TY - JOUR
T1 - Innate and Peripheral Immune Alterations after Traumatic Brain Injury Are Regulated in a Gut Microbiota-Dependent Manner in Mice
AU - Celorrio, Marta
AU - Shumilov, Kirill
AU - Rodgers, Rachel
AU - Schriefer, Lawrence
AU - Li, Yuhao
AU - Baldridge, Megan T.
AU - Friess, Stuart H.
N1 - Funding Information:
This work was supported by the National Institutes of Health (R01NS097721). Fluorescent imaging was performed on a Zeiss Axio Imager Z2 Fluorescence Microscope with ApoTome 2 optical sectioning grid imager at Washington University Center for Cellular Imaging (WUCCI) supported by Washington University School of Medicine, The Children's Discovery Institute of Washington University and St. Louis Children's Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813) and the Foundation for Barnes-Jewish Hospital (3770 and 4642). Confocal imaging was generated on a Zeiss LSM 880 Airyscan Confocal Microscope, which was purchased with support from the Office of Research Infrastructure Programs (ORIP), a part of the National Institute of Health (NIH) Office of the Director under grant OD021629.
Publisher Copyright:
© Copyright 2023, Mary Ann Liebert, Inc., publishers 2023.
PY - 2023/4/1
Y1 - 2023/4/1
N2 - Traumatic brain injury (TBI) patients are at high risk for disruption of the gut microbiome. Previously, we have demonstrated that broad-spectrum antibiotic exposure after TBI drastically alters the gut microbiota and modulates neuroinflammation, neurogenesis, and long-Term fear memory. However, these data did not determine if the impact of antibiotic exposure on the brain's response to injury was mediated directly by antibiotics or indirectly via modulation of the gut microbiota. We designed two different approaches to address this knowledge gap. One was utilizing fecal microbiota transplantation (FMT) from control and antibiotic-Treated mice (treated with vancomycin, neomycin, ampicillin, and metronidazole [VNAM]) into germ-free (GF) mice prior to injury, and the other was exposing specific pathogen-free (SPF) mice to a 2-week period of antibiotics prior to injury but discontinuing antibiotics 72 h prior to injury. GF mice receiving FMT from VNAM-Treated mice (GF-VNAM) demonstrated reduced gut bacterial alpha diversity and richness compared with GF mice receiving control FMT. At 7 days post-injury, GF-VNAM had increased microglial activation, reduced infiltration of T cells, and decreased neurogenesis. Similarly, SPF mice exposed to antibiotics prior to but not after injury demonstrated similar alterations in neuroinflammation and neurogenesis compared with control mice. These data support our hypothesis implicating the gut microbiota as an important modulator of the neuroinflammatory process and neurogenesis after TBI and provide an exciting new approach for neuroprotective therapeutics for TBI.
AB - Traumatic brain injury (TBI) patients are at high risk for disruption of the gut microbiome. Previously, we have demonstrated that broad-spectrum antibiotic exposure after TBI drastically alters the gut microbiota and modulates neuroinflammation, neurogenesis, and long-Term fear memory. However, these data did not determine if the impact of antibiotic exposure on the brain's response to injury was mediated directly by antibiotics or indirectly via modulation of the gut microbiota. We designed two different approaches to address this knowledge gap. One was utilizing fecal microbiota transplantation (FMT) from control and antibiotic-Treated mice (treated with vancomycin, neomycin, ampicillin, and metronidazole [VNAM]) into germ-free (GF) mice prior to injury, and the other was exposing specific pathogen-free (SPF) mice to a 2-week period of antibiotics prior to injury but discontinuing antibiotics 72 h prior to injury. GF mice receiving FMT from VNAM-Treated mice (GF-VNAM) demonstrated reduced gut bacterial alpha diversity and richness compared with GF mice receiving control FMT. At 7 days post-injury, GF-VNAM had increased microglial activation, reduced infiltration of T cells, and decreased neurogenesis. Similarly, SPF mice exposed to antibiotics prior to but not after injury demonstrated similar alterations in neuroinflammation and neurogenesis compared with control mice. These data support our hypothesis implicating the gut microbiota as an important modulator of the neuroinflammatory process and neurogenesis after TBI and provide an exciting new approach for neuroprotective therapeutics for TBI.
KW - T cells
KW - germ-free mice
KW - gut microbiome
KW - microglia
KW - neurogenesis
KW - traumatic brain injury
UR - http://www.scopus.com/inward/record.url?scp=85152155960&partnerID=8YFLogxK
U2 - 10.1089/neu.2022.0356
DO - 10.1089/neu.2022.0356
M3 - Article
C2 - 36259455
AN - SCOPUS:85152155960
SN - 0897-7151
VL - 40
SP - 772
EP - 787
JO - Journal of neurotrauma
JF - Journal of neurotrauma
IS - 7-8
ER -