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Where genes meet environment—integrating the role of gut luminal contents, immunity and pancreas in type 1 diabetes

Published:September 08, 2016DOI:https://doi.org/10.1016/j.trsl.2016.09.001
      The rise in new cases of type 1 diabetes (T1D) in genetically susceptible individuals over the past half century has been attributed to numerous environmental “triggers” or promoters such as enteroviruses, diet, and most recently, gut bacteria. No single cause has been identified in humans, likely because there are several pathways by which one can develop T1D. There is renewed attention to the role of the gut and its immune system in T1D pathogenesis based largely on recent animal studies demonstrating that altering the gut microbiota affects diabetes incidence. Although T1D patients display dysbiosis in the gut microbiome, it is unclear whether this is cause or effect. The heart of this question involves several moving parts including numerous risk genes, diet, viruses, gut microbiota, timing, and loss of immune tolerance to β-cells. Most clinical trials have addressed only one aspect of this puzzle using some form of immune suppression, without much success. The key location where our genes meet and deal with the environment is the gastrointestinal tract. The influence of all of its major contents, including microbes, diet, and immune system, must be understood as part of the integrative biology of T1D before we can develop durable means of preventing, treating, or curing this disease. In the present review, we expand our previous gut-centric model based on recent developments in the field.

      Abbreviations:

      BBdp (BioBreeding Diabetes-prone (rat)), CAMP (cathelicidin antimicrobial peptide), CD14 (cluster of differentiation 14), CD163 (cluster of differentiation 163), CRAMP (cathelicidin-related antimicrobial peptide), CCL2 (C-C Motif Chemokine Ligand 2), CCL5 (C-C Motif Chemokine Ligand 5), CCL3 (C-C Motif Chemokine Ligand 3), cMLN (colonic mesenteric lymph nodes), CTLA4 (Cytotoxic T-lymphocyte associated antigen 4), CXCL9 (Chemokine (C-X-C motif) ligand 9), CXCL10 (Chemokine (C-X-C motif) ligand 10), CXCL11 (Chemokine (C-X-C motif) ligand 11), DIPP (Diabetes Prediction and Prevention Trial), dsRNA (double-stranded ribonucleic acid), EGFR (epidermal growth factor receptor), GAD (glutamic acid decarboxylase), GM-CSF (granulocyte-macrophage colony-stimulating factor), GWAS (genome-wide association studies), HC (hydrolyzed casein), HLA (human leukocyte antigen), HO-1 (heme oxygenase-1), IEL (intra epithelial lymphocyte), IL2RA (interleukin-2 receptor alpha chain), IL-6 (interleukin-6), IL-8 (interleukin-8), IL-10 (interleukin-10), LPS (lipopolysaccharides), MHC (major histocompatibility complex), MLN (mesenteric lymph nodes), NOD (non-obese diabetic (mouse)), PBMC (peripheral blood mononuclear cells), PLN (pancreatic lymph nodes), PTPN22 (protein tyrosine phosphatase, non-receptor type 22), RNA (ribonucleic acid), rRNA (ribosomal ribonucleic acid), sMLN (small intestinal mesenteric lymph nodes), SNP (single nucleotide polymorphism), T1D (Type 1 diabetes), TEDDY (The Environmental Determinants of Diabetes in the Young Study), TLR4 (Toll Like Receptor 4), TRIGR (Trial to Reduce IDDM in the Genetically at Risk)
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      References

        • Stene L.C.
        Gaps in life expectancy for people with type 1 diabetes.
        Diabetologia. 2016; 59: 1150-1152
        • Wentworth J.M.
        • Fourlanos S.
        • Harrison L.C.
        Reappraising the stereotypes of diabetes in the modern diabetogenic environment.
        Nat Rev Endocrinol. 2009; 5: 483-489
        • Lefebvre D.E.
        • Powell K.L.
        • Strom A.
        • Scott F.W.
        Dietary proteins as environmental modifiers of type 1 diabetes mellitus.
        Annu Rev Nutr. 2006; 26: 175-202
        • Atkinson M.A.
        • von Herrath M.
        • Powers A.C.
        • Clare-Salzler M.
        Current concepts on the pathogenesis of type 1 diabetes–considerations for attempts to prevent and reverse the disease.
        Diabetes Care. 2015; 38: 979-988
        • Pociot F.
        • Akolkar B.
        • Concannon P.
        • et al.
        Genetics of type 1 diabetes: what's next?.
        Diabetes. 2010; 59: 1561-1571
        • Scalbert A.
        • Brennan L.
        • Manach C.
        • et al.
        The food metabolome: a window over dietary exposure.
        Am J Clin Nutr. 2014; 99: 1286-1308
        • Kondrashova A.
        • Reunanen A.
        • Romanov A.
        • et al.
        A six-fold gradient in the incidence of type 1 diabetes at the eastern border of Finland.
