Multi-modal Single-Cell Analysis Reveals Brain Immune Landscape Plasticity during Aging and Gut Microbiota Dysbiosis
Samantha M. Golomb,
Ian H. Guldner,
Anqi Zhao,
Qingfei Wang,
Bhavana Palakurthi,
Emilija A. Aleksandrovic,
Jacqueline A. Lopez,
Shaun W. Lee,
Kai Yang,
Siyuan Zhang
Affiliations
Samantha M. Golomb
Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA; Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617, USA
Ian H. Guldner
Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA; Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617, USA
Anqi Zhao
Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA; Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617, USA
Qingfei Wang
Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA; Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617, USA
Bhavana Palakurthi
Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA; Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617, USA
Emilija A. Aleksandrovic
Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA; Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617, USA
Jacqueline A. Lopez
Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA; Genomics, Disease Ecology & Global Health, University of Notre Dame, Notre Dame, IN 46656, USA
Shaun W. Lee
Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA
Kai Yang
Indiana University School of Medicine, Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA
Siyuan Zhang
Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA; Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617, USA; Indiana University School of Medicine, Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA; Corresponding author
Summary: Phenotypic and functional plasticity of brain immune cells contribute to brain tissue homeostasis and disease. Immune cell plasticity is profoundly influenced by tissue microenvironment cues and systemic factors. Aging and gut microbiota dysbiosis that reshape brain immune cell plasticity and homeostasis has not been fully delineated. Using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq), we analyze compositional and transcriptional changes of the brain immune landscape in response to aging and gut dysbiosis. Discordance between canonical surface-marker-defined immune cell types and their transcriptomes suggest transcriptional plasticity among immune cells. Ly6C+ monocytes predominate a pro-inflammatory signature in the aged brain, while innate lymphoid cells (ILCs) shift toward an ILC2-like profile. Aging increases ILC-like cells expressing a T memory stemness (Tscm) signature, which is reduced through antibiotics-induced gut dysbiosis. Systemic changes due to aging and gut dysbiosis increase propensity for neuroinflammation, providing insights into gut dysbiosis in age-related neurological diseases.
