The Role of Gut Microbiota and Environmental Factors in Type 1 Diabetes Pathogenesis

Sandra Dedrick, Bharathi Sundaresh, Qian Huang, Claudia Brady, Tessa Yoo, Catherine Cronin, Caitlin Rudnicki, Michael Flood, Babak Momeni, Johnny Ludvigsson, Emrah Altindis, Sandra Dedrick, Bharathi Sundaresh, Qian Huang, Claudia Brady, Tessa Yoo, Catherine Cronin, Caitlin Rudnicki, Michael Flood, Babak Momeni, Johnny Ludvigsson, Emrah Altindis

Abstract

Type 1 Diabetes (T1D) is regarded as an autoimmune disease characterized by insulin deficiency resulting from destruction of pancreatic β-cells. The incidence rates of T1D have increased worldwide. Over the past decades, progress has been made in understanding the complexity of the immune response and its role in T1D pathogenesis, however, the trigger of T1D autoimmunity remains unclear. The increasing incidence rates, immigrant studies, and twin studies suggest that environmental factors play an important role and the trigger cannot simply be explained by genetic predisposition. Several research initiatives have identified environmental factors that potentially contribute to the onset of T1D autoimmunity and the progression of disease in children/young adults. More recently, the interplay between gut microbiota and the immune system has been implicated as an important factor in T1D pathogenesis. Although results often vary between studies, broad compositional and diversity patterns have emerged from both longitudinal and cross-sectional human studies. T1D patients have a less diverse gut microbiota, an increased prevalence of Bacteriodetes taxa and an aberrant metabolomic profile compared to healthy controls. In this comprehensive review, we present the data obtained from both animal and human studies focusing on the large longitudinal human studies. These studies are particularly valuable in elucidating the environmental factors that lead to aberrant gut microbiota composition and potentially contribute to T1D. We also discuss how environmental factors, such as birth mode, diet, and antibiotic use modulate gut microbiota and how this potentially contributes to T1D. In the final section, we focus on existing recent literature on microbiota-produced metabolites, proteins, and gut virome function as potential protectants or triggers of T1D onset. Overall, current results indicate that higher levels of diversity along with the presence of beneficial microbes and the resulting microbial-produced metabolites can act as protectors against T1D onset. However, the specifics of the interplay between host and microbes are yet to be discovered.

Keywords: autoimmunity; environmental factors; longitudinal studies children; microbiome; type 1 diabetes.

Copyright © 2020 Dedrick, Sundaresh, Huang, Brady, Yoo, Cronin, Rudnicki, Flood, Momeni, Ludvigsson and Altindis.

Figures

Figure 1
Figure 1
Environmental factors modulate gut microbiota and potentially contribute to T1D onset. Environmental factors, such as birth mode, diet early in life, and use of antibiotics can influence gut microbiota composition and can to lead to lower bacterial diversity, decreased SCFA production and increased gut permeability. Bacterial phyla/genus/species that are affected by environmental factors and differ between T1D patients and healthy controls are depicted in the colors black/green/purple, respectively. Bacterial genus/species that have been identified in proteomic analyses and are increased in either T1D patients or healthy controls are shown in red. Bacterial genus/species that have been identified in metabolomics analyses and are increased in either T1D patients or healthy controls are shown in blue.

References

    1. Blum HE. The human microbiome. Adv Med Sci. (2017) 62:414–20. 10.1016/j.advms.2017.04.005
    1. Gordo I. Evolutionary change in the human gut microbiome: From a static to a dynamic view. PLoS Biol. (2019) 17:e3000126. 10.1371/journal.pbio.3000126
    1. Miller FW, Pollard KM, Parks CG, Germolec DR, Leung PS, Selmi C, et al. . Criteria for environmentally associated autoimmune diseases. J Autoimmun. (2012) 39:253–8. 10.1016/j.jaut.2012.05.001
    1. Ramos-Casals M, Brito-Zeron P, Kostov B, Siso-Almirall A, Bosch X, Buss D, et al. . Google-driven search for big data in autoimmune geoepidemiology: analysis of 394,827 patients with systemic autoimmune diseases. Autoimmun Rev. (2015) 14:670–9. 10.1016/j.autrev.2015.03.008
    1. De Luca F, Shoenfeld Y. The microbiome in autoimmune diseases. Clin Exp Immunol. (2019) 195:74–85. 10.1111/cei.13158
    1. Marietta E, Horwath I, Balakrishnan B, Taneja V. Role of the intestinal microbiome in autoimmune diseases and its use in treatments. Cell Immunol. (2019) 339:50–8. 10.1016/j.cellimm.2018.10.005
    1. Lloyd-Price J, Mahurkar A, Rahnavard G, Crabtree J, Orvis J, Hall AB, et al. . Strains, functions and dynamics in the expanded Human Microbiome Project. Nature. (2017) 550:61–6. 10.1038/nature23889
    1. Maruvada P, Leone V, Kaplan LM, Chang EB. The human microbiome and obesity: moving beyond associations. Cell Host Microbe. (2017) 22:589–99. 10.1016/j.chom.2017.10.005
    1. Young VB. The role of the microbiome in human health and disease: an introduction for clinicians. BMJ. (2017) 356:j831. 10.1136/bmj.j831
    1. Rinaldi M, Perricone R, Blank M, Perricone C, Shoenfeld Y. Anti-Saccharomyces cerevisiae autoantibodies in autoimmune diseases: from bread baking to autoimmunity. Clin Rev Allergy Immunol. (2013) 45:152–61. 10.1007/s12016-012-8344-9
    1. Lamps LW, Madhusudhan KT, Havens JM, Greenson JK, Bronner MP, Chiles MC, et al. . Pathogenic Yersinia DNA is detected in bowel and mesenteric lymph nodes from patients with Crohn's disease. Am J Surg Pathol. (2003) 27:220–7. 10.1097/00000478-200302000-00011
    1. Chassaing B, Rolhion N, De Vallee A, Salim SY, Prorok-Hamon M, Neut C, et al. . Crohn disease–associated adherent-invasive E. coli bacteria target mouse and human Peyer's patches via long polar fimbriae. J Clin Invest. (2011) 121:966–75. 10.1172/JCI44632
    1. Gevers D, Kugathasan S, Denson LA, Vazquez-Baeza Y, Van Treuren W, Ren B, et al. . The treatment-naive microbiome in new-onset Crohn's disease. Cell Host Microbe. (2014) 15:382–92. 10.1016/j.chom.2014.02.005
    1. Carding S, Verbeke K, Vipond DT, Corfe BM, Owen LJ. Dysbiosis of the gut microbiota in disease. Microb Ecol Health Dis. (2015) 26:26191. 10.3402/mehd.v26.26191
    1. Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci USA. (2007) 104:13780–5. 10.1073/pnas.0706625104
    1. Navaneethan U, Venkatesh PG, Shen B. Clostridium difficile infection and inflammatory bowel disease: understanding the evolving relationship. World J Gastroenterol. (2010) 16:4892–904. 10.3748/wjg.v16.i39.4892
    1. Quagliariello A, Aloisio I, Bozzi Cionci N, Luiselli D, D'auria G, Martinez-Priego L, et al. . Effect of bifidobacterium breve on the intestinal microbiota of coeliac children on a gluten free diet: a pilot study. Nutrients. (2016) 8:660. 10.3390/nu8100660
    1. Heintz-Buschart A, May P, Laczny CC, Lebrun LA, Bellora C, Krishna A, et al. . Erratum: integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes. Nat Microbiol. (2016) 2:16227. 10.1038/nmicrobiol.2016.227
    1. Vatanen T, Franzosa EA, Schwager R, Tripathi S, Arthur TD, Vehik K, et al. . The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. Nature. (2018) 562:589–94. 10.1038/s41586-018-0620-2
    1. Atarashi K, Honda K. Microbiota in autoimmunity and tolerance. Curr Opin Immunol. (2011) 23:761–8. 10.1016/j.coi.2011.11.002
    1. Gensollen T, Iyer SS, Kasper DL, Blumberg RS. How colonization by microbiota in early life shapes the immune system. Science. (2016) 352:539–44. 10.1126/science.aad9378
    1. Kriegel MA, Sefik E, Hill JA, Wu HJ, Benoist C, Mathis D. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc Natl Acad Sci USA. (2011) 108:11548–53. 10.1073/pnas.1108924108
    1. Russell JT, Roesch LFW, Ordberg M, Ilonen J, Atkinson MA, Schatz DA, et al. . Genetic risk for autoimmunity is associated with distinct changes in the human gut microbiome. Nat Commun. (2019) 10:3621. 10.1038/s41467-019-11460-x
