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  • MILESTONES

The rise of an uneducated immune system

Credit: S. Bradbrook/Springer Nature Limited

In recent years a curious phenomenon has been observed in many westernised countries: despite ever-improving healthcare, rates of autoimmune and allergic disease are on the rise. Food allergies, type-1 diabetes, ulcerative colitis and eczema (to name just a few) are at all-time highs in countries with high-quality and accessible healthcare. By contrast, less-westernised countries have seen no change.

Waning immune education

At first glance, this intriguing observation seems rather counter-intuitive. Better healthcare means less disease, right? The answer, it seems, is not quite so easy and starts from day one of life. In order to develop, a baby’s immune system is ‘educated’ through stimulation and challenge from various potential threats such as microorganisms or allergens. If the immune system is not adequately tested in the first few years of life, it does not mature properly and can later respond inappropriately to benign triggers. It has even been suggested that host–microbiota interactions are crucial for immune education and long-term homeostasis within the first months of life. Evidence for this was first published thirty years ago1 — children born into a household with many siblings were less likely to develop eczema in their first year and hay fever later in life. It was suggested that, in a household with many children, each child was more likely to be exposed to more microbiota, enabling the immune system to learn, develop and mature as it should.

This theory, dubbed the ‘hygiene hypothesis’, has since gained traction for a range of other allergic and autoimmune diseases.

Host–microbial interactions are key

Only recently have we begun to mechanistically understand how infant–microbial interactions can affect their risk of developing conditions such as asthma or food allergy. The microbiota has an important role in the regulation of mucosal immunity, and metabolites produced by commensal bacteria control the balance between anti- and pro-inflammatory mechanisms2, directly affecting inflammation-mediated immune allergen responses. For example, without gut microbiota, mice can become sensitive to peanut allergens — an effect that can be reversed with Clostridia colonisation due to reduced inflammation and lessened gut epithelial permeability3. Similarly, antibiotic exposure and higher abundance of yeast appears to increase the allergic airway response of mice to the common indoor allergen Aspergillus fumigatus4. Confirmatory results have now also been identified in human studies. Children at risk of asthma have been observed to have a reduced relative abundance of Lachnospira, Veillonella, Faecalibacterium and Rothia spp. in their guts5. The DIABIMMUNE project, which followed 1,000 Finnish, Estonian and Russian infants from birth to age three, has provided further insight into the role westernised lifestyles and diets play in allergic disease. The gut microbial communities in Finnish and Estonian children are distinct from Russian children, specifically with more abundant Bacteriodes species6. Lipopolysaccharides produced by Bacteriodes are less effective immune activators than the usual Escherichia coli, resulting in an inhibition of immune education and greater risk of developing conditions such as asthma6.

More exposure, not less hygiene

Support for the hygiene hypothesis is varied and extensive. Of course, it was never intended to suggest we should be less ‘hygienic’ — this would only increase the rate of infectious disease. Rather, we should be encouraging childhood exposure to natural immune challenges. It is clear that antibiotic use should be avoided, especially in young children. But this will require a culture shift; in many industrialised countries children can now expect to receive at least one course of antibiotics per year in their first two years of life7. For disease treatment, it is becoming increasingly apparent that personalised medicine, specifically tailored to an individual’s associated microbial community, may hold the key for reversing incidence trends. By identifying microorganisms that are directly involved in allergic disease3,5, we now have the basis for developing microbial treatments to complement allergen de-sensitisation. The hygiene hypothesis may not be about ‘hygiene’ per-se, but the underpinning research has shown us that perhaps the best we can do for our children’s health is simple and effective: provide a balanced, diverse and high-fibre diet, and allow them to get grubby outside with their pets.

References

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