metabolic pathway abundances were constant across time.

[ 13 Endesfelder D.

Engel M.

Davis-Richardson A.G.

Ardissone A.N.

Achenbach P.

Hummel S.

et al. Towards a functional hypothesis relating anti-islet cell autoimmunity to the dietary impact on microbial communities and butyrate production. Endesfelder D et al. 2016 0–3 Young children with persistent islet autoimmunity (n = 22) and healthy controls (n = 22); Germany Bacteroides-dominated subgroup associated with early introduction of non-milk diet, increased risk for early autoantibody development, and lower abundances of genes for butyrate production. Alterations in the composition of mucin-degrading bacteria associated with early development of islet autoimmunity. Functional associations between diet, gut microbiome and islet autoimmunity existed in microbial co-occurrence networks.

[ 14 Heintz-Buschart A.

May P.

Laczny C.C.

Lebrun L.A.

Bellora C.

Krishna A.

et al. Integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes. Heintz-Buschart A et al. 2016 5–62 Four families with ≥2 generations of ≥2 cases of T1D per family (n = 20); Netherlands Family membership has a pronounced effect on the structural and functional composition of the gastrointestinal microbiome. No differences in taxonomic or functional diversity and richness between T1D cases and their family members. Protein expression findings implicated that T1D cases may have slightly dysfunctional exocrine pancreas.

[ 15 Maffeis C.

Martina A.

Corradi M.

Quarella S.

Nori N.

Torriani S.

et al. Association between intestinal permeability and faecal microbiota composition in Italian children with beta cell autoimmunity at risk for type 1 diabetes. Maffeis C et al. 2016 6–16 Children with islet autoimmunity (10) and healthy controls (n = 10); Italy Group-specific differentiation between cases and controls was challenging. Intestinal permeability was higher in children with islet autoimmunity. Dialister invisus, Gemella sanguinis and Bifidobacterium longum were associated with prediabetes.

[ 16 Qi C.J.

Zhang Q.

Yu M.

Xu J.P.

Zheng J.

Wang T.

et al. Imbalance of fecal microbiota at newly diagnosed type 1 diabetes in Chinese children. Qi CJ et al. 2016 10–15 Children with T1D (n = 15) and healthy controls (n = 15); China T1D cases had decreased bacterial richness, decreased Haemophilus, Lachnospira, Dialister, and Acidaminococcus, and increased Blautia levels. Percentage of Blautia correlated with HbA1c, number of T1D-associated autoantibodies, and IA-2A levels.

[ 17 Vatanen T.

Kostic A.D.

d'Hennezel E.

Siljander H.

Franzosa E.A.

Yassour M.

et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Vatanen T et al. 2016 0–3 Young children with HLA-associated risk for T1D (n = 74 from each country); Finland, Estonia, and Russia Bacteroides strains were more abundant in Finnish infants compared to Russian Karelian infants, while E. coli was more frequent on Finnish infants Bacteroides LPS had immunoinhibitory properties that may preclude early immune education and contribute to development of T1D, while E. coli derived LPS was strongly immunostimulatory. Metabolism of human milk oligosaccharides (HMOs) maintained Bifidobacterium-dominant versus Bacteroides-dominant gut microbiota in the first year of life.

[ 18 Cinek O.

Kramna L.

Lin J.

Oikarinen S.

Kolarova K.

Ilonen J.

et al. Imbalance of bacteriome profiles within the Finnish diabetes prediction and prevention study: parallel use of 16S profiling and virome sequencing in stool samples from children with islet autoimmunity and matched controls. Cinek O et al. 2017 0–3 Young children with islet autoimmunity progressing to T1D (n = 18) and healthy controls (18); Finland Four operational taxonomic units were less abundant in children developing islet autoimmunity, most markedly Bacteroides vulgatus and Bifidobacterium bifidum. Potential relation existed between CrAssphage and Bacteroides dorei. No differences were observed between cases and controls in alpha or beta diversity, or the taxonomic levels of bacterial phyla, classes or genera.

[ 19 de Groot P.F.

Belzer C.

Aydin Ö.

Levin E.

Levels J.H.