    1. Wu HJ, Ivanov Ii, Darce J, Hattori K, Shima T, Umesaki Y, et al. . Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity. (2010) 32:815–27. 10.1016/j.immuni.2010.06.001
    1. Di Giacinto C, Marinaro M, Sanchez M, Strober W, Boirivant M. Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells. J Immunol. (2005) 174:3237–46. 10.4049/jimmunol.174.6.3237
    1. Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, et al. . Induction of colonic regulatory T cells by indigenous Clostridium species. Science. (2011) 331:337–41. 10.1126/science.1198469
    1. Rai E, Wakeland EK. Genetic predisposition to autoimmunity–what have we learned? Semin Immunol. (2011) 23:67–83. 10.1016/j.smim.2011.01.015
    1. Ceccarelli F, Agmon-Levin N, Perricone C. Genetic factors of autoimmune diseases 2017. J Immunol Res. (2017) 2017:2789242. 10.1155/2017/2789242
    1. Vojdani A, Pollard KM, Campbell AW. Environmental triggers and autoimmunity. Autoimmune Dis. (2014) 2014:798029 10.1155/2014/798029
    1. Jorg S, Grohme DA, Erzler M, Binsfeld M, Haghikia A, Muller DN, et al. . Environmental factors in autoimmune diseases and their role in multiple sclerosis. Cell Mol Life Sci. (2016) 73:4611–22. 10.1007/s00018-016-2311-1
    1. Agmon-Levin N, Ram M, Barzilai O, Porat-Katz BS, Parikman R, Selmi C, et al. . Prevalence of hepatitis C serum antibody in autoimmune diseases. J Autoimmun. (2009) 32:261–6. 10.1016/j.jaut.2009.02.017
    1. Getts DR, Chastain EM, Terry RL, Miller SD. Virus infection, antiviral immunity, and autoimmunity. Immunol Rev. (2013) 255:197–209. 10.1111/imr.12091
    1. Vojdani A. A potential link between environmental triggers and autoimmunity. Autoimmune Dis. (2014) 2014:437231. 10.1155/2014/437231
    1. Vanderlugt CJ, Miller SD. Epitope spreading. Curr Opin Immunol. (1996) 8:831–6. 10.1016/S0952-7915(96)80012-4
    1. Guilherme L, Kalil J, Cunningham M. Molecular mimicry in the autoimmune pathogenesis of rheumatic heart disease. Autoimmunity. (2006) 39:31–9. 10.1080/08916930500484674
    1. De Goffau MC, Luopajarvi K, Knip M, Ilonen J, Ruohtula T, Harkonen T, et al. . Fecal microbiota composition differs between children with beta-cell autoimmunity and those without. Diabetes. (2013) 62:1238–44. 10.2337/db12-0526
    1. Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. (2014) 157:121–41. 10.1016/j.cell.2014.03.011
    1. De Goffau MC, Fuentes S, Van Den Bogert B, Honkanen H, De Vos WM, Welling GW, et al. . Aberrant gut microbiota composition at the onset of type 1 diabetes in young children. Diabetologia. (2014) 57:1569–77. 10.1007/s00125-014-3274-0
    1. Chen J, Wright K, Davis JM, Jeraldo P, Marietta EV, Murray J, et al. . An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome Med. (2016) 8:43. 10.1186/s13073-016-0299-7
    1. Jangi S, Gandhi R, Cox LM, Li N, Von Glehn F, Yan R, et al. . Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. (2016) 7:12015. 10.1038/ncomms12015
    1. De Groot PF, Belzer C, Aydin O, Levin E, Levels JH, Aalvink S, et al. . Distinct fecal and oral microbiota composition in human type 1 diabetes, an observational study. PLoS ONE. (2017) 12:e0188475. 10.1371/journal.pone.0188475
    1. Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ. Epidemiology of type 1 diabetes. Endocrinol Metab Clin North Am. (2010) 39:481–97. 10.1016/j.ecl.2010.05.011
    1. Patterson CC, Dahlquist GG, Gyurus E, Green A, Soltesz G, Group ES. Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet. (2009) 373:2027–33. 10.1016/S0140-6736(09)60568-7
    1. Jin JS, Touyama M, Yamada S, Yamazaki T, Benno Y. Alteration of a human intestinal microbiota under extreme life environment in the Antarctica. Biol Pharm Bull. (2014) 37:1899–906. 10.1248/bpb.b14-00397
    1. Weets I, Kaufman L, Van Der Auwera B, Crenier L, Rooman RP, De Block C, et al. . Seasonality in clinical onset of type 1 diabetes in belgian patients above the age of 10 is restricted to HLA-DQ2/DQ8-negative males, which explains the male to female excess in incidence. Diabetologia. (2004) 47:614–21. 10.1007/s00125-004-1369-8
    1. Soderstrom U, Aman J, Hjern A. Being born in Sweden increases the risk for type 1 diabetes - a study of migration of children to Sweden as a natural experiment. Acta Paediatr. (2012) 101:73–7. 10.1111/j.1651-2227.2011.02410.x
    1. Voigt RM, Forsyth CB, Green SJ, Mutlu E, Engen P, Vitaterna MH, et al. . Circadian disorganization alters intestinal microbiota. PLoS ONE. (2014) 9:e97500. 10.1371/journal.pone.0097500
    1. Liang X, Bushman FD, Fitzgerald GA. Rhythmicity of the intestinal microbiota is regulated by gender and the host circadian clock. Proc Natl Acad Sci USA. (2015) 112:10479–84. 10.1073/pnas.1501305112
    1. Voigt RM, Forsyth CB, Green SJ, Engen PA, Keshavarzian A. Circadian rhythm and the gut microbiome. Int Rev Neurobiol. (2016) 131:193–205. 10.1016/bs.irn.2016.07.002
    1. Marre ML, James EA, Piganelli JD. beta cell ER stress and the implications for immunogenicity in type 1 diabetes. Front Cell Dev Biol. (2015) 3:67. 10.3389/fcell.2015.00067
    1. Atkinson M, Gale EA. Infant diets and type 1 diabetes: too early, too late, or just too complicated? JAMA. (2003) 290:1771–2. 10.1001/jama.290.13.1771
    1. Mannering SI, Di Carluccio AR, Elso CM. Neoepitopes: a new take on beta cell autoimmunity in type 1 diabetes. Diabetologia. (2019) 62:351–6. 10.1007/s00125-018-4760-6
    1. Purcell AW, Sechi S, Dilorenzo TP. The evolving landscape of autoantigen discovery and characterization in type 1 diabetes. Diabetes. (2019) 68:879–86. 10.2337/dbi18-0066
    1. Delong T, Wiles TA, Baker RL, Bradley B, Barbour G, Reisdorph R, et al. . Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science. (2016) 351:711–4. 10.1126/science.aad2791
    1. Duncan GE. Prevalence of diabetes and impaired fasting glucose levels among US adolescents: National Health and Nutrition Examination Survey, 1999-2002. Arch Pediatr Adolesc Med. (2006) 160:523–8. 10.1001/archpedi.160.5.523
    1. Group SFDIYS, Liese AD, D'agostino RB, Jr., Hamman RF, Kilgo PD, Lawrence JM, et al. The burden of diabetes mellitus among US youth: prevalence estimates from the SEARCH for Diabetes in Youth Study. Pediatrics. (2006) 118:1510–8. 10.1542/peds.2006-0690
    1. Bingley PJ, Gale EA. Rising incidence of IDDM in Europe. Diabetes Care. (1989) 12:289–95. 10.2337/diacare.12.4.289
    1. Gale EA. The rise of childhood type 1 diabetes in the 20th century. Diabetes. (2002) 51:3353–61. 10.2337/diabetes.51.12.3353
    1. Ludvigsson J. Increasing incidence but decreasing awareness of Type 1 diabetes in Sweden. Diabetes Care. (2017) 40:e143–4. 10.2337/dc17-1175
    1. Podar T, Solntsev A, Karvonen M, Padaiga Z, Brigis G, Urbonaite B, et al. . Increasing incidence of childhood-onset type I diabetes in 3 Baltic countries and Finland 1983-1998. Diabetologia. (2001) 44 (Suppl. 3):B17–20. 10.1007/PL00002947
    1. Dabelea D. The accelerating epidemic of childhood diabetes. Lancet. (2009) 373:1999–2000. 10.1016/S0140-6736(09)60874-6
    1. Barnett AH, Eff C, Leslie RD, Pyke DA. Diabetes in identical twins. A study of 200 pairs. Diabetologia. (1981) 20:87–93. 10.1007/BF00262007
    1. Kaprio J, Tuomilehto J, Koskenvuo M, Romanov K, Reunanen A, Eriksson J, et al. . Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia. (1992) 35:1060–7. 10.1007/BF02221682
    1. Redondo MJ, Jeffrey J, Fain PR, Eisenbarth GS, Orban T. Concordance for islet autoimmunity among monozygotic twins. N Engl J Med. (2008) 359:2849–50. 10.1056/NEJMc0805398
    1. Thayer TC, Wilson SB, Mathews CE. Use of nonobese diabetic mice to understand human type 1 diabetes. Endocrinol Metab Clin North Am. (2010) 39:541–61. 10.1016/j.ecl.2010.05.001
    1. Wicker LS, Clark J, Fraser HI, Garner VE, Gonzalez-Munoz A, Healy B, et al. . Type 1 diabetes genes and pathways shared by humans and NOD mice. J Autoimmun. (2005) 25 (Suppl):29–33. 10.1016/j.jaut.2005.09.009
    1. Pozzilli P, Signore A, Williams AJ, Beales PE. NOD mouse colonies around the world–recent facts and figures. Immunol Today. (1993) 14:193–6. 10.1016/0167-5699(93)90160-M
