Exposure to gluten during infancy appears to double the risk of celiac disease (CD) in babies genetically predisposed to gluten intolerance, according to a study published earlier this year in the journal Clinical Gastroenterology and Hepatology.
A combination of genetic and environmental factors, including early nutrition, influence the course of celiac disease development, and some researchers have posited that it is possible to induce tolerance to gluten in genetically susceptible individuals. A number of previous studies have explored the relationship between the age of an infant’s first exposure to gluten and subsequent disease risk, but the results have been mixed.
One hypothesis suggests that there may be an optimal time window for inducing gluten tolerance in susceptible children. Ivarsson et al. demonstrated that introducing gluten in small amounts to breastfed infants between the ages of 4 to 6 months reduced the risk of celiac disease, as compared with gluten introduction in larger quantities at older ages (Ivarsson, et al. Ped. 2013; 131(3): e687-e694).
Recent randomized controlled intervention studies have, on the other hand, failed to demonstrate a correlation between the timing of gluten exposure and CD risk.
A meta-analysis published in January reviewed research on the appropriate timing for introducing gluten into the infant diet and found that there is, “currently no evidence to support that early introduction of gluten to the infant diet increases the risk of CD.” The authors did, however, conclude that incorporating gluten into the diet later in life may be associated with increased CD risk (Pinto-Sánchez, et al. J Peds. 2016. 168: 132–143).
Clearing the Confusion
Investigators at Sweden’s Lund University examined the possibility that not only age of first exposure, but also the amount of gluten consumed during infancy, can affect the likelihood of CD development. In a press release, the study’s lead author Carin Andrén Aronsson, MSc, stated that while “the role of gluten intake in infants and the risk of later developing celiac disease has long been debated,” her new study “provides convincing evidence that the amount of gluten ingested at an early age plays a role in disease course, particularly in children with genetic risk of developing celiac disease” (Aronsson, et al. Clin Gast Hep. 2016; 14(3): 403–409).
Aronsson’s team looked specifically at gluten consumption during the first two years of life to determine whether it could be a risk factor for CD. They performed a case-control study including 436 pairs of Swedish children genetically at risk for celiac disease and matched for sex, birth year, and HLA genotype with non-risk patients. Previous research has shown that the risk for developing CD before age five is dependent on HLA genotype. Children with the HLA haplotype DR3–DQ2, especially homozygotes, seem to be at highest risk for CD autoimmunity and CD early in childhood (Liu, et al. N Engl J Med. 2014; 371(1): 42-49).
Between September 2004 and February 2010, the Lund participants’ gluten intake was calculated using three-day food records collected at ages nine, 12, 18, and 24 months. Because children at high risk for gluten intolerance develop CD-associated autoantibodies to tissue transglutaminase (tTGA) much earlier than patients at lower risk, participants were also screened annually for tTGA. When patients tested tTGA positive, a time point of seroconversion was determined from frozen serum samples collected every three months.
The investigators confirmed suspected cases of CD by intestinal biopsy.
They found that a high overall gluten intake during the first two years of life, and in particular at 12 months of age, increased the risk of CD during childhood at least two-fold.
Notably, there was no difference in the age of participants’ first introduction to gluten (median 22 weeks) between patients with confirmed CD cases and tTGA-negative controls.
The researchers also showed that the correlation between gluten intake and CD development did not differ according to the childrens’ level of genetic risk. “A high quantity of gluten still was associated with CD in children with no, 1, or 2 copies of the major celiac disease risk HLA-DR3-DQ2 haplotype.”
Tipping the Scale
At the visit before tTGA seroconversion, CD cases reported a larger level of gluten intake than controls (OR, 1.28; 95% confidence interval [CI], 1.13–1.46; P [ .0002). More cases than controls were found in the upper third tertile of gluten consumption (>5.0 g/d) before tTGA seroconversion (OR, 2.65; 95% CI, 1.70–4.13; P < .0001). Results were similar in regardless of the children who were heterozygous, homozygous, or non-carriers of the DR3-DQ2 genotype.
“This finding offers insight into why some, but not all, children at genetic risk develop celiac disease,” Aronsson stated.
Significantly, traditional Swedish infant feeding practices vary from other countries in that Swedish babies are commonly fed gluten-containing foods, including formulas and porridges, at an earlier age and in larger quantities than infants elsewhere. There are studies indicating that Swedish children are at higher risk for CD early in life than children in some other parts of the world. Though age of gluten exposure alone would not account for these differences in CD risk, it may play a role.
Aronsson and colleagues conclude that future studies in additional countries are necessary to confirm the role of gluten intake during infancy and susceptibility to CD in young children.
END
