Celiac disease is a chronic immune-mediated disorder caused by a T-cell-mediated response against gliadin peptides found in gluten-containing grains (1). A characteristic feature of celiac disease is an intestinal mucosa showing villous atrophy on a gluten-containing diet (2), which will result in the restoration of the intestinal mucosa structure after treatment with a gluten-free diet (GFD). Celiac disease is a lifelong condition currently without cure and will therefore lead to relapse of the disease when gluten is reintroduced to the diet even years after GFD (3).

The global prevalence of celiac disease is estimated to be approximately 1% but estimated as high as 3% in Sweden (4). The prevalence of celiac disease is higher in countries with high consumption of wheat (5). Despite that gluten is essential for celiac disease to develop, celiac disease only affects individuals with a genetic predisposition of carrying the human leukocyte antigen (HLA)-risk haplotypes. More than 95% of celiac disease patients carry the HLA-DQA1*05:01-DQB1*02:01 (abbreviated DQ2) and 5% DQA1*03:01-DQB1*03:02 (abbreviated DQ8) haplotypes (1). Moreover, there is a gene dose effect of HLA demonstrating that children with two copies of HLA-DQ2 are at the highest risk of celiac disease and at an early age (6–8). Prospective birth cohort studies have found that 20% of the children carrying the DQ2 haplotypes followed from birth develop celiac disease by the age of 10 years (6). Albeit gluten is considered to be driving a higher prevalence of celiac disease in populations with higher frequencies of HLA-risk genotypes, additional environmental factors such as birth mode, season of birth, viral infections, and altered microbiome may facilitate and/or trigger the immune response to dietary gluten (9–11). Celiac disease can develop at any time over a life span, although the incidence peaks in early childhood (12).

A lot of studies have focused on gluten infant feeding since the steep increase in incidence of celiac disease that affected children younger than age 2 years in Sweden after change in gluten infant feeding recommendations occurred in the mid-1980s, which dropped again a decade later (13). This so-called celiac epidemic co-occurred when the gluten content was changed in the baby formulas and the breastfeeding recommendations were revised, indicating that there could be a window of opportunity to induce tolerance to gluten in young children. Although there is no consensus when is the optimal time point of introducing gluten in the diet, the European Society for Pediatric Gastroenterology, Hepatology, Nutrition (ESPGHAN) recommends gluten to be introduced to the infant’s diet anytime between 4 and 12 months of age, and large gluten amounts during the first months of introduction should be avoided (14). More recent birth cohort studies following children at genetic risk demonstrate that the incidence of celiac disease is highest between 2 and 3 years of life (15, 16) and found an association between gluten intake and celiac disease both in the general population (17) and in genetically at-risk populations (15, 16). However, it has not yet been confirmed whether a reduced intake of gluten amounts will prevent or delay the diagnosis of celiac disease, since many clinical trials performed so far have been underpowered to prove causality (18, 19). Previous primary prevention studies focusing on early infant feeding practices have shown no protection of celiac disease if gluten introduction was delayed (20) or introduced in small amounts during the child’s first year of life (19). The aim of the present mini-review was to provide an overview of completed and ongoing randomized clinical trials with focus on dietary interventions to prevent celiac disease.

MEDLINE (PubMed) and Clinical Trials (www.clinicaltrials.gov) were searched for randomized RCTs investigating the potential association between feeding practices and celiac disease, from inception up until October 2022. All completed RCTs investigated dietary interventions with focus on early tolerization to gluten consumption or the effect of timing on gluten introduction. For the current review, five completed and two ongoing trials were included ( Table 1 ).

The first 1,000 days of life (i.e., from conception to the child’s second birthday) are often mentioned as the most important window for shaping the child’s immune system and microbiome (30). Furthermore, studies have suggested that the gut microbiota affects gluten digestion, intestinal permeability, and the host immune system (31). Vice versa, early infant diet shapes the microbiome, and gluten may modify the composition of the intestinal flora (30, 32, 33). Despite the fact that incidence of celiac disease peaks in early childhood and has been found to be associated with both higher gluten intake and frequent gastrointestinal viral infections in previous prospective observational studies (15, 34, 35), infant gluten intervention with either delayed gluten introduction or introduction to small amounts during the child’s first year of life have failed to protect genetic-susceptible children from celiac disease in clinical trials (19, 20, 22). Gluten infant feeding may have an impact on the gut microbiome composition and diversity and, if being deranged during the early phase of development, may lead to autoimmunity (18, 36). Therefore, more clinical trials on dietary intervention with reduced gluten, probiotics, or both need to be evaluated in genetically at-risk children if primary prevention of celiac disease is even possible. Moreover, larger randomized clinical trials (RCTs) with longer follow-up are therefore required to prove the causality of reduced gluten amounts introduced to the child’s diet, not only at the time of introduction but also in a longer time frame, preventing genetic at-risk individuals from lifelong celiac disease.

So far, an introduction of small amounts of gluten in a time window between 4 and 6 months of age, given to induce tolerization, did not prevent celiac disease. However, infant gluten interventions beyond this tight time window with longer intervals have not been fully evaluated. However, recent publications with longer follow-up in the PREVENT-CD cohort show contradictory results (37–39). A study based on the Italian study population found that children who developed celiac disease by the age of 6 years had significantly higher gluten consumption after 24 months of age compared with children who did not develop celiac disease (39). Results from clinical trials testing these hypotheses are still pending. It is therefore too early to rule out that gluten intervention strategies may or may not be efficient targets of primary prevention of celiac disease in genetically at-risk children.

