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  • Review Article
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Antibiotics in the pathogenesis of diabetes and inflammatory diseases of the gastrointestinal tract

Nature Reviews Gastroenterology & Hepatology volume 20, pages 81–100 (2023)Cite this article

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Abstract

Antibiotic use is increasing worldwide. However, the use of antibiotics is clearly associated with changes in gut microbiome composition and function, and perturbations have been identified as potential environmental risk factors for chronic inflammatory disorders of the gastrointestinal tract. In this Review, we examine the association between the use of antibiotics and the onset and development of both type 1 and type 2 diabetes, inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, as well as coeliac disease and eosinophilic oesophagitis. We discuss the key findings of epidemiological studies, provide mechanistic insights into the pathways by which the gut microbiota might contribute to these diseases, and assess clinical trials investigating the effects of antibiotics. Such studies indicate that antibiotic exposures, varying in type, timing and dosage, could explain differences in disease risk. There seems to be a critical window in early life in which perturbation of the microbiome has a substantial effect on disease development. Identifying the antibiotic-perturbed gut microbiota as a factor that contributes to the pathophysiology of these inflammatory disorders might stimulate new approaches to prevention, diagnosis and treatment.

Key points

  • The widespread use of antibiotics worldwide is consistent with a rise in chronic inflammatory diseases of the gastrointestinal tract, including inflammatory bowel disease, coeliac disease, eosinophilic oesophagitis, and type 1 and type 2 diabetes.

  • Exposure to antibiotics leads to profound effects on both the composition and the functionality of the gut microbiota, leading to potential pathogenic mechanisms for disease onset.

  • Experimental studies have shown that antibiotic-induced perturbations of the microbiota are transferable and affect disease development.

  • Differential levels of antibiotic exposures, and their types and timing — particularly exposure in early childhood — could explain differences in disease risk.

  • A growing body of evidence indicates that an antibiotic-perturbed microbiota is associated with disease development, although current knowledge is limited by microbiota complexity. Research including prospective epidemiological studies, clinical trials and experimental studies is required.

  • Novel therapies aiming to remediate the perturbation of the gut microbiome are being researched, including prebiotics, probiotics, synbiotics and faecal microbiota transplantation; however, the strong application of antibiotic stewardship is most warranted to prevent perturbing the microbiome.

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Fig. 1: The gut microbiota and antibiotics in the pathogenesis of inflammatory diseases of the gastrointestinal tract.
Fig. 2: Complex interplay between the gut microbiota and the immune system in diabetes and IBD.
Fig. 3: Influence of the gut microbiota on inflammatory bowel disease activity.

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References

  1. Ferretti, P. et al. Mother-to-infant microbial transmission from different body sites shapes the developing infant gut microbiome. Cell Host Microbe 24, 133–145.e5 (2018).

    Article  CAS  Google Scholar 

  2. Korpela, K. & de Vos, W. M. Early life colonization of the human gut: microbes matter everywhere. Curr. Opin. Microbiol. 44, 70–78 (2018).

    Article  Google Scholar 

  3. Bokulich, N. et al. Antibiotics, birth mode, and diet shape microbiome maturation during early life. Sci. Transl Med. 176, 139–148 (2016). This paper shows the profound effects of caesarean section and antibiotic exposure on how the early-life microbiome develops.

    Google Scholar 

  4. Yassour, M. et al. Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability. Sci. Transl Med. 8, 343ra81 (2016).

    Article  Google Scholar 

  5. Bäckhed, F. et al. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe 17, 690–703 (2015).

    Article  Google Scholar 

  6. Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012).

    Article  CAS  Google Scholar 

  7. Cho, I. et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 488, 621–626 (2012).

    Article  CAS  Google Scholar 

  8. Cox, L. M. et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 158, 705–721 (2014). This paper shows that transient antibiotic-induced perturbation in early life can lead to late long-term metabolic changes in experimental models of obesity.

    Article  CAS  Google Scholar 

  9. Ruiz, V. E. et al. A single early-in-life macrolide course has lasting effects on murine microbial network topology and immunity. Nat. Commun. 8, 518 (2017).

    Article  Google Scholar 

  10. Macpherson, A. J. & Harris, N. L. Interactions between commensal intestinal bacteria and the immune system. Nat. Rev. Immunol. 4, 478–485 (2004).

    Article  CAS  Google Scholar 

  11. Honda, K. & Littman, D. R. The microbiota in adaptive immune homeostasis and disease. Nature 535, 75–84 (2016).

    Article  CAS  Google Scholar 

  12. Hsiao, E. Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451–1463 (2013). This paper provides direct evidence of linkage of the gut microbiome with neurodevelopment.

    Article  CAS  Google Scholar 

  13. Blaser, M. J. Who are we? Indigenous microbes and the ecology of human diseases. EMBO Rep. 7, 956–960 (2006). This paper introduces the concept that loss of ancestral commensals is leading to the modern epidemics of chronic diseases.

    Article  CAS  Google Scholar 

  14. Blaser, M. J. The past and future biology of the human microbiome in an age of extinctions. Cell 172, 1173–1177 (2018).

    Article  CAS  Google Scholar 

  15. Guo, R., Chen, L.-H., Xing, C. & Liu, T. Pain regulation by gut microbiota: molecular mechanisms and therapeutic potential. Br. J. Anaesth. 123, 637–654 (2019).

    Article  CAS  Google Scholar 

  16. O’ Mahony, S. M., Dinan, T. G. & Cryan, J. F. The gut microbiota as a key regulator of visceral pain. Pain 158 (Suppl. 1), S19–S28 (2017).

    Article  Google Scholar 

  17. Ding, W. et al. Gut microbiota influences neuropathic pain through modulating proinflammatory and anti-inflammatory T cells. Anesth. Analg. 132, 1146–1155 (2021).

    Article  CAS  Google Scholar 

  18. Esquerre, N. et al. Colitis-induced microbial perturbation promotes postinflammatory visceral hypersensitivity. Cell Mol. Gastroenterol. Hepatol. 10, 225–244 (2020).

    Article  Google Scholar 

  19. Amaral, F. A. et al. Commensal microbiota is fundamental for the development of inflammatory pain. Proc. Natl Acad. Sci. USA 105, 2193–2197 (2008).

    Article  CAS  Google Scholar 

  20. di Biase, A. R. et al. Gut microbiota signatures and clinical manifestations in celiac disease children at onset: a pilot study. J. Gastroenterol. Hepatol. 36, 446–454 (2021).

    Article  Google Scholar 

  21. van Boeckel, T. P. et al. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. Lancet Infect. Dis. 14, 742–750 (2014).

    Article  Google Scholar 

  22. Blaser, M. J., Melby, M. K., Lock, M. & Nichter, M. Accounting for variation in and overuse of antibiotics among humans. Bioessays 43, e2000163 (2021). This paper indicates the extensive variation in antibiotic use and the means to rationalize therapeutic approaches.

    Article  Google Scholar 

  23. Maier, L. et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555, 623–628 (2018).

    Article  CAS  Google Scholar 

  24. Dethlefsen, L. & Relman, D. A. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc. Natl Acad. Sci. USA 108, 4554–4561 (2011).

    Article  CAS  Google Scholar 

  25. Korpela, K. et al. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children. Nat. Commun. 7, 10410 (2016). This study shows long-term effects of early-life antibiotic exposures.

    Article  CAS  Google Scholar 

  26. Abeles, S. R. et al. Microbial diversity in individuals and their household contacts following typical antibiotic courses. Microbiome 4, 39 (2016).

    Article  Google Scholar 

  27. Ventin-Holmberg, R. et al. The effect of antibiotics on the infant gut fungal microbiota. J. Fungi 8, 328 (2022).

    Article  CAS  Google Scholar 

  28. Basmaciyan, L., Bon, F., Paradis, T., Lapaquette, P. & Dalle, F. Candida albicans interactions with the host: crossing the intestinal epithelial barrier. Tissue Barriers 7, 1612661 (2019).

