What Could Be the Causes of Celiac Disease (CeD)?

Celiac disease (CeD) is an autoimmune disorder triggered by gluten ingestion in genetically susceptible individuals (primarily those with HLA-DQ2 or HLA-DQ8 genes). While genetics and gluten exposure are essential, they do not fully explain the rising prevalence of CeD in developed countries over recent decades. Scientists increasingly point to environmental factors that disrupt immune tolerance to gluten, with the hygiene hypothesis (or its refined "Old Friends" variant) as a leading explanation.

The Hygiene Hypothesis and CeD

The hygiene hypothesis proposes that modern "cleaner" environments reduce early-life exposure to certain microbes, parasites, and infections (especially via the fecal-oral route), depriving the developing immune system of essential "training." This leads to an overly reactive immune system that may lose tolerance to harmless dietary proteins like gluten, contributing to autoimmune conditions such as CeD.

Supporting evidence includes stark contrasts between similar populations in different environments:

• Russian vs. Finnish Karelia — These adjacent regions share similar genetics and ancestry, but Russian Karelia has poorer sanitation, more frequent fecal-oral infections, and significantly lower rates of CeD (prevalence ~1 in 496 children vs. ~1 in 107 in Finland). Transglutaminase antibodies (a marker of CeD) were also less common in Russian Karelia. Follow-up analyses confirm this hygiene contrast persists.
• Tsimane people (Amazon, Bolivia) — This indigenous group lives in near-traditional conditions with near-universal parasite exposure (e.g., hookworm). Their extremely low overall autoimmune disease rates, despite high parasite exposure, align with protective hygiene effects, though direct CeD prevalence data are limited.
• Hepatitis A virus (HAV) exposure — Case-control studies show that individuals with anti-HAV antibodies (indicating past fecal-oral infection) have reduced allergic and autoimmune risks, supporting the idea that such exposures may modulate immunity beneficially (though not CeD-specific).

These observations suggest that limited early exposure to "Old Friends" microbes (commensals, parasites, and certain pathogens co-evolved with humans) may impair immune regulation, increasing CeD susceptibility in cleaner, industrialized settings.

Certain viruses can act as environmental "hits" in genetically predisposed individuals, especially when infection overlaps with gluten introduction (e.g., during weaning in early childhood).A landmark 2017 study (published in Science) demonstrated that an asymptomatic reovirus infection (a common, usually harmless gut virus) can break oral tolerance to gluten in mouse models. In mouse models, the T1L reovirus strain created a pro-inflammatory gut environment, blocking protective regulatory T cells and promoting Th1 responses to gluten — mimicking CeD pathology. Humans with CeD showed higher anti-reovirus antibodies. This finding has been widely cited in recent reviews (2023–2025) as strong mechanistic evidence for viral involvement in CeD, without major rebuttals. 

Viral Infections as Potential Triggers

Certain viruses can act as environmental "hits" in genetically predisposed individuals, especially when infection overlaps with gluten introduction (e.g., during weaning in early childhood).

A landmark 2017 study (published in Science) demonstrated that an asymptomatic reovirus infection (a common, usually harmless gut virus) can break oral tolerance to gluten in mouse models. In mouse models, the T1L reovirus strain created a pro-inflammatory gut environment, blocking protective regulatory T cells and promoting Th1 responses to gluten — mimicking CeD pathology. Humans with CeD showed higher anti-reovirus antibodies. This finding has been widely cited in recent reviews (2023–2025) as strong mechanistic evidence for viral involvement in CeD, without major rebuttals. Other viruses (e.g., rotavirus, enteroviruses) show associations with increased CeD risk, while some (e.g., certain herpesviruses) may be protective in specific contexts. Overall, viruses highlight multifactorial triggers: protective via hygiene hypothesis in many cases, but potentially initiating autoimmunity in susceptible people.

Recent 2025 studies, including a review on environmental factors in children, continue to validate the 2017 reovirus findings and explore how early infections interact with genetics and gluten timing to modify risk.  For instance, a 2025 article emphasizes that while gluten is the known trigger, other environmental factors like season of birth and gene interactions may contribute to CeD onset.

Broader Perspective

Humans and our microbiomes/parasites have co-evolved as a "super-organism" (William Parker, Duke University), with intertwined development. Modern hygiene, antibiotics, C-sections, and reduced fecal-oral exposures may disrupt this balance, altering gut microbiota and immune pathways in ways that favor CeD onset. This multifactorial view supports experts like Dr. Andrew Weil, who caution that gluten is benign for most but problematic in true CeD due to immune dysregulation. While multifactorial, no single trigger explains all cases; ongoing research (e.g., 2025 longitudinal studies) explores microbiota-viral interactions.

In summary, while genetics provide the vulnerability and gluten the trigger, the rise in CeD likely stems from lost protective microbial exposures in cleaner environments — combined with potential viral "sparks" in some cases. This multifactorial view explains why CeD remains rare even in genetically at-risk individuals, and it underscores the need for ongoing research into prevention (e.g., optimizing early microbial exposures). Prevention research is promising (e.g., optimizing early microbial exposures). If symptoms like fatigue, bloating, or family history arise, consult a doctor for serology testing — early gluten-free management prevents complications.

References

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