    1. Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, et al. . Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature. (2008) 455:1109–13. 10.1038/nature07336
    1. Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, et al. . Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science. (2013) 339:1084–8. 10.1126/science.1233521
    1. Onengut-Gumuscu S, Chen WM, Burren O, Cooper NJ, Quinlan AR, Mychaleckyj JC, et al. . Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat Genet. (2015) 47:381–6. 10.1038/ng.3245
    1. She JX. Susceptibility to type I diabetes: HLA-DQ and DR revisited. Immunol Today. (1996) 17:323–9. 10.1016/0167-5699(96)10014-1
    1. Hagopian WA, Erlich H, Lernmark A, Rewers M, Ziegler AG, Simell O, et al. . The Environmental Determinants of Diabetes in the Young (TEDDY): genetic criteria and international diabetes risk screening of 421 000 infants. Pediatr Diabetes. (2011) 12:733–43. 10.1111/j.1399-5448.2011.00774.x
    1. Rewers M, Ludvigsson J. Environmental risk factors for type 1 diabetes. Lancet. (2016) 387:2340–8. 10.1016/S0140-6736(16)30507-4
    1. Stewart CJ, Ajami NJ, O'brien JL, Hutchinson DS, Smith DP, Wong MC, et al. . Temporal development of the gut microbiome in early childhood from the TEDDY study. Nature. (2018) 562:583–8. 10.1038/s41586-018-0617-x
    1. Kostic AD, Gevers D, Siljander H, Vatanen T, Hyotylainen T, Hamalainen AM, et al. . The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe. (2015) 17:260–73. 10.1016/j.chom.2015.01.001
    1. Vatanen T, Kostic AD, D'hennezel E, Siljander H, Franzosa EA, Yassour M, et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell. (2016) 165:842–53. 10.1016/j.cell.2016.04.007
    1. Vaarala O, Ilonen J, Ruohtula T, Pesola J, Virtanen SM, Harkonen T, et al. . Removal of bovine insulin from cow's milk formula and early initiation of beta-cell autoimmunity in the FINDIA pilot study. Arch Pediatr Adolesc Med. (2012) 166:608–14. 10.1001/archpediatrics.2011.1559
    1. Kondrashova A, Reunanen A, Romanov A, Karvonen A, Viskari H, Vesikari T, 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. 10.1080/07853890410018952
    1. Gale EA. A missing link in the hygiene hypothesis? Diabetologia. (2002) 45:588–94. 10.1007/s00125-002-0801-1
    1. Bach JF. Six questions about the hygiene hypothesis. Cell Immunol. (2005) 233:158–61. 10.1016/j.cellimm.2005.04.006
    1. D'angeli MA, Merzon E, Valbuena LF, Tirschwell D, Paris CA, Mueller BA. Environmental factors associated with childhood-onset type 1 diabetes mellitus: an exploration of the hygiene and overload hypotheses. Arch Pediatr Adolesc Med. (2010) 164:732–8. 10.1001/archpediatrics.2010.115
    1. Britton RA, Young VB. Role of the intestinal microbiota in resistance to colonization by Clostridium difficile. Gastroenterology. (2014) 146:1547–53. 10.1053/j.gastro.2014.01.059
    1. Akerman L, Ludvigsson J, Swartling U, Casas R. Characteristics of the pre-diabetic period in children with high risk of type 1 diabetes recruited from the general Swedish population-The ABIS study. Diabetes Metab Res Rev. (2017) 33. 10.1002/dmrr.2900
    1. Silverman M, Kua L, Tanca A, Pala M, Palomba A, Tanes C, et al. . Protective major histocompatibility complex allele prevents type 1 diabetes by shaping the intestinal microbiota early in ontogeny. Proc Natl Acad Sci USA. (2017) 114:9671–6. 10.1073/pnas.1712280114
    1. Kubinak JL, Stephens WZ, Soto R, Petersen C, Chiaro T, Gogokhia L, et al. . MHC variation sculpts individualized microbial communities that control susceptibility to enteric infection. Nat Commun. (2015) 6:8642. 10.1038/ncomms9642
    1. Toivanen P, Vaahtovuo J, Eerola E. Influence of major histocompatibility complex on bacterial composition of fecal flora. Infect Immun. (2001) 69:2372–7. 10.1128/IAI.69.4.2372-2377.2001
    1. Faresjo AO, Ludvigsson J. Pet exposure in the family during pregnancy and risk for type 1 diabetes-The prospective ABIS study. Pediatr Diabetes. (2018) 19:1206–10. 10.1111/pedi.12721
    1. Tun HM, Konya T, Takaro TK, Brook JR, Chari R, Field CJ, et al. . Exposure to household furry pets influences the gut microbiota of infant at 3-4 months following various birth scenarios. Microbiome. (2017) 5:40. 10.1186/s40168-017-0254-x
    1. Walker WA. The importance of appropriate initial bacterial colonization of the intestine in newborn, child, and adult health. Pediatr Res. (2017) 82:387–95. 10.1038/pr.2017.111
    1. Blaser MJ, Dominguez-Bello MG. The human microbiome before birth. Cell Host Microbe. (2016) 20:558–60. 10.1016/j.chom.2016.10.014
    1. Koren O, Goodrich JK, Cullender TC, Spor A, Laitinen K, Backhed HK, et al. . Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell. (2012) 150:470–80. 10.1016/j.cell.2012.07.008
    1. Gronlund MM, Lehtonen OP, Eerola E, Kero P. Fecal microflora in healthy infants born by different methods of delivery: permanent changes in intestinal flora after cesarean delivery. J Pediatr Gastroenterol Nutr. (1999) 28:19–25. 10.1097/00005176-199901000-00007
    1. Mackie RI, Sghir A, Gaskins HR. Developmental microbial ecology of the neonatal gastrointestinal tract. Am J Clin Nutr. (1999) 69:1035S−45S. 10.1093/ajcn/69.5.1035s
    1. Penders J, Thijs C, Vink C, Stelma FF, Snijders B, Kummeling I, et al. . Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics. (2006) 118:511–21. 10.1542/peds.2005-2824
    1. Biasucci G, Benenati B, Morelli L, Bessi E, Boehm G. Cesarean delivery may affect the early biodiversity of intestinal bacteria. J Nutr. (2008) 138:1796S−1800S. 10.1093/jn/138.9.1796S
    1. Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, et al. . Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci USA. (2010) 107:11971–5. 10.1073/pnas.1002601107
    1. Pistiner M, Gold DR, Abdulkerim H, Hoffman E, Celedon JC. Birth by cesarean section, allergic rhinitis, and allergic sensitization among children with a parental history of atopy. J Allergy Clin Immunol. (2008) 122:274–9. 10.1016/j.jaci.2008.05.007
    1. Thavagnanam S, Fleming J, Bromley A, Shields MD, Cardwell CR. A meta-analysis of the association between Caesarean section and childhood asthma. Clin Exp Allergy. (2008) 38:629–33. 10.1111/j.1365-2222.2007.02780.x
    1. Almqvist C, Cnattingius S, Lichtenstein P, Lundholm C. The impact of birth mode of delivery on childhood asthma and allergic diseases–a sibling study. Clin Exp Allergy. (2012) 42:1369–76. 10.1111/j.1365-2222.2012.04021.x
    1. Huh SY, Rifas-Shiman SL, Zera CA, Edwards JW, Oken E, Weiss ST, et al. . Delivery by caesarean section and risk of obesity in preschool age children: a prospective cohort study. Arch Dis Child. (2012) 97:610–6. 10.1136/archdischild-2011-301141
    1. Penders J, Gerhold K, Thijs C, Zimmermann K, Wahn U, Lau S, et al. . New insights into the hygiene hypothesis in allergic diseases: mediation of sibling and birth mode effects by the gut microbiota. Gut Microbes. (2014) 5:239–44. 10.4161/gmic.27905
    1. Kuhle S, Tong OS, Woolcott CG. Association between caesarean section and childhood obesity: a systematic review and meta-analysis. Obes Rev. (2015) 16:295–303. 10.1111/obr.12267
    1. Sevelsted A, Stokholm J, Bonnelykke K, Bisgaard H. Cesarean section and chronic immune disorders. Pediatrics. (2015) 135:e92–8. 10.1542/peds.2014-0596
    1. Yuan C, Gaskins AJ, Blaine AI, Zhang C, Gillman MW, Missmer SA, et al. . Association between cesarean birth and risk of obesity in offspring in childhood, adolescence, and early adulthood. JAMA Pediatr. (2016) 170:e162385. 10.1001/jamapediatrics.2016.2385
    1. Tun HM, Bridgman SL, Chari R, Field CJ, Guttman DS, Becker AB, et al. . Roles of birth mode and infant gut microbiota in intergenerational transmission of overweight and obesity from mother to offspring. JAMA Pediatr. (2018) 172:368–77. 10.1001/jamapediatrics.2017.5535
    1. Adlerberth I, Lindberg E, Aberg N, Hesselmar B, Saalman R, Strannegard IL, et al. . Reduced enterobacterial and increased staphylococcal colonization of the infantile bowel: an effect of hygienic lifestyle? Pediatr Res. (2006) 59:96–101. 10.1203/01.pdr.0000191137.12774.b2
