Traumatic brain injury (TBI) is a global public health issue affecting many millions each year. Management requires an understanding of both the primary brain injury and the secondary sequelae that affect peripheral organs, including the gastrointestinal (GI) tract. The gut-brain axis is composed of bidirectional pathways between the gut and brain, hence TBI-induced neuroinflammation and neurodegeneration also impact gut function, which in turn influences secondary injury progression. Restoration of the gut microbiome to modulate the pathways may be a promising avenue for therapy in TBI.
Traumatic brain injury, in brief
Sixty-nine million individuals worldwide are estimated to sustain a TBI each year. The most common causes arefrom a fall, firearm-related injuries, motor vehicle crashes, or an assault. There are three main types of TBI: Mild (concussion), moderate, and severe. TBI is a major cause of death and disability.
Following the initial TBI, a secondary injury cascade may induce complex metabolic alterations, including aberrant cellular metabolism, hormonal changes, inflammatory cascade, and immune dysfunction. Importantly, these responses are not limited to the area of brain injury; they can also alter other areas such as the GI tract.
Gut microbiome & TBI
The multitude of cellular and molecular processes triggered by a TBI leads to rapid changes in the gut microbiome. In the immediate aftermath, the motility and permeability of the intestinal wall are disrupted, shaping and being shaped by changes in microbiota composition as well as activation of immune cells.
Studies in both animals and humans have demonstrated that TBI significantly affects the abundance and diversity of bacterial species, resulting in gut dysbiosis.
A 2018 study in mice analyzed microbial changes that occur 24 hours after TBI compared to controls. The results showed a rapid shift in the relative abundance of five species, including changes in the diversity of the psychoactive Lactobacillaceae family and protective Lachnospiraceae family, both commonly found in the human gut microbiome.
A later study found that dysbiosis was evident as early as two hours after TBI as compared with pre-injured samples and sham rats. Some changes persisted through seven days after TBI; dysbiosis was correlated with lesion volume.
Dysbiosis can persist. In mice, alterations lasting up to 30 days after TBI have been reported.
TBI modified the abundance of 26 bacterial genera in another study using a murine model. The most notable change observed was a dramatic reduction in the abundance of Agathobacter species, which are beneficial butyrate-producing bacteria.
Analysis of healthy volunteers and patients 24 hours after the TBI event demonstrated that Enterococcus, Parabacteroides, Akkermansia, and Lachnoclostridium levels were significantly increased, while Bifidobacterium and Faecalibacterium were decreased in TBI patients.
When compared to healthy controls, the fecal microbiome profile of 22 TBI patients was significantly different. Notably, the fecal microbiome of the TBI cohort had absent or reduced Prevotella spp. and Bacteroides spp. Bacteria in the Ruminococcaceae family were higher in abundance in TBI compared to control profiles.
Changes were also evident in the fecal microbiome in a study following college football players throughout the sports season. A decrease in abundance for two bacterial species, Eubacterium rectale, and Anaerostipes hadrus, was observed after a diagnosed concussion.
Gut dysbiosis effect on pathophysiology of TBI
The TBI-triggered gut dysbiosis in turn may affect TBI outcomes.
Gut dysbiosis can trigger the abnormal secretion of inflammatory cytokines, which may result in systemic inflammation and poorer neurological prognosis. Moreover, the integrity and permeability of the blood-brain barrier are affected by gut dysbiosis.
Depletion in commensal gut bacteria comes at a cost to the host.
The progression of TBI secondary effects may be affected when disruption occurs in the balanced microbiota, a homeostasis that may offer many benefits including:
Metabolites such as short-chain fatty acids (SCFAs) are produced which can cross the blood-brain barrier and affect brain function. Gut microbiota-generated butyrate serves as a histone deacetylation (HDAC) inhibitor, offering additional benefits, as HDACs play an important role in neuroprotection following TBI.
Gut microbiome products such as SCFAs may serve as alternative energy sources for the injured brain and may improve bioenergetics function following TBI.