        Ann Med. 2005; 37: 67-72
        • Scott F.W.
        Food-induced type 1 diabetes in the BB rat.
        Diabetes Metab Rev. 1996; 12: 341-359
        • Scott F.W.
        • Cloutier H.E.
        • Kleemann R.
        • et al.
        Potential mechanisms by which certain foods promote or inhibit the development of spontaneous diabetes in BB rats: dose, timing, early effect on islet area, and switch in infiltrate from Th1 to Th2 cells.
        Diabetes. 1997; 46: 589-598
        • Scott F.W.
        • Rowsell P.
        • Wang G.S.
        • Burghardt K.
        • Kolb H.
        • Flohe S.
        Oral exposure to diabetes-promoting food or immunomodulators in neonates alters gut cytokines and diabetes.
        Diabetes. 2002; 51: 73-78
        • Houston S.A.
        • Cerovic V.
        • Thomson C.
        • Brewer J.
        • Mowat A.M.
        • Milling S.
        The lymph nodes draining the small intestine and colon are anatomically separate and immunologically distinct.
        Mucosal Immunol. 2016; 9: 468-478
        • Patrick C.
        • Wang G.S.
        • Lefebvre D.E.
        • et al.
        Promotion of autoimmune diabetes by cereal diet in the presence or absence of microbes associated with gut immune activation, regulatory imbalance and altered cathelicidin antimicrobial peptide.
        Diabetes. 2013; 62: 2036-2047
        • Husseini M.
        • Wang G.S.
        • Patrick C.
        • et al.
        Heme Oxygenase-1 induction prevents autoimmune diabetes in association with pancreatic recruitment of M2-like macrophages, mesenchymal cells, and fibrocytes.
        Endocrinology. 2015; 156: 3937-3949
        • Pound L.D.
        • Patrick C.
        • Eberhard C.E.
        • et al.
        Cathelicidin antimicrobial peptide: a novel regulator of islet function, islet regeneration, and selected gut bacteria.
        Diabetes. 2015; 64: 4135-4147
        • Wild C.P.
        Complementing the genome with an “exposome”: the outstanding challenge of environmental exposure measurement in molecular epidemiology.
        Cancer Epidemiol Biomarkers Prev. 2005; 14: 1847-1850
        • Wild C.P.
        The exposome: from concept to utility.
        Int J Epidemiol. 2012; 41: 24-32
        • Floyel T.
        • Kaur S.
        • Pociot F.
        Genes affecting beta-cell function in type 1 diabetes.
        Curr Diab Rep. 2015; 15: 97
        • Onengut-Gumuscu S.
        • Chen W.M.
        • Burren O.
        • et al.
        Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers.
        Nat Genet. 2015; 47: 381-386
        • Bergholdt R.
        • Brorsson C.
        • Palleja A.
        • et al.
        Identification of novel type 1 diabetes candidate genes by integrating genome-wide association data, protein-protein interactions, and human pancreatic islet gene expression.
        Diabetes. 2012; 61: 954-962
        • Eizirik D.L.
        • Sammeth M.
        • Bouckenooghe T.
        • et al.
        The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines.
        PLoS Genet. 2012; 8: e1002552
        • Lysy P.A.
        • Weir G.C.
        • Bonner-Weir S.
        Concise review: pancreas regeneration: recent advances and perspectives.
        Stem Cells Transl Med. 2012; 1: 150-159
        • Kaddis J.S.
        • Pugliese A.
        • Atkinson M.A.
        A run on the biobank: what have we learned about type 1 diabetes from the nPOD tissue repository?.
        Curr Opin Endocrinol Diabetes Obes. 2015; 22: 290-295
        • Leete P.
        • Willcox A.
        • Krogvold L.
        • et al.
        Differential insulitic profiles determine the extent of beta cell destruction and the age at onset of type 1 diabetes.
        Diabetes. 2016; 65: 1362-1369
        • Campbell-Thompson M.L.
        • Atkinson M.A.
        • Butler A.E.
        • et al.
        The diagnosis of insulitis in human type 1 diabetes.
        Diabetologia. 2013; 56: 2541-2543
        • Campbell-Thompson M.
        • Fu A.
        • Kaddis J.S.
        • et al.
        Insulitis and beta-cell mass in the natural history of type 1 diabetes.
        Diabetes. 2016; 65: 719-731
        • Campbell-Thompson M.
        • Wasserfall C.
        • Montgomery E.L.
        • Atkinson M.A.
        • Kaddis J.S.
        Pancreas organ weight in individuals with disease-associated autoantibodies at risk for type 1 diabetes.
        JAMA. 2012; 308: 2337-2339
        • Foulis A.K.
        • Stewart J.A.
        The pancreas in recent-onset type 1 (insulin-dependent) diabetes mellitus: insulin content of islets, insulitis and associated changes in the exocrine acinar tissue.
        Diabetologia. 1984; 26: 456-461
        • Gepts W.
