Coeliac disease: beyond genetic susceptibility and gluten. A narrative review

Figures & data

Table 1. Level of evidence for the association of environmental factors with coeliac disease.

Environmental factors	Possible mechanism	Association^a	Evidence^b	References
Dietary factors
Short duration of breastfeeding	Delayed contact of gluten with gut immune system	Moderate	Level 1	[27–31]
Vitamin D	Decreased production of regulatory TH17 cells	Weak	Level 2	[36]
Red wine	Residues of gluten after clarification	Weak	Level 5	[39,40]
Alcohol	Direct toxic effect on the small intestinal mucosa	Weak	Level 5	[80]
Infections
Viruses	Molecular mimicry between viral antigens and intestinal antigens
Rotavirus	Molecular mimicry	Moderate	Level 2	[46]
Adenovirus	Molecular mimicry	Conflicting data	Level 2	[49]
Hepatitis B virus	The specific mechanism of pathogenesis is unknown	Weak	Level 3	[62]
Hepatitis C virus	Release of interferons, increased intestinal permeability	Conflicting data	Level 2	[54–56]
Influenza	Molecular mimicry and modification of commensal flora	Moderate	Level 2	[43]
Bacteria	Molecular mimicry between bacterial antigens and intestinal antigens
H. pylori	The specific mechanism of pathogenesis is unknown	Conflicting data	Level 4	[71–73]
Helminths	Protective role by increasing the number of regulatory T cells	Weak	Level 2	[75]
Gut microbiota	Alteration of intestinal barrier and activation of the immune system	Strong	Level 1	[110,112–115]
Respiratory infections	The specific mechanism of pathogenesis is unknown	Moderate	Level 3	[44]
Gastrointestinal infections	Impaired intestinal permeability	Strong	Level 1	[31]
Drugs
Antibiotics	Direct “toxic” effect; changes in maternal and infant microbiota	Weak	Level 2	[81,82,123]
Proton pump inhibitors	Suppressing stomach acid secretion; altered protein digestion	Weak	Level 3	[84]
Non-steroidal anti-inflammatory drugs	Direct toxicity from the drug or a metabolite	Weak	Level 3	[80]
Histamine 2-receptor antagonists	Suppressing stomach acid secretion	Weak	Level 3	[80]
Colchicine	Metaphase arrest in crypt epithelial cells	Weak	Level 5	[80]
Methotrexate	Inhibition of mitotic activity; impaired absorption of folic acid and D-xylose	Weak	Level 5	[80]
Sartans	Impaired angiotensin II signalling; disruption of tight junctions and increased permeability	Weak	Level 3	[80]
Interferon	Immune mechanisms	Weak	Level 3	[80]
Birth-related factors
Delivery mode	Different composition of the intestinal microbiota.	Weak	Level 1	[89–95]
Seasonality	Selective susceptibility to seasonal infections	Weak	Level 1	[31,46,96,97]
Birth weight	Immaturity of immune system	Weak	Level 2	[91,94,104]
Parental factors
Maternal age	Unfavourable uterine environment	Weak	Level 1	[81,125]
Maternal education	Cleaner domestic environment, more attention to child’s health	Weak	Level 1	[31,81]
Family size		No association	Level 1	[31]
Socioeonomic status	Overcrowding. Infections	Conflicting	Level 3	[126–131]
Tobacco smoking	Suppression the CD8+ T cells	Weak	Level 3	[132–136]

^a The strength of association was reported on the basis of the study results (OR, HR, frequency, p value and so on).

^b The level of evidence was ranked according to Hadorn in descending order: (Level 1) meta-analyses of randomied studies; (Level 2) a single study; (Level 3) non-randomised studies; (Level 4) retrospective studies, and (Level 5) a series of cases without controls.

Figure 1. Mechanisms involved in the pathogenesis of coeliac disease. The figure shows the intestinal cells maintained in mutual contact by tight junctions. Luminal and early mucosal events able to alter intestinal barrier (e.g. mucine thinning) and/or to directly damage the intestinal mucosa (such as drugs, infections, changes in the microbiota) may facilitate macromolecules including gluten peptides to cross the leaking mucosa. Gluten not fully digested in the lamina propria is captured by tissue transglutaminase and deamidated. The more sticky fragments are bound to DQ2 or DQ8 antigen-presenting cells leading to the release of cytokines and activation of CD4+ T cells and, in turn, to tissue damage. INF: interferon; TCR: T cell receptor.

Kemppainen KM, Lynch KF, Liu E, TEDDY Study Group, et al. Factors that increase risk of celiac disease autoimmunity after a gastrointestinal infection in early life. Clin Gastroenterol Hepatol. 2017;15:694–702.

 PubMed Web of Science ®Google Scholar

Mårild K, Tapia G, Haugen M, et al. Maternal and neonatal vitamin D status, genotype and childhood celiac disease. PLoS One. 2017;12:e0179080.

 PubMed Web of Science ®Google Scholar

Cattaneo A, Ballabio C, Bertelli AA, et al. Evaluation of residual immunoreactivity in red and white wines clarified with gluten or gluten derivatives. Int J Tissue React. 2003;25:57–64.

 PubMedGoogle Scholar

Simonato B, Mainente F, Tolin S, et al. Immunochemical and mass spectrometry detection of residual proteins in gluten fined red wine. J Agric Food Chem. 2011;59:3101–3110.