    Article  Google Scholar 

  29. Ost, K. S. et al. Adaptive immunity induces mutualism between commensal eukaryotes. Nature 596, 114–118 (2021).

    Article  CAS  Google Scholar 

  30. Dominguez-Bello, M. G., Godoy-Vitorino, F., Knight, R. & Blaser, M. J. Role of the microbiome in human development. Gut 68, 1108–1114 (2019).

    Article  CAS  Google Scholar 

  31. International Diabetes Federation. IDF Diabetes Atlas 10th edn (IDF, 2021).

  32. Ilonen, J., Lempainen, J. & Veijola, R. The heterogeneous pathogenesis of type 1 diabetes mellitus. Nat. Rev. Endocrinol. 15, 635–650 (2019).

    Article  CAS  Google Scholar 

  33. Patterson, C. C. et al. Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet 373, 2027–2033 (2009).

    Article  Google Scholar 

  34. Hussen, H. I., Persson, M. & Moradi, T. The trends and the risk of type 1 diabetes over the past 40 years: an analysis by birth cohorts and by parental migration background in Sweden. BMJ Open 3, e003418 (2013).

    Article  Google Scholar 

  35. Akerblom, H. K., Vaarala, O., Hyöty, H., Ilonen, J. & Knip, M. Environmental factors in the etiology of type 1 diabetes. Am. J. Med. Genet. 115, 18–29 (2002).

    Article  Google Scholar 

  36. Giongo, A. et al. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. 5, 82–91 (2011).

    Article  CAS  Google Scholar 

  37. de Goffau, M. C. et al. Fecal microbiota composition differs between children with β-cell autoimmunity and those without. Diabetes 62, 1238–1244 (2013).

    Article  Google Scholar 

  38. de Groot, P. F. et al. Distinct fecal and oral microbiota composition in human type 1 diabetes, an observational study. PLoS ONE 12, e0188475 (2017).

    Article  Google Scholar 

  39. Kostic, A. D. et al. The dynamics of the human infant gut microbiome in development and in progression towards type 1 diabetes. Cell Host Microbe 17, 260–273 (2015). This study links changes in microbiome characteristics with type 1 diabetes risk.

    Article  CAS  Google Scholar 

  40. Rogers, M. A. M., Kim, C., Banerjee, T. & Lee, J. M. Fluctuations in the incidence of type 1 diabetes in the United States from 2001 to 2015: a longitudinal study. BMC Med. 15, 199 (2017).

    Article  Google Scholar 

  41. International Diabetes Federation. IDF Diabetes Atlas 2nd edn (IDF, 2003).

  42. Abela, A. G. & Fava, S. Why is the incidence of type 1 diabetes increasing? Curr. Diabetes Rev. 17, e030521193110 (2021).

    Article  CAS  Google Scholar 

  43. Gale, E. A. M. The rise of childhood type 1 diabetes in the 20th century. Diabetes 51, 3353–3361 (2002).

    Article  CAS  Google Scholar 

  44. Chapman, N. M., Coppieters, K., von Herrath, M. & Tracy, S. The microbiology of human hygiene and its impact on type 1 diabetes. Islets 4, 253–261 (2012).

    Article  Google Scholar 

  45. Korpela, K. et al. Antibiotics in early life associate with specific gut microbiota signatures in a prospective longitudinal infant cohort. Pediatr. Res. 88, 438–443 (2020).

    Article  CAS  Google Scholar 

  46. Dominguez-Bello, M. G. et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl Acad. Sci. USA 107, 11971–11975 (2010).

    Article  Google Scholar 

  47. Korpela, K. et al. Maternal fecal microbiota transplantation in cesarean-born infants rapidly restores normal gut microbial development: a proof-of-concept study. Cell 183, 324–334.e5 (2020).

    Article  CAS  Google Scholar 

  48. Mueller, N. T. et al. Prenatal exposure to antibiotics, cesarean section and risk of childhood obesity. Int. J. Obes. 39, 665–670 (2015).

    Article  CAS  Google Scholar 

  49. Williams, M. J., Ribeiro do Valle, C. C. & Gyte, G. M. L. Different classes of antibiotics given to women routinely for preventing infection at caesarean section. Cochrane Database Syst. Rev. 3, CD008726 (2021).

    Google Scholar 

  50. Wernroth, M.-L. et al. Early childhood antibiotic treatment for otitis media and other respiratory tract infections is associated with risk of type 1 diabetes: a nationwide register-based study with sibling analysis. Diabetes Care 43, 991–999 (2020).

    Article  CAS  Google Scholar 

  51. Clausen, T. D. et al. Broad-spectrum antibiotic treatment and subsequent childhood type 1 diabetes: a Nationwide Danish Cohort Study. PLoS ONE 11, e0161654 (2016).

    Article  Google Scholar 

  52. Hicks, L. A., Taylor, T. H.Jr & Hunkler, R. J. U.S. outpatient antibiotic prescribing, 2010. N. Engl. J. Med. 368, 1461–1462 (2013).

    Article  CAS  Google Scholar 

  53. Cars, O., Mölstad, S. & Melander, A. Variation in antibiotic use in the European Union. Lancet 357, 1851–1853 (2001).

    Article  CAS  Google Scholar 

  54. Hviid, A. & Svanström, H. Antibiotic use and type 1 diabetes in childhood. Am. J. Epidemiol. 169, 1079–1084 (2009).

    Article  Google Scholar 

  55. Tapia, G. et al. Antibiotics, acetaminophen and infections during prenatal and early life in relation to type 1 diabetes. Int. J. Epidemiol. 47, 1538–1548 (2018).

    Article  Google Scholar 

  56. Suzuki, K. et al. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Proc. Natl Acad. Sci. USA 101, 1981–1986 (2004).

    Article  CAS  Google Scholar 

  57. Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).

    Article  CAS  Google Scholar 

  58. Geuking, M. B. et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34, 794–806 (2011).

    Article  CAS  Google Scholar 

  59. El-Aidy, S., Hooiveld, G., Tremaroli, V., Bäckhed, F. & Kleerebezem, M. The gut microbiota and mucosal homeostasis: colonized at birth or at adulthood, does it matter? Gut Microbes 4, 118–124 (2013).

    Article  Google Scholar 

  60. Makino, S. et al. Breeding of a non-obese, diabetic strain of mice. Jikken Dobutsu 29, 1–13 (1980).

    CAS  Google Scholar 

  61. Alam, C. et al. Effects of a germ-free environment on gut immune regulation and diabetes progression in non-obese diabetic (NOD) mice. Diabetologia 54, 1398–1406 (2011).

    Article  CAS  Google Scholar 

  62. King, C. & Sarvetnick, N. The incidence of type-1 diabetes in NOD mice is modulated by restricted flora not germ-free conditions. PLoS ONE 6, 6–8 (2011).

    Article  Google Scholar 

  63. Kriegel, M. A. et al. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc. Natl Acad. Sci. USA 108, 11548–11553 (2011).

    Article  CAS  Google Scholar 

  64. Pozzilli, P., Signore, A., Williams, A. J. & Beales, P. E. NOD mouse colonies around the world–recent facts and figures. Immunol. Today 14, 193–196 (1993).

    Article  CAS  Google Scholar 

  65. Wen, L. et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455, 1109–1113 (2008).

    Article  CAS  Google Scholar 

  66. Hu, Y. et al. Different immunological responses to early-life antibiotic exposure affecting autoimmune diabetes development in NOD mice. J. Autoimmun. 72, 47–56 (2016).

    Article  CAS  Google Scholar 

  67. Brugman, S. 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 49, 2105–2108 (2006).

    Article  CAS  Google Scholar 

  68. Candon, S. et al. Antibiotics in early life alter the gut microbiome and increase disease incidence in a spontaneous mouse model of autoimmune insulin-dependent diabetes. PLoS ONE 10, e0125448 (2015).

    Article  Google Scholar 

  69. Hansen, C. H. F. et al. Early life treatment with vancomycin propagates Akkermansia muciniphila and reduces diabetes incidence in the NOD mouse. Diabetologia 55, 2285–2294 (2012).