        Pathologic anatomy of the pancreas in juvenile diabetes mellitus.
        Diabetes. 1965; 14: 619-633
        • Rodriguez-Calvo T.
        • Ekwall O.
        • Amirian N.
        • Zapardiel-Gonzalo J.
        • von Herrath M.G.
        Increased immune cell infiltration of the exocrine pancreas: a possible contribution to the pathogenesis of type 1 diabetes.
        Diabetes. 2014; 63: 3880-3890
        • Koskinen M.K.
        • Helminen O.
        • Matomaki J.
        • et al.
        Reduced beta-cell function in early preclinical type 1 diabetes.
        Eur J Endocrinol. 2016; 174: 251-259
        • Brorsson C.A.
        • Onengut S.
        • Chen W.M.
        • et al.
        Novel association between immune-mediated susceptibility loci and persistent autoantibody positivity in type 1 diabetes.
        Diabetes. 2015; 64: 3017-3027
        • Frederiksen B.N.
        • Steck A.K.
        • Kroehl M.
        • et al.
        Evidence of stage- and age-related heterogeneity of non-HLA SNPs and risk of islet autoimmunity and type 1 diabetes: the diabetes autoimmunity study in the young.
        Clin Dev Immunol. 2013; 2013: 417657
        • Keenan H.A.
        • Sun J.K.
        • Levine J.
        • et al.
        Residual insulin production and pancreatic ss-cell turnover after 50 years of diabetes: Joslin Medalist Study.
        Diabetes. 2011; 59: 2846-2853
        • Kauri L.M.
        • Wang G.S.
        • Patrick C.
        • Bareggi M.
        • Hill D.J.
        • Scott F.W.
        Increased islet neogenesis without increased islet mass precedes autoimmune attack in diabetes-prone rats.
        Lab Invest. 2007; 87: 1240-1251
        • Wang G.S.
        • Karamchandani J.
        • Pulido O.
        • Rosenberg L.
        • Scott F.W.
        Altered islet homeostasis before classic insulitis in BB rats.
        Diabetes Metab. 2002; 28 (3S90–3S97)
        • Wang G.S.
        • Rosenberg L.
        • Scott F.W.
        Tubular complexes as a source for islet neogenesis in the pancreas of diabetes-prone BB rats.
        Lab Invest. 2005; 85: 675-688
        • Seemayer T.A.
        • Colle E.
        • Tannenbaum G.S.
        • Oligny L.L.
        • Guttmann R.D.
        • Goldman H.
        Spontaneous diabetes mellitus syndrome in the rat. III. Pancreatic alterations in aglycosuric and untreated diabetic BB Wistar-derived rats.
        Metabolism. 1983; 32: 26-32
        • Hattori M.
        • Fukuda M.
        • Ichikawa T.
        • Baumgartl H.J.
        • Katoh H.
        • Makino S.
        A single recessive non-MHC diabetogenic gene determines the development of insulitis in the presence of an MHC-linked diabetogenic gene in NOD mice.
        J Autoimmun. 1990; 3: 1-10
        • Parsa R.
        • Andresen P.
        • Gillett A.
        • et al.
        Adoptive transfer of immunomodulatory M2 macrophages prevents type 1 diabetes in NOD mice.
        Diabetes. 2012; 61: 2881-2892
        • Herold K.C.
        • Vignali D.A.
        • Cooke A.
        • Bluestone J.A.
        Type 1 diabetes: translating mechanistic observations into effective clinical outcomes.
        Nat Rev Immunol. 2013; 13: 243-256
        • Morgan N.G.
        • Leete P.
        • Foulis A.K.
        • Richardson S.J.
        Islet inflammation in human type 1 diabetes mellitus.
        IUBMB Life. 2015; 66: 723-734
        • Vegas A.J.
        • Veiseh O.
        • Gurtler M.
        • et al.
        Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice.
        Nat Med. 2016; 22: 306-311
        • Keeney K.M.
        • Yurist-Doutsch S.
        • Arrieta M.C.
        • Finlay B.B.
        Effects of antibiotics on human microbiota and subsequent disease.
        Annu Rev Microbiol. 2014; 68: 217-235
        • Dunne J.L.
        • Triplett E.W.
        • Gevers D.
        • et al.
        The intestinal microbiome in type 1 diabetes.
        Clin Exp Immunol. 2014; 177: 30-37
        • Hu C.
        • Wong F.S.
        • Wen L.
        Type 1 diabetes and gut microbiota: Friend or foe?.
        Pharmacol Res. 2015; 98: 9-15
        • McLean M.H.
        • Dieguez Jr., D.
        • Miller L.M.
        • Young H.A.
        Does the microbiota play a role in the pathogenesis of autoimmune diseases?.
        Gut. 2015; 64: 332-341
        • Neu J.
        • Lorca G.
        • Kingma S.D.
