Abstract
The presence of a complex and diverse intestinal flora is functionally important for regulating intestinal mucosal immune responses. However, the extent to which a balanced intestinal flora regulates systemic immune responses is still being defined. In order to specifically examine whether the acquisition of a less complex flora influences responses to immunization in the pre-weaning stages of life, we utilize a model in which infant mice acquire an intestinal flora from their mothers that has been altered by broad-spectrum antibiotics. In this model, pregnant dams are treated with a cocktail of antibiotics that alters both the density and microbial diversity of the intestinal flora. After challenge with a subcutaneous immunization, the antibiotic altered flora infant mice have lower antigen specific antibody titers compared to control age-matched mice. In a second model, we examined germ free (GF) mice to analyze how the complete lack of flora influences the ability to mount normal antibody responses following subcutaneous immunization. GF mice do not respond well to immunization and introduction of a normal flora into GF mice restores the capacity of these mice to respond. These results indicate that a gastrointestinal flora reduced in density and complexity at critical time points during development adversely impacts immune responses to systemic antigens.
Highlights
The gastrointestinal tract (GIT), in terms of mass and cellularity, is the largest immune organ in the body
To alter the GIT flora, we selected a combination of ampicillin, clindamycin, and streptomycin for their broad-spectrum activity against bacteria represented within the intestinal flora of mice and humans
We focused our analysis on antibody responses during the period of infancy to weaning by using antibiotics to alter the intestinal flora
Summary
The gastrointestinal tract (GIT), in terms of mass and cellularity, is the largest immune organ in the body. These populations include: CD4+FoxP3+ regulatory T (Treg) cells, Th17 cells, and cd+T cells [3,4,5,6,7] Deficiencies of these cell populations, as noted in germ free mice or as induced by treatment with antibiotics to alter the intestinal flora [8], are associated with immune dysregulation and the development of allergic and autoimmune diseases (i.e. type 1 diabetes, rheumatoid arthritis, inflammatory bowel disease) in humans and in mouse models [9,10,11,12]. The exact mechanisms involved in how members of the intestinal flora mediate these effects are not yet entirely clear
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