Maternal Antibiotic Treatment Impacts Development of the Neonatal Intestinal Microbiome and Antiviral Immunity

Abstract

Microbial colonization of the infant gastrointestinal tract (GIT) begins at birth, is shaped by the maternal microbiota, and is profoundly altered by antibiotic treatment. Antibiotic treatment of mothers during pregnancy influences colonization of the GIT microbiota of their infants. The role of the GIT microbiota in regulating adaptive immune function against systemic viral infections during infancy remains undefined. We used a mouse model of perinatal antibiotic exposure to examine the effect of GIT microbial dysbiosis on infant CD8+ T cell–mediated antiviral immunity. Maternal antibiotic treatment/treated (MAT) during pregnancy and lactation resulted in profound alterations in the composition of the GIT microbiota in mothers and infants. Streptococcus spp. dominated the GIT microbiota of MAT mothers, whereas Enterococcus faecalis predominated within the MAT infant GIT. MAT infant mice subsequently exhibited increased and accelerated mortality following vaccinia virus infection. Ag-specific IFN-γ–producing CD8+ T cells were reduced in sublethally infected MAT infant mice. MAT CD8+ T cells from uninfected infant mice also demonstrated a reduced capacity to sustain IFN-γ production following in vitro activation. We additionally determined that control infant mice became more susceptible to infection if they were born in an animal facility using stricter standards of hygiene. These data indicate that undisturbed colonization and progression of the GIT microbiota during infancy are necessary to promote robust adaptive antiviral immune responses.

Gastrointestinal Microbiome Dysbiosis in Infant Mice Alters Peripheral CD8+ T Cell Receptor Signaling

“…These results illustrate that Ag-specific CD8 + T cells derived from MAT mice despite initial priming in a normal microbiota environment under optimal activation conditions, overall maintain a differential phenotype from CTRL Ag-specific CD8 + T cells in exhibiting decreased polyfunctional antiviral cytokine responses. This behavior is consistent with the hypothesis that intrinsic differences in MAT infant CD8 + T cells exist (36) possibly imprinted by their development in a GIM-depleted environment.…”

“…We recently reported that infant mice whose mothers were treated with antibiotics (MAT) in the last days of pregnancy and during lactation have significantly altered composition of the GIM, enhanced susceptibility to systemic viral infection, altered innate immune cell populations, and poor effector CD8 + T cell responses compared with CTRL infants (36). Particularly, MAT effector CD8 + T cells are unable to sustain IFN-γ production in vivo following vaccinia virus infection and in vitro upon TCR and CD28 stimulation (36).…”

“…Particularly, MAT effector CD8 + T cells are unable to sustain IFN-γ production in vivo following vaccinia virus infection and in vitro upon TCR and CD28 stimulation (36). These findings led us to hypothesize that the dysfunction observed in MAT CD8 + T cells was due to intrinsic cell defects.…”

“…We have demonstrated that infant mice with GIM dysbiosis caused by maternal antibiotic treatment (MAT) in the last days of pregnancy confer increased susceptibility to death following a systemic viral infection (36). We observe that CD8 + effector T cells from MAT infant mice consistently demonstrate the inability to sustain IFN-γ production in vivo following vaccinia virus infection and in vitro upon TCR stimulation.…”

Antibiotic treatment in infants: effect on the gastro-intestinal microbiome and long term consequences

“…Maternal antibiotic treatment, administered during pregnancy and lactation results in profound alterations in the composition of the microbiota in mothers and infants. 10 Prenatal antibiotics are associated with a larger body mass index (BMI) at the age of two years. 11 Children experiencing a higher number of respiratory tract infections in the first year of life already demonstrate an aberrant microbial developmental trajectory from the first month of life on.…”