        • Triplett E.W.
        The intestinal microbiome: relationship to type 1 diabetes.
        Endocrinol Metab Clin North Am. 2010; 39: 563-571
        • Nielsen D.S.
        • Krych L.
        • Buschard K.
        • Hansen C.H.
        • Hansen A.K.
        Beyond genetics. Influence of dietary factors and gut microbiota on type 1 diabetes.
        FEBS Lett. 2014; 588: 4234-4243
        • Paun A.
        • Danska J.S.
        Immuno-ecology: how the microbiome regulates tolerance and autoimmunity.
        Curr Opin Immunol. 2015; 37: 34-39
        • Giongo A.
        • Gano K.A.
        • Crabb D.B.
        • et al.
        Toward defining the autoimmune microbiome for type 1 diabetes.
        ISME J. 2011; 5: 82-91
        • Knip M.
        • Siljander H.
        The role of the intestinal microbiota in type 1 diabetes mellitus.
        Nat Rev Endocrinol. 2016; 12: 154-167
        • Tai N.
        • Wong F.S.
        • Wen L.
        The role of gut microbiota in the development of type 1, type 2 diabetes mellitus and obesity.
        Rev Endocr Metab Disord. 2015; 16: 55-65
        • Daft J.G.
        • Lorenz R.G.
        Role of the gastrointestinal ecosystem in the development of type 1 diabetes.
        Pediatr Diabetes. 2015; 16: 407-418
        • Gulden E.
        • Wong F.S.
        • Wen L.
        The gut microbiota and Type 1 Diabetes.
        Clin Immunol. 2015; 159: 143-153
        • Mejia-Leon M.E.
        • Barca A.M.
        Diet, microbiota and immune system in type 1 diabetes development and Evolution.
        Nutrients. 2015; 7: 9171-9184
        • Ji B.
        • Nielsen J.
        From next-generation sequencing to systematic modeling of the gut microbiome.
        Front Genet. 2015; 6: 219
        • Roesch L.F.
        • Lorca G.L.
        • Casella G.
        • et al.
        Culture-independent identification of gut bacteria correlated with the onset of diabetes in a rat model.
        ISME J. 2009; 3: 536-548
        • Brugman S.
        • Klatter F.A.
        • Visser J.T.
        • et al.
        Antibiotic treatment partially protects against type 1 diabetes in the Bio-Breeding diabetes-prone rat. Is the gut flora involved in the development of type 1 diabetes?.
        Diabetologia. 2006; 49: 2105-2108
        • Markle J.G.
        • Frank D.N.
        • Mortin-Toth S.
        • et al.
        Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity.
        Science. 2013; 339: 1084-1088
        • Wen L.
        • Ley R.E.
        • Volchkov P.Y.
        • et al.
        Innate immunity and intestinal microbiota in the development of Type 1 diabetes.
        Nature. 2008; 455: 1109-1113
        • Yurkovetskiy L.
        • Burrows M.
        • Khan A.A.
        • et al.
        Gender bias in autoimmunity is influenced by microbiota.
        Immunity. 2013; 39: 400-412
        • Alam C.
        • Bittoun E.
        • Bhagwat D.
        • et al.
        Effects of a germ-free environment on gut immune regulation and diabetes progression in non-obese diabetic (NOD) mice.
        Diabetologia. 2011; 54: 1398-1406
        • King C.
        • Sarvetnick N.
        The incidence of type-1 diabetes in NOD mice is modulated by restricted flora not germ-free conditions.
        PLoS One. 2011; 6: e17049
        • Kugelberg E.
        Mucosal immunology: bacteria get T(Reg) cells into shape.
        Nat Rev Immunol. 2014; 14: 2-3
        • Kostic A.D.
        • Gevers D.
        • Siljander H.
        • et al.
        The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes.
        Cell Host Microbe. 2015; 17: 260-273
        • Auricchio R.
        • Paparo F.
        • Maglio M.
        • et al.
        In vitro-deranged intestinal immune response to gliadin in type 1 diabetes.
        Diabetes. 2004; 53: 1680-1683
        • Sapone A.
        • de Magistris L.
        • Pietzak M.
        • et al.
        Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives.
        Diabetes. 2006; 55: 1443-1449
        • Secondulfo M.
        • Iafusco D.
        • Carratu R.
        • et al.
        Ultrastructural mucosal alterations and increased intestinal permeability in non-celiac, type I diabetic patients.
        Dig Liver Dis. 2004; 36: 35-45
        • Westerholm-Ormio M.
        • Vaarala O.
        • Pihkala P.
        • Ilonen J.
        • Savilahti E.
        Immunologic activity in the small intestinal mucosa of pediatric patients with type 1 diabetes.
        Diabetes. 2003; 52: 2287-2295
        • Benson A.K.
        • Kelly S.A.
        • Legge R.
        • et al.