Peak incidence of seroconversion to celiac disease occurs early (15), suggesting that possible prevention strategies should be initiated probably before the age of 3 years. Prospective studies have shown that a high gluten intake compared to a low gluten intake during the second year of life is associated with increased risk of celiac disease (15–17, 39). Especially, in a multinational pediatric at-risk population, it was shown that daily gluten intake was associated with higher increased risk of developing CDA and with celiac disease for every 1-g/day increase in gluten intake, and a daily gluten intake above 2 g/day almost doubled the risk of developing celiac disease by the age of 3 years (15). These observational prospective studies suggest that preventive strategies should be targeted not only for a short time window during the introduction of gluten and weaning but maybe also for a longer period and up to 2 years of age at least. The two ongoing clinical trials (PreCiSe and GRAIn) have adopted this approach of a late gluten introduction or restricted gluten consumption, but it will take several years with longitudinal follow-up to find out if a delayed full gluten consumption to age 3 or 5 years will prevent celiac disease or only postpone the diagnosis to older ages.

It is hypothesized that exposures to viral infections while inducing tolerance to gluten may modify the risk of celiac disease. The steep increase in amount of gluten consumption during the first years of life coincides with a period with repeated virus infections (35). A previous study showed that children who later developed CDA had been more exposed to rotavirus infections (40). Later, the TEDDY study demonstrated that rotavirus vaccination protected children from CDA, but only in children that were introduced to gluten before 6 months of age (41). Many countries have implemented rotavirus vaccination into their national vaccination programs during the past decades. In Sweden, which has one of the highest prevalence of celiac disease in the world, reaching almost 3% (42), two rotavirus vaccines that are FDA approved (Rotarix^® and RotaTeq^®) are currently given to all newborn babies born after the first of September, 2019. Only in a few years, it will be possible to perform a nationwide registry study to see if the national rotavirus vaccination program has an incipient effect on celiac disease incidence.

Another study from TEDDY showed that frequent exposures of enterovirus B during the first 2 years of life was associated with increased risk of CDA (41) and that higher amounts of gluten intake confer a cumulative effect on the risk of developing celiac disease autoimmunity after an enterovirus B infection, suggesting an interaction between infections and gluten in the etiology of celiac disease (35). The main findings from these studies showing complex interactions between gluten and virus infections support the notion that frequent viral infections may act as triggers, whereas gluten drives the inflammation in celiac disease. The mechanisms of why a potential viral infection would trigger an immune activation of T cells against gluten peptides and activation of B cells to produce tTGA in celiac disease are not fully understood. Although a potential causal role of virus and gluten in celiac disease pathogenesis remains to be confirmed, no RCT has yet studied if excluding gluten in young children leads to a lower incidence of celiac disease.

Although many baby formulas are fortified with probiotics to maintain the intestinal barrier by preventing crossing of immunogenic polypeptides to the lamina propria, few studies have evaluated their potential protective effects on celiac disease. Probiotics are live microorganisms that have demonstrated beneficial effects on human health after being administered in adequate amounts (43) and is considered promising additional treatments for various intestinal diseases by contributing to the stability of the gut microbiome and regulation of innate and adaptive immune systems (31, 44). A change in the gut microbiota homeostasis may eventually lead to dysbiosis and hypothetically contribute to the pathogenesis of autoimmune diseases (31). There are some indications showing that a combination of two Lactobacillus strains have dampening effects on the peripheral immune response in smaller studies on children with CDA (24). Probiotics may therefore have potential anti-autoinflammatory effects by promoting a healthy gut. Larger clinical trials on the use probiotics to prevent celiac disease are scarce, and it needs to be further evaluated if probiotics should be included in the arsenal of preventive measures of celiac disease. We have therefore extended our previous findings on Lactobacillus, which have proven effects on the gut permeability and positive immunoregulatory functions (24), to test if these two strains could act favorably on the gut mucosa layer. In PreCiSe, children will be randomized to either GFD, Lactobacillus, or placebo for the first 3 years of life, the period in life when children are being exposed and develop immunization to many common viruses. The study is ongoing and will be the first clinical trial to compare if interventions with probiotics will prevent children from having celiac disease as compared with children on a GFD or normal diet.

In conclusion, there are credible evidence from prospective studies that a higher intake of gluten in early childhood is associated with higher incidences of celiac disease. There are indications of a viral trigger in celiac disease, but no study has proven the causality of a virus in the celiac disease etiology, although prospective studies show interactions between gluten amount and frequent virus infections and subsequent risk of CDA. A cost-effective, safe, and tolerable prevention method of celiac disease has been long searched for. So far, no clinical trial has yet proven that an early gluten intervention is fully successful in preventing celiac disease. Several clinical trials are ongoing to evaluate long-term preventive effects of late gluten introduction in the diet and probiotics after the child’s immune system is fully developed by age 3. These longitudinal studies are pending and will take many years before being completed.

CA drafted the manuscript. CA and DA both contributed and wrote the review. Both authors approved the submitted version.