Role of the Microbiome in Programming the Immune Phenotype

The regulation of the immune system by gut microbiota has been drawing the attention of many researchers. To discuss the involved mechanisms, potential immune programing, and the physiological consequences, Paul Forsythe, PhD, from the McMaster University, Canada, talked at the American Academy of Allergy, Asthma and Immunology’s 2015 annual conference in Houston, TX.

Forsythe reminded the audience that there is epidemiological evidence that the gut microbiota has an important role on the immune system. In numerous studies that evaluated children with asthma and allergy have shown the participation of the gut microbiota in the development of these diseases. Children that were exposed to higher diversity of microorganisms developed less allergic diseases; conversely, those exposed to lower diversity had increased risk. Studies in germ-free mice have provided direct evidence of the gut microbiota role. These animals have smaller Peyer’s patches, decreased levels of T helper 17 cells (Th17), and secretory IgA. Interestingly, the exposure of these mice to normal microbiota reverses these changes.

Several key components in the gut microbiota have been identified, and evidence is that each of them has a distinct role in the development of the immune profile. One of the most important is the presence of segmented filamentous bacteria (SFB). Studies in mice have shown that absence of SFB is associated with lower levels of Th17. Additionally, the transfer of SFB into germ-free mice increases the levels of Th17. Studies in mice that are prone to the development of autoimmune arthritis have confirmed an association between the disease and the modulation of Th17 by SFB in the gut. Another important factor is the presence of non-pathogenic Clostridia. These bacteria induce the expression of immunosuppressive regulatory T cells (Treg). Germ-free mice have lower levels of Treg, and when these mice are inoculated with a selection of clostridia, there is an important increase in the Treg levels. This effect is also observed in conventional animals. Forsythe mentioned that the mechanisms behind this regulation most likely involve the metabolism of carbohydrates by Clostridia, which generates short-chain fatty acids. It has already been demonstratedthat SCFA induce the expression of Treg. Indeed, inoculation of mice with Clostridia causes a parallel increase in Treg and SCFA.

To investigate the role of specific bacteria on the development of allergic diseases, Forsythe has inoculated mice with Lactobacillus rhamnosus (JB-1). He has observed that such treatment had a potent immunoregulatory response, decreasing airway responsiveness. One of the novel mechanisms identified in this protective effect is the production of microvesicles by JB-1, which are important for bacteria-cell communication and seem to have an important role on immune response. He concluded that the gut microbiota is determinant in the development of the immune profile, and that the immune response depends on the type of bacteria in the gut.

Next, Forsythe remarked that the body’s homeostasis is built upon the coordinate interaction between the nervous, immune and endocrine systems. According to him, the gut microbiota influences each of these systems. In fact, it has been demonstrated that germ-free mice have increased hypothalamo-pituitary-adrenal (HPA) axis activity. Conventionalization of these mice reversed the phenotype. In 2011, Bravo and collaborators indicated that ingestion of Lactobacillus regulates emotional behavior.

In conclusion, the gut microbiota modulates immune development and is an important component of neuroendocrine system. These interactions interfere with neuroendocrine development and, consequently, the patient’s immune function.