        Individuality in gut microbiota composition is a complex polygenic trait shaped by multiple environmental and host genetic factors.
        Proc Natl Acad Sci U S A. 2010; 107: 18933-18938
        • Carmody R.N.
        • Gerber G.K.
        • Luevano Jr., J.M.
        • et al.
        Diet dominates host genotype in shaping the murine gut microbiota.
        Cell Host Microbe. 2015; 17: 72-84
        • Org E.
        • Parks B.W.
        • Joo J.W.
        • et al.
        Genetic and environmental control of host-gut microbiota interactions.
        Genome Res. 2015; 25: 1558-1569
        • Snell-Bergeon J.K.
        • Smith J.
        • Dong F.
        • et al.
        Early childhood infections and the risk of islet autoimmunity: the diabetes autoimmunity study in the young (DAISY).
        Diabetes Care. 2012; 35: 2553-2558
        • Yurkovetskiy L.A.
        • Pickard J.M.
        • Chervonsky A.V.
        Microbiota and autoimmunity: exploring new avenues.
        Cell Host Microbe. 2015; 17: 548-552
        • Hummel S.
        • Pfluger M.
        • Hummel M.
        • Bonifacio E.
        • Ziegler A.G.
        Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study.
        Diabetes Care. 2011; 34: 1301-1305
        • Endesfelder D.
        • zu Castell W.
        • Ardissone A.
        • et al.
        Compromised gut microbiota networks in children with anti-islet cell autoimmunity.
        Diabetes. 2014; 63: 2006-2014
        • Tormo-Badia N.
        • Hakansson A.
        • Vasudevan K.
        • Molin G.
        • Ahrne S.
        • Cilio C.M.
        Antibiotic treatment of pregnant non-obese diabetic mice leads to altered gut microbiota and intestinal immunological changes in the offspring.
        Scand J Immunol. 2014; 80: 250-260
        • Hansen C.H.
        • Krych L.
        • Nielsen D.S.
        • et al.
        Early life treatment with vancomycin propagates Akkermansia muciniphila and reduces diabetes incidence in the NOD mouse.
        Diabetologia. 2012; 55: 2285-2294
        • Brown K.
        • Godovannyi A.
        • Ma C.
        • et al.
        Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice.
        ISME J. 2015; 10: 321-332
        • Hara N.
        • Alkanani A.K.
        • Ir D.
        • et al.
        Prevention of virus-induced type 1 diabetes with antibiotic therapy.
        J Immunol. 2012; 189: 3805-3814
        • Rossini A.A.
        • Williams R.M.
        • Mordes J.P.
        • Appel M.C.
        • Like A.A.
        Spontaneous diabetes in the gnotobiotic BB/W rat.
        Diabetes. 1979; 28: 1031-1032
      1. Funda D, Fundova P, Harrison LC. Microflora-dependency of selective diabetes-preventive diets: germ-free and ex-germ-free monocolonized NOD mice as models for studying environmental factors in type 1 diabetes. Proc 13th Int Congress Immunology MS-114 16 2007.

        • EURODIAB
        Infections and vaccinations as risk factors for childhood type I (insulin-dependent) diabetes mellitus: a multicentre case-control investigation. EURODIAB Substudy 2 Study Group.
        Diabetologia. 2000; 43: 47-53
        • Cardwell C.R.
        • Carson D.J.
        • Patterson C.C.
        No association between routinely recorded infections in early life and subsequent risk of childhood-onset Type 1 diabetes: a matched case-control study using the UK General Practice Research Database.
        Diabet Med. 2008; 25: 261-267
        • Hviid A.
        • Svanstrom H.
        Antibiotic use and type 1 diabetes in childhood.
        Am J Epidemiol. 2009; 169: 1079-1084
        • Abela A.G.
        • Fava S.
        Association of incidence of type 1 diabetes with mortality from infectious disease and with antibiotic susceptibility at a country level.
        Acta Diabetol. 2013; 50: 859-865
        • Boursi B.
        • Mamtani R.
        • Haynes K.
        • Yang Y.X.
        The effect of past antibiotic exposure on diabetes risk.
        Eur J Endocrinol. 2015; 172: 639-648
        • Uusitalo U.
        • Liu X.
        • Yang J.
        • et al.
        Association of early exposure of probiotics and islet autoimmunity in the TEDDY study.
        JAMA Pediatr. 2016; 170: 20-28
        • Fazeli Farsani S.
        • Souverein P.C.
        • van der Vorst M.M.
        • Knibbe C.A.
        • de Boer A.
        • Mantel-Teeuwisse A.K.
        Population-based cohort study of anti-infective medication use before and after the onset of type 1 diabetes in children and adolescents.
        Antimicrob Agents Chemother. 2014; 58: 4666-4674
        • Muegge B.D.
        • Kuczynski J.
        • Knights D.
        • et al.
        Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans.
        Science. 2011; 332: 970-974
        • Walter J.