    Article  CAS  Google Scholar 

  70. Brown, K. et al. Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice. ISME J. 10, 321–332 (2016).

    Article  CAS  Google Scholar 

  71. Livanos, A. E. et al. Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice. Nat. Microbiol. 1, 16140 (2016). This paper discusses the use of an experimental model showing a causal role for an antibiotic-perturbed microbiota in type 1 diabetes.

    Article  CAS  Google Scholar 

  72. Zhang, X.-S. et al. Antibiotic-induced acceleration of type 1 diabetes alters maturation of innate intestinal immunity. eLife 7, e37816 (2018).

    Article  Google Scholar 

  73. Zhang, X. et al. Maternal cecal microbiota transfer rescues early-life antibiotic-induced enhancement of type 1 diabetes in mice. Cell Host Microbe 29, 1249–1265.e9 (2021). This study demonstrated that after antibiotic-induced increases in experimental type 1 diabetes, microbiome transplant can return phenotype to the baseline.

    Article  CAS  Google Scholar 

  74. Conget, I. et al. Lack of effect of intermittently administered sodium fusidate in patients with newly diagnosed type 1 diabetes mellitus: the FUSIDM trial. Diabetologia 48, 1464–1468 (2005).

    Article  CAS  Google Scholar 

  75. de Groot, P. F. et al. Oral butyrate does not affect innate immunity and islet autoimmunity in individuals with longstanding type 1 diabetes: a randomised controlled trial. Diabetologia 63, 597–610 (2020).

    Article  Google Scholar 

  76. de Groot, P. et al. Faecal microbiota transplantation halts progression of human new-onset type 1 diabetes in a randomised controlled trial. Gut 70, 92–105 (2021).

    Article  Google Scholar 

  77. National Center for Chronic Disease Prevention and Health Promotion (U.S.). Division of Diabetes Translation. Long-term trends in diabetes. April 2017. CDC https://stacks.cdc.gov/view/cdc/46096 (2017).

  78. Centers for Disease Control and Prevention. Diabetes Report Card 2019 (CDC, 2020).

  79. Wang, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012).

    Article  Google Scholar 

  80. Zhao, L. et al. Comprehensive relationships between gut microbiome and faecal metabolome in individuals with type 2 diabetes and its complications. Endocrine 66, 526–537 (2019).

    Article  CAS  Google Scholar 

  81. Ahmad, A. et al. Analysis of gut microbiota of obese individuals with type 2 diabetes and healthy individuals. PLoS ONE 14, e0226372 (2019).

    Article  CAS  Google Scholar 

  82. Magne, F. et al. The firmicutes/bacteroidetes ratio: a relevant marker of gut dysbiosis in obese patients? Nutrients 12, 1474 (2020).

    Article  CAS  Google Scholar 

  83. Zmora, N., Suez, J. & Elinav, E. You are what you eat: diet, health and the gut microbiota. Nat. Rev. Gastroenterol. Hepatol. 16, 35–56 (2019).

    Article  CAS  Google Scholar 

  84. Deschasaux, M. et al. Depicting the composition of gut microbiota in a population with varied ethnic origins but shared geography. Nat. Med. 24, 1526–1531 (2018).

    Article  CAS  Google Scholar 

  85. Muilwijk, M. et al. The high risk for type 2 diabetes among ethnic minority populations is not explained by low-grade inflammation. Sci. Rep. 9, 19871 (2019).

    Article  CAS  Google Scholar 

  86. Tillin, T. et al. Insulin resistance and truncal obesity as important determinants of the greater incidence of diabetes in Indian Asians and African Caribbeans compared with Europeans: the Southall and Brent Revisited (SABRE) cohort. Diabetes Care 36, 383–393 (2013).

    Article  Google Scholar 

  87. Mikkelsen, K. H., Knop, F. K., Frost, M., Hallas, J. & Pottegard, A. Use of antibiotics and risk of type 2 diabetes: a population-based case-control study. J. Clin. Endocrinol. Metab. 100, 3633–3640 (2015). This was a large epidemiological study in Denmark linking prior antibiotic exposures, even years earlier, with the risk of developing T2DM.

    Article  CAS  Google Scholar 

  88. Davis, P. J. et al. Prior antibiotic exposure and risk of type 2 diabetes among veterans. Prim. Care Diabetes 13, 49–56 (2019).

    Article  Google Scholar 

  89. Boursi, B., Mamtani, R., Haynes, K. & Yang, Y.-X. The effect of past antibiotic exposure on diabetes risk. Eur. J. Endocrinol. 172, 639–648 (2015). This was a large epidemiological study in the UK linking prior antibiotic exposures to risk of type 2 diabetes in adults.

    Article  CAS  Google Scholar 

  90. Trasande, L. et al. Infant antibiotic exposures and early-life body mass. Int. J. Obes. 37, 16–23 (2013).

    Article  CAS  Google Scholar 

  91. Bailey, L. C. et al. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr. 168, 1063–1069 (2014).

    Article  Google Scholar 

  92. Azad, M. B., Bridgman, S. L., Becker, A. B. & Kozyrskyj, A. L. Infant antibiotic exposure and the development of childhood overweight and central adiposity. Int. J. Obes. 38, 1290–1298 (2014).

    Article  CAS  Google Scholar 

  93. Murphy, R. et al. Antibiotic treatment during infancy and increased body mass index in boys: an international cross-sectional study. Int. J. Obes. 38, 1115–1119 (2014).

    Article  Google Scholar 

  94. Aversa, Z. et al. Association of infant antibiotic exposure with childhood health outcomes. Mayo Clin. Proc. 96, 66–77 (2021). This was an epidemiological study linking early-life antibiotic exposure to ten common childhood disorders.

    Article  Google Scholar 

  95. Mbakwa, C. A. et al. Early life antibiotic exposure and weight development in children. J. Pediatrics 176, 105–113.e2 (2016).

    Article  CAS  Google Scholar 

  96. Rogawski, E. T. et al. Use of antibiotics in children younger than two years in eight countries: a prospective cohort study. Bull. World Health Organ. 95, 49–61 (2017). This study indicates the extremely high use of antibiotics in young children in many developing countries/regions.

    Article  Google Scholar 

  97. Klein, E. Y. et al. Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proc. Natl Acad. Sci. USA 115, E3463–E3470 (2018).

    Article  CAS  Google Scholar 

  98. Dierikx, T. H. et al. The influence of prenatal and intrapartum antibiotics on intestinal microbiota colonisation in infants: a systematic review. J. Infect. 81, 190–204 (2020).

    Article  CAS  Google Scholar 

  99. Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005).

    Article  CAS  Google Scholar 

  100. Verhaar, B. J. H. et al. Associations between gut microbiota, faecal short-chain fatty acids, and blood pressure across ethnic groups: the HELIUS study. Eur. Heart J. 41, 4259–4267 (2020).

    Article  CAS  Google Scholar 

  101. Rothschild, D. et al. Environment dominates over host genetics in shaping human gut microbiota. Nature 555, 210–215 (2018).

    Article  CAS  Google Scholar 

  102. Schulfer, A. F. et al. The impact of early-life sub-therapeutic antibiotic treatment (STAT) on excessive weight is robust despite transfer of intestinal microbes. ISME J. 13, 1280–1292 (2019).

    Article  CAS  Google Scholar 

  103. Mahana, D. et al. Antibiotic perturbation of the murine gut microbiome enhances the adiposity, insulin resistance, and liver disease associated with high-fat diet. Genome Med. 8, 48 (2016).

    Article  Google Scholar 

  104. Turnbaugh, P. J., Bäckhed, F., Fulton, L. & Gordon, J. I. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 3, 213–223 (2008).

    Article  CAS  Google Scholar 

  105. Cherbut, C. et al. Short-chain fatty acids modify colonic motility through nerves and polypeptide YY release in the rat. Am. J. Physiol. 275, G1415–G1422 (1998).

