insights

                                                                                                                                                                                                                    Read time 5 minutes

Allergic diseases, including asthma, food allergy, and atopic dermatitis, are widespread and increasing in prevalence, particularly in children of westernized countries.^1-4 The hygiene hypothesis suggests that the modern aversion to all microbes may be largely to blame for influencing the atopic march—the natural history or typical progression of allergic diseases that often begins early in life—but certainly there may be other factors at play. What are some of the most common factors that affect an individual’s susceptibility to allergies, and what prevention and treatment options does functional medicine provide?

Research suggests that immunoglobulin E (IgE) is a pathophysiologic mediator and carrier of hypersensitivity in some, but not all, “atopic” diseases as they develop over the course of infancy and childhood.⁵ More specifically, the atopic march can be considered a progression of allergic conditions that have common genetic and environmental predisposing factors and share the immunologic feature of one or more allergen-specific T helper type 2 (T_H2) responses. It is also characterized by a “type 2” effector phase that can include generation of specific IgE, activation of granulocytes, and other innate features such as mucous production and edema. The presence of one allergic condition may also increase the risk for development of others.⁵

While genetic predisposition influences the development of allergic sensitization, environmental factors like lifestyle changes in industrial society also play an important role.^4-6 A 2023 systematic review and meta-analysis of cohort studies suggests that the risk of asthma is higher in urban areas compared to rural areas (RR, 1.27; 95% CI, 1.12-1.44, p<0.001), but not for the risk of allergic rhinitis (RR, 1.17; 95% CI, 0.87-1.59, p=0.30).⁷ Furthermore, the risk of asthma in urban areas compared to rural areas was higher in the 0-6 years and 0-18 years age groups, with RRs of 1.21 (95% CI, 1.01-1.46, p=0.04) and 1.35 (95% CI, 1.12-1.63, p=0.002), respectively. However, there was no significant difference in the risk of asthma between urban and rural areas for children aged 0-2 years, with a RR of 3.10 (95% CI, 0.44-21.56, p=0.25).⁷

Influence of the Microbiome on Immune Response

The microbiota has a leading role in shaping early immune responses; most environmental and lifestyle factors impact the formation of a diverse microbiota that colonizes the skin and intestinal tract.^3-5 As such, the hygiene hypothesis has been updated to encompass the commensal microbiota, based on the identification of bacteria that are allergy-protective as well as the presence of potentially harmful bacteria that can drive allergic disease.⁴ Factors that may affect an individual’s predisposition and susceptibility to allergies include, but are not limited to:

• A westernized diet^3-4
• The mode of delivery during childbirth⁴
• Early-life antibiotics/overuse of antibiotics^3-8
• Dust in the home^9,10
• Mold exposure¹¹
• Outdoor air pollution^5,12-13

Dust in the home,¹⁴ mold exposure and mycotoxins,¹⁵ and outdoor air pollution¹⁶ may also effect changes in the human intestinal microbiome—a determinant of health and disease.

Intestinal dysbiosis in early infancy may be associated with an increased risk for asthma development later in life.^4,17 One study assessed asthma risk using positive skin prick testing and the presence of clinical wheeze at one year of age; the combination of those two factors was associated with a positive Asthma Predictive Index at age three and thereby an increased risk of having active asthma at school age. The authors described a decrease in the genera Rothia, Faecalibacterium, Lachnospira, and Veillonella (the latter three of which are Firmicutes and known short-chain fatty acid [SCFA] producers) as well as a reduction in fecal acetate in those infants with an elevated risk of becoming asthmatic.^4,16 SCFAs such as butyrate, acetate, and propionate are key drivers of T-cell subset proliferation and activity.¹⁷ In addition to acting as an energy source for gastrointestinal colonocytes, SCFAs are anti-inflammatory and increase significantly upon induction of colonic CD103⁺FoxP3⁺ cells and IL-10 production.¹⁸

This study, and others like it, further emphasizes the influence of the microbiome on systemic aspects of the immune response.¹⁷ Because the microbiota has a leading role in shaping early immune responses, multiple studies have attempted to influence the atopic march through diet or probiotic-based interventions.^4-5,19 While the data are mixed, there is little doubt that the microbiome can have a significant effect on the immune response.^4-5

Supporting a healthy microbiome is a cornerstone of functional medicine and essential for strengthening immune responses and improving overall health. Personalized therapeutic interventions that focus on modifiable lifestyle factors may optimize immune system function while supporting gut health, and may include the following:

• Therapeutic food plans
• Multi-strain probiotic supplementation & prebiotics
• Adequate sleep and sleep quality
• Movement and exercise plans
• Reduction of toxic exposures

Endotoxins & Outdoor Pollutant Exposure: Allergy Risk

One interesting study examined the prevalence of asthma and allergy in two communities: the Amish and the Hutterite.⁹ These two communities have genetic and environmental overlap, as well as similar lifestyle factors—with one major difference: the Amish still farm in small family farms while Hutterites have larger, more industrialized communal farms. The study found that the Amish children displayed significantly lower allergic sensitization and asthma than the Hutterite children.⁹

When the researchers examined the dust from each environment, they found it contained strikingly different levels of endotoxins.⁹ Mice exposed to the dust from Hutterite homes went on to develop asthma or allergy symptoms while those exposed to dust from Amish homes did not. They also found that genes that modulate the innate inflammatory response and genes that depend upon nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) were expressed differently in the Amish versus the Hutterite children. The results of this study indicate that the Amish environment may have provided protection against asthma by engaging and shaping the innate immune response.⁹

Overall, endotoxin levels in the air do not change drastically when comparing farming and urban environments, but endotoxins in dust are much higher around dairy farms.²⁰ Even in urban environments, some children exposed to higher levels of endotoxins at school also have worsened asthma symptoms.²⁰ However, for children who do not yet have allergic reactions or asthma, increased endotoxin exposure may be protective, reducing the likelihood of developing either condition.^5,22-23

More recent research suggests that outdoor pollutants like ozone and particulate matter may be associated with increased asthma morbidity and may contribute to the development of disease, with tobacco smoke and diesel exhaust particles augmenting primary sensitization to antigens, leading to an IgE response.^11-12 Studies on human B cells found that diesel exhaust particles and their derivative, polyaromatic hydrocarbons may induce the synthesis of IgE in the presence of IL-4, suggesting that this pollutant may potentiate the sensitivity to common allergens.¹²

Among people living in Southern California, pollutant exposure has been associated with decreased lung volume and increased episodes of acute asthma and bronchitis.¹¹ Studies over the past 20 years, however, show there has been a significant reduction in ambient air pollutants in the region; with decreased levels of ambient air pollutants, both of these outcomes have improved. Thus, some within the medical community believe that the field of allergy and immunology is poised to bring environmental awareness to clinical practice, including patient education on the effect of pollutants on disease outcomes.¹¹

In functional medicine, individual intake assessments are extremely important for the identification and evaluation of symptoms and patterns from potential toxic exposures. These assessments assist in the development of personalized comprehensive strategies to ultimately identify and reduce the exposure, enhance biotransformation through appropriate avenues, and promote the body’s healing. Personalized treatments may include lifestyle modifications and other techniques to support the body’s own natural methods to increase toxicant elimination. Examples include:

• Therapeutic diets with increased fiber and specific nutrients
• Promotion of glutathione production in the body
• Use of saunas to increase elimination of certain toxicants through sweat and urine

Conclusion

Functional medicine emphasizes the importance of a healthy microbiome for the prevention of allergic diseases and provides a framework for patient education, bringing awareness to the environmental factors that affect disease and disease management. IFM’s Applying Functional Medicine in Clinical Practice (AFMCP) provides clinicians with an understanding of underlying immune mechanisms and effective interventions to support and balance immune function. Learn more about the latest research and clinical tools for treating patients with immune dysfunction:

Innate Immunity: Diet and Lifestyle Support

The Role of the Microbiome in Immune-Related Diseases

Immune Aging & Therapeutic Targets

References

1. Dogruel D, Bingöl G, Altintas DU, Seydaoglu G, Erkan A, Yilmaz M. The trend of change of allergic diseases over the years: three repeated surveys from 1994 to 2014. Int Arch Allergy Immunol.2017;173(3):178-182. doi:1159/000477726
2. Brozek G, Lawson J, Szumilas D, Zejda J. Increasing prevalence of asthma, respiratory symptoms, and allergic diseases: four repeated surveys from 1993-2014. Respir Med.2015;109(8):982-990. doi:1016/j.rmed.2015.05.010
3. Renz H, Skevaki C. Early life microbial exposures and allergy risks: opportunities for prevention. Nat Rev Immunol. 2021;21(3):177-191. doi:1038/s41577-020-00420-y
4. Kemter AM, Nagler CR. Influences on allergic mechanisms through gut, lung, and skin microbiome exposures. J Clin Invest. 2019;129(4):1483-1492. doi:1172/JCI124610
5. Hill DA, Spergel JM. The atopic march: critical evidence and clinical relevance. Ann Allergy Asthma Immunol. 2018;120(2):131-137. doi:1016/j.anai.2017.10.037
6. Chong-Neto HJ, D’amato G, Rosário Filho NA. Impact of the environment on the microbiome. J Pediatr (Rio J). 2022;98(Suppl 1):S32-S37. doi:1016/j.jped.2021.10.001
7. Song M, Hwang S, Son E, et al. Geographical differences of risk of asthma and allergic rhinitis according to urban/rural area: a systematic review and meta-analysis of cohort studies. J Urban Health. 2023;100(3):478-492. doi:1007/s11524-023-00735-w
8. Yamamoto-Hanada K, Yang L, Narita M, Saito H, Ohya Y. Influence of antibiotic use in early childhood on asthma and allergic diseases at age 5. Ann Allergy Asthma Immunol. 2017;119(1):54-58. doi:1016/j.anai.2017.05.013
9. Tischer C, Weikl F, Probst AJ, Standl M, Heinrich J, Pritsch K. Urban dust microbiome: impact on later atopy and wheezing. Environ Health Perspect. 2016;124(12):1919-1923. doi:1289/ehp158
10.  Stein MM, Hrusch CL, Gozdz J, et al. Innate immunity and asthma risk in Amish and Hutterite farm children. N Engl J Med. 2016;375(5):411-421. doi:1056/NEJMoa1508749
11.  Herr M, Just J, Nikasinovic L, et al. Risk factors and characteristics of respiratory and allergic phenotypes in early childhood. J Allergy Clin Immunol. 2012;130(2):389-396.e4. doi:1016/j.jaci.2012.05.054
12.  Peden DB. Effect of pollution on allergy/immunology. J Allergy Clin Immunol. 2018;141(3):P878-P879. doi:1016/j.jaci.2018.01.017
13.  Schiavoni G, D’Amato G, Afferni C. The dangerous liaison between pollens and pollution in respiratory allergy. Ann Allergy Asthma Immunol. 2017;118(3):269-275. doi:1016/j.anai.2016.12.019
14.  Shan Y, Wu W, Fan W, Haahtela T, Zhang G. House dust microbiome and human health risks. Int Microbiol. 2019;22(3):297-304. doi:1007/s10123-019-00057-5
15.  Liew WPP, Mohd-Redzwan S. Mycotoxin: its impact on gut health and microbiota. Front Cell Infect Microbiol. 2018;8:60. doi:3389/fcimb.2018.00060
16.  Moelling K, Broecker F. Air microbiome and pollution: composition and potential effects on human health, including SARS coronavirus infection. J Environ Public Health. 2020;2020:1646943. doi:1155/2020/1646943
17.  Arrieta MC, Stiemsma LT, Dimitriu PA, et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci Transl Med. 2015;7(307):307ra152. doi:1126/scitranslmed.aab2271
18.  Lynch SV. Gut microbiota and allergic disease. New insights. Ann Am Thorac Soc. 2016;13(Suppl 1):S51-S54. doi:1513/AnnalsATS.201507-451MG
19.  McKenzie C, Tan J, Macia L, Mackay CR. The nutrition-gut microbiome-physiology axis and allergic diseases. Immunol Rev. 2017;278(1):27-295. doi:1111/imr.12556
20.  Barnig C, Reboux G, Roussel S, et al. Indoor dust and air concentrations of endotoxin in urban and rural environments. Lett Appl Microbiol. 2013;56(3):161-167. doi:1111/lam.12024
21.  Lai PS, Sheehan WJ, Gaffin JM, et al. School endotoxin exposure and asthma morbidity in inner-city children. Chest. 2015;148(5):1251-1258. doi:1378/chest.15-0098
22.  Gehring U, Bischof W, Fahlbusch B, Wichmann HE, Heinrich J. House dust endotoxin and allergic sensitization in children. Am J Respir Crit Care Med.2002;166(7):939-944. doi:1164/rccm.200203-256OC
23.  Gehring U, Strikwold M, Schram-Bijkerk D, et al. Asthma and allergic symptoms in relation to house dust endotoxin: phase two of the International Study on Asthma and Allergies in Childhood (ISAAC II). Clin Exp Allergy. 2008;38(12):1911-1920. doi:1111/j.1365-2222.2008.03087.x