Aalvink S.

et al. Distinct fecal and oral microbiota composition in human type 1 diabetes, an observational study. de Groot PF et al. 2017 25–45 Adults with T1D (n = 53) and healthy controls (n = 50); Netherlands Both oral and gut microbiota differed between cases and controls. Oral microbiota had higher abundance of streptococci in cases, while gut microbiota showed decreased butyrate-producing species and less butyryl-CoA transferase genes. Plasma levels of acetate and propionate were lower in T1D. Christensenella and Subdoligranulum strains correlated with glycaemic control, inflammatory parameters, and level of short-chain fatty acids (SCFAs).

[ 20 Pellegrini S.

Sordi V.

Bolla A.M.

Saita D.

Ferrarese R.

Canducci F.

et al. Duodenal mucosa of patients with type 1 diabetes shows distinctive inflammatory profile and microbiota. Pellegrini S et al. 2017 1–65 Children and adults with T1D (n = 19) or celiac disease (CD, n = 19) vs. controls (n = 16); Italy T1D-specific increase in monocyte/macrophage infiltration in the intestinal biopsies. Cases had increase in Firmicutes and Firmicutes/Bacteroidetes ratio, and a reduction in Proteobacteria and Bacteroidetes in the duodenal mucosa. The expression levels of genes specific for T1D inflammation were associated with the abundance of specific bacteria in the duodenum.

[ 21 Pinto E.

Anselmo M.

Calha M.

Bottrill A.

Duarte I.

Andrew P.W.

et al. The intestinal proteome of diabetic and control children is enriched with different microbial and host proteins. Pinto E et al. 2017 8–11 Children with T1D (n = 3) and healthy controls (n = 3); Portugal T1D cases had a microbial intestinal proteome enriched with proteins of clostridial cluster XVa and cluster IV and Bacteroides, while controls had more often bifidobacterial proteins. T1D children had lower levels of exocrine pancreatic enzymes.

[ 22 Stewart C.J.

Nelson A.

Campbell M.D.

Walker M.

Stevenson E.J.

Shaw J.A.

et al. Gut microbiota of type 1 diabetes patients with good glycaemic control and high physical fitness is similar to people without diabetes: an observational study. Stewart CJ et al. 2017 25–30 Young adults with T1D (n = 10) and healthy controls (n = 10); UK Faecalibacterium sp., Roseburia sp. and Bacteroides sp. were the most abundant microbes in both groups. Each bacterial profile was individual and no significant differences in the profiles or in the diversity indices were observed between the groups.

[ 23 Cinek O.

Kramna L.

Mazankova K.

Odeh R.

Alassaf A.

Ibekwe M.U.

et al. The bacteriome at the onset of type 1 diabetes: a study from four geographically distant African and Asian countries. Cinek O et al. 2018 7–15 Children at T1D onset (n = 73; 14–20 per country) and healthy controls (n = 104); Azerbaijan, Jordan, Nigeria, and Sudan Genus Escherichia spp. correlated with T1D. T1D cases showed an inverse association with Eubacterium and Roseburia (Firmicutes), and clostridial clusters IV and XIVa. No T1D-associations for microbial richness or enterotypes were observed.

[ 24 Gao X.

Huynh B.T.

Guillemot D.

Glaser P.

Opatowski L. Inference of significant microbial interactions from longitudinal metagenomics data. Gao X et al. 2018 0–3 Young children with islet autoimmunity (n = 11) and healthy controls (n = 22). All have HLA-conferred risk for T1D; Finland and Estonia More microbial interactions and the inhibition of Clostridia by Gammaproteobacteria were maintained throughout the first 3 years of life in healthy children. Gammaproteobacteria inhibited Bacteroidia in the cases, but not in controls. The inhibitory effects from Actinobacteria and Bacilli on Bacteroidia, from Bacteroidia on Clostridia, and the beneficial effect from Clostridiao on Bacteroidia were shared between cases and controls.

[ 25 Gavin P.G.

Mullaney J.A.

Loo D.

Cao K.L.

Gottlieb P.A.

Hill M.M.

et al. Intestinal metaproteomics reveals host-microbiota interactions in subjects at risk for type 1 diabetes. Gavin PG et al. 2018 2–45 Children and adults with recent-onset T1D (33) or islet autoimmunity (n = 17), and low-risk autoantibody-negative subjects (n = 29) and healthy controls (n = 22); USA T1D patients had increased intestinal inflammation and decreased barrier function. Microbial taxa capable of promoting the host's mucous barrier, microvilli adhesion, and functions of the exocrine pancreas were depleted in T1D. Pancreatic exocrine dysfunction appeared in high-risk individuals before the disease onset. Both host-derived and microbial-derived proteins were able to differentiate the new-onset and the islet autoantibody-positive subjects from the low-risk subjects.