    1. Rutayisire E, Huang K, Liu Y, Tao F. The mode of delivery affects the diversity and colonization pattern of the gut microbiota during the first year of infants' life: a systematic review. BMC Gastroenterol. (2016) 16:86. 10.1186/s12876-016-0498-0
    1. Mitsou EK, Kirtzalidou E, Oikonomou I, Liosis G, Kyriacou A. Fecal microflora of Greek healthy neonates. Anaerobe. (2008) 14:94–101. 10.1016/j.anaerobe.2007.11.002
    1. Kabeerdoss J, Ferdous S, Balamurugan R, Mechenro J, Vidya R, Santhanam S, et al. . Development of the gut microbiota in southern Indian infants from birth to 6 months: a molecular analysis. J Nutr Sci. (2013) 2:e18. 10.1017/jns.2013.6
    1. Hesla HM, Stenius F, Jaderlund L, Nelson R, Engstrand L, Alm J, et al. . Impact of lifestyle on the gut microbiota of healthy infants and their mothers-the ALADDIN birth cohort. FEMS Microbiol Ecol. (2014) 90:791–801. 10.1111/1574-6941.12434
    1. Jakobsson HE, Abrahamsson TR, Jenmalm MC, Harris K, Quince C, Jernberg C, et al. . Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by caesarean section. Gut. (2014) 63:559–66. 10.1136/gutjnl-2012-303249
    1. Dogra S, Sakwinska O, Soh SE, Ngom-Bru C, Bruck WM, Berger B, et al. . Dynamics of infant gut microbiota are influenced by delivery mode and gestational duration and are associated with subsequent adiposity. MBio. (2015) 6:e02419-14. 10.1128/mBio.02419-14
    1. Cardwell CR, Stene LC, Joner G, Cinek O, Svensson J, Goldacre MJ, et al. . Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies. Diabetologia. (2008) 51:726–35. 10.1007/s00125-008-0941-z
    1. Algert CS, Mcelduff A, Morris JM, Roberts CL. Perinatal risk factors for early onset of Type 1 diabetes in a 2000-2005 birth cohort. Diabet Med. (2009) 26:1193–7. 10.1111/j.1464-5491.2009.02878.x
    1. Black M, Bhattacharya S, Philip S, Norman JE, Mclernon DJ. Planned cesarean delivery at term and adverse outcomes in childhood health. JAMA. (2015) 314:2271–9. 10.1001/jama.2015.16176
    1. Magne F, Puchi Silva A, Carvajal B, Gotteland M. The elevated rate of cesarean section and its contribution to non-communicable chronic diseases in Latin America: the growing involvement of the microbiota. Front Pediatr. (2017) 5:192. 10.3389/fped.2017.00192
    1. Samuelsson U, Lindell N, Bladh M, Akesson K, Carlsson A, Josefsson A. Caesarean section per se does not increase the risk of offspring developing type 1 diabetes: a Swedish population-based study. Diabetologia. (2015) 58:2517–24. 10.1007/s00125-015-3716-3
    1. Clausen TD, Bergholt T, Eriksson F, Rasmussen S, Keiding N, Lokkegaard EC. prelabor cesarean section and risk of childhood type 1 diabetes: a nationwide register-based cohort study. Epidemiology. (2016) 27:547–55. 10.1097/EDE.0000000000000488
    1. Hansen CH, Andersen LS, Krych L, Metzdorff SB, Hasselby JP, Skov S, et al. . Mode of delivery shapes gut colonization pattern and modulates regulatory immunity in mice. J Immunol. (2014) 193:1213–22. 10.4049/jimmunol.1400085
    1. He B, Xu W, Santini PA, Polydorides AD, Chiu A, Estrella J, et al. . Intestinal bacteria trigger T cell-independent immunoglobulin A(2) class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity. (2007) 26:812–26. 10.1016/j.immuni.2007.04.014
    1. Lopez-Boado YS, Wilson CL, Hooper LV, Gordon JI, Hultgren SJ, Parks WC. Bacterial exposure induces and activates matrilysin in mucosal epithelial cells. J Cell Biol. (2000) 148:1305–15. 10.1083/jcb.148.6.1305
    1. Rhee KJ, Sethupathi P, Driks A, Lanning DK, Knight KL. Role of commensal bacteria in development of gut-associated lymphoid tissues and preimmune antibody repertoire. J Immunol. (2004) 172:1118–24. 10.4049/jimmunol.172.2.1118
    1. Lutgendorff F, Akkermans LM, Soderholm JD. The role of microbiota and probiotics in stress-induced gastro-intestinal damage. Curr Mol Med. (2008) 8:282–98. 10.2174/156652408784533779
    1. Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature. (2008) 453:620–5. 10.1038/nature07008
    1. Nejentsev S, Sjoroos M, Soukka T, Knip M, Simell O, Lovgren T, et al. . Population-based genetic screening for the estimation of Type 1 diabetes mellitus risk in Finland: selective genotyping of markers in the HLA-DQB1, HLA-DQA1 and HLA-DRB1 loci. Diabet Med. (1999) 16:985–92. 10.1046/j.1464-5491.1999.00186.x
    1. Kupila A, Muona P, Simell T, Arvilommi P, Savolainen H, Hamalainen AM, et al. . Feasibility of genetic and immunological prediction of type I diabetes in a population-based birth cohort. Diabetologia. (2001) 44:290–7. 10.1007/s001250051616
    1. Giongo A, Gano KA, Crabb DB, Mukherjee N, Novelo LL, Casella G, et al. . Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. (2011) 5:82–91. 10.1038/ismej.2010.92
    1. Davis-Richardson AG, Ardissone AN, Dias R, Simell V, Leonard MT, Kemppainen KM, et al. . Bacteroides dorei dominates gut microbiome prior to autoimmunity in Finnish children at high risk for type 1 diabetes. Front Microbiol. (2014) 5:678. 10.3389/fmicb.2014.00678
    1. Stene LC, Magnus P, Lie RT, Sovik O, Joner G, Norwegian Childhood Diabetes Study G . No association between preeclampsia or cesarean section and incidence of type 1 diabetes among children: a large, population-based cohort study. Pediatr Res. (2003) 54:487–90. 10.1203/01.PDR.0000081301.25600.5D
    1. Knol J, Scholtens P, Kafka C, Steenbakkers J, Gro S, Helm K, et al. . Colon microflora in infants fed formula with galacto- and fructo-oligosaccharides: more like breast-fed infants. J Pediatr Gastroenterol Nutr. (2005) 40:36–42. 10.1097/00005176-200501000-00007
    1. Palmer C, Bik EM, Digiulio DB, Relman DA, Brown PO. Development of the human infant intestinal microbiota. PLoS Biol. (2007) 5:e177. 10.1371/journal.pbio.0050177
    1. Mueller NT, Bakacs E, Combellick J, Grigoryan Z, Dominguez-Bello MG. The infant microbiome development: mom matters. Trends Mol Med. (2015) 21:109–17. 10.1016/j.molmed.2014.12.002
    1. Lopez NM, Ponce S, Piccinini D, Perez E, Roberti M. From hospital to home care: creating a domotic environment for elderly and disabled people. IEEE Pulse. (2016) 7:38–41. 10.1109/MPUL.2016.2539105
    1. Gale C, Logan KM, Santhakumaran S, Parkinson JR, Hyde MJ, Modi N. Effect of breastfeeding compared with formula feeding on infant body composition: a systematic review and meta-analysis. Am J Clin Nutr. (2012) 95:656–69. 10.3945/ajcn.111.027284
    1. Pannaraj PS, Li F, Cerini C, Bender JM, Yang S, Rollie A, et al. . Association between breast milk bacterial communities and establishment and development of the infant gut microbiome. JAMA Pediatr. (2017) 171:647–54. 10.1001/jamapediatrics.2017.0378
    1. Martin R, Heilig GH, Zoetendal EG, Smidt H, Rodriguez JM. Diversity of the Lactobacillus group in breast milk and vagina of healthy women and potential role in the colonization of the infant gut. J Appl Microbiol. (2007) 103:2638–44. 10.1111/j.1365-2672.2007.03497.x
    1. Solis G, De Los Reyes-Gavilan CG, Fernandez N, Margolles A, Gueimonde M. Establishment and development of lactic acid bacteria and bifidobacteria microbiota in breast-milk and the infant gut. Anaerobe. (2010) 16:307–10. 10.1016/j.anaerobe.2010.02.004
    1. Duffy LC, Zielezny MA, Riepenhoff-Talty M, Dryja D, Sayahtaheri-Altaie S, Griffiths E, et al. . Effectiveness of Bifidobacterium bifidum in mediating the clinical course of murine rotavirus diarrhea. Pediatr Res. (1994) 35:690–5. 10.1203/00006450-199406000-00014
    1. Gibson GR, Wang X. Regulatory effects of bifidobacteria on the growth of other colonic bacteria. J Appl Bacteriol. (1994) 77:412–20. 10.1111/j.1365-2672.1994.tb03443.x
    1. Perdigon G, Alvarez S, Rachid M, Aguero G, Gobbato N. Immune system stimulation by probiotics. J Dairy Sci. (1995) 78:1597–606. 10.3168/jds.S0022-0302(95)76784-4
    1. Fujiwara S, Hashiba H, Hirota T, Forstner JF. Proteinaceous factor(s) in culture supernatant fluids of bifidobacteria which prevents the binding of enterotoxigenic Escherichia coli to gangliotetraosylceramide. Appl Environ Microbiol. (1997) 63:506–12. 10.1128/AEM.63.2.506-512.1997
    1. Sudo N, Sawamura S, Tanaka K, Aiba Y, Kubo C, Koga Y. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol. (1997) 159:1739–45.
