Immune tolerance attenuates gut dysbiosis, dysregulated uterine gene expression and high-fat diet potentiated preterm birth in mice

Clarence R. Manuel, Mariam S. Latuga, Charles R. Ashby, Sandra E. Reznik

Research output: Contribution to journalArticle

Abstract

Background: Preterm delivery accounts for 85% of perinatal morbidity and mortality. Although the consumption of a high-fat diet leads to exaggerated proinflammatory responses and, in pregnant women, increased rates of spontaneous preterm birth, the underlying mechanisms remain unclear. Objective: We sought to elucidate the mechanisms by which maternal consumption of a high-fat diet leads to a dysregulated immune response and, subsequently, spontaneous preterm birth. Study Design: We performed 16S ribosomal RNA sequencing of DNA extracted and amplified from stool samples and compared the gut microbiomes of lipopolysaccharide-induced pregnant mice that were maintained on a high-fat diet compared to a normal control diet. Next, we sequenced the uterine transcriptomes of the mice. To test the effect of dampening of the immune response on the microbiome, transcriptome, and risk of spontaneous preterm birth, we induced immune tolerance with repetitive subclinical doses (0.2 mg/kg/week for 8 weeks) of endotoxin and performed 16S ribosomal RNA and uterine transcriptome sequencing on these immunotolerized mice. Results: High-fat diet potentiates lipopolysaccharide-induced preterm birth by affecting the maternal gut microbiome and uterine transcriptome and reduces antioxidant capacity in a murine model. High-fat diet consumption also increases the colonization of the gut by 5 immunogenic bacteria and decreases colonization by Lachnospiraceae_NK4A136_group. Uteri from high-fat diet mice had increased expression of genes that stimulate the inflammatory-oxidative stress axis, autophagy/apoptosis, and smooth muscle contraction. Repetitive endotoxin priming protects high-fat diet dams from spontaneous preterm birth, increases colonization of the gut by Lachnospiraceae_NK4A136_group, decreases levels of immunogenic bacteria in the gut microbiome, and reduces the number of dysregulated genes after high-fat diet consumption from 994 to 74. Conclusion: High-fat diet-potentiated spontaneous preterm birth is mediated by increased inflammation, oxidative stress, and gut dysbiosis. The induction of immune tolerance via endotoxin priming reverses these effects and protects high-fat diet dams from spontaneous preterm birth. Based on this work, the role of immunomodulation as a novel therapeutic approach to prevent preterm birth among women who consume high-fat diets should be explored.

Original languageEnglish (US)
JournalAmerican Journal of Obstetrics and Gynecology
DOIs
StatePublished - Jan 1 2019

Fingerprint

Dysbiosis
Immune Tolerance
Premature Birth
High Fat Diet
Gene Expression
Transcriptome
Endotoxins
16S Ribosomal RNA
Lipopolysaccharides
Oxidative Stress
Mothers
RNA Sequence Analysis
Bacteria
Immunomodulation
Perinatal Mortality
Microbiota
Autophagy
Muscle Contraction
Uterus
Smooth Muscle

Keywords

  • endotoxin
  • immune tolerance
  • microbiome
  • preterm birth
  • priming

ASJC Scopus subject areas

  • Obstetrics and Gynecology

Cite this

@article{f15d1c104a5c4999a0e38573455b2892,
title = "Immune tolerance attenuates gut dysbiosis, dysregulated uterine gene expression and high-fat diet potentiated preterm birth in mice",
abstract = "Background: Preterm delivery accounts for 85{\%} of perinatal morbidity and mortality. Although the consumption of a high-fat diet leads to exaggerated proinflammatory responses and, in pregnant women, increased rates of spontaneous preterm birth, the underlying mechanisms remain unclear. Objective: We sought to elucidate the mechanisms by which maternal consumption of a high-fat diet leads to a dysregulated immune response and, subsequently, spontaneous preterm birth. Study Design: We performed 16S ribosomal RNA sequencing of DNA extracted and amplified from stool samples and compared the gut microbiomes of lipopolysaccharide-induced pregnant mice that were maintained on a high-fat diet compared to a normal control diet. Next, we sequenced the uterine transcriptomes of the mice. To test the effect of dampening of the immune response on the microbiome, transcriptome, and risk of spontaneous preterm birth, we induced immune tolerance with repetitive subclinical doses (0.2 mg/kg/week for 8 weeks) of endotoxin and performed 16S ribosomal RNA and uterine transcriptome sequencing on these immunotolerized mice. Results: High-fat diet potentiates lipopolysaccharide-induced preterm birth by affecting the maternal gut microbiome and uterine transcriptome and reduces antioxidant capacity in a murine model. High-fat diet consumption also increases the colonization of the gut by 5 immunogenic bacteria and decreases colonization by Lachnospiraceae_NK4A136_group. Uteri from high-fat diet mice had increased expression of genes that stimulate the inflammatory-oxidative stress axis, autophagy/apoptosis, and smooth muscle contraction. Repetitive endotoxin priming protects high-fat diet dams from spontaneous preterm birth, increases colonization of the gut by Lachnospiraceae_NK4A136_group, decreases levels of immunogenic bacteria in the gut microbiome, and reduces the number of dysregulated genes after high-fat diet consumption from 994 to 74. Conclusion: High-fat diet-potentiated spontaneous preterm birth is mediated by increased inflammation, oxidative stress, and gut dysbiosis. The induction of immune tolerance via endotoxin priming reverses these effects and protects high-fat diet dams from spontaneous preterm birth. Based on this work, the role of immunomodulation as a novel therapeutic approach to prevent preterm birth among women who consume high-fat diets should be explored.",
keywords = "endotoxin, immune tolerance, microbiome, preterm birth, priming",
author = "Manuel, {Clarence R.} and Latuga, {Mariam S.} and Ashby, {Charles R.} and Reznik, {Sandra E.}",
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T1 - Immune tolerance attenuates gut dysbiosis, dysregulated uterine gene expression and high-fat diet potentiated preterm birth in mice

AU - Manuel, Clarence R.