[ 26 Higuchi B.S.

Rodrigues N.

Gonzaga M.I.

Paiolo J.C.C.

Stefanutto N.

Omori W.P.

et al. Intestinal dysbiosis in autoimmune diabetes is correlated with poor glycemic control and increased interleukin-6: a pilot study. Higuchi BS et al. 2018 15–35 Teenagers and young adults with T1D (n = 20) and healthy controls (n = 28); Brazil T1D patients had intestinal dysbiosis with prevalent Gram-negative bacteria like Bacteroides vulgatus, Bacteroides rodentium, Prevotella copri, and Bacteroides xylanisolvens. Cases had increased plasma levels of the proinflammatory interleukin-6. Poor glycaemic control associated with the relative abundance of Bacteroidetes, Lactobacillales, and Bacteroides dorei.

[ 27 Huang Y.

Li S.C.

Hu J.

Ruan H.B.

Guo H.M.

Zhang H.H.

et al. Gut microbiota profiling in Han Chinese with type 1 diabetes. Huang Y et al. 2018 18–25 Young adults with T1D (n = 12) and healthy controls (n = 10); China Various bacterial taxonomic clades differed between cases and controls. Bacteroidetes and Firmicutes were the dominant phyla in cases and controls, respectively. Abundance of Faecalibacterium correlated inveresly with HbA1c levels. Numbers of islet autoantibodies correlated positively with Bacteriodes and Bilophila abundances and inversely with Streptococcus and Ruminococcaceae abundances.

[ 28 Leiva-Gea I.

Sánchez-Alcoholado L.

Martín-Tejedor B.

Castellano-Castillo D.

Moreno-Indias I.

Urda-Cardona A.

et al. Gut microbiota differs in composition and functionality between children with type 1 diabetes and MODY2 and healthy control subjects: a case-control study. Leiva-Gea I et al. 2018 9–16 Children with T1D (n = 15) or MODY2 (n = 15), and healthy controls (n = 13); Spain T1D associated with (i) lower microbial diversity, (II) higher relative abundance of Bacteroides, Ruminococcus, Veillonella, Blautia, and Streptococcus genera, and (III) lower relative abundance of Bifidobacterium, Roseburia, Faecalibacterium, and Lachnospira. Proinflammatory cytokines and lipopolysaccharides were increased in T1D cases, as were the expression of genes related to lipid and amino acid metabolism, ATP-binding cassette transport, lipopolysaccharide biosynthesis, arachidonic acid metabolism, antigen processing and presentation, and chemokine signalling pathways. MODY2 associated with higher Prevotella abundance and a lower Ruminococcus and Bacteroides abundance. Intestinal permeability was increased both in T1D and in MODY2 cases.

[ 29 Mejía-León M.E.

López-Domínguez L.

Aguayo-Patrón S.V.

Caire-Juvera G. Calderón de la Barca AM. Dietary changes and gut dysbiosis in children with type 1 diabetes. Mejía-León ME et al. 2018 9–14 Children with newly diagnosed T1D (n = 10) The increasing Bacteroides proportion (during the first months after diagnosis) correlated with the consumption of saturated fat and carbohydrates at 3 months. After adjusting for HbA1C, consumption of carbohydrates associated with decreased Bacteroides abundance over time.

[ 30 Stewart C.J.

Ajami N.J.

O'Brien J.L.

Hutchinson D.S.

Smith D.P.

Wong M.C.

et al. Temporal development of the gut microbiome in early childhood from the TEDDY study. Stewart CJ et al. 2018 0–4 Young children (n = 903) with high risk HLA genotype; Finland, Sweden, Germany, and USA Feeding with breast milk was the most significant factor associated with the microbiome structure. It associated with higher levels of Bifidobacterium sp. (B. breve and B. bifidum). Bacteroides associated with increased microbial diversity and faster maturation of the gut. Only subtle associations were observed between microbial taxonomy and islet autoimmunity: i) higher relative abundance of an unclassified Erysipelotrichaceae in children with autoimmunity; ii) five bacterial genera associated with T1D onset (Parabacteroides the most significant); iii) eleven bacterial genera were lower in T1D cases, including four unclassified Ruminococcaceae, Lactococcus, Streptococcus, and Akkermansia.