Gluten in infants and celiac disease risk

KEYWORDS:

• Breastfeeding
• celiac disease
• gluten
• HLA
• infant
• prevention

Celiac disease is a small-bowel disorder caused by exposure to dietary gluten present in wheat, rye, and barley. Recent population-based screening studies have revealed it to be one of the most common food-related disorders with an estimated prevalence of 1–3% [1,2]. The disease is initiated when immunological response to gluten leads to inflammation and structural changes of the intestinal mucosa, eventually resulting to characteristic histopathological findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Further, a well-known feature of untreated celiac disease is formation of autoantibodies against the gluten-modifying enzyme tissue transglutaminase, endomysial antibodies, and/or deamidated antigliadin antibodies, all of which strongly support the diagnosis of celiac disease [3]. A strict gluten-free diet leads to healing of the intestinal mucosa and normalization of the autoantibodies, giving further evidence for the autoimmune features directed by the external food antigen.

There is strong linkage between genetics and celiac disease. Approximately 10–20% of first-degree relatives and 75% of monozygotic twins to an individual with celiac disease are at lifelong risk to develop the disease. By far the most important genetic factor is the human leukocyte antigen (HLA) located on chromosome region 6p21.3. HLA encodes the major histocompatibility complex II molecules found on the surfaces of antigen-presenting cells. More than 90% of celiac disease patients carry HLA-DQA1*0501-DQB1*02 (abbreviated as HLA-DQ2) and virtually all the remainder HLA-DQA1*0301-DQB1*0302 (abbreviated as HLA-DQ8) [4]. However, both of these haplotypes are common among subjects in the general population of whom the vast majority will never develop the disease. This has led to the search of non-HLA loci associated with celiac disease of which several genes have been discovered in recent genome-wide association studies [4].

Although the association between HLA and celiac disease is quite well characterized, the difference in prevalence of celiac disease between neighboring countries with similar ethnicity and genetic background suggests that celiac disease cannot solely be explained by genetics [5]. Differences in infant feeding traditions of wheat consumption between the neighboring countries of Denmark and Sweden with a much higher frequency of celiac disease reported among Swedish as compared to Danish children support the role of gluten in infants on the disease risk [6]. The markedly increased incidence of celiac disease observed among Swedish young children after changes in national infant feeding recommendation in the mid-1980s further suggested that the age when infants are introduced to gluten in relation to breast-feeding could alter the disease risk [7].

Extensive efforts have, since then, been made to determine an optimal time-point to feed infants with gluten, of which two previous studies [8,9], albeit not confirmed in another prospective birth cohort [10], were indicative of a higher risk among infants exposed to gluten either early (<4 months) or late (>7 months). Based on these findings, it was endorsed that, in order to induce tolerance, gluten should be initiated gradually at the age of 4–6 months, preferably during ongoing breast-feeding [11]. However, two independent randomized studies demonstrated that genetic at-risk children were neither protected from celiac disease by gradually introducing very small amounts of gluten [12] nor by postponing age at first introduction to gluten from 6 to 12 months [13]. Thereafter, several original papers including systemic reviews and meta-analyses had further scrutinized this issue and have come to the general consensus that there is no evidence to give specific recommendations for the age of gluten introduction or breast-feeding to prevent celiac disease [14,15]. Accordingly, the recommendations by the European Society for Gastroenterology and Nutrition have also been recently revised [16].

So, what about the amount of gluten intake in infancy? In vitro studies have demonstrated that the immune response triggered by gluten is dependent on the HLA genotype. This suggests that there could be different thresholds of tolerance to gluten in genetic at-risk individuals [17]. Still, no previous prospective study has investigated whether the amount of gluten associates with the risk for celiac disease. In a recent case–control study in children that were prospectively followed from birth, we noted that a higher gluten intake during the first 2 years of life conferred increased risk for celiac disease during early childhood [18]. Although the study only enrolled Swedish children who by tradition consume cereal-based foods in forms of gruels and porridges, it clearly showed that high gluten amount was an independent risk, particularly if given between 9 and 12 months of age. What our study was also able to demonstrate was that children reporting high amount of gluten seemed to be at similar risk regardless of the HLA-risk genotype. Yet, many important questions remain to be answered. It remains elusive whether there is a specific threshold of daily intake that can be recommended as safe or hazardous in at-risk individuals. In the Swedish study, the threshold of gluten amount was arbitrarily set to ‘high’ when daily intake exceeded 5 g/day and the study was restricted to dietary recordings only up to 2 years of age. The question whether a high-daily gluten intake also confers a risk for older children still needs to be determined.

There is no doubt that gluten is central for celiac disease to develop. However, as elucidated above, the recent advance in research points to the direction that neither time to first introduction of gluten nor breast-feeding during infancy has an effect on the celiac disease risk during childhood. Still, there are no unequivocal conclusions about whether there is a safe threshold of gluten amount that can be implemented in the current infant feeding recommendations. Swedish data suggest that gluten amount matters for development of celiac disease in young children, but this is the result from only one study with a rather short-term follow-up and needs to be confirmed by studies from other populations. Longer follow-up studies performed on populations with different infant feeding traditions are, therefore, warranted to test the hypothesis whether the amount together with type of gluten truly affects the risk in older children and adolescents.

Declaration of interest

The authors were funded by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, and Contract No. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Juvenile Diabetes Research Foundation (JDRF), and Centers for Disease Control and Prevention (CDC). This work supported in part by the NIH/NCATS Clinical and Translational Science Awards to the University of Florida (UL1 TR000064) and the University of Colorado (UL1 TR001082). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.