The microbiota and T cells non-genetically modulate inherited phenotypes transgenerationally
Jordan C. Harris,
Natalie A. Trigg,
Bruktawit Goshu,
Yuichi Yokoyama,
Lenka Dohnalová,
Ellen K. White,
Adele Harman,
Sofía M. Murga-Garrido,
Jamie Ting-Chun Pan,
Preeti Bhanap,
Christoph A. Thaiss,
Elizabeth A. Grice,
Colin C. Conine,
Taku Kambayashi
Affiliations
Jordan C. Harris
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Natalie A. Trigg
Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Departments of Genetics and Pediatrics - Penn Epigenetics Institute, Institute of Regenerative Medicine, and Center for Research on Reproduction and Women’s Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Bruktawit Goshu
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Yuichi Yokoyama
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Lenka Dohnalová
Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Ellen K. White
Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Adele Harman
Transgenic Core, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Sofía M. Murga-Garrido
Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Jamie Ting-Chun Pan
Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Preeti Bhanap
Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Christoph A. Thaiss
Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Elizabeth A. Grice
Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
Colin C. Conine
Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Departments of Genetics and Pediatrics - Penn Epigenetics Institute, Institute of Regenerative Medicine, and Center for Research on Reproduction and Women’s Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Corresponding author
Taku Kambayashi
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
Summary: The host-microbiota relationship has evolved to shape mammalian physiology, including immunity, metabolism, and development. Germ-free models are widely used to study microbial effects on host processes such as immunity. Here, we find that both germ-free and T cell-deficient mice exhibit a robust sebum secretion defect persisting across multiple generations despite microbial colonization and T cell repletion. These phenotypes are inherited by progeny conceived during in vitro fertilization using germ-free sperm and eggs, demonstrating that non-genetic information in the gametes is required for microbial-dependent phenotypic transmission. Accordingly, gene expression in early embryos derived from gametes from germ-free or T cell-deficient mice is strikingly and similarly altered. Our findings demonstrate that microbial- and immune-dependent regulation of non-genetic information in the gametes can transmit inherited phenotypes transgenerationally in mice. This mechanism could rapidly generate phenotypic diversity to enhance host adaptation to environmental perturbations.