AU - Latuga, Mariam S.

AU - Ashby, Charles R.

AU - Reznik, Sandra E.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Preterm delivery accounts for 85% of perinatal morbidity and mortality. Although the consumption of a high-fat diet leads to exaggerated proinflammatory responses and, in pregnant women, increased rates of spontaneous preterm birth, the underlying mechanisms remain unclear. Objective: We sought to elucidate the mechanisms by which maternal consumption of a high-fat diet leads to a dysregulated immune response and, subsequently, spontaneous preterm birth. Study Design: We performed 16S ribosomal RNA sequencing of DNA extracted and amplified from stool samples and compared the gut microbiomes of lipopolysaccharide-induced pregnant mice that were maintained on a high-fat diet compared to a normal control diet. Next, we sequenced the uterine transcriptomes of the mice. To test the effect of dampening of the immune response on the microbiome, transcriptome, and risk of spontaneous preterm birth, we induced immune tolerance with repetitive subclinical doses (0.2 mg/kg/week for 8 weeks) of endotoxin and performed 16S ribosomal RNA and uterine transcriptome sequencing on these immunotolerized mice. Results: High-fat diet potentiates lipopolysaccharide-induced preterm birth by affecting the maternal gut microbiome and uterine transcriptome and reduces antioxidant capacity in a murine model. High-fat diet consumption also increases the colonization of the gut by 5 immunogenic bacteria and decreases colonization by Lachnospiraceae_NK4A136_group. Uteri from high-fat diet mice had increased expression of genes that stimulate the inflammatory-oxidative stress axis, autophagy/apoptosis, and smooth muscle contraction. Repetitive endotoxin priming protects high-fat diet dams from spontaneous preterm birth, increases colonization of the gut by Lachnospiraceae_NK4A136_group, decreases levels of immunogenic bacteria in the gut microbiome, and reduces the number of dysregulated genes after high-fat diet consumption from 994 to 74. Conclusion: High-fat diet-potentiated spontaneous preterm birth is mediated by increased inflammation, oxidative stress, and gut dysbiosis. The induction of immune tolerance via endotoxin priming reverses these effects and protects high-fat diet dams from spontaneous preterm birth. Based on this work, the role of immunomodulation as a novel therapeutic approach to prevent preterm birth among women who consume high-fat diets should be explored.

AB - Background: Preterm delivery accounts for 85% of perinatal morbidity and mortality. Although the consumption of a high-fat diet leads to exaggerated proinflammatory responses and, in pregnant women, increased rates of spontaneous preterm birth, the underlying mechanisms remain unclear. Objective: We sought to elucidate the mechanisms by which maternal consumption of a high-fat diet leads to a dysregulated immune response and, subsequently, spontaneous preterm birth. Study Design: We performed 16S ribosomal RNA sequencing of DNA extracted and amplified from stool samples and compared the gut microbiomes of lipopolysaccharide-induced pregnant mice that were maintained on a high-fat diet compared to a normal control diet. Next, we sequenced the uterine transcriptomes of the mice. To test the effect of dampening of the immune response on the microbiome, transcriptome, and risk of spontaneous preterm birth, we induced immune tolerance with repetitive subclinical doses (0.2 mg/kg/week for 8 weeks) of endotoxin and performed 16S ribosomal RNA and uterine transcriptome sequencing on these immunotolerized mice. Results: High-fat diet potentiates lipopolysaccharide-induced preterm birth by affecting the maternal gut microbiome and uterine transcriptome and reduces antioxidant capacity in a murine model. High-fat diet consumption also increases the colonization of the gut by 5 immunogenic bacteria and decreases colonization by Lachnospiraceae_NK4A136_group. Uteri from high-fat diet mice had increased expression of genes that stimulate the inflammatory-oxidative stress axis, autophagy/apoptosis, and smooth muscle contraction. Repetitive endotoxin priming protects high-fat diet dams from spontaneous preterm birth, increases colonization of the gut by Lachnospiraceae_NK4A136_group, decreases levels of immunogenic bacteria in the gut microbiome, and reduces the number of dysregulated genes after high-fat diet consumption from 994 to 74. Conclusion: High-fat diet-potentiated spontaneous preterm birth is mediated by increased inflammation, oxidative stress, and gut dysbiosis. The induction of immune tolerance via endotoxin priming reverses these effects and protects high-fat diet dams from spontaneous preterm birth. Based on this work, the role of immunomodulation as a novel therapeutic approach to prevent preterm birth among women who consume high-fat diets should be explored.

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