The Young Gut Microbiome: A Fountain of Youth for Brain Injury in the Aged?

PI: Steven Schwulst, MD, associate professor of Surgery in the Division of Trauma and Critical Care 

Sponsor: National Institute of Neurological Disorders and Stroke 

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Patients aged 65 years and older account for an increasing proportion of patients with TBI and less than half of aged TBI patients become functionally independent after injury. In fact, TBI is one of the greatest non-genetic risk factors for the subsequent development of Alzheimer’s disease (AD) and Alzheimer’s disease-related dementias (ADRD). Chronic neuroinflammation resulting from the constitutive activation of microglia is complicit in AD, ADRD and related disease processes, and represents a complex interplay between aged microglia and the structure and function of the aged gut microbiome. However, the mechanism(s) underlying gut microbiota-microglia interaction in AD, ADRD, and aging have yet to be elucidated. 

Published data from our laboratory shows that aged microglia adopt a constitutively activated state. These “primed” microglia are then capable of producing an exaggerated inflammatory response and may represent one of the mechanisms leading to the increased incidence of Alzheimer’s disease and Alzheimer’s disease-related dementia in aged patients after TBI. Published and preliminary data from our laboratory further demonstrates that post-injury gut microbial community structure is a contributing factor in the degree of neurocognitive impairment including in AD and ADRD diagnoses after TBI. Our data shows that restoration of a preinjury gut microbial community markedly improved neurocognitive including AD/ADRD-related outcomes and attenuated the constitutive activation of microglia after TBI in mice. We published similar findings within the gut microbial community associated with normal aging with an increase in the relative abundance of several microbial taxa strongly associated with AD and ADRD. Nonetheless, mechanism(s) linking alterations in the aged gut microbial community to the development of subsequent AD and ADRD have yet to be fully elucidated. We hypothesize that restoration of a youthful gut microbial community before or after TBI will attenuate the constitutive activation of microglia and improve neurocognitive and AD/ADRD-related outcomes in aged TBI mice.  

To test this hypothesis, we will determine whether restoring a youthful gut microbial community structure via fecal microbiota transplant with stool from young mice will attenuate the activation of microglia in aged mice. We will utilize both a pre-injury “prebiotic” model as well as a post-injury treatment paradigm. We will use bulk population cell sorting (FACSorting) of microglia followed by single cell RNA sequencing (scRNAseq). We will compare candidate genes to microbial activity via fecal 16S rRNA gene amplicon sequencing and fecal metabolite analysis. Harmonized with the transcriptomic and gut microbial community profiling, we will utilize longitudinal PET/CT imaging of the 18-kDa translocator protein (TSPO) with a novel fluorine-based radiotracer developed by our group to track and compare the onset, progression and degree of microglial activation before, during and after gut microbial intervention after TBI. Collectively, the proposed studies will identify the key role of an aged gut microbiome in the onset and progression of constitutive microglial activation over the course of TBI, thus raising the potential for novel therapeutic and biomarker development in aged TBI, AD and ADRD patients. 

Learn more about this project.