The hygiene hypothesis offers an explanation for the rise of allergies and autoimmune diseases in developed countries. The evidence supporting the importance of stimulating the naïve immune system during infancy for development of healthy immune responses is substantial, however it may only partially explain the rise in these diseases. Perhaps of equal importance for allergy and autoimmune disease pathogenesis is the continuous immune stimulation by bacteria and other microorganisms residing in mucosal surfaces.
Throughout human evolution, the human immune system has developed an immunological tolerance for microbes that have traditionally colonized mucosal surfaces. However, use of antibiotics and changes in the modern diet can induce drastic changes in mucosal bacteria populations. Antibiotic use effectively kills a large proportion of mucosal bacteria, decreasing the colonization resistance of the mucosa and opening this niche to bacterial populations that would not normally colonize mucosa. Furthermore, a diet of highly processed foods provides an environment that allows potentially pathogenic bacteria to thrive, while stifling the proliferation of bacteria that are traditionally found in the gastrointestinal tract. These changes in mucosal bacterial populations, termed dysbiosis, affect the development of regulatory T cells (Tregs), key mediators of anti-inflammatory responses, and can lead to the development of aberrant immune responses to normally innocuous environmental antigens, as observed in allergic airway reactions to house dust mite (HDM). This is called the microflora hypothesis of allergic diseases (1).
Previous blog posts have demonstrated that oral feeding of Lactobacillus species can improve intestinal barrier function while reducing inflammatory markers of obesity, as well as prevent the development collagen-induced arthritis in mice. If the microflora hypothesis is correct, than manipulation of gastrointestinal microbiota could be a viable treatment for allergic diseases. A study conducted at Shenzhen Children’s Hospital investigated the effect of Bifidobacterium infantis, a commonly used probiotic, on two mouse models of allergic inflammation: ovalbumin (OVA)-induced airway asthma and β-lactoglobulin (BLG)-induced intestinal food allergy (2).
In this study researchers established four groups for both the asthma and food allergy models to determine the effect of either preventative or pre-treatment with B. infantis (Figure 1).
Figure 1. Summary of control and experimental groups used to determine the effect of preventative treatment and pre-treatment of B. infantis.
Histological examination of lung tissue and intestinal tissue revealed that both preventative treatment and pre-treatment with B. infantis reduced inflammation in these tissues as compared to the positive controls. Furthermore, leukocyte counts in bronchoalveolar lavage fluid (BALF) revealed that both modes of B. infantis treatment were able to significantly decrease the number of leukocytes infiltrating lung tissue in the OVA-induced asthma model.
These results suggest that B. infantis treatment alleviates tissue-specific inflammation in both OVA-induced asthma and BLG-induced intestinal food allergy models. To analyze the biological mechanisms linking B. infantis treatment with the reduction in inflammation, antibody responses to OVA (asthma model only) and cytokine levels (IL-4, IL-13, IL-10, IFN-γ) in BALF and serum were measured.
In the OVA-induced asthma model, both the preventative treatment and the pre-treatment groups had serum IgG1 and IgE antibody levels that were lower than the positive control (although still higher than the normal control). These results are consistent with the reduced inflammation seen in the histological analysis. Since BLG-specific antibodies could not be determined for the BLG-induced food allergy model, serum total IgE levels were determined instead. Again, both the preventative treatment and pre-treatment groups had lower total IgE levels than the positive control. Interestingly, in the OVA-induced asthma groups the preventative treatment reduced IgE levels more than pre-treatment, while the inverse was true for the BLG-induced food allergy groups.
The antibody responses to the allergens in these disease models indicates that B. infantis treatment can reduce IgE response, attenuating allergic responses to the antigens. To further explain this modified immune response, the researchers determined cytokine levels in BALF (OVA-induced asthma) or serum (BLG-induced food allergy), which led to mixed results. In the OVA-induced asthma groups, preventative treatment and pre-treatment of B. infantis significantly reduced IL-4 and IL-13 levels in BALF. IL-4 and IL-13 are both Th2 cytokines involved in the production of IgE antibodies, therefore their decrease in BALF is consistent with the reduced IgE response to OVA.
In the BLG-induced food allergy groups, the results of the cytokine ELISAs were the same as with the OVA-induced asthma groups, with one major exception. Serum IL-4 levels in the B. infantis pre-treatment group were significantly higher than the preventative treatment and even positive control groups. Furthermore, serum IL-10 levels in the positive control and both B. infantis treatment groups were equal, while also being significantly less than the IL-10 levels of the normal control. Since IL-10 induces Treg development and promotes immunotolerance, the lack of difference in IL-10 between the positive controls and treatment groups was surprising and requires further examination. IL-10 was not determined in BALF samples, and IFN-γ could not be determined for either group.
This research suggests that B. infantis CGMCC313-2 can reduce inflammatory reactions observed in OVA-induced asthma and BLG-induced food allergy mouse models. While the decrease in antibody response and shift in IL-4 and IL-13 levels support the anti-inflammatory effect of B. infantis, future studies could further elucidate the physiological effects of B. infantis treatment a couple ways. First, quantifying anti-BLG antibodies would be useful for determining how B. infantis can modify antibody responses to a food allergen, rather than using serum total IgE levels as a marker. Additionally, the cytokine networks underlying allergic reactions are complex and not completely understood. A study that determines the levels of several Th1 and Th2 cytokine at different time intervals after the allergen challenge could provide more information on the capabilities of B. infantis as a treatment for allergies.