An Antibiotic-Impacted Microbiota Compromises the Development of Colonic Regulatory T Cells and Predisposes to Dysregulated Immune Responses.
Antibiotic exposure early in life and other practices impacting the vertical transmission and ordered assembly of a diverse and balanced gut microbiota are associated with a higher risk of immunological and metabolic disorders such as asthma and allergy, autoimmunity, obesity, and susceptibility to opportunistic infections. In this study, we used a model of perinatal exposure to the broad-spectrum antibiotic ampicillin to examine how the acquisition of a dysbiotic microbiota affects neonatal immune system development. We found that the resultant dysbiosis imprints in a manner that is irreversible after weaning, leading to specific and selective alteration of the colonic CD4+ T-cell compartment. In contrast, colonic granulocyte and myeloid lineages and other mucosal T-cell compartments are unaffected. Among colonic CD4+ T cells, we observed the most pronounced effects on neuropilin-negative, RORγt- and Foxp3-positive regulatory T cells, which are largely absent in antibiotic-exposed mice even as they reach adulthood. Immunomagnetically isolated dendritic cells from antibiotic-exposed mice fail to support the generation of Foxp3+ regulatory T cells (Tregs) from naive T cells ex vivo The perinatally acquired dysbiotic microbiota predisposes to dysregulated effector T-cell responses to Citrobacter rodentium or ovalbumin challenge. The transfer of the antibiotic-impacted, but not healthy, fecal microbiota into germfree recipients recapitulates the selective loss of colonic neuropilin-negative, RORγt- and Foxp3-positive Tregs. The combined data indicate that the early-life acquisition of a dysbiotic microbiota has detrimental effects on the diversity and microbial community composition of offspring that persist into adulthood and predisposes to inappropriate T-cell responses that are linked to compromised immune tolerance.IMPORTANCE The assembly of microbial communities that populate all mucosal surfaces of the human body begins right after birth. This process is prone to disruption as newborns and young infants are increasingly exposed to antibiotics, both deliberately for therapeutic purposes, and as a consequence of transmaternal exposure. We show here using a model of ampicillin administration to lactating dams during their newborn offspring's early life that such exposures have consequences that persist into adulthood. Offspring acquire their mother's antibiotic-impacted microbiota, which compromises their ability to generate a colonic pool of CD4+ T cells, particularly of colonic regulatory T cells. This Treg deficiency cannot be corrected by cohousing with normal mice later and is recapitulated by reconstitution of germfree mice with microbiota harvested from antibiotic-exposed donors. As a consequence of their dysbiosis, and possibly of their Treg deficiency, antibiotic-impacted offspring generate dysregulated Th1 responses to bacterial challenge infection and develop more severe symptoms of ovalbumin-induced anaphylaxis.
['Zhang|Xiaozhou|X|', 'Borbet|Timothy C|TC|', 'Fallegger|Angela|A|', 'Wipperman|Matthew F|MF|', 'Blaser|Martin J|MJ|0000-0003-2447-2443', 'Müller|Anne|A|']
D000818:Animals D000900:Anti-Bacterial Agents D003106:Colon D003713:Dendritic Cells D064806:Dysbiosis D005260:Female D000069196:Gastrointestinal Microbiome D051379:Mice D008810:Mice, Inbred C57BL D050378:T-Lymphocytes, Regulatory
microbiota colonic regulatory T cells dysregulated immune response metabolic disorders broad-spectrum antibiotics transmaternal exposure Treg deficiency dysregulated Th1 responses CD4 T cells