Potential Mechanism Behind The Hygiene Hypothesis

Jun Kim Ph.D.

Previously the association between the gut microbiota and allergy was discussed[Here] . To describe worldwide increased rates of allergies in school children, the hygiene hypothesis was proposed, which subsequently led to the microbial hypothesis as a potential explanation. Given the strong evidence supporting these hypotheses, probiotics treatment has been suggested as a viable strategy to prevent allergic diseases. This article will discuss some of the proposed molecular mechanisms behind the microbial hypothesis.

Helper T cell 1 (Th1) and helper T cell 2 (Th2) are types of immunes cells that modulate activities of other immune cells. While Th1 is known to be mainly involved in the cellular immune system Th2 is known to be involved in the humoral immune system. It has been observed that while Th2 reacts to allergens Th1 reacts to microbes. Interestingly Th1-inducing molecules have been demonstrated to reduce allergen-specific Th2 response and vice versa[1]. This reciprocal down-regulation of Th1 and Th2 cells led some researchers to suggest that in developed countries the lack of microbial burden, which normally favors a strong Th1-mediated immunity, redirects the immune response toward a Th2 phenotype and therefore predisposes the host to allergic disorders[2]. The problem with this explanation is that Th1 cell-mediated autoimmune diseases have also been shown to be protected by Th1 activating infections and that Th2 activating allergic response can be prevented by parasites that induce a Th2 response[3]. But these observations still fit with the concept of a common mechanism underlying infection-mediated protection against allergy and autoimmunity, and other mechanisms have been proposed.

Another proposed mechanism is antigenic competition. Two immune responses elicited by distinct antigens occurring simultaneously tend to inhibit each other. For example, given the limited resource for the immune system, activation of the immune response for one antigen reduces the resource to activate for the second antigen. Therefore, the development of strong immune responses against antigens from infectious agents could inhibit responses to ‘weak’ antigens such as autoantigens and allergens[4]. Immune cells compete for cytokines, recognition for major histocompatibility complex (MHC)/self-peptide complexes and growth factors necessary for the differentiation and proliferation of B and T cells during immune responses. Some of the molecules known to play an important role are IL-2, IL-7, and IL-15[5].

Other mechanisms involve a specific type of cells activated by microbes inhibiting activating signals for allergies. For example, regulatory T cells (Tregs) can suppress immune responses distinct from responses against the antigen in question. So it is hypothesized that when these cells are activated by microbes they suppress signals that are activated by other antigens such as allergens. Evidence from mouse models shows CD4+CD25+ forkhead box P3 (FoxP3+) T cells are involved in this mechanism[6]. Also, these cells have been observed to be especially abundant in newborns of mothers exposed to farming. Other data suggest a role for IL-10 producing B cells and natural killer T cells[7]. At the molecular level production of cytokines IL-10 and TGF-beta, and activation of Toll-like receptors by microbial molecules have been observed to prevent allergic reactions[8].

It remains to be seen which mechanism plays the most critical role for pathological outcomes. It may turn out that different mechanisms apply for different infections. These mechanisms open interesting therapeutic perspectives for the prevention of allergic and autoimmune diseases. Of course, infecting people at high risk of developing allergic diseases to prevent them will cause infectious diseases instead. Specific molecules with the bacterial origin and potentially have a preventative effect are being discovered. However, such chemical could be limited by short half-life. Probiotics can be a safe and effective approach to preventing various allergic diseases by modifying the gut microbiota, but further work is needed to determine the exact mechanism and the most optimal composition.

Disclaimer: The above article is sponsored by Thyrve, the world’s first Gut Health Program that incorporates microbiome testing and personalized probiotics to ensure a healthier gut, happier life, and a brighter future. 

Sources:

[1] Bellanti JA: Cytokines and allergic diseases: clinical aspects. Allergy Asthma Proc 1998, 19:337–341.

[2] Maggi E: The TH1/TH2 paradigm in allergy. Immunotechnology 1998, 3:233–244.

[3] Okada H, Kuhn C, Feillet H, Bach JF: The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update. Clin Exp Immunol 2010, 160:1–9.

[4] Bach JF: The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002, 347:911–920.

[5] Surh CD, Sprent J: Homeostasis of naive and memory T cells. Immunity 2008, 29:848–862.

[6] Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL: CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 2002, 420:502–507.

[7] Schaub B, Liu J, Hoppler S, Schleich I, Huehn J, Olek S, Wieczorek G, Illi S, von Mutius E: Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. J Allergy Clin Immunol 2009, 123:774–782 e775.

[8] Aumeunier A, Grela F, Ramadan A, Pham Van L, Bardel E, Gomez Alcala A, Jeannin P, Akira S, Bach JF, Thieblemont N: Systemic Toll-like receptor stimulation suppresses experimental allergic asthma and autoimmune diabetes in NOD mice. PLoS One 2010, 5:e11484.