    1. Lievin V, Peiffer I, Hudault S, Rochat F, Brassart D, Neeser JR, et al. . Bifidobacterium strains from resident infant human gastrointestinal microflora exert antimicrobial activity. Gut. (2000) 47:646–52. 10.1136/gut.47.5.646
    1. Picard C, Fioramonti J, Francois A, Robinson T, Neant F, Matuchansky C. Review article: bifidobacteria as probiotic agents – physiological effects and clinical benefits. Aliment Pharmacol Ther. (2005) 22:495–512. 10.1111/j.1365-2036.2005.02615.x
    1. Insel R, Knip M. Prospects for primary prevention of type 1 diabetes by restoring a disappearing microbe. Pediatr Diabetes. (2018) 19:1400–6. 10.1111/pedi.12756
    1. Schroeder BO, Birchenough GMH, Stahlman M, Arike L, Johansson MEV, Hansson GC, et al. . Bifidobacteria or fiber protects against diet-induced microbiota-mediated colonic mucus deterioration. Cell Host Microbe. (2018) 23:27–40.e27. 10.1016/j.chom.2017.11.004
    1. Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. (2012) 336:1268–73. 10.1126/science.1223490
    1. Gerstein HC. Cow's milk exposure and type I diabetes mellitus. A critical overview of the clinical literature. Diabetes Care. (1994) 17:13–9. 10.2337/diacare.17.1.13
    1. Alves JG, Figueiroa JN, Meneses J, Alves GV. Breastfeeding protects against type 1 diabetes mellitus: a case-sibling study. Breastfeed Med. (2012) 7:25–8. 10.1089/bfm.2011.0009
    1. Lundequist B, Nord CE, Winberg J. The composition of the faecal microflora in breastfed and bottle fed infants from birth to eight weeks. Acta Paediatr Scand. (1985) 74:45–51. 10.1111/j.1651-2227.1985.tb10919.x
    1. Fanaro S, Chierici R, Guerrini P, Vigi V. Intestinal microflora in early infancy: composition and development. Acta Paediatr Suppl. (2003) 91:48–55. 10.1111/j.1651-2227.2003.tb00646.x
    1. Azad MB, Konya T, Maughan H, Guttman DS, Field CJ, Chari RS, et al. . Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months. CMAJ. (2013) 185:385–94. 10.1503/cmaj.121189
    1. Albenberg LG, Wu GD. Diet and the intestinal microbiome: associations, functions, and implications for health and disease. Gastroenterology. (2014) 146:1564–72. 10.1053/j.gastro.2014.01.058
    1. O'sullivan A, Farver M, Smilowitz JT. The influence of early infant-feeding practices on the intestinal microbiome and body composition in infants. Nutr Metab Insights. (2015) 8:1–9. 10.4137/NMI.S41125
    1. Madan JC, Hoen AG, Lundgren SN, Farzan SF, Cottingham KL, Morrison HG, et al. . Association of cesarean delivery and formula supplementation with the intestinal microbiome of 6-week-old infants. JAMA Pediatr. (2016) 170:212–9. 10.1001/jamapediatrics.2015.3732
    1. Lund-Blix NA, Stene LC, Rasmussen T, Torjesen PA, Andersen LF, Ronningen KS. Infant feeding in relation to islet autoimmunity and type 1 diabetes in genetically susceptible children: the MIDIA Study. Diabetes Care. (2015) 38:257–63. 10.2337/dc14-1130
    1. Sadauskaite-Kuehne V, Ludvigsson J, Padaiga Z, Jasinskiene E, Samuelsson U. Longer breastfeeding is an independent protective factor against development of type 1 diabetes mellitus in childhood. Diabetes Metab Res Rev. (2004) 20:150–7. 10.1002/dmrr.425
    1. Wahlberg J, Vaarala O, Ludvigsson J, Group AB-S. Dietary risk factors for the emergence of type 1 diabetes-related autoantibodies in 21/2 year-old Swedish children. Br J Nutr. (2006) 95:603–8. 10.1079/BJN20051676
    1. Holmberg H, Wahlberg J, Vaarala O, Ludvigsson J, Group AS. Short duration of breast-feeding as a risk-factor for beta-cell autoantibodies in 5-year-old children from the general population. Br J Nutr. (2007) 97:111–6. 10.1017/S0007114507210189
    1. Marcobal A, Barboza M, Sonnenburg ED, Pudlo N, Martens EC, Desai P, et al. . Bacteroides in the infant gut consume milk oligosaccharides via mucus-utilization pathways. Cell Host Microbe. (2011) 10:507–14. 10.1016/j.chom.2011.10.007
    1. Vatanen T, Kostic AD, D'hennezel E, Siljander H, Franzosa EA, Yassour M, et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell. (2016) 165:1551 10.1016/j.cell.2016.05.056
    1. Mejía-Leon ME, Petrosino JF, Ajami NJ, Dominguez-Bello MG, De La Barca AM. Fecal microbiota imbalance in Mexican children with type 1 diabetes. Sci Rep. (2014) 4:3814. 10.1038/srep03814
    1. Qureshi ST, Lariviere L, Leveque G, Clermont S, Moore KJ, Gros P, et al. . Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J Exp Med. (1999) 189:615–25. 10.1084/jem.189.4.615
    1. Nomura F, Akashi S, Sakao Y, Sato S, Kawai T, Matsumoto M, et al. . Cutting edge: endotoxin tolerance in mouse peritoneal macrophages correlates with down-regulation of surface toll-like receptor 4 expression. J Immunol. (2000) 164:3476–9. 10.4049/jimmunol.164.7.3476
    1. Lu YC, Yeh WC, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine. (2008) 42:145–51. 10.1016/j.cyto.2008.01.006
    1. Biswas SK, Lopez-Collazo E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. (2009) 30:475–87. 10.1016/j.it.2009.07.009
    1. Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, et al. Pillars article: cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol. (1999) 162:3749–52.
    1. Sai P, Rivereau AS. Prevention of diabetes in the nonobese diabetic mouse by oral immunological treatments. Comparative efficiency of human insulin and two bacterial antigens, lipopolysacharide from Escherichia coli and glycoprotein extract from Klebsiella pneumoniae. Diabetes Metab. (1996) 22:341–8.
