Role of Postnatal Acquisition of the Intestinal Microbiome in the Early Development of Immune Function

Abstract

Objectives Therapy with broad-spectrum antibiotics is a common practice for premature infants. This treatment can reduce the biodiversity of the fecal microbiota and may be a factor in the cause of necrotizing enterocolitis (NEC). In contrast, probiotic treatment of premature infants reduces the incidence of NEC. We hypothesized that one mechanism for these observations is the influence of bacteria on postnatal development of the mucosal immune system. Methods Expression of immune molecules and microbial sensors was investigated in the postnatal mouse gastrointestinal tract by real-time PCR. Subsequently, two-week-old specific pathogen free (SPF) and microbial reduced (antibiotic treated, MR) mice were compared for immune molecule and microbial sensor expression, mesenteric lymph node (MLN) T-cell numbers and activation, intestinal barrier function/permeability, systemic lymphocyte numbers, and T-cell phenotype commitment. Results Toll-like receptor (TLR) 2, 4, and 5 expression was highest in 2-week-old SPF mice, and this expression was decreased in MR mice. There was no difference in intestinal tight-junctional function, as evaluated by FITC-dextran uptake, but MR mice had increased bacteria translocation across the intestinal epithelial barrier. MR mice had significantly fewer splenic B-cells and MLN CD4+ T-cells, but there were normal numbers of splenic T-cells. These systemic T-cells from MR mice produced more IL-4, and less interferon-γ and IL-17, indicative of a maintenance of the fetal, T-helper cell type 2 phenotype. Conclusions This study shows that intestinal commensal microbiota have an influence on early postnatal immune development. Determining specific bacteria and/or bacterial ligands critical for this development could provide insight into the mechanisms by which broad-spectrum antibiotics and/or probiotic therapy influences the development of the mucosal immune system and mucosal-related diseases.

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