Review Article

Exposure to Microbes and Risk of Coeliac Disease

Ketil Størdal; Christian Kahrs; German Tapia; Daniel Agardh; Kalle Kurppa; Lars C. Stene

Disclosures

Aliment Pharmacol Ther. 2020;53(1):43-62. 

In This Article

Abstract and Introduction

Abstract

Background: Coeliac disease is an immune-mediated intestinal disease characterised by lifelong intolerance to dietary gluten in genetically predisposed individuals. Microbial factors including infections or bacterial microbiota have long been suspected to be involved in the aetiology, but the scientific literature on the topic is scattered and heterogeneous.

Aims: To review human observational studies on microbes and coeliac disease

Methods: We identified 135 publications judged relevant. Most studies were cross-sectional, and prone to reverse causation and other biases. Only a few were prospective. Cohort studies and longitudinal studies that have sampled biological specimens before disease onset are emphasised in the review.

Results: Infections during early childhood were associated with an increased risk of subsequent coeliac disease in nine studies, whereas maternal infections during pregnancy did not show a clear association. For the most frequently studied microbial factors, some evidence for an association was found, including Helicobacter pylori (four out of 16 studies), adenovirus (two out of nine studies) and enterovirus (two out of six studies). Rotavirus infections have been associated with disease development, and rotavirus vaccination may reduce the risk. Among the many studies of gut microbiota, most were cross-sectional and, therefore, potentially influenced by reverse causation. Only two smaller prospective case-control studies with sampling before disease onset were identified; they reported inconsistent findings regarding the faecal microbiome.

Conclusions: Several microbes are potentially linked to coeliac disease. As microbial factors are amenable to interventions, larger prospective studies are still warranted.

Introduction

Coeliac disease (CD) is defined as a chronic immune-mediated enteropathy which is precipitated by the intake of gluten in genetically predisposed individuals.[1] The prevalence of CD is increasing worldwide, which is probably attributed to increased recognition as well as a true increase, as demonstrated in population-based screening studies.[2–4]

Genetic factors are clearly important for CD to develop.[5–7] Only individuals carrying the HLA-DQ2 or DQ8 haplotypes seem to develop CD,[8] but these alleles are also highly prevalent in the general population of whom the majority will maintain tolerance towards gluten. HLA DQ2 or DQ8 molecules and the modification of certain proline-rich parts of the gluten protein by the enzyme tissue transglutaminase (tTG) are cornerstones in the understanding of CD aetiology.[9,10] In addition, more than 40 genetic variants outside the HLA region have been identified, with markedly smaller effects on the risk of CD compared to HLA.[11,12] Interestingly, many of the non-HLA SNPs are located in regulatory regions of genes involved in immunity and response to microbes.[13] Thus, recent genetic developments point towards an interaction between genes and microbes in the pathogenesis of CD.

The rapid change in occurrence of CD over time cannot be attributed to genes, and clearly indicates a role of environmental factors in disease development. Attempts to identify these environmental factors have in the past focused on infant diet including breastfeeding and timing of gluten introduction[14] and, more recently, on the amount of gluten in early childhood.[15,16]

The gut harbours trillions of microbes, many of which are thought to play an important role in health and disease.[17] The interaction between nutrients and microbes is complex: Microbes may modify the immunogenicity of nutrients including gluten peptides, and the microbiome is also able to modulate immune responses. Conversely, the diet modifies the microbiome.[17] It has been hypothesised that gluten exposure, alone or together with other factors, leads to life-long gluten intolerance partially through microbial pathways. An interaction between enteric viruses and bacteria is a recent field of research, adding complexity to the role of microbes in disease and health.[18,19]

In a recent experimental study of a rodent model, infection with reovirus was shown to suppress regulatory T-cell conversion and induce Th1 immunity towards dietary antigens.[20] Murine norovirus was shown to induce Th1 immunity, and signs of loss of tolerance in transcriptional profiling from mesenteric lymph nodes was observed.[21] In addition, bacterial peptides from commensal gut bacteria share homology with immunogenic gluten peptides, and were able to activate gliadin-reactive T cells from CD patients.[22] This cross-reaction suggests that microbial exposure is a potential environmental factor in the aetiology of CD. Though the molecular mechanism linking microbes to development of CD is outside the scope of this review, there is an increasing recognition that host genetics, gut microbes and dietary gluten can interact in CD development.

Although CD can occur at any age, there is a paucity of longitudinal screening studies in adults. Prospective studies with repeated serological screening of children at genetic risk indicate that the majority of cases develop CD during preschool age.[23,24] The peak incidence of developing autoantibodies against tTG, the first sign of the peripheral autoimmune response in CD, occurs already at 2–3 years of age.[15] This suggests that the search for environmental exposures should be focused on early life (Figure 1).

Figure 1.

Succession of potential environmental influences and events leading to CD with a frequently observed extended time lag between appearance of CD antibodies and clinical diagnosis

The time lag from seroconversion to diagnosis opens the possibility that factors observed at diagnosis could be a consequence of undetected disease as well as being a cause.[23,25] Thus, prospective studies with sample and data collection before development of antibodies and repeated antibody screening are highly valuable (Figure 1). The wide range in the clinical picture from asymptomatic to severe malabsorption also hampers the study of temporal environmental factors.

Here we aimed to review human studies of microbial factors as potential aetiological factors in CD, with emphasis on results from longitudinal studies that have sampled biological specimens before disease onset.

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