Traumatic injury renders an organism less tolerant to infection, with 40% of trauma patients dying from infection within about 76 hours of injury. In addition, an elevated state of inflammation at the time of injury is correlated with poor healing and longer convalescence time. Therefore, understanding the interconnection between immune state and healing is of high biomedical importance. Despite major advances in biomic approaches, very little progress has been made in this area, and effective strategies for improving rational design of therapeutic treatments have not advanced. One hypothesis is that a microbial gut-brain axis exists that is critical in modulating our immune system and helping our bodies heal in the event of a traumatic injury.
Using antibiotic treatment to deplete the normal gut biome, we examined how joint healing and drug metabolism are influenced by gut dysbiosis. First, we determined that chronic antibiotic exposure prior to injury affected healing in two models of traumatic injury: bone fracture and anterior cruciate ligament rupture. We interrogated global gene expression by RNAseq (an RNA sequencing technique) in a time course experiment and identified mechanisms contributing to healing. Next, we determined how elevated inflammation prior- and post-injury affects healing. We conducted proof-of-principle experiments in an endotoxin-induced (Lipopolysaccharide, LPS) inflammation model of sepsis and found that high inflammation prior to injury has a profoundly negative effect on healing. Enhancement of inflammation post injury affected healing outcome. Lastly, we determined that drug metabolism is significantly affected by antibiotic treatment. Specifically, alterations in the gut biome change drug absorption and metabolism. We generated and analyzed RNAseq data as a function of disease progression and traumatic injury. We created a framework for generating in-depth genomic, molecular, and drug-related data that can address key aspects of host-pathogen immunity gut-brain interactions in a whole organism.
Our study countered two prevalent misconceptions in immunology and microbiology: 1) host is static and individual response is universal, and 2) pathogen is static and unmodulated by host. Rather, both host and pathogen are dynamic, and they synergistically change and respond to each other. Our outcome supports the view that humans possess a highly intricate, multi-directional communication network where the gut, immune system, and brain are constantly communicating and adjusting to the needs of the organism.
Our study supported and leveraged Lawrence Livermore National Laboratory's core competency in bioscience and advanced the Department of Energy's strategic objective to deliver science discoveries that transform understanding of nature and strengthen the connection between scientific discovery and technology innovation. Funding agencies including the Department of Defense, National Institutes of Health, and Defense Advanced Research Projects Agency (DARPA) have prioritized research to understand and simulate human responses as predictors for pathogenic infectious outcomes, to study adverse drug interactions and reactions, and to identify sensitive / resistant individuals.
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Malfatti, M., et al. 2016. "Determining the Role of the Gut Microbiome in Altering Drug Metabolism." Society of Toxicology 55th Annual Meeting, New Orleans, LA, March 2016. LLNL-POST-684459.
——— . 2018. "Manipulation of the Gut Microbiome Alters Acetaminophen Metabolism in Mice." Society of Toxicology 57th Annual Meeting, San Antonio, TX, March 2018. LLNL-POST-746770.
Mendez, M. et al. 2017. "Effects of LPS Induced Inflammation Pre-Injury on ACL Rupture Mouse Models of Post-Traumatic Osteoarthritis." Orthopedic Research Society 2017 Annual Meeting, San Diego, CA, March 2017. LLNL-ABS-737738.
——— . 2019. "LPS Induced Inflammation Prior to Anterior Cruciate Ligament (ACL) Injury Increases the Severity of Post-Traumatic Osteoarthritis in C57Bl/6J Mice." American Society for Bone and Mineral Research Annual Meeting, Orlando FL, September 2019. LLNL-POST-790257.
Sebastian, A. and G. Loots. 2017. "Genetics of Sost/SOST in Sclerosteosis and van Buchem Disease Animal Models." Metabolism, October 25, 2017. doi: 10.1016/j.metabol.2017.10.005. LLNL-JRNL-730352.
——— . 2017. "Transcriptional Control of Sclerostin." Bone, March; 96:76–84. LLNL-JRNL-723818.
——— . 2018. "Genetics of Sost/SOST in sclerosteosis and van Buchem Disease Animal Models." Metabolism, Mar 80:38–47. doi: 10.1016/j.metabol.2017.10.005. Epub 2017 Oct 25. LLNL-JRNL-730352.
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