    CAS  Google Scholar 

  106. Samuel, B. S. et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl Acad. Sci. USA 105, 16767–16772 (2008).

    Article  CAS  Google Scholar 

  107. Kimura, I. et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat. Commun. 4, 1829 (2013).

    Article  Google Scholar 

  108. Ang, Z. & Ding, J. L. GPR41 and GPR43 in obesity and inflammation–protective or causative? Front. Immunol. 7, 1–5 (2016).

    Article  Google Scholar 

  109. Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).

    Article  CAS  Google Scholar 

  110. Cani, P. D., Bibiloni, R., Knauf, C., Neyrinck, A. M. & Delzenne, N. M. Changes in gut microbiota control metabolic diet-induced obesity and diabetes in mice. Diabetes 57, 1470–1481 (2008).

    Article  CAS  Google Scholar 

  111. Moreno-Navarrete, J. M. et al. Circulating lipopolysaccharide-binding protein (LBP) as a marker of obesity-related insulin resistance. Int. J. Obes. 36, 1442–1449 (2012).

    Article  CAS  Google Scholar 

  112. Gonzalez-Quintela, A. et al. Determinants of serum concentrations of lipopolysaccharide-binding protein (LBP) in the adult population: the role of obesity. PLoS ONE 8, e54600 (2013).

    Article  CAS  Google Scholar 

  113. Ortiz, S. et al. Bacterial DNA translocation holds increased insulin resistance and systemic inflammatory levels in morbid obese patients. J. Clin. Endocrinol. Metab. 99, 2575–2583 (2014).

    Article  CAS  Google Scholar 

  114. Lassenius, M. I. et al. Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation. Diabetes Care 34, 1809–1815 (2011).

    Article  CAS  Google Scholar 

  115. Rodrigues, R. R. et al. Antibiotic-induced alterations in gut microbiota are associated with changes in glucose metabolism in healthy mice. Front. Microbiol. 8, 2306 (2017).

    Article  Google Scholar 

  116. Miao, Z. H. et al. Dysbiosis of intestinal microbiota in early life aggravates high-fat diet induced dysmetabolism in adult mice. BMC Microbiol. 21, 209 (2021).

    Article  CAS  Google Scholar 

  117. Liu, Y. et al. Gut microbiome alterations in high-fat-diet-fed mice are associated with antibiotic tolerance. Nat. Microbiol. 6, 874–884 (2021).

    Article  CAS  Google Scholar 

  118. Gough, E. K. et al. The impact of antibiotics on growth in children in low and middle income countries: systematic review and meta-analysis of randomised controlled trials. BMJ 348, g2267 (2014).

    Article  Google Scholar 

  119. Edmonson, M. B. & Eickhoff, J. C. Weight gain and obesity in infants and young children exposed to prolonged antibiotic prophylaxis. JAMA Pediatr. 171, 150–156 (2017).

    Article  Google Scholar 

  120. Mikkelsen, K. H. et al. Effect of antibiotics on gut microbiota, gut hormones and glucose metabolism. PLoS ONE 10, e0142352 (2015).

    Article  Google Scholar 

  121. Vrieze, A. et al. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. J. Hepatol. 60, 824–831 (2014).

    Article  CAS  Google Scholar 

  122. Bakker, G. J. et al. Oral vancomycin treatment does not alter markers of postprandial inflammation in lean and obese subjects. Physiol. Rep. 7, e14199 (2019).

    Article  Google Scholar 

  123. Thuny, F. et al. Vancomycin treatment of infective endocarditis is linked with recently acquired obesity. PLoS ONE 5, e9074 (2010).

    Article  Google Scholar 

  124. Colantonio, A. G., Werner, S. L. & Brown, M. The effects of prebiotics and substances with prebiotic properties on metabolic and inflammatory biomarkers in individuals with type 2 diabetes mellitus: a systematic review. J. Acad. Nutr. Diet. 120, 587–607.e2 (2020).

    Article  Google Scholar 

  125. Hendijani, F. & Akbari, V. Probiotic supplementation for management of cardiovascular risk factors in adults with type II diabetes: a systematic review and meta-analysis. Clin. Nutr. 37, 532–541 (2018).

    Article  Google Scholar 

  126. Tabrizi, R. et al. The effects of synbiotic supplementation on glucose metabolism and lipid profiles in patients with diabetes: a systematic review and meta-analysis of randomized controlled trials. Probiotics Antimicrob. Proteins 10, 329–342 (2018).

    Article  CAS  Google Scholar 

  127. Vrieze, A. et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143, 913–916.e7 (2012).

    Article  CAS  Google Scholar 

  128. Kootte, R. S. et al. Improvement of insulin sensitivity after lean donor feces in metabolic syndrome is driven by baseline intestinal microbiota composition. Cell Metab. 26, 611–619.e6 (2017).

    Article  CAS  Google Scholar 

  129. Hanssen, N. M. J., de Vos, W. M. & Nieuwdorp, M. Fecal microbiota transplantation in human metabolic diseases: from a murky past to a bright future? Cell Metab. 33, 1098–1110 (2021).

    Article  CAS  Google Scholar 

  130. Ng, S. C. et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 390, 2769–2778 (2017).

    Article  Google Scholar 

  131. Alatab, S. et al. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol. Hepatol. 5, 17–30 (2020).

    Article  Google Scholar 

  132. Molodecky, N. A. et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142, 46–54.e42; quiz e30 (2012).

    Article  Google Scholar 

  133. King, J. A. et al. Trends in hospitalisation rates for inflammatory bowel disease in western versus newly industrialised countries: a population-based study of countries in the Organisation for Economic Co-operation and Development. Lancet Gastroenterol. Hepatol. 4, 287–295 (2019).

    Article  Google Scholar 

  134. Ng, S. C. et al. Early course of inflammatory bowel disease in a population-based inception cohort study from 8 countries in Asia and Australia. Gastroenterology 150, 84–86 (2016).

    Article  Google Scholar 

  135. Thia, K. T., Sandborn, W. J., Harmsen, W. S., Zinsmeister, A. R. & Loftus, E. V. J. Risk factors associated with progression to intestinal complications of Crohn’s disease in a population-based cohort. Gastroenterology 139, 1147–1155 (2010).

    Article  Google Scholar 

  136. Fumery, M. et al. Natural history of adult ulcerative colitis in population-based cohorts: a systematic review. Clin. Gastroenterol. Hepatol. 16, 343–356.e3 (2018).

    Article  Google Scholar 

  137. Benchimol, E. I. et al. Changing age demographics of inflammatory bowel disease in Ontario, Canada: a population-based cohort study of epidemiology trends. Inflamm. Bowel Dis. 20, 1761–1769 (2014).

    Article  Google Scholar 

  138. Benchimol, E. I. et al. Incidence, outcomes, and health services burden of very early onset inflammatory bowel disease. Gastroenterology 147, 803–805 (2014).

    Article  Google Scholar 

  139. Ghione, S. et al. Dramatic increase in incidence of ulcerative colitis and Crohn’s disease (1988–2011): a population-based study of French adolescents. Am. J. Gastroenterol. 113, 265–272 (2018).

    Article  Google Scholar 

  140. Benchimol, E. I. et al. Inflammatory bowel disease in immigrants to Canada and their children: a population-based cohort study. Am. J. Gastroenterol. 110, 553–563 (2015).

    Article  Google Scholar 

  141. Benchimol, E. I. et al. Asthma, type 1 and type 2 diabetes mellitus, and inflammatory bowel disease amongst South Asian immigrants to Canada and their children: a population-based cohort study. PLoS ONE 10, e0123599 (2015).

    Article  Google Scholar 

  142. Li, X., Sundquist, J., Hemminki, K. & Sundquist, K. Risk of inflammatory bowel disease in first- and second-generation immigrants in Sweden: a nationwide follow-up study. Inflamm. Bowel Dis. 17, 1784–1791 (2011).