 PubMed Web of Science ®Google Scholar

Freeman HJ. Drug-induced sprue-like intestinal disease. Int J Celiac Dis. 2014;2:49–53.

 Google Scholar

Stene LC, Honeyman MC, Hoffenberg EJ, et al. Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study. Am J Gastroenterology. 2006;101:2333–2340.

 PubMed Web of Science ®Google Scholar

Kagnoff MF, Paterson YJ, Kumar PJ, et al. Evidence for the role of a human intestinal adenovirus in the pathogenesis of coeliac disease. Gut. 1987;28:995–1001.

 PubMed Web of Science ®Google Scholar

Opri R, Veneri D, Mengoli C, et al. Immune response to Hepatitis B vaccine in patients with celiac disease: a systematic review and meta-analysis. Hum Vaccin Immunother. 2015;11:2800–2805.

 PubMed Web of Science ®Google Scholar

Casella G, Viganò D, Settanni CR, et al. Association between celiac disease and chronic hepatitis C. Gastroenterol Hepatol Bed Bench. 2016;9:153–157.

 PubMedGoogle Scholar

Kårhus LL, Gunnes N, Størdal K, et al. Influenza and risk of later celiac disease: a cohort study of 2.6 million people. Scand J Gastroenterol. 2018;53:15–23.

 PubMed Web of Science ®Google Scholar

Basyigit S, Unsal O, Uzman M, et al. Relationship between Helicobacter pylori infection and celiac disease: a cross-sectional study and a brief review of the literature. Prz Gastroenterol. 2017;12:49–54.

 PubMed Web of Science ®Google Scholar

Ludvigsson J, Jones MP, Faresjö Å. Worm infestations and development of autoimmunity in children - The ABIS study. PLoS One. 2017;12:e0173988.

 PubMed Web of Science ®Google Scholar

De Palma G, Capilla A, Nova E, et al. Influence of milk-feeding type and genetic risk of developing coeliac disease on intestinal microbiota of infants: the PROFICEL study. PLoS ONE. 2012;7:e30791.

 PubMed Web of Science ®Google Scholar

Olivares M, Walke AW, Capilla A, et al. Gut microbiota trajectory in early life may predict development of celiac disease. Microbiome. 2018;6:36.

 PubMed Web of Science ®Google Scholar

Auricchio R, Cielo D, de Falco R, et al. Respiratory infections and the risk of celiac disease. Pediatrics. 2017;140:e20164102.

 PubMed Web of Science ®Google Scholar

Canova C, Zabeo V, Pitter G, 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. 2014;180:76–85.

 PubMed Web of Science ®Google Scholar

Kemppainen KM, Vehik K, Lynch KF, Environmental Determinants of Diabetes in the Young (TEDDY) Study Group, et al. Association between early-life antibiotic use and the risk of islet or celiac disease autoimmunity. JAMA Pediatr. 2017;171:1217–1225.

 PubMed Web of Science ®Google Scholar

Mårild K, Ludvigsson J, Sanz Y, et al. Antibiotic exposure in pregnancy and risk of coeliac disease in offspring: a cohort study. BMC Gastroenterol. 2014;14:75.

 PubMed Web of Science ®Google Scholar

Lebwohl B, Spechler SJ, Wang TC, et al. Use of proton pump inhibitors and subsequent risk of celiac disease. Dig Liver Dis. 2014;46:36–40.

 PubMedGoogle Scholar

Koletzko S, Lee HS, Beyerlein A, TEDDY Study Group, et al. Cesarean section on the risk of celiac disease in the offspring: the TEDDY study. J Pediatr Gastroenterol Nutr. 2018;66:417–424.

 PubMed Web of Science ®Google Scholar

Lebwohl B, Green PH, Murray JA, et al. Season of birth in a nationwide cohort of coeliac disease patients. Arch Dis Child. 2013;98:48–51.

 PubMed Web of Science ®Google Scholar

Ivarsson A, Hernell O, Nyström L, et al. Children born in the summer have increased risk for coeliac disease. J Epidemiol Community Health. 2003;57:36–39.

 PubMed Web of Science ®Google Scholar

Mårild K, Stephansson O, Montgomery S, et al. Pregnancy outcome and risk of celiac disease in offspring: a nationwide case-control study. Gastroenterology. 2012;142:39–45.

 PubMed Web of Science ®Google Scholar

Emilsson L, Magnus MC, Størdal K. Perinatal risk factors for development of celiac disease in children, based on the prospective Norwegian Mother and Child Cohort Study. Clin Gastroenterol Hepatol. 2015;13:921–927.

 PubMed Web of Science ®Google Scholar

Kuja-Halkola R, Lebwohl B, Halfvarson J, et al. Birth weight, sex, and celiac disease: a nationwide twin study. Clin Epidemiol. 2017;9:567–577.

 PubMed Web of Science ®Google Scholar

Thompson MW. Heredity, maternal age, and birth order in the etiology of celiac disease. Am J Hum Genet. 1951;3:159–166.

 PubMed Web of Science ®Google Scholar

Ludvigsson JF, ABIS Study Group. Socio-economic characteristics in children with coeliac disease. Acta Paediatr. 2005;94:107–113.

 PubMed Web of Science ®Google Scholar

Suman S, Williams EJ, Thomas PW, et al. Is the risk of adult coeliac disease causally related to cigarette exposure? Eur J Gastroenterol Hepatol. 2003;15:995–1000.

 PubMed Web of Science ®Google Scholar