Microbiota & Seasonal Allergies

First introduced in 1989, the “hygiene hypothesis” proposed that exposure to specific microbes, perhaps during crucial windows of development, educates the immune system in a way that modifies the risk for allergic, inflammatory, and autoimmune diseases. Initially, this was proposed in response to the observation that the position of a child in a family (their place in the birth order) was associated with the risk for hay fever in a large national sample from the UK. It was suggested that younger children were more likely to be exposed to microbes (“unhygienic contact”) from their older siblings, thereby conferring some type of protection to the younger children. This idea has gained support and modifications over the years, such as adding the “old friends hypothesis,” the idea that exposure to harmless microorganisms (bacteria, helminths, etc.) that have co-evolved with humans helps the maturation of T_reg cells, as deficiencies in these cells leads to either excessive T helper 1 (Th1) or Th2 responses.

A more recent theory, the epithelial barrier hypothesis, builds on these earlier theories and adds an additional component that may help to explain some of the theoretical gaps; briefly, damage to lining of the GI tract promotes a poorly regulated immune system. This theory posits an initial insult to the epithelial barrier that leads to a vicious cycle, characterized by colonization of the gut with pathogens, loss of healthy commensal organisms, and altered immune function and inflammation in response to these changes in the microbiome. The authors also provide examples of many of the agents capable of damaging the epithelial barrier, ranging from cigarette smoke and air pollution to plastics.

There is mounting evidence for a link between allergic rhinitis and the composition of the microbiota, especially early in life, as well as modulation of gut microbiota as a possible intervention. For example, in a recent review, several studies describe an altered microbiome among study participants with allergic rhinitis compared to healthy controls. In an analysis published in the American Journal of Rhinology & Allergy, study participants with allergic rhinitis had significantly lower diversity of their gut microbiota, and specific shifts in relative abundance, including elevated amounts of Bacteroidetes and reduced levels of Actinobacteria and Proteobacteria (compared to controls). A second analysis published in the International Archives of Allergy and Immunology also found substantially reduced diversity among participants with allergic rhinitis compared to controls, as well as increased Bacteroidetes and reduced levels of Firmicutes, among other differences. Although the precise differences observed between controls and those with allergic rhinitis are not the same from study to study, they consistently have significant differences.

A number of mechanisms help to explain the effect these differences have on immune tolerance and activation. For example, healthy commensal bacteria produce short-chain fatty acids (SCFAs) which modulate the inflammatory process; this includes inhibiting the production of inflammatory compounds in response to LPS, also known as endotoxin, a component of Gram-negative bacteria which generally activates the immune response. But commensal bacteria that produce SCFAs can inhibit LPS-induced inflammatory compounds, such as TNF-α, IL-1β, IL-6, and nitric oxide while inducing the production of anti-inflammatory mediators, such as IL-10. 

The promotion of anti-inflammatory mediators may have clinical benefit. For example, supplementation of a combination of Bifidobacterium longum and Lactobacillus plantarum was associated with higher IL-10 levels after 4 weeks (they remained stable while in the placebo group, IL-10 level dropped), and significant improvement in symptoms along participants with allergic rhinitis, including reductions in rhinorrhea, nasal congestion, watery eyes, and sleep complaints.

That probiotic supplementation may shift the abundance of microbiota to a more favorable profile and improve allergic symptoms has been documented in large meta-analyses as well. For example, in a systematic review of 30 randomized and controlled trials with nearly 3,000 total patients, symptoms and quality of life among those receiving probiotics were significantly improved compared to placebo. A second systematic review and meta-analysis had similar conclusions; probiotics effectively reduced symptoms and improved quality of life among people with allergic rhinitis, though there was significant heterogeneity among trials, largely due to variations in the methodology and type of probiotics given.

In a very interesting randomized and controlled trial which seems to support the hygiene hypothesis (as well as the subsequently discovered immune mechanisms), children aged 3-5 played twice a day for 20 minutes in a sandbox. However, the sand in the sandbox was either comprised of microbially enriched sand or microbially poor sand, though it was visibly similar. Those children that played in the microbially rich sand had greater bacterial richness and diversity, as well as changes in IL-10 and Treg cell frequency consistent with favorable immune modulation. 

For interested readers, it is also worth examining the ARIA-MeDALL hypothesis (ARIA - Allergic Rhinitis and its Impact on Asthma, MeDaLL - Mechanisms of the Development of Allergy), which relates to the overlap and important distinctions found between allergic rhinitis, asthma, and atopic dermatitis, all of which have clear associations with both gut microbiota and epithelial barrier integrity, and their interaction with key signaling molecules, specifically IL-17, and IL-33.

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