        Murine gut microbiota-diet trumps genes.
        Cell Host Microbe. 2015; 17: 3-5
        • Yatsunenko T.
        • Rey F.E.
        • Manary M.J.
        • et al.
        Human gut microbiome viewed across age and geography.
        Nature. 2012; 486: 222-227
        • Kemppainen K.M.
        • Ardissone A.N.
        • Davis-Richardson A.G.
        • et al.
        Early childhood gut microbiomes show strong geographic differences among subjects at high risk for type 1 diabetes.
        Diabetes Care. 2015; 38: 329-332
        • Mojibian M.
        • Chakir H.
        • Lefebvre D.E.
        • et al.
        A diabetes-specific HLA-DR restricted pro-inflammatory T cell response to wheat polypeptides in tissue transglutaminase antibody negative patients with type 1 diabetes.
        Diabetes. 2009; 58: 1789-1796
        • Alam C.
        • Valkonen S.
        • Palagani V.
        • Jalava J.
        • Eerola E.
        • Hanninen A.
        Inflammatory tendencies and overproduction of IL-17 in the colon of young NOD mice are counteracted with diet change.
        Diabetes. 2010; 59: 2237-2246
        • Courtois P.
        • Nsimba G.
        • Jijakli H.
        • Sener A.
        • Scott F.W.
        • Malaisse W.J.
        Gut permeability and intestinal mucins, invertase, and peroxidase in control and diabetes-prone BB rats fed either a protective or a diabetogenic diet.
        Dig Dis Sci. 2005; 50: 266-275
        • Watts T.
        • Berti I.
        • Sapone A.
        • et al.
        Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats.
        Proc Natl Acad Sci U S A. 2005; 102: 2916-2921
        • Courtois P.
        • Jurysta C.
        • Sener A.
        • Scott F.W.
        • Malaisse W.J.
        Quantitative and qualitative alterations of intestinal mucins in BioBreeding rats.
        Int J Mol Med. 2005; 15: 105-108
        • Emani R.
        • Alam C.
        • Pekkala S.
        • Zafar S.
        • Emani M.R.
        • Hanninen A.
        Peritoneal cavity is a route for gut-derived microbial signals to promote autoimmunity in non-obese diabetic mice.
        Scand J Immunol. 2015; 81: 102-109
        • Visser J.T.
        • Lammers K.
        • Hoogendijk A.
        • et al.
        Restoration of impaired intestinal barrier function by the hydrolysed casein diet contributes to the prevention of type 1 diabetes in the diabetes-prone BioBreeding rat.
        Diabetologia. 2010; 53: 2621-2628
        • Beyan H.
        • Wen L.
        • Leslie R.D.
        Guts, germs, and meals: the origin of type 1 diabetes.
        Curr Diab Rep. 2012; 12: 456-462
        • Gale E.A.
        The rise of childhood type 1 diabetes in the 20th century.
        Diabetes. 2002; 51: 3353-3361
        • Knip M.
        • Akerblom H.K.
        • Becker D.
        • et al.
        Hydrolyzed infant formula and early beta-cell autoimmunity: a randomized clinical trial.
        JAMA. 2015; 311: 2279-2287
        • Knip M.
        • Virtanen S.M.
        • Seppa K.
        • et al.
        Dietary intervention in infancy and later signs of beta-cell autoimmunity.
        N Engl J Med. 2010; 363: 1900-1908
        • Ziegler A.G.
        • Nepom G.T.
        Prediction and pathogenesis in type 1 diabetes.
        Immunity. 2010; 32: 468-478
        • Caicedo R.A.
        • Li N.
        • Des Robert C.
        • et al.
        Neonatal formula feeding leads to immunological alterations in an animal model of type 1 diabetes.
        Pediatr Res. 2008; 63: 303-307
        • Frederiksen B.N.
        • Kroehl M.
        • Baron A.
        • et al.
        Assessing age-related etiologic heterogeneity in the onset of islet autoimmunity.
        Biomed Res Int. 2015; 2015: 708289
        • Ray K.
        Going against the grain.
        Nat Rev Gastroenterol Hepatol. 2015; 12: 547
        • Scott F.W.
        • Sarwar G.
        • Cloutier H.E.
        Diabetogenicity of various protein sources in the diet of the diabetes-prone BB rat.
        Adv Exp Med Biol. 1988; 246: 277-285
        • Funda D.P.
        • Kaas A.
        • Bock T.
        • Tlaskalova-Hogenova H.
        • Buschard K.
        Gluten-free diet prevents diabetes in NOD mice.
        Diabetes Metab Res Rev. 1999; 15: 323-327
        • Barbeau W.E.
        What is the key environmental trigger in type 1 diabetes–is it viruses, or wheat gluten, or both?.
        Autoimmun Rev. 2012; 12: 295-299
        • Barbeau W.E.
        • Hontecillas R.
        • Horne W.
        • Carbo A.
