A Case for Antibiotic Perturbation of the Microbiota Leading to Allergy Development

Lisa A Reynolds; B Brett Finlay


Expert Rev Clin Immunol. 2013;9(11):1019-1030. 

In This Article

Immune Development & the Intestinal Microbiota

The intestinal tract of mammals is sterile until birth, after which colonization by microbes begins. Birth route (vaginal vs cesarean section), diet (formula vs breast-feeding), prematurity and antibiotic use (during the first month of life) are key factors which determine the initial microbiota composition of human infants.[7–9] Initial colonizers and early-life modifications of the microbiota likely influence the structure of the microbiota into adult life. The intestinal tract is by far the most densely colonized surface of mammals with a highly diverse microbiota consisting of bacteria, archaea, viruses and fungi. While the intestinal microbiota have received the most attention over the past decade, microbial communities also reside on the skin, in the respiratory tract and vagina of humans.[10,11]

The presence of the microbiota during development, and recognition of pathogen-associated molecular patterns (PAMPs) by innate pattern recognition receptors (PRRs) is required for normal immune development and for the maintenance of intestinal homeostasis.[12] Evidence for this has been gained by studying the immunodeficiencies of germ-free (GF) mice, and in mice genetically deficient for PRRs or their adaptor proteins.[13,14]

At birth, immune responses are Th2 biased; fetal T cells collected from human umbilical cord blood samples mount Th2-skewed responses toward common environmental antigens,[15] and fetal T cells proliferate to a greater extent than adult T cells following exposure to IL-4.[16] The capacity for Th1 responses in early life appears to be impaired, as circulating mononuclear cells produce less IL-12p70 in response to bacterial stimulation during infancy.[17] GF mice also have reduced IFN-γ-producing CD4+ T cells in their spleen compared with conventionally raised mice, which can be normalized by monocolonizing GF mice with the human commensal Bacteroides fragilis.[18] Whether this is a property solely of B. fragilis, or if this restoration of Th1 responsiveness occurs after colonization with any bacterial species, remains to be determined. Delayed induction of Th1 responses following birth, which could result from antibiotic treatment in early life, has been proposed as a mechanism leading to the development of atopy.[19] In support of this hypothesis, low IFN-γ levels in human cord blood samples correlate with the development of allergic symptoms at 1 year of age.[20]

As well as stimulating normal immune system development during early life, the composition of the adult microbiota has been shown in mice to influence the differentiation of intestinal T cells. The observation that C57BL/6 mice purchased from different commercial vendors have different levels of Th17 cells in their small intestinal lamina propria (LP) led to the hypothesis that specific microbes can drive Th17 development.[21] Further work has identified segmented filamentous bacteria (SFB), which are able to penetrate the mucus barrier and directly contact epithelial cells, as key drivers of intestinal Th17 cell development.[22,23] Specific bacterial species can also promote tolerance in the intestine, as colonization with a mix of Clostridium species derived from murine or human feces promotes Treg induction specifically in the colonic LP of mice.[24,25] Thus, the presence of certain species within the microbiota can dictate local T-cell differentiation. Additionally, the presence of certain species may be critical for limiting the differentiation of certain immune cells, for example, mice deficient in Toll-like receptor (TLR)9 signaling display increased frequencies of Tregs in their small intestinal LP and Peyer's patches (PP), and reduced constitutive IFN-γ and IL-17A production compared with TLR9-sufficient mice,[26] indicating that specific microbial signals are important for both promoting and inhibiting immune cell differentiation.