    Article  Google Scholar 

  143. Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    Article  CAS  Google Scholar 

  144. Liu, J. Z. et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47, 979–986 (2015).

    Article  CAS  Google Scholar 

  145. Ananthakrishnan, A. N. Epidemiology and risk factors for IBD. Nat. Rev. Gastroenterol. Hepatol. 12, 205–217 (2015).

    Article  Google Scholar 

  146. Xu, L. et al. Systematic review with meta-analysis: breastfeeding and the risk of Crohn’s disease and ulcerative colitis. Aliment. Pharmacol. Ther. 46, 780–789 (2017).

    Article  CAS  Google Scholar 

  147. Vangay, P. et al. US immigration westernizes the human gut microbiome. Cell 175, 962–972.e10 (2018). This study demonstrates the influence of the environment on microbiome characteristics, with the microbiome of immigrants becoming progressively more westernized.

    Article  CAS  Google Scholar 

  148. Lewis, J. D. & Abreu, M. T. Diet as a trigger or therapy for inflammatory bowel diseases. Gastroenterology 152, 398–414.e6 (2017).

    Article  CAS  Google Scholar 

  149. Pannaraj, P. S. et al. Association between breast milk bacterial communities and establishment and development of the infant gut microbiome. JAMA Pediatr. 171, 647–654 (2017).

    Article  Google Scholar 

  150. Kronman, M. P., Zaoutis, T. E., Haynes, K., Feng, R. & Coffin, S. E. Antibiotic exposure and IBD development among children: a population-based cohort study. Pediatrics 130, e794–e803 (2012).

    Article  Google Scholar 

  151. Hviid, A., Svanström, H. & Frisch, M. Antibiotic use and inflammatory bowel diseases in childhood. Gut 60, 49–54 (2011). This study shows a dose–response relationship between antibiotic exposure in the first year of life and subsequent IBD development.

    Article  Google Scholar 

  152. Nguyen, L. H. et al. Antibiotic use and the development of inflammatory bowel disease: a national case-control study in Sweden. Lancet Gastroenterol. Hepatol. 5, 986–995 (2020).

    Article  Google Scholar 

  153. Shaw, S. Y., Blanchard, J. F. & Bernstein, C. N. Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease. Am. J. Gastroenterol. 105, 2687–2692 (2010).

    Article  Google Scholar 

  154. Shaw, S. Y., Blanchard, J. F. & Bernstein, C. N. Association between the use of antibiotics and new diagnoses of Crohn’s disease and ulcerative colitis. Am. J. Gastroenterol. 106, 2133–2142 (2011).

    Article  Google Scholar 

  155. Ungaro, R. et al. Antibiotics associated with increased risk of new-onset Crohn’s disease but not ulcerative colitis: a meta-analysis. Am. J. Gastroenterol. 109, 1728–1738 (2014).

    Article  CAS  Google Scholar 

  156. Zou, Y. et al. Correlation between antibiotic use in childhood and subsequent inflammatory bowel disease: a systematic review and meta-analysis. Scand. J. Gastroenterol. 55, 301–311 (2020).

    Article  Google Scholar 

  157. Card, T., Logan, R. F. A., Rodrigues, L. C. & Wheeler, J. G. Antibiotic use and the development of Crohn’s disease. Gut 53, 246–250 (2004).

    Article  CAS  Google Scholar 

  158. Virta, L., Auvinen, A., Helenius, H., Huovinen, P. & Kolho, K.-L. Association of repeated exposure to antibiotics with the development of pediatric Crohn’s disease–a nationwide, register-based Finnish case-control study. Am. J. Epidemiol. 175, 775–784 (2012).

    Article  Google Scholar 

  159. Benchimol, E. I. et al. Trends in epidemiology of pediatric inflammatory bowel disease in Canada: distributed network analysis of multiple population-based provincial health administrative databases. Am. J. Gastroenterol. 112, 1120–1134 (2017).

    Article  Google Scholar 

  160. Uhlig, H. H. et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 147, 990–1007.e3 (2014).

    Article  Google Scholar 

  161. Hildebrand, H., Malmborg, P., Askling, J., Ekbom, A. & Montgomery, S. M. Early-life exposures associated with antibiotic use and risk of subsequent Crohn’s disease. Scand. J. Gastroenterol. 43, 961–966 (2008).

    Article  CAS  Google Scholar 

  162. Sellon, R. K. et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect. Immun. 66, 5224–5231 (1998).

    Article  CAS  Google Scholar 

  163. Pizarro, T. T. et al. SAMP1/YitFc mouse strain: a spontaneous model of Crohn’s disease-like ileitis. Inflamm. Bowel Dis. 17, 2566–2584 (2011).

    Article  Google Scholar 

  164. Oka, A. et al. Human-derived Clostridium VE202 strains reduce enterobacteriaceae and fusobacteria and reverse experimental colitis induced by human gut microbiota [abstract P074]. Inflamm. Bowel Dis. 26, S36–S37 (2020).

    Article  Google Scholar 

  165. Bamias, G. et al. Down-regulation of intestinal lymphocyte activation and Th1 cytokine production by antibiotic therapy in a murine model of Crohn’s disease. J. Immunol. 169, 5308–5314 (2002).

    Article  Google Scholar 

  166. Hoentjen, F. et al. Antibiotics with a selective aerobic or anaerobic spectrum have different therapeutic activities in various regions of the colon in interleukin 10 gene deficient mice. Gut 52, 1721–1727 (2003).

    Article  CAS  Google Scholar 

  167. Schulfer, A. F. et al. Intergenerational transfer of antibiotic-perturbed microbiota enhances colitis in susceptible mice. Nat. Microbiol. 3, 234–242 (2018). This study provides experimental evidence that an antibiotic-perturbed microbiota is sufficient to drive colitis in genetically susceptible individuals.

    Article  CAS  Google Scholar 

  168. Miyoshi, J. et al. Peripartum antibiotics promote gut dysbiosis, loss of immune tolerance, and inflammatory bowel disease in genetically prone offspring. Cell Rep. 20, 491–504 (2017). This study complements the study of Schulfer et al. (2018) in showing the effects of an altered microbiota on IBD development.

    Article  CAS  Google Scholar 

  169. Blaser, M. J. & Falkow, S. What are the consequences of the disappearing human microbiota? Nat. Rev. Microbiol. 7, 887–894 (2009).

    Article  CAS  Google Scholar 

  170. Torres, J. et al. Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice. Gut 69, 42–51 (2020).

    Article  CAS  Google Scholar 

  171. Okayasu, I. et al. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98, 694–702 (1990).

    Article  CAS  Google Scholar 

  172. Chassaing, B., Aitken, J. D., Malleshappa, M. & Vijay-Kumar, M. Dextran sulfate sodium (DSS)-induced colitis in mice. Curr. Protoc. Immunol. 104, 15.25.1–15.25.14 (2014).

    Article  Google Scholar 

  173. Ozkul, C. et al. A single early-in-life antibiotic course increases susceptibility to DSS-induced colitis. Genome Med. 12, 65 (2020).

    Article  CAS  Google Scholar 

  174. Roubaud-Baudron, C. et al. Long-term effects of early-life antibiotic exposure on resistance to subsequent bacterial infection. mBio 10, e02820-19 (2019).

    Article  Google Scholar 

  175. Bermejo, F. et al. Efficacy of different therapeutic options for spontaneous abdominal abscesses in Crohn’s disease: are antibiotics enough? Inflamm. Bowel Dis. 18, 1509–1514 (2012).

    Article  Google Scholar 

  176. Nitzan, O., Elias, M., Peretz, A. & Saliba, W. Role of antibiotics for treatment of inflammatory bowel disease. World J. Gastroenterol. 22, 1078–1087 (2016).

    Article  CAS  Google Scholar 

  177. Panés, J. & Rimola, J. Perianal fistulizing Crohn’s disease: pathogenesis, diagnosis and therapy. Nat. Rev. Gastroenterol. Hepatol. 14, 652–664 (2017).

    Article  Google Scholar 

  178. Akiyama, S., Rai, V. & Rubin, D. T. Pouchitis in inflammatory bowel disease: a review of diagnosis, prognosis, and treatment. Intest. Res. 19, 1–11 (2021).

