An antibiotic-impacted microbiota compromises the development of colonic regulatory t cells and predisposes to dysregulated immune responses

Xiaozhou Zhang; Timothy C. Borbet; Angela Fallegger; Matthew F. Wipperman; Martin J. Blaser; Anne Müller

doi:10.1128/mBio.03335-20

An antibiotic-impacted microbiota compromises the development of colonic regulatory t cells and predisposes to dysregulated immune responses

Xiaozhou Zhang, Timothy C. Borbet, Angela Fallegger, Matthew F. Wipperman, Martin J. Blaser, Anne Müller

Center for Advanced Biotechnology and Medicine (CABM)

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

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 CD4¹ T-cell compartment. In contrast, colonic granulocyte and myeloid lineages and other mucosal T-cell compartments are unaffected. Among colonic CD4¹ T cells, we observed the most pronounced effects on neuropilin-negative, RORgt-and Foxp3-positive regulatory T cells, which are largely absent in antibioticexposed mice even as they reach adulthood. Immunomagnetically isolated dendritic cells from antibiotic-exposed mice fail to support the generation of Foxp3¹ 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, RORgt-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 CD4¹ 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.

Original language	American English
Article number	e03335-20
Pages (from-to)	1-16
Number of pages	16
Journal	mBio
Volume	12
Issue number	1
DOIs	https://doi.org/10.1128/mBio.03335-20
State	Published - Jan 1 2021

ASJC Scopus subject areas

Microbiology
Virology

Keywords

Broad-spectrum antibiotics
CD4 T cells
Colonic regulatory T cells
Dysregulated Th1 responses
Dysregulated immune response
Metabolic disorders
Microbiota
Transmaternal exposure
Treg deficiency

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10.1128/mBio.03335-20

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@article{a3c47f36dfa84e4a878994a960a8374e,

title = "An antibiotic-impacted microbiota compromises the development of colonic regulatory t cells and predisposes to dysregulated immune responses",

abstract = "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 CD41 T-cell compartment. In contrast, colonic granulocyte and myeloid lineages and other mucosal T-cell compartments are unaffected. Among colonic CD41 T cells, we observed the most pronounced effects on neuropilin-negative, RORgt-and Foxp3-positive regulatory T cells, which are largely absent in antibioticexposed mice even as they reach adulthood. Immunomagnetically isolated dendritic cells from antibiotic-exposed mice fail to support the generation of Foxp31 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, RORgt-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{\textquoteright}s early life that such exposures have consequences that persist into adulthood. Offspring acquire their mother{\textquoteright}s antibiotic-impacted microbiota, which compromises their ability to generate a colonic pool of CD41 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.",

keywords = "Broad-spectrum antibiotics, CD4 T cells, Colonic regulatory T cells, Dysregulated Th1 responses, Dysregulated immune response, Metabolic disorders, Microbiota, Transmaternal exposure, Treg deficiency",

author = "Xiaozhou Zhang and Borbet, {Timothy C.} and Angela Fallegger and Wipperman, {Matthew F.} and Blaser, {Martin J.} and Anne M{\"u}ller",

note = "Publisher Copyright: {\textcopyright} 2021 Zhang et al.",

year = "2021",

month = jan,

day = "1",

doi = "10.1128/mBio.03335-20",

language = "American English",

volume = "12",

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journal = "mBio",

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T1 - An antibiotic-impacted microbiota compromises the development of colonic regulatory t cells and predisposes to dysregulated immune responses

AU - Zhang, Xiaozhou

AU - Borbet, Timothy C.

AU - Fallegger, Angela

AU - Wipperman, Matthew F.

AU - Blaser, Martin J.

AU - Müller, Anne

PY - 2021/1/1

Y1 - 2021/1/1

N2 - 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 CD41 T-cell compartment. In contrast, colonic granulocyte and myeloid lineages and other mucosal T-cell compartments are unaffected. Among colonic CD41 T cells, we observed the most pronounced effects on neuropilin-negative, RORgt-and Foxp3-positive regulatory T cells, which are largely absent in antibioticexposed mice even as they reach adulthood. Immunomagnetically isolated dendritic cells from antibiotic-exposed mice fail to support the generation of Foxp31 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, RORgt-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 CD41 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.

AB - 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 CD41 T-cell compartment. In contrast, colonic granulocyte and myeloid lineages and other mucosal T-cell compartments are unaffected. Among colonic CD41 T cells, we observed the most pronounced effects on neuropilin-negative, RORgt-and Foxp3-positive regulatory T cells, which are largely absent in antibioticexposed mice even as they reach adulthood. Immunomagnetically isolated dendritic cells from antibiotic-exposed mice fail to support the generation of Foxp31 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, RORgt-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 CD41 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.

KW - Broad-spectrum antibiotics

KW - CD4 T cells

KW - Colonic regulatory T cells

KW - Dysregulated Th1 responses

KW - Dysregulated immune response

KW - Metabolic disorders

KW - Microbiota

KW - Transmaternal exposure

KW - Treg deficiency

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DO - 10.1128/mBio.03335-20

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SN - 2161-2129

VL - 12

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EP - 16

JO - mBio

JF - mBio

IS - 1

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ER -

An antibiotic-impacted microbiota compromises the development of colonic regulatory t cells and predisposes to dysregulated immune responses

Abstract

ASJC Scopus subject areas

Keywords

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