    1. Gulden E, Ihira M, Ohashi A, Reinbeck AL, Freudenberg MA, Kolb H, et al. . Toll-like receptor 4 deficiency accelerates the development of insulin-deficient diabetes in non-obese diabetic mice. PLoS ONE. (2013) 8:e75385. 10.1371/journal.pone.0075385
    1. Frese SA, Hutton AA, Contreras LN, Shaw CA, Palumbo MC, Casaburi G, et al. . Persistence of supplemented bifidobacterium longum subsp. infantis EVC001 in breastfed infants. mSphere. (2017) 2:e00501-17. 10.1128/mSphere.00501-17
    1. Virtanen SM, Knip M. Nutritional risk predictors of beta cell autoimmunity and type 1 diabetes at a young age. Am J Clin Nutr. (2003) 78:1053–67. 10.1093/ajcn/78.6.1053
    1. Knip M, Virtanen SM, Seppa K, Ilonen J, Savilahti E, Vaarala O, et al. . Dietary intervention in infancy and later signs of beta-cell autoimmunity. N Engl J Med. (2010) 363:1900–8. 10.1056/NEJMoa1004809
    1. Lampeter EF, Klinghammer A, Scherbaum WA, Heinze E, Haastert B, Giani G, et al. . The Deutsche Nicotinamide Intervention Study: an attempt to prevent type 1 diabetes. DENIS Group Diabetes. (1998) 47:980–4. 10.2337/diabetes.47.6.980
    1. Kolb H, Burkart V. Nicotinamide in type 1 diabetes. Mechanism of action revisited. Diabetes Care. (1999) 22 (Suppl. 2):B16–20.
    1. Ohly P, Dohle C, Abel J, Seissler J, Gleichmann H. Zinc sulphate induces metallothionein in pancreatic islets of mice and protects against diabetes induced by multiple low doses of streptozotocin. Diabetologia. (2000) 43:1020–30. 10.1007/s001250050009
    1. Ho E, Quan N, Tsai YH, Lai W, Bray TM. Dietary zinc supplementation inhibits NFkappaB activation and protects against chemically induced diabetes in CD1 mice. Exp Biol Med. (2001) 226:103–11. 10.1177/153537020122600207
    1. Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. (2001) 358:1500–3. 10.1016/S0140-6736(01)06580-1
    1. Gale EA, Bingley PJ, Emmett CL, Collier T, European Nicotinamide Diabetes Intervention Trial G . European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet. (2004) 363:925–31. 10.1016/S0140-6736(04)15786-3
    1. Kawasaki E, Abiru N, Eguchi K. Prevention of type 1 diabetes: from the view point of beta cell damage. Diabetes Res Clin Pract. (2004) 66 (Suppl. 1):S27–32. 10.1016/j.diabres.2003.09.015
    1. Luong K, Nguyen LT, Nguyen DN. The role of vitamin D in protecting type 1 diabetes mellitus. Diabetes Metab Res Rev. (2005) 21:338–46. 10.1002/dmrr.557
    1. Zipitis CS, Akobeng AK. Vitamin D supplementation in early childhood and risk of type 1 diabetes: a systematic review and meta-analysis. Arch Dis Child. (2008) 93:512–7. 10.1136/adc.2007.128579
    1. Cantorna MT. Vitamin D and autoimmunity: is vitamin D status an environmental factor affecting autoimmune disease prevalence? Proc Soc Exp Biol Med. (2000) 223:230–3. 10.1046/j.1525-1373.2000.22333.x
    1. Gregori S, Giarratana N, Smiroldo S, Uskokovic M, Adorini L. A 1alpha,25-dihydroxyvitamin D(3) analog enhances regulatory T-cells and arrests autoimmune diabetes in NOD mice. Diabetes. (2002) 51:1367–74. 10.2337/diabetes.51.5.1367
    1. Scott FW. Cow milk and insulin-dependent diabetes mellitus: is there a relationship? Am J Clin Nutr. (1990) 51:489–91. 10.1093/ajcn/51.3.489
    1. Verge CF, Howard NJ, Irwig L, Simpson JM, Mackerras D, Silink M. Environmental factors in childhood IDDM. A population-based, case-control study. Diabetes Care. (1994) 17:1381–9. 10.2337/diacare.17.12.1381
    1. Scott FW, Cloutier HE, Kleemann R, Woerz-Pagenstert U, Rowsell P, Modler HW, 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) 46:589–98. 10.2337/diab.46.4.589
    1. Murri M, Leiva I, Gomez-Zumaquero JM, Tinahones FJ, Cardona F, Soriguer F, et al. . Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study. BMC Med. (2013) 11:46. 10.1186/1741-7015-11-46
    1. Maiuri L, Troncone R, Mayer M, Coletta S, Picarelli A, De Vincenzi M, et al. . In vitro activities of A-gliadin-related synthetic peptides: damaging effect on the atrophic coeliac mucosa and activation of mucosal immune response in the treated coeliac mucosa. Scand J Gastroenterol. (1996) 31:247–53. 10.3109/00365529609004874
    1. Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, et al. . Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology. (2008) 135:194–204.e193. 10.1053/j.gastro.2008.03.023
    1. Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev. (2011) 91:151–75. 10.1152/physrev.00003.2008
    1. Lammers KM, Khandelwal S, Chaudhry F, Kryszak D, Puppa EL, Casolaro V, et al. . Identification of a novel immunomodulatory gliadin peptide that causes interleukin-8 release in a chemokine receptor CXCR3-dependent manner only in patients with coeliac disease. Immunology. (2011) 132:432–40. 10.1111/j.1365-2567.2010.03378.x
    1. Brugman S, Klatter FA, Visser JT, Wildeboer-Veloo AC, Harmsen HJ, Rozing J, 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) 49:2105–8. 10.1007/s00125-006-0334-0
    1. Hansen AK, Ling F, Kaas A, Funda DP, Farlov H, Buschard K. Diabetes preventive gluten-free diet decreases the number of caecal bacteria in non-obese diabetic mice. Diabetes Metab Res Rev. (2006) 22:220–5. 10.1002/dmrr.609
    1. Marietta EV, Gomez AM, Yeoman C, Tilahun AY, Clark CR, Luckey DH, et al. . Low incidence of spontaneous type 1 diabetes in non-obese diabetic mice raised on gluten-free diets is associated with changes in the intestinal microbiome. PLoS One. (2013) 8:e78687. 10.1371/journal.pone.0078687
    1. Qin H, Zhang Z, Hang X, Jiang Y. L. plantarum prevents enteroinvasive Escherichia coli-induced tight junction proteins changes in intestinal epithelial cells. BMC Microbiol. (2009) 9:63. 10.1186/1471-2180-9-63
    1. Karczewski J, Troost FJ, Konings I, Dekker J, Kleerebezem M, Brummer RJ, et al. . Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the epithelial barrier. Am J Physiol Gastrointest Liver Physiol. (2010) 298:G851–9. 10.1152/ajpgi.00327.2009
    1. Pastore MR, Bazzigaluppi E, Belloni C, Arcovio C, Bonifacio E, Bosi E. Six months of gluten-free diet do not influence autoantibody titers, but improve insulin secretion in subjects at high risk for type 1 diabetes. J Clin Endocrinol Metab. (2003) 88:162–5. 10.1210/jc.2002-021177
    1. Fuchtenbusch M, Ziegler AG, Hummel M. Elimination of dietary gluten and development of type 1 diabetes in high risk subjects. Rev Diabet Stud. (2004) 1:39–41. 10.1900/RDS.2004.1.39
    1. Saadah OI, Zacharin M, O'callaghan A, Oliver MR, Catto-Smith AG. Effect of gluten-free diet and adherence on growth and diabetic control in diabetics with coeliac disease. Arch Dis Child. (2004) 89:871–6. 10.1136/adc.2002.012799
    1. Westman E, Ambler GR, Royle M, Peat J, Chan A. Children with coeliac disease and insulin dependent diabetes mellitus–growth, diabetes control and dietary intake. J Pediatr Endocrinol Metab. (1999) 12:433–42. 10.1515/JPEM.1999.12.3.433
    1. Rami B, Sumnik Z, Schober E, Waldhor T, Battelino T, Bratanic N, et al. . Screening detected celiac disease in children with type 1 diabetes mellitus: effect on the clinical course (a case control study). J Pediatr Gastroenterol Nutr. (2005) 41:317–21. 10.1097/01.mpg.0000174846.67797.87
    1. Strobel S, Mowat AM. Immune responses to dietary antigens: oral tolerance. Immunol Today. (1998) 19:173–81. 10.1016/S0167-5699(97)01239-5
    1. Norris JM, Barriga K, Klingensmith G, Hoffman M, Eisenbarth GS, Erlich HA, et al. . Timing of initial cereal exposure in infancy and risk of islet autoimmunity. JAMA. (2003) 290:1713–20. 10.1001/jama.290.13.1713