    Article  Google Scholar 

  179. Khan, K. J. et al. Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis. Am. J. Gastroenterol. 106, 661–673 (2011).

    Article  CAS  Google Scholar 

  180. Townsend, C. M. et al. Antibiotics for induction and maintenance of remission in Crohn’s disease. Cochrane Database Syst. Rev. 2, CD012730 (2019).

    Google Scholar 

  181. Halpin, S. J. & Ford, A. C. Prevalence of symptoms meeting criteria for irritable bowel syndrome in inflammatory bowel disease: systematic review and meta-analysis. Am. J. Gastroenterol. 107, 1474–1482 (2012).

    Article  Google Scholar 

  182. Pimentel, M., Park, S., Mirocha, J., Kane, S. V. & Kong, Y. The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann. Intern. Med. 145, 557–563 (2006).

    Article  Google Scholar 

  183. Rutgeerts, P. et al. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology 108, 1617–1621 (1995).

    Article  CAS  Google Scholar 

  184. Rutgeerts, P. et al. Ornidazole for prophylaxis of postoperative Crohn’s disease recurrence: a randomized, double-blind, placebo-controlled trial. Gastroenterology 128, 856–861 (2005).

    Article  CAS  Google Scholar 

  185. Spanogiannopoulos, P., Bess, E. N., Carmody, R. N. & Turnbaugh, P. J. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat. Rev. Microbiol. 14, 273–287 (2016).

    Article  CAS  Google Scholar 

  186. Crouwel, F., Buiter, H. J. C. & de Boer, N. K. Gut microbiota-driven drug metabolism in inflammatory bowel disease. J. Crohns Colitis 15, 307–315 (2020).

    Article  Google Scholar 

  187. Rafii, F., Franklin, W. & Cerniglia, C. E. Azoreductase activity of anaerobic bacteria isolated from human intestinal microflora. Appl. Env. Microbiol. 56, 2146–2151 (1990).

    Article  CAS  Google Scholar 

  188. Yadav, V., Gaisford, S., Merchant, H. A. & Basit, A. W. Colonic bacterial metabolism of corticosteroids. Int. J. Pharm. 457, 268–274 (2013).

    Article  CAS  Google Scholar 

  189. Valerino, D. M., Johns, D. G., Zaharko, D. S. & Oliverio, V. T. Studies of the metabolism of methotrexate by intestinal flora. I. Identification and study of biological properties of the metabolite 4-amino-4-deoxy-N10-methylpteroic acid. Biochem. Pharmacol. 21, 821–831 (1972).

    Article  CAS  Google Scholar 

  190. Oancea, I. et al. Colonic microbiota can promote rapid local improvement of murine colitis by thioguanine independently of T lymphocytes and host metabolism. Gut 66, 59–69 (2017).

    Article  CAS  Google Scholar 

  191. Moayyedi, P. et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 149, 102–109.e6 (2015).

    Article  Google Scholar 

  192. Rossen, N. G. et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology 149, 110–118.e4 (2015).

    Article  Google Scholar 

  193. Paramsothy, S. et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 389, 1218–1228 (2017).

    Article  Google Scholar 

  194. Costelloe, C., Metcalfe, C., Lovering, A., Mant, D. & Hay, A. D. Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. BMJ 340, c2096 (2010).

    Article  Google Scholar 

  195. Crothers, J. W. et al. Daily, oral FMT for long-term maintenance therapy in ulcerative colitis: results of a single-center, prospective, randomized pilot study. BMC Gastroenterol. 21, 281 (2021).

    Article  CAS  Google Scholar 

  196. Fehily, S. R., Basnayake, C., Wright, E. K. & Kamm, M. A. Fecal microbiota transplantation therapy in Crohn’s disease: systematic review. J. Gastroenterol. Hepatol. 36, 2672–2686 (2021).

    Article  CAS  Google Scholar 

  197. Sokol, H. et al. Fecal microbiota transplantation to maintain remission in Crohn’s disease: a pilot randomized controlled study. Microbiome 8, 12 (2020).

    Article  CAS  Google Scholar 

  198. Yang, Z. et al. Fecal microbiota transplant via endoscopic delivering through small intestine and colon: no difference for Crohn’s disease. Dig. Dis. Sci. 65, 150–157 (2020).

    Article  Google Scholar 

  199. Mustalahti, K. et al. The prevalence of celiac disease in Europe: results of a centralized, international mass screening project. Ann. Med. 42, 587–595 (2010).

    Article  Google Scholar 

  200. Rubio-Tapia, A., Ludvigsson, J. F., Brantner, T. L., Murray, J. A. & Everhart, J. E. The prevalence of celiac disease in the United States. Am. J. Gastroenterol. 107, 1538–1544 quiz 1537–1545 (2012).

    Article  Google Scholar 

  201. Ludvigsson, J. F., Montgomery, S. M., Ekbom, A., Brandt, L. & Granath, F. Small-intestinal histopathology and mortality risk in celiac disease. JAMA 302, 1171–1178 (2009).

    Article  CAS  Google Scholar 

  202. Rubio-Tapia, A. et al. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology 137, 88–93 (2009).

    Article  Google Scholar 

  203. King, J. A. et al. Incidence of celiac disease is increasing over time: a systematic review and meta-analysis. Am. J. Gastroenterol. 115, 507–525 (2020).

    Article  Google Scholar 

  204. Catassi, C. et al. Natural history of celiac disease autoimmunity in a USA cohort followed since 1974. Ann. Med. 42, 530–538 (2010).

    Article  Google Scholar 

  205. Sollid, L. M. et al. Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer. J. Exp. Med. 169, 345–350 (1989).

    Article  CAS  Google Scholar 

  206. Collado, M. C., Calabuig, M. & Sanz, Y. Differences between the fecal microbiota of coeliac infants and healthy controls. Curr. Issues Intest. Microbiol. 8, 9–14 (2007).

    CAS  Google Scholar 

  207. Collado, M. C., Donat, E., Ribes-Koninckx, C., Calabuig, M. & Sanz, Y. Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease. J. Clin. Pathol. 62, 264–269 (2009).

    Article  CAS  Google Scholar 

  208. Schippa, S. et al. A distinctive ‘microbial signature’ in celiac pediatric patients. BMC Microbiol. 10, 175 (2010).

    Article  Google Scholar 

  209. Nadal, I., Donant, E., Ribes-Koninckx, C., Calabuig, M. & Sanz, Y. Imbalance in the composition of the duodenal microbiota of children with coeliac disease. J. Med. Microbiol. 56, 1669–1674 (2007).

    Article  CAS  Google Scholar 

  210. de Palma, G. et al. Intestinal dysbiosis and reduced immunoglobulin-coated bacteria associated with coeliac disease in children. BMC Microbiol. 10, 63 (2010).

    Article  Google Scholar 

  211. di Cagno, R. et al. Duodenal and faecal microbiota of celiac children: molecular, phenotype and metabolome characterization. BMC Microbiol. 11, 219 (2011).

    Article  Google Scholar 

  212. Galipeau, H. J. et al. Intestinal microbiota modulates gluten-induced immunopathology in humanized mice. Am. J. Pathol. 185, 2969–2982 (2015).

    Article  CAS  Google Scholar 

  213. Mårild, K., Stephansson, O., Montgomery, S., Murray, J. A. & Ludvigsson, J. F. Pregnancy outcome and risk of celiac disease in offspring: a nationwide case-control study. Gastroenterology 142, 39–45.e3 (2012).

    Article  Google Scholar 

  214. Lebwohl, B., Spechler, S. J., Wang, T. C., Green, P. H. R. & Ludvigsson, J. F. Use of proton pump inhibitors and subsequent risk of celiac disease. Dig. Liver Dis. 46, 36–40 (2014).

    Article  CAS  Google Scholar 

  215. Caminero, A. & Verdu, E. F. Celiac disease: should we care about microbes? Am. J. Physiol. Gastrointest. Liver Physiol. 317, G161–G170 (2019).

