Systematic Review: Early Infant Feeding and the Prevention of Coeliac Disease

H. Szajewska; A. Chmielewska; M. Pieścik-Lech; A. Ivarsson; S. Kolacek; S. Koletzko; M. L. Mearin; R. Shamir; R. Auricchio; R. Troncone


Aliment Pharmacol Ther. 2012;36(7):607-618. 

In This Article


Breastfeeding and CD

There are studies that show a protective effect of breastfeeding as well as studies that show no effect. No studies have shown a long-term preventive effect of BF. Thus, whether or not BF protects or delays the clinical presentation of CD remains controversial. Despite the fact that there is controversy in the literature, this does not mean that breastfeeding does not have significant effects in preventing CD. Rather, this is more likely a reflection of the methodological inadequacy of investigating breastfeeding in ways that take into account all the complexity of interactions. The methodological problems likely to contribute to inconsistent results include first, the inability to randomise and blind. In general, the studies on breastfeeding are nonrandomised, retrospective or observational in design and, thus, produce inconclusive results. Second, the retrospective design of many studies addressing the association between breastfeeding and CD and the potential for parental recall bias impose methodological challenges. One may overcome the problem of parental recall bias by obtaining prospective feeding histories. Third, most of the studies that have examined the effect of breastfeeding on CD were carried out in unselected birth cohorts with regard to CD risk. Only a limited number of studies have assessed the effect of breastfeeding in high-risk infants. Inconsistencies may be also due to imprecise definitions of the intervention. Fourth, many studies do not make the distinction between 'exclusive breastfeeding' and 'any breastfeeding'. Finally, ideally, the diagnosis of CD should be based on widely agreed-upon criteria. However, in some of the studies on the effect of breastfeeding, CD-specific serology, not biopsy-proven CD, was assessed, making comparisons between the studies difficult.

The exact mechanisms that underlie the relationship between breastfeeding and possible protection against CD remain uncertain. Likely explanations have been extensively discussed in earlier studies and reviews.[28] In brief, it has been postulated that breast milk contains factors such as secretory IgA antibodies, lactoferrin, lysozyme and others that contribute to passive immunity. These factors may contribute to the reduced number of gastrointestinal infections potentially contributing to the pathogenesis of CD by increasing gut permeability or alterations to the immune system.[29] Moreover, human milk contains cytokines such as down-regulatory transforming growth factor β that may influence immune development and the type of immune response. When studying the interaction between breastfeeding and CD, the complex interactions between intestinal immunology, gut microbiome, genetic predisposition, gluten consumption and breastfeeding should be considered. In addition, human milk contains gluten in small quantities;[30,31] this can perhaps induce tolerance to gluten as it has been suggested for other antigens.[32] Future studies are needed to fully understand the relationship between BF and CD.

BF at the Time of Gluten Introduction and CD

Results from a meta-analysis of five observational case-control studies suggest that BF at the time of gluten introduction is associated with a lower risk of CD compared with formula feeding. However, the majority of these studies were based on retrospectively collected feeding data. It is unclear whether BF provides a permanent protection or only delays the onset of CD. Available data are insufficient to prove causality. Moreover, one more recent prospective study found no effect of BF at the time of gluten introduction on CD autoimmunity, but the effect on biopsy-proven CD is unknown.[21]

Timing of Gluten Introduction

The role of age at gluten introduction with respect to the risk of CD is unclear. The data from observational studies suggest that early (≤3 months after birth), and possibly late (≥7 months after birth), introduction of gluten may be associated with an increased risk of CD and probably should be avoided. The only interventional study suggested that delayed introduction of gluten (12 months of age) may be beneficial. However, the results of this RCT should be viewed with caution given the small sample size and unclear risk of bias.

Amount of Gluten at Weaning (and Later) and CD

The results of one incident case-referent study documented that the introduction of gluten in large amounts compared with small or medium amounts increased the risk of CD.[20] These data support previous findings from the same country, i.e. Sweden. In the mid 1980s, this country experienced an epidemic of CD in children younger than 2 years of age. A twofold increase in the average daily consumption of gluten was followed by a fourfold rise in the incidence of CD. When gluten consumption decreased 10 years later, an abrupt fall in the incidence of CD was observed.[6] However, also the recommended age for gluten introduction was changed preceding both the start of the epidemic (from 4 to 6 months) and the end (back to 4 months), which changed the proportion of infants introduced to gluten while being breastfed. Still, the amount of gluten is likely to be a contributing risk factor for CD. Whether this is a dose–response or a threshold effect remains unknown. However, more recently, a quantitative model of CD development was suggested and an HLA-DQ2 gene dose effect in the development of CD was proposed.[33] An interaction between HLA-DQ2 expression and the available number of T-cell stimulatory gluten peptides was documented. In particular, the strongly increased risk of CD development for HLA-DQ2.5 homozygous and HLA-DQ2.2/2.5 heterozygous individuals was found, while HLA-DQ2.5/non-DQ2 heterozygous individuals had only a slightly increased risk of CD. If the threshold effect is valid, the amount of gluten needed to initiate the immunological response may be different in HLA-DQ2 homozygous and heterozygous individuals. On the other hand, a lack of in vivo/ex vivo evidence of gluten epitope diversity being greater in HLA DQ2 homozygotes with CD, and considering that information about children and gluten-specific T cells is limited to a single study, call for caution in the interpretation. Furthermore, a recent study supports greater T-cell epitope diversity in HLA DQ2/DQ8 + heterozygotes than in HLA DQ2 + individuals because of the efficient transdimer presentation of gluten peptides. However, HLA DQ2/DQ8 + individuals are at no greater risk of CD than HLA DQ2 + heterozygotes, suggesting epitope diversity is not clearly influencing susceptibility.[34]

Administration of Probiotics and/or Prebiotics

In other conditions characterised by a deranged immune response of the mucosal immune system, attention has been given to the possible role of manipulation of the gut microbiota. Probiotics and/or prebiotics have been suggested to influence immune development and the type of immune response. Therefore, it could be envisaged that probiotics/prebiotics may influence the type of immune reactivity to gluten in subjects with CD. The composition of the gut microbiota differs between individuals with CD and healthy individuals with respect to phylogenetic diversity and abundance of microbial taxa. For example, some of the most recent data, albeit obtained from a relatively small group of subjects, have shown that gut microbiota of infants at risk for CD exhibited reduced proportions of Bacteroidetes and an increased proportion of Firmicutes compared with those with a nonselected genetic background.[8] However, other studies have reported a higher abundance of Bacteroidetes.[9,11] We were unable to identify intervention studies on supplementation of pre/probiotics and prevention of CD. Future studies need to establish the exact role of gut microbiota in the development of CD. If so, strategies to manipulate and reshape gut microbiota to a more healthy type may be of interest.