TRAUMATIC BRAIN INJURY-INDUCED INFLAMMATION AND GASTROINTESTINAL MOTILITY DYSFUNCTION

Abstract

Background: Traumatic brain injury (TBI) is a significant cause of morbidity and mortality in the United States, with an annual cost of 60 billion dollars. There is evidence suggesting that in the post-TBI period, the gastrointestinal tract plays a central role in driving organ and immune dysfunction and may be the source of increased circulating proinflammatory mediators. In this study, we examined systemic inflammation and bacterial dysbiosis in patients who sustained a TBI with or without polytrauma. Using a mouse model of TBI, we further show how neuroinflammation after TBI is potentially linked to disruptions in gut homeostasis such as intestinal transit and inflammation. Methods: During a study of trauma patients performed from September 1, 2018, to September 1, 2019, at a single, level 1 trauma center, TBI patients aged 21 to 95 years were enrolled. Patients were categorized as TBI based on evidence of acute abnormal findings on head computed tomographic scan, which was a combination of isolated TBI and TBI with polytrauma. Blood and stool samples were collected between 24 h and 3 days after admission. Twelve plasma samples and 10 fecal samples were used for this study. Healthy control samples were obtained from a healthy control biobank. We examined systemic inflammation and bacterial changes in patients who sustained a TBI. In addition, TBI was induced in 9- to 10-week-old male mice; we assessed neuroinflammation, and intestine transit (motility) and bacterial changes 24 h after TBI. Results: When compared with healthy controls, TBI patients had increased systemic inflammation as evidenced by increased levels of IFN-γ and MCP-1 and a trend toward an increase of IL-6 and IL-8 ( P = 0.0551 and P = 0.0549), respectively. The anti-inflammatory cytokine, IL-4, was also decreased in TBI patients. Although there was a trend of an increase in copy number of Enterobacteriaceae and a decrease in copy number of Lactobacillus in both patients and mice after TBI, these trends were not found to be significantly different. However, TBI significantly increased the copy number of another potential pathogenic bacteria Bilophila wadsworthia in TBI patients compared with healthy controls. After a moderate TBI, mice had increased expression of TNF-α, IL-6 and IL-1β, CXCL1, s100a9, and Ly6G and decreased IL-10 in the brain lesion after TBI. This accompanied decreased transit and increased TNF-α in the small intestine of mice after TBI. Conclusions: Our findings suggest that TBI increases systemic inflammation, intestinal dysfunction, and neuroinflammation. More studies are needed to confirm whether changes in intestinal motility play a role in post-TBI neuroinflammation and cognitive deficit.