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Wise et al.

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exposed to farm animals and stables. 522,649-655 The protective effect is greatest with highest exposure occurring early in life. 650

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Bacterial endotoxin.: Exposure to bacterial endotoxin has been studied as a possible protective factor. Inverse association between exposure to endotoxin in infancy and childhood and the development of allergic sensitization has been shown in rural and urban environments, but the results have not been uniform between the studies. 656,657 Probiotics.: A meta-analysis of 29 randomized controlled studies showed no significant association of probiotics supplementation of pregnant or breastfeeding mothers or infants with sensitization or allergic rhinitis at age 12 to 36 months. 658 (See section IX.B.9. Management – Pharmacotherapy – Probiotics for additional information on this topic.) Microbial diversity.: Changes in lifestyle, urbanization, diet, and the use of antibiotics have changed the microbiota of the environment, human skin and mucosal membranes. Differences in the microbiota may explain the difference in atopic diseases between rural and urban areas, as well as Finland and the Russian Karelia (a part of Russia geographically adjacent to Finland). 659-661 Households with dogs have rich, diverse house dust microbiota with abundance of Firmicutes and Bacteroides species. 662 In the GABRIEL study the mattress dust of farm children and their controls was analyzed by quantitative DNA analysis. Especially high mattress levels of Mycobacterium sp., Bifidobacteriaceae sp., and Clostridium sp. were found among farm children, and that high level was inversely associated with atopy. 661 Low diversity of gut microbiota in early infancy has been related to greater risk of asthma and sensitization in some longitudinal studies with different designs in childhood. 442,445,449,663 The dysbiosis of the microbiome driven by higher Bacteroides and reduced Clostridia taxa in adulthood was associated with greater prevalence of seasonal and nut allergies in adulthood in the American Gut Project. 664 Skin microbiota may also be associated with protection from atopy. Compared with healthy individuals, atopic individuals have shown to have lower environmental bio-diversity at home and significantly lower generic diversity of gammaproteobacteria on their skin. 665 Skin Acinetobacter (gammaproteobacteria) species were associated with anti-inflammatory immune responses only in healthy subjects. 666 In summary, hygiene is important to prevent infections worldwide. Urbanization first in affluent and later in developing countries has led to reduced microbial diversity in the environment. Large microbial diversity of the skin, airways, and gut in childhood is important for the prevention of sensitization and of allergic disease in populations. More longitudinal studies are needed to show the association. • Aggregate Grade of Evidence: B (Level 2a: 2 studies; Level 2b: 10 studies; Level 3a: 2 studies; Level 3b: 1 study; Table VI.G.3). • Studies included in the Aggregate Grade of Evidence are systematic reviews and meta-analyses for the various aspects of the hygiene hypothesis discussed above.

Int Forum Allergy Rhinol . Author manuscript; available in PMC 2020 June 10.