        • Koch M.H.
        • Bassaganya-Riera J.
        Elevated CD8 T cell responses in type 1 diabetes patients to a 13 amino acid coeliac-active peptide from alpha-gliadin.
        Clin Exp Immunol. 2014; 175: 167-171
        • Norris J.M.
        • Barriga K.
        • Klingensmith G.
        • et al.
        Timing of initial cereal exposure in infancy and risk of islet autoimmunity.
        JAMA. 2003; 290: 1713-1720
        • Sildorf S.M.
        • Fredheim S.
        • Svensson J.
        • Buschard K.
        Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus.
        BMJ Case Rep. 2012; 2012https://doi.org/10.1136/bcr.1102.2012.5878
        • Ziegler A.G.
        • Schmid S.
        • Huber D.
        • Hummel M.
        • Bonifacio E.
        Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies.
        JAMA. 2003; 290: 1721-1728
        • Svensson J.
        • Sildorf S.M.
        • Pipper C.B.
        • et al.
        Potential beneficial effects of a gluten-free diet in newly diagnosed children with type 1 diabetes: a pilot study.
        Springerplus. 2016; 5: 994
        • Hamari S.
        • Kirveskoski T.
        • Glumoff V.
        • et al.
        CD4(+) T-cell proliferation responses to wheat polypeptide stimulation in children at different stages of type 1 diabetes autoimmunity.
        Pediatr Diabetes. 2015; 16: 177-188
        • Catassi C.
        • Guerrieri A.
        • Bartolotta E.
        • Coppa G.V.
        • Giorgi P.L.
        Antigliadin antibodies at onset of diabetes in children.
        Lancet. 1987; 2: 158
        • Chmiel R.
        • Beyerlein A.
        • Knopff A.
        • Hummel S.
        • Ziegler A.G.
        • Winkler C.
        Early infant feeding and risk of developing islet autoimmunity and type 1 diabetes.
        Acta Diabetol. 2015; 52: 621-624
        • Funda D.P.
        • Fundova P.
        • Hansen A.K.
        • Buschard K.
        Prevention or early cure of type 1 diabetes by intranasal administration of gliadin in NOD mice.
        PLoS One. 2014; 9: e94530
        • Pabst O.
        • Mowat A.M.
        Oral tolerance to food protein.
        Mucosal Immunol. 2012; 5: 232-239
        • Hanenberg H.
        • Kolb-Bachofen V.
        • Kantwerk-Funke G.
        • Kolb H.
        Macrophage infiltration precedes and is a prerequisite for lymphocytic insulitis in pancreatic islets of pre-diabetic BB rats.
        Diabetologia. 1989; 32: 126-134
        • Ihm S.H.
        • Yoon J.W.
        Studies on autoimmunity for initiation of beta-cell destruction. VI. Macrophages essential for development of beta-cell-specific cytotoxic effectors and insulitis in NOD mice.
        Diabetes. 1990; 39: 1273-1278
        • Jorns A.
        • Gunther A.
        • Hedrich H.J.
        • Wedekind D.
        • Tiedge M.
        • Lenzen S.
        Immune cell infiltration, cytokine expression, and beta-cell apoptosis during the development of type 1 diabetes in the spontaneously diabetic LEW.1AR1/Ztm-iddm rat.
        Diabetes. 2005; 54: 2041-2052
        • Jun H.S.
        • Yoon C.S.
        • Zbytnuik L.
        • van Rooijen N.
        • Yoon J.W.
        The role of macrophages in T cell-mediated autoimmune diabetes in nonobese diabetic mice.
        J Exp Med. 1999; 189: 347-358
        • Kolb-Bachofen V.
        • Schraermeyer U.
        • Hoppe T.
        • Hanenberg H.
        • Kolb H.
        Diabetes manifestation in BB rats is preceded by pan-pancreatic presence of activated inflammatory macrophages.
        Pancreas. 1992; 7: 578-584
        • Cabrera S.M.
        • Chen Y.G.
        • Hagopian W.A.
        • Hessner M.J.
        Blood-based signatures in type 1 diabetes.
        Diabetologia. 2016; 59: 414-425
        • Cabrera S.M.
        • Henschel A.M.
        • Hessner M.J.
        Innate inflammation in type 1 diabetes.
        Transl Res. 2016; 167: 214-227
        • Mantovani A.
        • Sica A.
        • Sozzani S.
        • Allavena P.
        • Vecchi A.
        • Locati M.
        The chemokine system in diverse forms of macrophage activation and polarization.
        Trends Immunol. 2004; 25: 677-686
        • Sica A.
        • Mantovani A.
        Macrophage plasticity and polarization: in vivo veritas.
        J Clin Invest. 2012; 122: 787-795
        • Martinez F.O.
        • Helming L.
        • Gordon S.
        Alternative activation of macrophages: an immunologic functional perspective.