    1. Ziegler AG, Schmid S, Huber D, Hummel M, Bonifacio E. Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA. (2003) 290:1721–8. 10.1001/jama.290.13.1721
    1. Schmid S, Koczwara K, Schwinghammer S, Lampasona V, Ziegler AG, Bonifacio E. Delayed exposure to wheat and barley proteins reduces diabetes incidence in non-obese diabetic mice. Clin Immunol. (2004) 111:108–18. 10.1016/j.clim.2003.09.012
    1. Funda DP, Kaas A, Tlaskalova-Hogenova H, Buschard K. Gluten-free but also gluten-enriched (gluten+) diet prevent diabetes in NOD mice; the gluten enigma in type 1 diabetes. Diabetes Metab Res Rev. (2008) 24:59–63. 10.1002/dmrr.748
    1. Mueller DB, Koczwara K, Mueller AS, Pallauf J, Ziegler AG, Bonifacio E. Influence of early nutritional components on the development of murine autoimmune diabetes. Ann Nutr Metab. (2009) 54:208–17. 10.1159/000220416
    1. Hansen CH, Krych L, Buschard K, Metzdorff SB, Nellemann C, Hansen LH, et al. . A maternal gluten-free diet reduces inflammation and diabetes incidence in the offspring of NOD mice. Diabetes. (2014) 63:2821–32. 10.2337/db13-1612
    1. Antvorskov JC, Josefsen K, Haupt-Jorgensen M, Fundova P, Funda DP, Buschard K. Gluten-free diet only during pregnancy efficiently prevents diabetes in NOD mouse offspring. J Diabetes Res. (2016) 2016:3047574. 10.1155/2016/3047574
    1. Antvorskov JC, Halldorsson TI, Josefsen K, Svensson J, Granstrom C, Roep BO, et al. . Association between maternal gluten intake and type 1 diabetes in offspring: national prospective cohort study in Denmark. BMJ. (2018) 362:k3547. 10.1136/bmj.k3547
    1. Lamb MM, Myers MA, Barriga K, Zimmet PZ, Rewers M, Norris JM. Maternal diet during pregnancy and islet autoimmunity in offspring. Pediatr Diabetes. (2008) 9:135–41. 10.1111/j.1399-5448.2007.00311.x
    1. Virtanen SM, Uusitalo L, Kenward MG, Nevalainen J, Uusitalo U, Kronberg-Kippila C, et al. . Maternal food consumption during pregnancy and risk of advanced beta-cell autoimmunity in the offspring. Pediatr Diabetes. (2011) 12:95–9. 10.1111/j.1399-5448.2010.00668.x
    1. Sildorf SM, 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) 2012:bcr0220125878. 10.1136/bcr.02.2012.5878
    1. Svensson J, Sildorf SM, Pipper CB, Kyvsgaard JN, Bojstrup J, Pociot FM, 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. 10.1186/s40064-016-2641-3
    1. Endesfelder D, Zu Castell W, Ardissone A, Davis-Richardson AG, Achenbach P, Hagen M, et al. . Compromised gut microbiota networks in children with anti-islet cell autoimmunity. Diabetes. (2014) 63:2006–14. 10.2337/db13-1676
    1. Paun A, Yau C, Danska JS. The influence of the microbiome on Type 1 diabetes. J Immunol. (2017) 198:590–5. 10.4049/jimmunol.1601519
    1. Muntoni S, Cocco P, Aru G, Cucca F. Nutritional factors and worldwide incidence of childhood type 1 diabetes. Am J Clin Nutr. (2000) 71:1525–9. 10.1093/ajcn/71.6.1525
    1. Elliott RB, Harris DP, Hill JP, Bibby NJ, Wasmuth HE. Type I (insulin-dependent) diabetes mellitus and cow milk: casein variant consumption. Diabetologia. (1999) 42:292–6. 10.1007/s001250051153
    1. Virtanen SM, Nevalainen J, Kronberg-Kippila C, Ahonen S, Tapanainen H, Uusitalo L, et al. . Food consumption and advanced beta cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes: a nested case-control design. Am J Clin Nutr. (2012) 95:471–8. 10.3945/ajcn.111.018879
    1. Savilahti E, Akerblom HK, Tainio VM, Koskimies S. Children with newly diagnosed insulin dependent diabetes mellitus have increased levels of cow's milk antibodies. Diabetes Res. (1988) 7:137–40.
    1. Dahlquist G, Savilahti E, Landin-Olsson M. An increased level of antibodies to beta-lactoglobulin is a risk determinant for early-onset type 1 (insulin-dependent) diabetes mellitus independent of islet cell antibodies and early introduction of cow's milk. Diabetologia. (1992) 35:980–4. 10.1007/BF00401429
    1. Savilahti E, Saukkonen TT, Virtala ET, Tuomilehto J, Akerblom HK. Increased levels of cow's milk and beta-lactoglobulin antibodies in young children with newly diagnosed IDDM. The Childhood Diabetes in Finland Study Group. Diabetes Care. (1993) 16:984–9. 10.2337/diacare.16.7.984
    1. Robertson L, Harrild K. Maternal and neonatal risk factors for childhood type 1 diabetes: a matched case-control study. BMC Public Health. (2010) 10:281. 10.1186/1471-2458-10-281
    1. Savilahti E, Saarinen KM. Early infant feeding and type 1 diabetes. Eur J Nutr. (2009) 48:243–9. 10.1007/s00394-009-0008-z
    1. Writing Group for The TSG. Knip M, Akerblom HK, Al Taji E, Becker D, Bruining J, et al. . Effect of hydrolyzed infant formula vs conventional formula on risk of type 1 diabetes: the TRIGR randomized clinical trial. JAMA. (2018) 319:38–48. 10.1001/jama.2017.19826
    1. Palleja A, Mikkelsen KH, Forslund SK, Kashani A, Allin KH, Nielsen T, et al. . Recovery of gut microbiota of healthy adults following antibiotic exposure. Nat Microbiol. (2018) 3:1255–65. 10.1038/s41564-018-0257-9
    1. Hicks LA, Taylor TH, Jr., Hunkler RJ. U.S. outpatient antibiotic prescribing, 2010. N Engl J Med. (2013) 368:1461–2. 10.1056/NEJMc1212055
    1. Bokulich NA, Chung J, Battaglia T, Henderson N, Jay M, Li H, et al. . Antibiotics, birth mode, and diet shape microbiome maturation during early life. Sci Transl Med. (2016) 8:343ra382. 10.1126/scitranslmed.aad7121
    1. Tapia G, Stordal K, Marild K, Kahrs CR, Skrivarhaug T, Njolstad PR, et al. . Antibiotics, acetaminophen and infections during prenatal and early life in relation to type 1 diabetes. Int J Epidemiol. (2018) 47:1538–48. 10.1093/ije/dyy092
    1. Kemppainen KM, Vehik K, Lynch KF, Larsson HE, Canepa RJ, Simell V, et al. association between early-life antibiotic use and the risk of islet or celiac disease autoimmunity. JAMA Pediatr. (2017) 171:1217–25. 10.1001/jamapediatrics.2017.2905
    1. Mikkelsen KH, Knop FK, Vilsboll T, Frost M, Hallas J, Pottegard A. Use of antibiotics in childhood and risk of Type 1 diabetes: a population-based case-control study. Diabet Med. (2017) 34:272–7. 10.1111/dme.13262
    1. Kilkkinen A, Virtanen SM, Klaukka T, Kenward MG, Salkinoja-Salonen M, Gissler M, et al. . Use of antimicrobials and risk of type 1 diabetes in a population-based mother-child cohort. Diabetologia. (2006) 49:66–70. 10.1007/s00125-005-0078-2
    1. Boursi B, Mamtani R, Haynes K, Yang YX. The effect of past antibiotic exposure on diabetes risk. Eur J Endocrinol. (2015) 172:639–48. 10.1530/EJE-14-1163
    1. Hara N, Alkanani AK, Ir D, Robertson CE, Wagner BD, Frank DN, et al. . Prevention of virus-induced type 1 diabetes with antibiotic therapy. J Immunol. (2012) 189:3805–14. 10.4049/jimmunol.1201257
    1. Livanos AE, Greiner TU, Vangay P, Pathmasiri W, Stewart D, Mcritchie S, et al. . Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice. Nat Microbiol. (2016) 1:16140. 10.1038/nmicrobiol.2016.140
    1. Hansen CH, Krych L, Nielsen DS, Vogensen FK, Hansen LH, Sorensen SJ, et al. . Early life treatment with vancomycin propagates Akkermansia muciniphila and reduces diabetes incidence in the NOD mouse. Diabetologia. (2012) 55:2285–94. 10.1007/s00125-012-2564-7
    1. Hu Y, Peng J, Tai N, Hu C, Zhang X, Wong FS, et al. . Maternal antibiotic treatment protects offspring from diabetes development in nonobese diabetic mice by generation of tolerogenic APCs. J Immunol. (2015) 195:4176–84. 10.4049/jimmunol.1500884
