Sonia Villapol, PhD - US grants

PROJECT SUMMARY / ABSTRACT Traumatic Brain Injury (TBI) triggers a loss of brain tissue and, subsequently, a strong inflammatory response in the brain. In addition, TBI can alter the function of peripheral regions and other organs, eliciting systemic responses and global consequences. A focal injury to the brain elicits a rapid hepatic response, the production of chemokines by the liver acts as an amplifier of the focal injury response providing a route of CNS-liver communication. However, little is currently known regarding the inflammatory mediators and acute-phase proteins involved in the peripheral regions after brain injury, such as the liver. Furthermore, the extent of damage TBI inflicts on the peripheral organs remains largely unexplored. Serum Amyloid A1 (SAA1) is an acute phase protein involved in the chemotactic recruitment of inflammatory cells to the site of inflammation. After tissue damage, SAA1 is mainly produced in the liver and exported via peripheral circulation, directly affecting the pathogenesis of inflammation in other organs. The role of SAA1 after TBI is unknown, however we have recently shown that TBI induces the production and release of SAA1 from the liver into the circulatory system, and our preliminary data will show that SAA1 relocates to the brain lesion where it interacts with microglial cells. In this grant proposal we will test the hypothesis that hepatic SAA1 exacerbates the brain?s inflammatory response to TBI, leading to enhanced cell death, inflammation and behavioral deficits. We will rigorously test this hypothesis using two specific aims: 1) Determine the effect of TBI severity on SAA1 expression in periphery and in the brain; 2) Investigate whether peripherally-produced SAA1 stimulates neuroinflammation, neuronal damage and behavioral dysfunction after TBI. In conclusion, since inflammation appears to be a common link between brain injury and the periphery, one is led to hypothesize that inflammatory signals released after TBI could regulate components of hepatic response and that consequently induce detrimental changes damaged brain regions. As an acute phase protein with pleiotropic pro-inflammatory properties, SAA1 may represent an important link between brain injury and hepatic and systemic inflammation. Elucidation of the role SAA1 plays in the general inflammatory response after TBI will aid in the design of more efficient therapeutic approaches for acute inflammation, using agents that most effectively suppress SAA1 and mitigating subsequent, secondary brain injury.

SUMMARY/ABSTRACT Traumatic Brain Injury (TBI) is a major health problem in the US. It is estimated that over 3 million people live with disabilities caused by TBI with many suffering from disorders including depression or anxiety. The goal of this research proposal is to elucidate how TBI affects the function of peripheral systems and alters the microbiome and the resultant impact on TBI-induced affective disorders. Our preliminary data indicate that CCI causes a rapid shift in microbiota diversity within 24h of TBI, including a dramatic change in the diversity of the psychoactive Lactobacillus family. Based on our data, we are testing the hypothesis that changes to commensal gut microbiota after TBI modulates brain inflammation and drives the development of affective disorder phenotypes in mice. Using 16S rRNA gene sequencing analysis, we will look for differentially abundant taxa, comparing sham to TBI mice. We will also examine if these changes are altered by injury severity, and we will study the impact of sex on the outcome. To test our hypothesis, we will: 1) identify differentially abundant bacteria before and after mild and severe control cortical impact by 16S and metagenomics analysis; 2) perform rescue experiments with probiotics containing TBI-impacted bacteria to study the progression of neuroinflammation process, neuronal death, and neurobehavioral abnormalities; and 3) compare the recovery of germ-free mice exposed to TBI following either sham or TBI mouse fecal transplants. This project will help to further elucidate the gut-brain axis cross-talk and clarify the role of the microbiome on recovery from TBI. Specifically, this project will explore if fecal transplants alter brain function and represent a potential novel therapeutic avenue for TBI. In summary, this research is based on the scientific premise that bacterial within the gut and bacterial diversity can impact behavior, and that brain injury can disrupt diversity in a healthy gut microbiome. !