Some bacteria produce neurotransmitters including dopamine, norepinephrine, serotonin, or gamma-aminobutyric acid (GABA), vital to proper neural function.
As noted, the secondary impacts of TBI on the gut microbiota happen quickly. Some research suggests that probiotics and fecal microbiota transplantation (FMT) could shift the gut microbiome to a beneficial state in time to mitigate aspects of TBI-associated secondary injury.
The administration of probiotics has improved several of the conditions associated with TBI-induced pathology: intestinal motility and permeability, the health of the intestinal cellular lining, intestinal inflammation, and systemic immune response.
In a study using TBI mouse models, the butyric acid-producing probiotic Clostridium butyricum improved neurological deficits, reduced brain edema, attenuated neurodegeneration, and ameliorated blood-brain barrier impairment.
Lactobacillus acidophilus exerted neuroprotective effects in another study with TBI mice.
Drosophila is emerging as a valuable model to explore secondary injury cascades and therapeutic intervention after TBI. Treatment with probiotics was observed to have a positive effect on traumatized flies. Climbing behaviors were preserved.
In another study, an orally administered brain protein, given alone or combined with probiotics, was given to surgical brain injury rats. Notably, the improved intestinal barrier, the reduced proinflammatory cytokines, and the activation of microglia all demonstrated that excessive inflammatory damage was better controlled in the combined group (brain protein and probiotics) than in the brain protein only group.
As for many hospitalized patients, manipulation of the gut microbiome in brain injury patients through probiotic supplementation also yielded positive results, attributed by researchers to probiotic-induced reductions in systemic and central inflammation.
In one study, daily supplementation with a lactobacilli-rich probiotic, started within the first 48 hours of admission and continued for 5 to 21 days, reduced nosocomial (hospital-acquired) infection rate.
Another study using early probiotic intervention in TBI patients showed promising results: decreased infection rates, reduced incidence of ventilator-associated pneumonia, reduced GI dysfunction, and shortened time in intensive care.
In another human trial, (corresponding to the aforementioned animal study that used a combination of brain protein and probiotics, excessive inflammatory damage was better controlled in the combined brain protein and probiotic group than in the brain protein group alone.
No studies have yet examined the behavioral and cognitive outcomes of probiotic supplementation in TBI patients, although the metabolic disorders linked to cognitive dysfunction after TBI could theoretically be improved by probiotic supplementation.
Notably, the long-term use of antibiotics is recommended in TBI for the reduction of infection, morbidity, and mortality rates. Adjunctive probiotic treatments to minimize complex downstream responses following TBI deserve further study.
Fecal Microbiota Transplantation
Evidence from a 2021 trial suggests that fecal microbiota transplantation (FMT) may rescue microbiota changes and ameliorate neurological deficits after TBI in rats.
A bidirectional relationship exists between the gut microbiome and the brain, which also plays a role in TBI- associated pathology. TBI leads to rapid changes in the gut microbiome. The resulting dysbiosis may impact the progression of secondary injury.
In animal models, gut dysbiosis further aggravates behavioral impairments. Manipulation of the gut microbiome with probiotics or FMT represents a promising therapeutic avenue.
In humans, probiotics have been shown to reduce the incidence of infection and ventilator-associated pneumonia, alleviate GI dysfunction, and shorten the time spent in intensive care after suffering from brain trauma.
More studies are needed to identify the specific changes occurring in the gut microbiota according to TBI type and severity and to determine the optimal dose, treatment window, duration of treatment, and efficacy across age and gender.