    Article  CAS  Google Scholar 

  216. Caminero, A. et al. Duodenal bacteria from patients with celiac disease and healthy subjects distinctly affect gluten breakdown and immunogenicity. Gastroenterology 151, 670–683 (2016).

    Article  CAS  Google Scholar 

  217. Petersen, J. et al. T cell receptor cross-reactivity between gliadin and bacterial peptides in celiac disease. Nat. Struct. Mol. Biol. 27, 49–61 (2020).

    Article  CAS  Google Scholar 

  218. Jiang, H.-Y., Zhang, X., Zhou, Y.-Y., Jiang, C.-M. & Shi, Y.-D. Infection, antibiotic exposure, and risk of celiac disease: a systematic review and meta-analysis. J. Gastroenterol. Hepatol. 35, 557–566 (2020).

    Article  Google Scholar 

  219. Kamphorst, K. et al. Early life antibiotics and childhood gastrointestinal disorders: a systematic review. BMJ Paediatr. Open. 5, e001028 (2021).

    Article  Google Scholar 

  220. Kołodziej, M. et al. Association between early life (prenatal and postnatal) antibiotic administration and coeliac disease: a systematic review. Arch. Dis. Child. 104, 1083–1089 (2019).

    Article  Google Scholar 

  221. Canova, C. et al. Association of maternal education, early infections, and antibiotic use with celiac disease: a population-based birth cohort study in northeastern Italy. Am. J. Epidemiol. 180, 76–85 (2014).

    Article  Google Scholar 

  222. Dydensborg Sander, S. et al. Association between antibiotics in the first year of life and celiac disease. Gastroenterology 156, 2217–2229 (2019).

    Article  Google Scholar 

  223. Bittker, S. S. & Bell, K. R. Potential risk factors for celiac disease in childhood: a case-control epidemiological survey. Clin. Exp. Gastroenterol. 12, 303–319 (2019).

    Article  CAS  Google Scholar 

  224. Mårild, K. et al. Antibiotic exposure and the development of coeliac disease: a nationwide case-control study. BMC Gastroenterol. 13, 109 (2013).

    Article  Google Scholar 

  225. Mårild, K., Ludvigsson, J., Sanz, Y. & Ludvigsson, J. F. Antibiotic exposure in pregnancy and risk of coeliac disease in offspring: a cohort study. BMC Gastroenterol. 14, 75 (2014).

    Article  Google Scholar 

  226. Mårild, K., Kahrs, C. R., Tapia, G., Stene, L. C. & Størdal, K. Maternal infections, antibiotics, and paracetamol in pregnancy and offspring celiac disease: a cohort study. J. Pediatr. Gastroenterol. Nutr. 64, 730–736 (2017).

    Article  Google Scholar 

  227. Simre, K. et al. Exploring the risk factors for differences in the cumulative incidence of coeliac disease in two neighboring countries: the prospective DIABIMMUNE study. Dig. Liver Dis. 48, 1296–1301 (2016).

    Article  Google Scholar 

  228. Kemppainen, K. M. et al. Association between early-life antibiotic use and the risk of islet or celiac disease autoimmunity. JAMA Pediatr. 171, 1217–1225 (2017).

    Article  Google Scholar 

  229. Martínez-Ojinaga, E. et al. Influence of HLA on clinical and analytical features of pediatric celiac disease. BMC Gastroenterol. 19, 91 (2019).

    Article  Google Scholar 

  230. Abadie, V. et al. IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease. Nature 578, 600–604 (2020).

    Article  CAS  Google Scholar 

  231. Hill, A. B. The environment and disease: association or causation? Proc. R. Soc. Med. 58, 295–300 (1965). This study is a classic: it established nine criteria to examine causal relationships.

    CAS  Google Scholar 

  232. Myléus, A. et al. Early infections are associated with increased risk for celiac disease: an incident case-referent study. BMC Pediatr. 12, 194 (2012).

    Article  Google Scholar 

  233. Witmer, C. P., Susi, A., Min, S. B. & Nylund, C. M. Early infant risk factors for pediatric eosinophilic esophagitis. J. Pediatr. Gastroenterol. Nutr. 67, 610–615 (2018).

    Article  Google Scholar 

  234. Jensen, E. T., Kappelman, M. D., Kim, H. P., Ringel-Kulka, T. & Dellon, E. S. Early life exposures as risk factors for pediatric eosinophilic esophagitis. J. Pediatr. Gastroenterol. Nutr. 57, 67–71 (2013).

    Article  Google Scholar 

  235. Radano, M. C. et al. Cesarean section and antibiotic use found to be associated with eosinophilic esophagitis. J. Allergy Clin. Immunol. Pract. 2, 475–477.e1 (2014).

    Article  Google Scholar 

  236. Jensen, E. T., Kuhl, J. T., Martin, L. J., Rothenberg, M. E. & Dellon, E. S. Prenatal, intrapartum, and postnatal factors are associated with pediatric eosinophilic esophagitis. J. Allergy Clin. Immunol. 141, 214–222 (2018).

    Article  Google Scholar 

  237. Dellon, E. S. et al. Early life factors are associated with risk for eosinophilic esophagitis diagnosed in adulthood. Dis. Esophagus 34, doaa074 (2021).

    Article  Google Scholar 

  238. Slae, M. et al. Role of environmental factors in the development of pediatric eosinophilic esophagitis. Dig. Dis. Sci. 60, 3364–3372 (2015).

    Article  CAS  Google Scholar 

  239. Walsh, D., McCarthy, J., O’Driscoll, C. & Melgar, S. Pattern recognition receptors–molecular orchestrators of inflammation in inflammatory bowel disease. Cytokine Growth Factor. Rev. 24, 91–104 (2013).

    Article  CAS  Google Scholar 

  240. Klotz, U., Maier, K., Fischer, C. & Heinkel, K. Therapeutic efficacy of sulfasalazine and its metabolites in patients with ulcerative colitis and Crohn’s disease. N. Engl. J. Med. 303, 1499–1502 (1980).

    Article  CAS  Google Scholar 

  241. Pellock, S. J. & Redinbo, M. R. Glucuronides in the gut: sugar-driven symbioses between microbe and host. J. Biol. Chem. 292, 8569–8576 (2017).

    Article  CAS  Google Scholar 

  242. Khalili, H. et al. Hormone therapy increases risk of ulcerative colitis but not Crohn’s disease. Gastroenterology 143, 1199–1206 (2012).

    Article  CAS  Google Scholar 

  243. Costello, S. P. et al. Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: a randomized clinical trial. JAMA 321, 156–164 (2019).

    Article  Google Scholar 

  244. Reed, C. C. & Dellon, E. S. Eosinophilic esophagitis. Med. Clin. North. Am. 103, 29–42 (2019).

    Article  Google Scholar 

  245. Dellon, E. S. et al. Updated international consensus diagnostic criteria for eosinophilic esophagitis: proceedings of the AGREE conference. Gastroenterology 155, 1022–1033.e10 (2018).

    Article  Google Scholar 

  246. Blanchard, C. et al. IL-13 involvement in eosinophilic esophagitis: transcriptome analysis and reversibility with glucocorticoids. J. Allergy Clin. Immunol. 120, 1292–1300 (2007).

    Article  CAS  Google Scholar 

  247. Zuo, L. et al. IL-13 induces esophageal remodeling and gene expression by an eosinophil-independent, IL-13Rα2-inhibited pathway. J. Immunol. 185, 660–669 (2010).

    Article  CAS  Google Scholar 

  248. Mishra, A. & Rothenberg, M. E. Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, eotaxin-1, and STAT6-dependent mechanism. Gastroenterology 125, 1419–1427 (2003).

    Article  CAS  Google Scholar 

  249. Blanchard, C. et al. Inhibition of human interleukin-13-induced respiratory and oesophageal inflammation by anti-human-interleukin-13 antibody (CAT-354). Clin. Exp. Allergy 35, 1096–1103 (2005).

