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Investigating Alterations in Caecum Microbiota After Traumatic Brain Injury in Mice
Published on: September 19, 2019
Innate and Peripheral Immune Alterations after Traumatic Brain Injury Are Regulated in a Gut Microbiota-Dependent
Marta Celorrio1, Kirill Shumilov1, Rachel Rodgers2
1Department of Pediatrics, and Division of Infectious Diseases, Edison Family Center for Genome Sciences and Systems Biology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.
Abstract:
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.
Insights
Traumatic brain injury (TBI) disrupts the gut microbiome. Modulating gut bacteria, not antibiotics directly, impacts neuroinflammation and neurogenesis after TBI, suggesting new therapeutic avenues.
Area of Science:
- Neuroscience
- Microbiology
- Immunology
Background:
- Traumatic brain injury (TBI) is linked to gut microbiome disruption.
- Antibiotic use post-TBI alters gut microbiota, neuroinflammation, neurogenesis, and memory.
- The direct vs. indirect effects of antibiotics on TBI's brain response remain unclear.
Purpose of the Study:
- To determine if antibiotic effects on TBI brain response are direct or mediated by gut microbiota changes.
- To investigate the role of gut microbiota modulation in TBI-induced neuroinflammation and neurogenesis.
Main Methods:
- Fecal microbiota transplantation (FMT) from antibiotic-treated mice to germ-free (GF) mice before TBI.
- Antibiotic exposure in specific pathogen-free (SPF) mice before TBI, with antibiotics discontinued 72 hours prior.
- Analysis of gut bacterial diversity, microglial activation, T cell infiltration, and neurogenesis post-TBI.
Main Results:
- GF mice receiving FMT from antibiotic-treated donors (GF-VNAM) showed reduced gut bacterial diversity.
- GF-VNAM mice exhibited increased microglial activation, reduced T cell infiltration, and decreased neurogenesis at 7 days post-TBI.
- SPF mice exposed to antibiotics pre-injury showed similar neuroinflammation and neurogenesis alterations compared to controls.
Conclusions:
- Gut microbiota composition significantly modulates neuroinflammation and neurogenesis following TBI.
- These findings implicate the gut microbiota as a key mediator in the brain's response to TBI.
- Targeting the gut microbiota presents a potential neuroprotective therapeutic strategy for TBI.