        Annu Rev Immunol. 2009; 27: 451-483
        • Scaglia L.
        • Cahill C.J.
        • Finegood D.T.
        • Bonner-Weir S.
        Apoptosis participates in the remodeling of the endocrine pancreas in the neonatal rat.
        Endocrinology. 1997; 138: 1736-1741
        • Stoffels K.
        • Overbergh L.
        • Giulietti A.
        • et al.
        NOD macrophages produce high levels of inflammatory cytokines upon encounter of apoptotic or necrotic cells.
        J Autoimmun. 2004; 23: 9-15
        • O'Brien B.A.
        • Fieldus W.E.
        • Field C.J.
        • Finegood D.T.
        Clearance of apoptotic beta-cells is reduced in neonatal autoimmune diabetes-prone rats.
        Cell Death Differ. 2002; 9: 457-464
        • Devaraj S.
        • Glaser N.
        • Griffen S.
        • Wang-Polagruto J.
        • Miguelino E.
        • Jialal I.
        Increased monocytic activity and biomarkers of inflammation in patients with type 1 diabetes.
        Diabetes. 2006; 55: 774-779
        • Calderon B.
        • Suri A.
        • Pan X.O.
        • Mills J.C.
        • Unanue E.R.
        IFN-gamma-dependent regulatory circuits in immune inflammation highlighted in diabetes.
        J Immunol. 2008; 181: 6964-6974
        • Thayer T.C.
        • Delano M.
        • Liu C.
        • et al.
        Superoxide production by macrophages and T cells is critical for the induction of autoreactivity and type 1 diabetes.
        Diabetes. 2011; 60: 2144-2151
        • Valle A.
        • Giamporcaro G.M.
        • Scavini M.
        • et al.
        Reduction of circulating neutrophils precedes and accompanies type 1 diabetes.
        Diabetes. 2013; 62: 2072-2077
        • Sun J.
        • Xu M.
        • Ortsater H.
        • et al.
        Cathelicidins positively regulate pancreatic beta-cell functions.
        FASEB J. 2016; 30: 884-894
        • Sun J.
        • Furio L.
        • Mecheri R.
        • et al.
        Pancreatic beta-cells limit autoimmune diabetes via an immunoregulatory antimicrobial peptide expressed under the influence of the gut microbiota.
        Immunity. 2015; 43: 304-317
        • Shaykhiev R.
        • Beisswenger C.
        • Kandler K.
        • et al.
        Human endogenous antibiotic LL-37 stimulates airway epithelial cell proliferation and wound closure.
        Am J Physiol Lung Cell Mol Physiol. 2005; 289: L842-L848
        • Mathews C.E.
        Utility of murine models for the study of spontaneous autoimmune type 1 diabetes.
        Pediatr Diabetes. 2005; 6: 165-177
        • Jorns A.
        • Arndt T.
        • Meyer zu Vilsendorf A.
        • et al.
        Islet infiltration, cytokine expression and beta cell death in the NOD mouse, BB rat, Komeda rat, LEW.1AR1-iddm rat and humans with type 1 diabetes.
        Diabetologia. 2014; 57: 512-521
        • Cardozo A.K.
        • Proost P.
        • Gysemans C.
        • Chen M.C.
        • Mathieu C.
        • Eizirik D.L.
        IL-1beta and IFN-gamma induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice.
        Diabetologia. 2003; 46: 255-266
        • Nica A.C.
        • Ongen H.
        • Irminger J.C.
        • et al.
        Cell-type, allelic, and genetic signatures in the human pancreatic beta cell transcriptome.
        Genome Res. 2013; 23: 1554-1562
        • Marinkovic T.
        • Oresic M.
        Modeling strategies to study metabolic pathways in progression to type 1 diabetes–Challenges and opportunities.
        Arch Biochem Biophys. 2015; 589: 131-137
        • Zeevi D.
        • Korem T.
        • Zmora N.
        • et al.
        Personalized nutrition by prediction of glycemic responses.
        Cell. 2015; 163: 1079-1094
        • Sonnenburg E.D.
        • Sonnenburg J.L.
        Nutrition: a personal forecast.
        Nature. 2015; 528: 484-486
        • Kaldunski M.
        • Jia S.
        • Geoffrey R.
        • et al.
        Identification of a serum-induced transcriptional signature associated with type 1 diabetes in the BioBreeding rat.
        Diabetes. 2010; 59: 2375-2385
        • Chen Y.G.
        • Cabrera S.M.
        • Jia S.
        • et al.
        Molecular signatures differentiate immune states in type 1 diabetic families.
        Diabetes. 2014; 63: 3960-3973
        • Cabrera S.M.
        • Wang X.
        • Chen Y.G.
        • et al.
        Interleukin-1 antagonism moderates the inflammatory state associated with Type 1 diabetes during clinical trials conducted at disease onset.
        Eur J Immunol. 2016; 46: 1030-1046