The Gut Microbiome as an Outcome Measure of Dietary Therapy Efficacy After Traumatic Brain Injury (TBI)

Abstract

TBI is caused by a physical impact on the brain that results in cellular damage and pathological processes that lead to the enduring symptoms observed in the patients. The cellular damage observed after TBI induces the release of proinflammatory signals locally (neuroinflammation) and in the periphery (peripheral inflammatory response). The proinflammatory signals flow from the brain to the bloodstream and activate a peripheral inflammatory response, causing damage to other organs, including the gut. Gut dysfunction is commonly observed after TBI and can lead to gut microbiome alterations. The gut microbiome is the collection of bacteria, fungi, viruses, and protozoa in the gut. After brain injury, peripheral inflammation has been associated with gut microbiome disbalance. Furthermore, gut dysfunction and gut microbiome alterations advance neurological disease. This is due to the bidirectional relationship between the gut microbiome and the brain, known as the microbiota-gut-brain axis. This leads us to hypothesize that interventions that modulate the gut microbiome, such as dietary therapies, have the potential to reduce peripheral inflammation and, ultimately, brain inflammation. Dietary therapies are modifications of regular diet to fit the nutritional needs of the patients. Dietary therapies like probiotics modulate the gut microbiome and reduce inflammation in the gut and peripheral blood. On the other hand, there is a need for monitoring outcome measures that can inform disease progression and treatment effectiveness. Here, we asked if the microbiota-gut-brain axis could be used as an outcome measure of the efficacy of dietary therapy after traumatic brain injury. To answer that question, we first determined the effects of brain injury on the gut microbiome diversity and composition in Chapter 2. We observed an initial change in fecal microbiome diversity at 1 DPI in the female group. We also evaluated changes in gut microbiome composition after brain injury and found that members of the phylum Firmicutes were enriched in the injury group at different time points while other members of the same phylum decreased. In Chapter 2, we studied the interaction between peripheral inflammation and the gut microbiome, as it is a communication mechanism in the microbiota-gut-brain axis. We identify that the level of neutrophils interacts with the rate of change in beta diversity over time according to injury group and sex. In Chapter 3, we studied two probiotic administration regimens (dietary therapy). We evaluated the effects of probiotic pretreatment and treatment after brain injury on the gut microbiome. In the pretreatment experiment, we observed that gut microbiome diversity and composition changes were related to probiotic dose. The pretreatment with probiotics had an effect on the interaction between the neutrophil populations and gut microbiome diversity. Then, we evaluated the effect of a probiotic treatment post-injury on the gut microbiome diversity and composition. In the treatment experiment, we observed that gut microbiome diversity can discriminate probiotic treatment groups from water control or sham. We also identified bacterial genera that increased with probiotic administration and the ones that decreased after brain injury. Interestingly, most of the bacterial taxa that change with probiotic administration belong to the Phylum Firmicutes, a phylum that produces metabolic intermediaries that reduce the inflammatory response in the gut. Our combined results from Chapters 2 and 3 indicate that gut microbiome diversity and composition can discriminate between injury vs sham, probiotic doses, and probiotic treatment. Our results also suggest that the effect of probiotic therapy is through modulation of gut microbiome composition. Furthermore, we observed an interaction between the gut microbiome diversity, inflammatory markers, and sex that is time point-specific (Chapters 2 and 3). We conclude that the gut microbiome diversity and composition (and microbiota-gut-brain axis) are promising translational outcome measures of dietary therapy efficacy after brain injury. At a higher level of discussion, we will include data science principles and practices applied during this research. As those principles and practices improved and advanced, the analysis of the results.