    Article  CAS  Google Scholar 

  250. Dellon, E. S. Epidemiology of eosinophilic esophagitis. Gastroenterol. Clin. North. Am. 43, 201–218 (2014).

    Article  Google Scholar 

  251. Soon, I. S., Butzner, J. D., Kaplan, G. G. & deBruyn, J. C. C. Incidence and prevalence of eosinophilic esophagitis in children. J. Pediatr. Gastroenterol. Nutr. 57, 72–80 (2013).

    Article  Google Scholar 

  252. Dellon, E. S. et al. The increasing incidence and prevalence of eosinophilic oesophagitis outpaces changes in endoscopic and biopsy practice: national population-based estimates from Denmark. Aliment. Pharmacol. Ther. 41, 662–670 (2015).

    Article  CAS  Google Scholar 

  253. Giriens, B. et al. Escalating incidence of eosinophilic esophagitis in Canton of Vaud, Switzerland, 1993-2013: a population-based study. Allergy 70, 1633–1639 (2015).

    Article  CAS  Google Scholar 

  254. Homan, M., Blagus, R., Jeverica, A. K. & Orel, R. Pediatric eosinophilic esophagitis in Slovenia: data from a retrospective 2005-2012 epidemiological study. J. Pediatr. Gastroenterol. Nutr. 61, 313–318 (2015).

    Article  CAS  Google Scholar 

  255. Alexander, E. S. et al. Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis. J. Allergy Clin. Immunol. 134, 1084–1092.e1 (2014).

    Article  Google Scholar 

  256. Dellon, E. S. et al. Clinical, endoscopic, and histologic findings distinguish eosinophilic esophagitis from gastroesophageal reflux disease. Clin. Gastroenterol. Hepatol. 7, 1305–1313 quiz 1261 (2009).

    Article  Google Scholar 

  257. Kummeling, I. et al. Early life exposure to antibiotics and the subsequent development of eczema, wheeze, and allergic sensitization in the first 2 years of life: the KOALA birth cohort study. Pediatrics 119, e225–e231 (2007).

    Article  Google Scholar 

  258. Chen, Y. & Blaser, M. J. Helicobacter pylori colonization is inversely associated with childhood asthma. J. Infect. Dis. 198, 553–560 (2008).

    Article  Google Scholar 

  259. Mou, W.-L., Feng, M.-Y. & Hu, L.-H. Eradication of Helicobacter pylori infections and GERD: a systematic review and meta-analysis. Turk. J. Gastroenterol. 31, 853–859 (2020).

    Article  Google Scholar 

  260. Vicari, J. J. et al. The seroprevalence of cagA-positive Helicobacter pylori strains in the spectrum of gastroesophageal reflux disease. Gastroenterology 115, 50–57 (1998).

    Article  CAS  Google Scholar 

  261. Loffeld, R. J. et al. Colonization with cagA-positive Helicobacter pylori strains inversely associated with reflux esophagitis and Barrett’s esophagus. Digestion 62, 95–99 (2000).

    Article  CAS  Google Scholar 

  262. Chow, W. H. et al. An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma. Cancer Res. 58, 588–590 (1998).

    CAS  Google Scholar 

  263. Ronkainen, J. et al. Prevalence of oesophageal eosinophils and eosinophilic oesophagitis in adults: the population-based Kalixanda study. Gut 56, 615–620 (2007).

    Article  Google Scholar 

  264. Dellon, E. S. et al. Inverse association of esophageal eosinophilia with Helicobacter pylori based on analysis of a US pathology database. Gastroenterology 141, 1586–1592 (2011).

    Article  Google Scholar 

  265. Furuta, K. et al. Case-control study of association of eosinophilic gastrointestinal disorders with Helicobacter pylori infection in Japan. J. Clin. Biochem. Nutr. 53, 60–62 (2013).

    Article  Google Scholar 

  266. Elitsur, Y., Alrazzak, B. A., Preston, D. & Demetieva, Y. Does Helicobacter pylori protect against eosinophilic esophagitis in children? Helicobacter 19, 367–371 (2014).

    Article  Google Scholar 

  267. Sonnenberg, A., Dellon, E. S., Turner, K. O. & Genta, R. M. The influence of Helicobacter pylori on the ethnic distribution of esophageal eosinophilia. Helicobacter 22, e12370 (2017).

    Article  Google Scholar 

  268. von Arnim, U. et al. Helicobacter pylori infection is associated with a reduced risk of developing eosinophilic oesophagitis. Aliment. Pharmacol. Ther. 43, 825–830 (2016).

    Article  Google Scholar 

  269. Atherton, J. C. & Blaser, M. J. Coadaptation of Helicobacter pylori and humans: ancient history, modern implications. J. Clin. Invest. 119, 2475–2487 (2009).

    Article  CAS  Google Scholar 

  270. Ridolo, E., Martignago, I., Pellicelli, I. & Incorvaia, C. Assessing the risk factors for refractory eosinophilic esophagitis in children and adults. Gastroenterol. Res. Pract. 2019, 1654543 (2019).

    Article  Google Scholar 

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Acknowledgements

Supported in part by 1K23DK119544-01A1 (L.A.C.) and U01AI22285 (M.J.B.) from the National Institutes of Health, and Sergei S. Zlinkoff Fund (M.J.B.), a personal ZONMW VICI grant 2020 (09150182010020) (M.N.), and the TransAtlantic Networks of Excellence Program (33.17CVD01) from the Fondation Leducq (all authors).

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Authors and Affiliations

  1. Department of Clinical and Experimental Vascular Medicine, Amsterdam Cardiovascular Sciences (ACS), Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands

    Aline C. Fenneman & Max Nieuwdorp

  2. Department of Endocrinology and Metabolism, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands

    Aline C. Fenneman & Max Nieuwdorp

  3. Department of Paediatrics, Rutgers University, New Brunswick, NJ, USA

    Melissa Weidner

  4. Department of Medicine, Rutgers University, New Brunswick, NJ, USA

    Lea Ann Chen & Martin J. Blaser

  5. Department of Pathology and Laboratory Medicine, Rutgers University, New Brunswick, NJ, USA

    Martin J. Blaser

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Contributions

A.C.F. and M.J.B. researched data for the article, made substantial contributions to discussion of content, wrote the article, and reviewed/edited the manuscript before submission. M.W., and L.A.C. researched data for the article, wrote the article, and reviewed/edited the manuscript before submission. M.N. researched data for the article and reviewed/edited the manuscript before submission.

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Glossary

Lipopolysaccharide

(LPS). A microbiota-derived endotoxin found in the outer membranes of Gram-negative bacteria. Bacterial LPS has a key role as an elicitor of innate immune responses through binding to CD44, LBP and Toll-like receptor 4.

Germ-free mice

Mice born and raised in sterile conditions and thus free of bacteria and fungi.

Dysbiosis

Perturbation of the homeostasis of gut microbiota composition, potentially leading to changes in both functional and metabolic activities.

Short-chain fatty acids

(SCFAs). Predominantly butyrate, propionate and acetate. Metabolic products of complex carbohydrate fermentation, chiefly from anaerobic bacteria, that are both energy sources for hosts as well as signalling molecules to host tissues.

Probiotics

Viable microorganisms that reach the intestine in an active state and might elicit a favourable effect on host metabolism or re-establishment of gut microbial composition.

Non-obese diabetic mice

(NOD mice). A mouse strain developing an autoimmune illness resembling type 1 diabetes mellitus in humans. The substrain NOD/Caj have membrane-bound immunoglobulins and do not secrete antibodies, so as to understand the role of B cells as antigen-presenting cells rather than production of auto-antibodies only.

Prebiotic

Dietary components, mostly consisting of non-digestible fibres, that might have a potential beneficial effect on gut microbial composition and function.

Synbiotic

Nutritional supplements that consist of a synergistic combination of both prebiotics and probiotics.

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Fenneman, A.C., Weidner, M., Chen, L.A. et al. Antibiotics in the pathogenesis of diabetes and inflammatory diseases of the gastrointestinal tract. Nat Rev Gastroenterol Hepatol 20, 81–100 (2023). https://doi.org/10.1038/s41575-022-00685-9

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