Innate and peripheral immune alterations after TBI are regulated in a gut microbiota-dependent manner
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 utilizing fecal microbiota transplantation (FMT) from control and antibiotic-treated mice (VNAM: vancomycin, neomycin, ampicillin and metronidazole) into germ free (GF) mice prior to injury and exposing single pathogen free (SPF) mice to a 2-week period of antibiotics prior to injury but discontinuing antibiotics 72 hours prior to injury. GF mice receiving FMT from VNAM exposed mice (GF-VNAM) demonstrated reduced gut bacterial alpha diversity and richness compared with GF mice receiving FMT from control. At 7 days post injury, GF-VNAM had increased microglial activation, reduced infiltration of T cells, and decreased neurogenesis 7 days after injury. Similarly, SPF mice exposed to antibiotics prior to but not after injury demonstrated similar alterations in neuroinflammation and neurogenesis compared to 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.