Role of postnatal acquisition of the intestinal microbiome in the early development of immune function.
OBJECTIVE
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. In contrast, probiotic treatment of premature infants reduces the incidence of necrotizing enterocolitis. We hypothesized that 1 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 polymerase chain reaction. Subsequently, 2-week-old specific pathogen-free and microbial-reduced (MR; antibiotic treated) mice were compared for immune molecule and microbial sensor expression, mesenteric lymph node T-cell numbers and activation, intestinal barrier function/permeability, systemic lymphocyte numbers, and T-cell phenotype commitment.


RESULTS
Toll-like receptor 2, 4, and 5 expression was highest in 2-week-old specific pathogen-free mice, and this expression was decreased in MR mice. There was no difference in intestinal tight-junctional function, as evaluated by fluorescein isothiocyanate-dextran uptake, but MR mice had increased bacterial translocation across the intestinal epithelial barrier. MR mice had significantly fewer splenic B cells and mesenteric lymph node CD4+ T cells, but there were normal numbers of splenic T cells. These systemic T cells from MR mice produced more interleukin-4 and less interferon-gamma and IL-17, indicative of maintenance of the fetal, T-helper cell type 2 phenotype.


CONCLUSIONS
The present 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 influence the development of the mucosal immune system and mucosal-related diseases.
Dimmitt
Reed A
RA
Department of Microbiology, University of Alabama, Birmingham, AL, USA.
Staley
Elizabeth M
EM
Chuang
Gin
G
Tanner
Scott M
SM
Soltau
Thomas D
TD
Lorenz
Robin G
RG
D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D018988:Bacterial Translocation; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000276:immunology / Q000382:microbiology*; D007107:Immune System / Q000166:cytology / Q000502:physiology*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D016207:Cytokines; D020381:Interleukin-17; D051193:Toll-Like Receptors; D015847:Interleukin-4; D007371:Interferon-gamma