Author ORCID Identifier

Date Available


Year of Publication


Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation





First Advisor

Kathryn E. Saatman


Traumatic brain injury (TBI) initiates not only complex neurovascular and glial changes within the brain but also pathophysiological responses that extend beyond the central nervous system. The peripheral response to TBI has become an intensive area of research, as these systemic perturbations can induce dysfunction in multiple organ systems. As there are no approved therapeutics for TBI, it is imperative that we investigate the peripheral response to TBI to identify targets for future intervention. Of particular interest is the gastrointestinal (GI) system. Even in the absence of polytrauma, brain-injured individuals are at increased risk of suffering from GI-related morbidity and mortality. Symptoms such as intestinal dysmotility, inflammation, ulceration, and fecal incontinence can drastically diminish quality of life. The GI tract is inhabited by trillions of microbes that have been implicated as modulators of many neurological disorders. Clinical and preclinical studies implicate gut dysbiosis, a pathological imbalance in the normally symbiotic microbiota, as both a consequence of TBI as well as a contributing factor to brain damage.However, our understanding of this interplay is still limited. While relatively little is known about the effects of TBI on the structure and function of the GI tract, prior studies report that experimental TBI induces intestinal barrier dysfunction and morphological changes. To confirm these findings, male C57BL/6J mice underwent a sham control or a controlled cortical impact (CCI) procedure to induce a contusive brain injury, and intestinal permeability was assessed at 4 h, 8 h, 1 d, and 3 d post-injury. An acute, transient increase in permeability was observed at 4 h after CCI. Histological analyses of the ileum and colon at multiple time points from 4 h to 4 wks revealed no overt morphological changes, suggesting that CCI induced a short-lived physiologic dysfunction without major structural alterations to the GI tract. As the microbiome is a modulator of GI physiology, we performed 16s gene sequencing on fecal samples collected prior to and over the first month after CCI or sham injury. Microbial community diversity was assessed using common metrics of alpha and beta diversity. Alpha diversity was lower in the CCI injury group and beta diversity differed among groups, although these effects were not observed in all metrics. Subsequent differential abundance analysis revealed that the phylum Verrucomicrobiota was increased in CCI mice at 1, 2, and 3 d post-injury when compared to sham mice. Subsequent qPCR identified the Verrucomicrobiota species as Akkermansia muciniphila, an obligate anaerobe that resides in and helps regulate the intestinal mucus layer and barrier. To determine whether TBI promotes changes to the GI tract favorable for the proliferation of A. muciniphila, mucus-producing goblet cells and the level of GI hypoxia were evaluated. Goblet cell density in the medial colon was significantly increased at 1 d, while colon hypoxia was significantly increased at 3 d. Taken together, these studies show that CCI induces transient intestinal barrier dysfunction followed by increased goblet cell density and hypoxia in the colon with a concomitant increase in A. muciniphila that may suggest a compensatory response to systemic stress after TBI.

Digital Object Identifier (DOI)

Funding Information

NIH Training Grant 5T32 NS077889, Neurobiology of CNS Injury and Repair

Kentucky Spinal Cord & Head Injury Research Trust (KSCHIRT) Fellowship Funds