Maternal cecal microbiota transfer rescues early-life antibiotic-induced enhancement of type 1 diabetes in mice

Xue-Song Zhang; Yue Sandra Yin; Jincheng Wang; Thomas Battaglia; Kimberly Krautkramer; Wei Vivian Li; Jackie Li; Mark Brown; Meifan Zhang; Michelle H Badri; Abigail J S Armstrong; Christopher M Strauch; Zeneng Wang; Ina Nemet; Nicole Altomare; Joseph C Devlin; Linchen He; Jamie T Morton; John Alex Chalk; Kelly Needles; Viviane Liao; Julia Mount; Huilin Li; Kelly V Ruggles; Richard A Bonneau; Maria Gloria Dominguez-Bello; Fredrik Bäckhed; Stanley L Hazen; Martin J Blaser

doi:10.1016/j.chom.2021.06.014

Maternal cecal microbiota transfer rescues early-life antibiotic-induced enhancement of type 1 diabetes in mice

Cell Host Microbe. 2021 Aug 11;29(8):1249-1265.e9. doi: 10.1016/j.chom.2021.06.014. Epub 2021 Jul 21.

Authors

Xue-Song Zhang¹, Yue Sandra Yin², Jincheng Wang³, Thomas Battaglia⁴, Kimberly Krautkramer⁵, Wei Vivian Li⁶, Jackie Li⁴, Mark Brown⁷, Meifan Zhang², Michelle H Badri⁸, Abigail J S Armstrong⁹, Christopher M Strauch¹⁰, Zeneng Wang¹⁰, Ina Nemet¹⁰, Nicole Altomare⁹, Joseph C Devlin⁴, Linchen He¹¹, Jamie T Morton¹², John Alex Chalk⁹, Kelly Needles⁹, Viviane Liao⁹, Julia Mount⁴, Huilin Li¹¹, Kelly V Ruggles⁴, Richard A Bonneau¹³, Maria Gloria Dominguez-Bello¹⁴, Fredrik Bäckhed¹⁵, Stanley L Hazen¹⁶, Martin J Blaser¹⁷

Affiliations

¹ Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, USA; Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA. Electronic address: [email protected].
² Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, USA; Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA.
³ Department of Biochemistry and Microbiology, Rutgers University - New Brunswick, New Brunswick, NJ, USA.
⁴ Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA.
⁵ The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg 41345, Sweden.
⁶ Department of Biostatistics and Epidemiology, Rutgers University School of Public Health, Piscataway, NJ, USA.
⁷ Cardiovascular & Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH 44195, USA.
⁸ Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA; New York University, Center for Data Science, New York, NY, USA.
⁹ Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, USA.
¹⁰ Cardiovascular & Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA.
¹¹ Department of Population Health, New York University Langone Medical Center, New York, NY, USA.
¹² Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA; Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, NY, USA.
¹³ Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA; New York University, Center for Data Science, New York, NY, USA; Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, NY, USA.
¹⁴ Department of Biochemistry and Microbiology, Rutgers University - New Brunswick, New Brunswick, NJ, USA; Institute for Food, Nutrition and Health, Rutgers University - New Brunswick, New Brunswick, NJ, USA.
¹⁵ The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg 41345, Sweden; Region västra Götaland, Sahlgrenska University Hospital, Department of Clinical Physiology, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁶ Cardiovascular & Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH 44195, USA; Heart, Vascular & Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA.
¹⁷ Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, USA; Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA. Electronic address: [email protected].

Abstract

Early-life antibiotic exposure perturbs the intestinal microbiota and accelerates type 1 diabetes (T1D) development in the NOD mouse model. Here, we found that maternal cecal microbiota transfer (CMT) to NOD mice after early-life antibiotic perturbation largely rescued the induced T1D enhancement. Restoration of the intestinal microbiome was significant and persistent, remediating the antibiotic-depleted diversity, relative abundance of particular taxa, and metabolic pathways. CMT also protected against perturbed metabolites and normalized innate and adaptive immune effectors. CMT restored major patterns of ileal microRNA and histone regulation of gene expression. Further experiments suggest a gut-microbiota-regulated T1D protection mechanism centered on Reg3γ, in an innate intestinal immune network involving CD44, TLR2, and Reg3γ. This regulation affects downstream immunological tone, which may lead to protection against tissue-specific T1D injury.

Keywords: NOD mice; animal models; autoimmune; cecal material transfer; gene expression; histone modification; innate immune; microRNA; microbiome; type 1 diabetes.

MeSH terms

Animals
Anti-Bacterial Agents / pharmacology*
Autoimmune Diseases
Bacteria / classification
Bacteria / drug effects
Cecum / immunology*
Cecum / microbiology*
Diabetes Mellitus, Type 1 / immunology*
Disease Models, Animal
Female
Gastrointestinal Microbiome / drug effects*
Gastrointestinal Microbiome / physiology*
Gene Expression
Histone Code
Intestines / immunology
Male
Metabolic Networks and Pathways
Metagenome
Mice
Mice, Inbred NOD
MicroRNAs

Substances

Anti-Bacterial Agents
MicroRNAs

Abstract

MeSH terms

Substances

Grants and funding