Priyanka Basu

Background: Traumatic brain injury (TBI) is a global public health issue affecting millions of people each year with more than 64,000 deaths in the United States in 2020.¹ It is commonly caused by a bump or blow to the head. Recent advances in research have confirmed that the effect of TBI is not restricted to neuroinflammatory disorders in the brain but also impacts the gut-brain axis.⁴ In fact, 75-100% of TBI cases are followed by gastrointestinal dysfunction.⁴ The gut-brain axis is bidirectional, connecting the enteric and central nervous systems.³ Through the use of these systems, TBI is able to impact gastrointestinal health by affecting mucosal permeability, gut microbiota, intestinal immunity, and systemic inflammation, which can worsen TBI induced neurological deficits.³ Further research is needed to understand this phenomenon, however, TBI related immunological malfunction of the gut-brain axis can ultimately promote the onset of other neurological comorbidities such as Alzheimer’s disease, stroke, or Parkinson’s disease.⁵ In terms of TBI’s mechanism of action, there are two major stages of TBI: the primary and secondary stage.¹ The primary stage involves the direct physical impacts of the brain, while the secondary stage involves the several molecular and physiologic disfunctions within the brain after impact.^2,3 TBI-focused treatment and studies involve the pathways of the secondary injury phase.¹

Objective: We explored the mechanisms of how TBI may induce immunological malfunction of the neurological networking of the gut-brain axis. This also included reports and studies on recent therapeutics for this disease.

Search Methods: Online search engines were used to find research data between 2017 and 2023, specifically using the PubMed database. Keywords such as “gut-brain axis”, “TBI”, and “adaptive immune system” were used to help with the search.

Results: Studies have shown that post-traumatic stress following TBI releases a multitude of stress hormones such as glucocorticoids and catecholamines.⁴ Overtime, this stress response evokes a “systemic immune response syndrome” (SIRS) which can persist for an extended period of time.⁴ Neuronal injury from TBI induces the activation of reactive oxygen species (ROS) and the release of damage-associated molecular patterns (DAMPs), triggering a larger inflammatory response throughout the body.³ A constant stimulation of these pathways cause a secondary injury via leukocyte recruitment, triggering further inflammation and ultimately the breakdown of the blood-brain-barrier initially. This leads to neuroinflammation in other areas of the body including the gut.³ Research has shown that the main mechanism of this specific inflammation involves NF-kB activation and interleukin-1 beta creating an inflammatory cascade.⁴ These effects hinder the gut-brain axis since the human microbiota highly influences the human immune system, including, regulation of homeostatic responses, intestinal barriers, and the initiation of immune function.¹ As the body mounts inflammatory responses to TBI, there is an ultimate dysbiosis of the microbiome triggering its imbalance.³ These imbalances include: diminished alpha- and beta- bacterial diversity⁷, diminished short-chain fatty acid signaling damage⁸, and diminished conjunctive HPA axis activity⁹. These numbers were tested by monitoring bacterial diversity counts, metabolite volume, and procaspase activity in numerous scientific studies. As a result, TBI is seen to induce neuroinflammatory factors that may heavily reduce gut microbiome diversity, further dysregulating the gut-brain axis.¹

Conclusions: The gut-brain axis involves rampant communication between the CNS and the GI-tract allowing for major immunological pathways to render inflammatory mechanisms in these areas during the secondary injury phase.⁷ Further research is needed to understand the TBI-induced immunological mechanisms, however several current studies have clarified a few of the resultant inflammatory responses post-injury including diminishing bacterial diversity, SCFA count and HPA axis dysfunction.^7,8,9 Consideration of TBI therapies involving Vagus Nerve stimulation and Fecal Microbiota transplantation could lead to newer and more profound avenues for effective research.^4,5

Works Cited:

1. Centers for Disease Control and Prevention. TBI: Get the Facts. CDC. 2022. https://www.cdc.gov/traumaticbraininjury/get_the_facts.html
2. Nicholson SE, Watts LT, Burmeister DM, et al. Moderate Traumatic Brain Injury Alters the Gastrointestinal Microbiome in a Time-Dependent Manner. Shock. 2019; 52(2)
3. Glynn H, et al. Prevalence and impact of post-traumatic stress disorder in gastrointestinal conditions: a systematic review. Dig Dis Sci. 2021.
4. Hanscom M, Loane DJ, Shea-Donohue T. Brain-gut axis dysfunction in the pathogenesis of traumatic brain injury. J Clin Invest. 2021; 131(12)
5. Celorrio M, Friess SH. Gut-brain axis in traumatic brain injury: impact on neuroinflammation. Neural Regen Res. 2022; 17(5):1007-1008
6. Zhu, C.S.; Grandhi, R.; Patterson, T.T.; Nicholson, S.E. A Review of Traumatic Brain Injury and the Gut Microbiome: Insights into Novel Mechanisms of Secondary Brain Injury and Promising Targets for Neuroprotection. Brain Sci. 2018; 8,113.
7. Rice MW., Pandya JD., Shear DA. Gut Microbiota as a Therapeutic Target to Ameliorate the Biochemical, Neuroanatomical, and Behavioral Effects of Traumatic Brain Injuries. Front Neurol. 2019; 10:875
8. Nicholson SE, et al. Moderate Traumatic Brain Injury Alters the Gastrointestinal Microbiome in a Time-Dependent Manner. Shock. 2019; 52(2)
9. Oluwasinmisola M, et al. Sustained Dysbiosis and Decreased Fecal Short-Chain Fatty Acids after Traumatic Brain Injury and Impact on Neurologic Outcome.Journal of Neurotrauma.2021;2610-2621.
10. Taheri S, et al. The Role of Apoptosis and Autophagy in the Hypothalamic-Pituitary-Adrenal (HPA) Axis after Traumatic Brain Injury (TBI). Int J Mol Sci. 2022;23(24).
11. Tang Y, et al. Vagus Nerve Stimulation Attenuates Early Traumatic Brain Injury by Regulating the NF-κB/NLRP3 Signaling Pathway. Neurorehabilitation and Neural Repair. 2020;34(9):831-843.
12. Donglin Du, et al. Fecal Microbiota Transplantation Is a Promising Method to Restore Gut Microbiota Dysbiosis and Relieve Neurological Deficits after Traumatic Brain Injury.Oxidative Medicine and Cellular Longevity. vol. 2021.
13. Kang DW, et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017 Jan 23;5(1):10.
14. Sirena S, et al. Alterations to the gut microbiome after sport-related concussion in a collegiate football players cohort: A pilot study. Brain, Behavior, & Immunity – Health. 2022. Volume 21.