In this report, we found that GI illnesses are associated with increased risk of IA among children who are exposed to wheat or barley either early or late in infancy. Although children who attended daycare had significantly more infections during the first 9 months of life, neither the number of hours spent in daycare per week nor the attendance at any daycare was associated with IA.
Childhood infections have been considered as a potential environmental trigger of type 1 diabetes for many years, although the exact nature of this relationship and potential mechanisms are not clear. It has been thought that infectious agents could trigger an immune system response to proteins in the body that appear similar. Alternatively, infection could cause localized inflammation, and chronic infections could therefore lead to a more active immune system, which could be prone to develop autoimmunity. Another theory is that the infectious organisms could activate polyclonal B-cells (24
A common virus implicated in GI illnesses is rotavirus, which has been shown to have similar protein sequences to T-cell epitopes in the autoantigens GAD and IA-2, perhaps triggering autoimmunity through molecular mimicry. Seroconversion with rotavirus has been demonstrated to increase levels of IA in children with a FDR with type 1 diabetes in the BabyDiab study (25
). In addition, animal models have provided evidence that the timing of rotavirus infection may be important. In NOD mice, oral infection with rotavirus accelerated the development of diabetes when insulitis was already present (26
). In contrast, infection with rotavirus in young NOD mice without insulitis appears to delay the onset of type 1 diabetes (27
We have previously reported an association of early and late cereal exposure with the development of IA (5
), although this particular exposure variable included oats and rice in addition to wheat and barley. In this report, we found that the association of GI illnesses with IA was only significant among children who were introduced to wheat or barley before 4 months of age or after 6 months of age, and there was a further association among children who had a GI illness during the same 3-month interval as the introduction of wheat or barley or in the 3 months after wheat or barley introduction. Wheat protein antigens can induce an inflammatory response in the gut (28
) and so could prime the immune system for a detrimental response to infection with a viral agent. Enteroviruses are the most prevalent viral infectious agents in humans and have been found in pancreatic tissues from patients with type 1 diabetes (29
) and in people with islet cell autoantibodies (30
). Enteroviruses must enter the epithelial cells of the respiratory or intestinal systems in order to infect the host. Increased gut permeability is found among individuals with IA (31
), suggesting that factors leading to a damaged endothelial barrier in the gut, such as gluten exposure, may allow for infection with enteroviruses, which may then damage the pancreatic β-cells. Rotavirus, the most common viral agent causing diarrhea in children, affects gut permeability and intestinal cytokine balance, and so exposure to this virus may have varying effects on immune modulation depending on the concurrent exposure to grain antigens. The data in the current report suggest that exposure to gluten either prior to or during the same 3-month period as a GI illness increases the risk of persistent IA, but it is difficult to tell from these data whether this is attributed to an inflammatory response to gluten antigens or increased gut permeability due to viral illness at the same time as gluten antigens are introduced.
Incidence of type 1 diabetes varies across countries and has been increasing over the past several decades globally. According to a publication from the American Dietetic Association, ~10% of infants in the U.S. are exposed to grains before 4 months of age, and consumption of grains among those 4–5.9 month of age has decreased from 2002 to 2008 (32
), suggesting that grain intake may have been shifted either earlier or later than this time frame over time. In a study of infant feeding in Norway, in which type 1 diabetes incidence is higher than in the U.S., 21% of infants began eating solid foods before 4 months of age (33
). Not only the timing of gluten introduction but also the quantity can vary across countries. In countries with high rates of type 1 diabetes such as a Finland and Sweden, there are also varying rates and ages at presentation of celiac disease, with earlier onset and more traditional symptoms in Sweden than in Finland. Ascher et al. (34
) reported that wheat protein intake was much higher among infants in Sweden than in Finland at 9 and 12 months of age, perhaps accounting for these differences in celiac disease. More information is needed about how differences in infant feeding across countries and over time may relate to incidence of type 1 diabetes,
Increasing rates of cesarean section may also contribute to the growing incidence of type 1 diabetes, as mode of delivery has been shown to modify the gut flora in infants (35
). However, an association between cesarean delivery and risk for developing type 1 diabetes has been inconsistent in various studies (36
In addition to evidence that some childhood infections can increase the risk of IA and type 1 diabetes, it has been noted that the increase in type 1 diabetes incidence has occurred in countries with greater hygiene and less overall rates of infection. This observation has led to the hygiene hypothesis, which postulates that some infections can protect against the development of autoimmune disorders. In the current study, we did not find that an increased number of childhood infections were associated with a lower risk of IA, as proposed by the hygiene hypothesis. Our findings are consistent with those reported by Cardwell et al. (17
) in a study of early childhood infections in children with type 1 diabetes and matched controls, in whom common infections in the first year of life were not associated with the later development of type 1 diabetes (17
There are important limitations to the current study. Childhood infections were reported by the primary caregiver at visits every 3 months during the first 9 months of life. It is possible that some infections were overreported, if they resulted in multiple symptoms (e.g., GI symptoms and upper respiratory symptoms during one infection), or underreported, if they occurred more remotely from the study visit. However, it is unlikely that these errors would have been related to later antibody development, and misclassification because of over- or underreporting of illnesses would bias our results toward the null. Further, it is not possible for us to determine which infectious agent was responsible for each illness, which limits our interpretation of results.
We found that more frequent GI illnesses were associated with increased risk of IA. However, when examined in conjunction with infant diet, we found that the increased risk of IA associated with GI illnesses was only among children first exposed to wheat or barley either early or late, particularly if a GI illness occurred during the same interval as the cereal introduction or just after. As a result, it appears that pathogens affecting the GI system may increase the risk of IA in the presence of existing inflammation induced by diet.