    1. Pinto E, Anselmo M, Calha M, Bottrill A, Duarte I, Andrew PW, et al. . The intestinal proteome of diabetic and control children is enriched with different microbial and host proteins. Microbiology. (2017) 163:161–74. 10.1099/mic.0.000412
    1. Gavin PG, Mullaney JA, Loo D, Cao KL, Gottlieb PA, Hill MM, et al. . Intestinal metaproteomics reveals host-microbiota interactions in subjects at risk for type 1 diabetes. Diabetes Care. (2018) 41:2178–86. 10.2337/dc18-0777
    1. Coppieters KT, Wiberg A, Von Herrath MG. Viral infections and molecular mimicry in type 1 diabetes. APMIS. (2012) 120:941–9. 10.1111/apm.12011
    1. Kramna L, Kolarova K, Oikarinen S, Pursiheimo JP, Ilonen J, Simell O, et al. . Gut virome sequencing in children with early islet autoimmunity. Diabetes Care. (2015) 38:930–3. 10.2337/dc14-2490
    1. Zhao G, Vatanen T, Droit L, Park A, Kostic AD, Poon TW, et al. . Intestinal virome changes precede autoimmunity in type I diabetes-susceptible children. Proc Natl Acad Sci USA. (2017) 114:E6166–75. 10.1073/pnas.1706359114
    1. Kim KW, Horton JL, Pang CNI, Jain K, Leung P, Isaacs SR, et al. . Higher abundance of enterovirus A species in the gut of children with islet autoimmunity. Sci Rep. (2019) 9:1749. 10.1038/s41598-018-38368-8
    1. Martin FP, Wang Y, Sprenger N, Yap IK, Lundstedt T, Lek P, et al. . Probiotic modulation of symbiotic gut microbial-host metabolic interactions in a humanized microbiome mouse model. Mol Syst Biol. (2008) 4:157. 10.1038/msb4100190
    1. Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, et al. . Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci USA. (2009) 106:3698–703. 10.1073/pnas.0812874106
    1. Aw W, Fukuda S. Toward the comprehensive understanding of the gut ecosystem via metabolomics-based integrated omics approach. Semin Immunopathol. (2015) 37:5–16. 10.1007/s00281-014-0456-2
    1. Bridgman SL, Azad MB, Field CJ, Haqq AM, Becker AB, Mandhane PJ, et al. . Fecal short-chain fatty acid variations by breastfeeding status in infants at 4 months: differences in relative versus absolute concentrations. Front Nutr. (2017) 4:11. 10.3389/fnut.2017.00011
    1. Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N, Ngom-Bru C, et al. . Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med. (2014) 20:159–66. 10.1038/nm.3444
    1. Benus RF, Van Der Werf TS, Welling GW, Judd PA, Taylor MA, Harmsen HJ, et al. . Association between Faecalibacterium prausnitzii and dietary fibre in colonic fermentation in healthy human subjects. Br J Nutr. (2010) 104:693–700. 10.1017/S0007114510001030
    1. Donohoe DR, Garge N, Zhang X, Sun W, O'connell TM, Bunger MK, et al. . The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. (2011) 13:517–26.
    1. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, et al. . Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. (2013) 504:446–50. 10.1038/nature12721
    1. De Vadder F, Kovatcheva-Datchary P, Goncalves D, Vinera J, Zitoun C, Duchampt A, et al. . Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell. (2014) 156:84–96. 10.1016/j.cell.2013.12.016
    1. Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, et al. . Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity. (2014) 40:128–39. 10.1016/j.immuni.2013.12.007
    1. Marino E, Richards JL, Mcleod KH, Stanley D, Yap YA, Knight J, et al. Erratum: gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes. Nat Immunol. (2017) 18:1271 10.1038/ni1117-1271c
    1. Songini M, Bernardinelli L, Clayton D, Montomoli C, Pascutto C, Ghislandi M, et al. . The Sardinian IDDM study: 1. Epidemiology and geographical distribution of IDDM in Sardinia during 1989 to 1994. Diabetologia. (1998) 41:221–7. 10.1007/s001250050893
    1. Culeddu N, Chessa M, Porcu MC, Fresu P, Tonolo G, Virgilio G, et al. NMR-based metabolomic study of type 1 diabetes. Metabolomics. (2012) 8:1162–9. 10.1007/s11306-012-0420-x
    1. Oresic M, Simell S, Sysi-Aho M, Nanto-Salonen K, Seppanen-Laakso T, Parikka V, et al. . Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes. J Exp Med. (2008) 205:2975–84. 10.1084/jem.20081800
    1. Atkinson MA, Leiter EH. The NOD mouse model of type 1 diabetes: as good as it gets? Nat Med. (1999) 5:601–4. 10.1038/9442
    1. Dolensek J, Rupnik MS, Stozer A. Structural similarities and differences between the human and the mouse pancreas. Islets. (2015) 7:e1024405. 10.1080/19382014.2015.1024405
    1. Blohme G, Nystrom L, Arnqvist HJ, Lithner F, Littorin B, Olsson PO, et al. . Male predominance of type 1 (insulin-dependent) diabetes mellitus in young adults: results from a 5-year prospective nationwide study of the 15-34-year age group in Sweden. Diabetologia. (1992) 35:56–62. 10.1007/BF00400852
    1. Williams AJ, Bingley PJ, Moore WP, Gale EA, Trial ESGENDI. Islet autoantibodies, nationality and gender: a multinational screening study in first-degree relatives of patients with Type I diabetes. Diabetologia. (2002) 45:217–23. 10.1007/s00125-001-0749-6
    1. Wandell PE, Carlsson AC. Time trends and gender differences in incidence and prevalence of type 1 diabetes in Sweden. Curr Diabetes Rev. (2013) 9:342–9. 10.2174/15733998113099990064
    1. Roep BO, Atkinson M, Von Herrath M. Satisfaction (not) guaranteed: re-evaluating the use of animal models of type 1 diabetes. Nat Rev Immunol. (2004) 4:989–97. 10.1038/nri1502
    1. Atkinson MA, Roep BO, Posgai A, Wheeler DCS, Peakman M. The challenge of modulating beta-cell autoimmunity in type 1 diabetes. Lancet Diabetes Endocrinol. (2019) 7:52–64. 10.1016/S2213-8587(18)30112-8
    1. Manrique P, Bolduc B, Walk ST, Van Der Oost J, De Vos WM, Young MJ. Healthy human gut phageome. Proc Natl Acad Sci USA. (2016) 113:10400–5. 10.1073/pnas.1601060113
    1. Sokol H, Leducq V, Aschard H, Pham HP, Jegou S, Landman C, et al. . Fungal microbiota dysbiosis in IBD. Gut. (2017) 66:1039–48. 10.1136/gutjnl-2015-310746
    1. Koskinen K, Pausan MR, Perras AK, Beck M, Bang C, Mora M, et al. . First insights into the diverse human archaeome: specific detection of archaea in the gastrointestinal tract, lung, and nose and on skin. MBio. (2017) 8:e00824-17. 10.1128/mBio.00824-17
    1. Abu-Ali GS, Mehta RS, Lloyd-Price J, Mallick H, Branck T, Ivey KL, et al. . Metatranscriptome of human faecal microbial communities in a cohort of adult men. Nat Microbiol. (2018) 3:356–66. 10.1038/s41564-017-0084-4
    1. Wilson MT, Hamilos DL. The nasal and sinus microbiome in health and disease. Curr Allergy Asthma Rep. (2014) 14:485. 10.1007/s11882-014-0485-x
    1. Byrd AL, Belkaid Y, Segre JA. The human skin microbiome. Nat Rev Microbiol. (2018) 16:143–55. 10.1038/nrmicro.2017.157
    1. Ma B, Forney LJ, Ravel J. Vaginal microbiome: rethinking health and disease. Annu Rev Microbiol. (2012) 66:371–89. 10.1146/annurev-micro-092611-150157
    1. Niehaus L, Boland I, Liu M, Chen K, Fu D, Henckel C, et al. . Microbial coexistence through chemical-mediated interactions. Nat Commun. (2019) 10:2052. 10.1038/s41467-019-10062-x
    1. Altindis E, Cai W, Sakaguchi M, Zhang F, Guoxiao W, Liu F, et al. . Viral insulin-like peptides activate human insulin and IGF-1 receptor signaling: a paradigm shift for host-microbe interactions. Proc Natl Acad Sci USA. (2018) 115:2461–6. 10.1073/pnas.1721117115
    1. Huang Q, Kahn CR, Altindis E. Viral hormones: expanding dimensions in endocrinology. Endocrinology. (2019) 160:2165–79. 10.1210/en.2019-00271

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