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Braniste, Viorica et al. “The gut microbiota influences blood-brain barrier permeability in mice.” Science translational medicine vol. 6,263 (2014): 263ra158. doi:10.1126/scitranslmed.3009759
Buhlman, Lori M et al. “Drosophila as a model to explore secondary injury cascades after traumatic brain injury.” Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie vol. 142 (2021): 112079. doi:10.1016/j.biopha.2021.112079
Celorrio, Marta, and Stuart H Friess. “Gut-brain axis in traumatic brain injury: impact on neuroinflammation.” Neural regeneration research vol. 17,5 (2022): 1007-1008. doi:10.4103/1673-5374.324839
Dewan, Michael C et al. “Estimating the global incidence of traumatic brain injury.” Journal of neurosurgery, 1-18. 1 Apr. 2018, doi:10.3171/2017.10.JNS17352
Du, Donglin 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 5816837. 10 Feb. 2021, doi:10.1155/2021/5816837
Hanscom, Marie et al. “Brain-gut axis dysfunction in the pathogenesis of traumatic brain injury.” The Journal of clinical investigation vol. 131,12 (2021): e143777. doi:10.1172/JCI143777
Hou, Yongxin et al. “Oral Administration of Brain Protein Combined With Probiotics Induces Immune Tolerance Through the Tryptophan Pathway.” Frontiers in molecular neuroscience vol. 14 634631. 28 May. 2021, doi:10.3389/fnmol.2021.634631
Lai, Jin-Qing et al. “Metabolic disorders on cognitive dysfunction after traumatic brain injury.” Trends in endocrinology and metabolism: TEM vol. 33,7 (2022): 451-462. doi:10.1016/j.tem.2022.04.003
Li, H et al. “Clostridium butyricum exerts a neuroprotective effect in a mouse model of traumatic brain injury via the gut-brain axis.” Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society vol. 30,5 (2018): e13260. doi:10.1111/nmo.13260
Lu, Jie et al. “Histone deacetylase inhibitors are neuroprotective and preserve NGF-mediated cell survival following traumatic brain injury.” Proceedings of the National Academy of Sciences of the United States of America vol. 110,26 (2013): 10747-52. doi:10.1073/pnas.1308950110
Ma, Yuanyuan et al. “Lactobacillus acidophilus Exerts Neuroprotective Effects in Mice with Traumatic Brain Injury.” The Journal of nutrition vol. 149,9 (2019): 1543-1552. doi:10.1093/jn/nxz105
Matharu, Dollwin et al. “Repeated mild traumatic brain injury affects microbial diversity in rat jejunum.” Journal of biosciences vol. 44,5 (2019): 120.
Molina, Brandon et al. “Treatment with Bacterial Biologics Promotes Healthy Aging and Traumatic Brain Injury Responses in Adult Drosophila, Modeling the Gut-Brain Axis and Inflammation Responses.” Cells vol. 10,4 900. 14 Apr. 2021, doi:10.3390/cells10040900
Nicholson, Susannah E et al. “Moderate Traumatic Brain Injury Alters the Gastrointestinal Microbiome in a Time-Dependent Manner.” Shock (Augusta, Ga.) vol. 52,2 (2019): 240-248. doi:10.1097/SHK.0000000000001211
Pavelescu, D. et al. Could selected probiotics have beneficial effects on clinical outcome of severe traumatic brain injury patients?. Crit Care 18, P472 (2014).
Rice, Matthew W et al. “Gut Microbiota as a Therapeutic Target to Ameliorate the Biochemical, Neuroanatomical, and Behavioral Effects of Traumatic Brain Injuries.” Frontiers in neurology vol. 10 875. 16 Aug. 2019, doi:10.3389/fneur.2019.00875
Silva, Ygor Parladore et al. “The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication.” Frontiers in endocrinology vol. 11 25. 31 Jan. 2020, doi:10.3389/fendo.2020.00025
Soriano, Sirena et al. “Alterations to the gut microbiome after sport-related concussion in a collegiate football players cohort: A pilot study.” Brain, behavior, & immunity – health vol. 21 100438. 1 Mar. 2022, doi:10.1016/j.bbih.2022.100438
Stilling, Roman M et al. “The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis?.” Neurochemistry international vol. 99 (2016): 110-132. doi:10.1016/j.neuint.2016.06.011
Strandwitz, Philip. “Neurotransmitter modulation by the gut microbiota.” Brain research vol. 1693,Pt B (2018): 128-133. doi:10.1016/j.brainres.2018.03.015
Tan, Min et al. “Effects of probiotics on serum levels of Th1/Th2 cytokine and clinical outcomes in severe traumatic brain-injured patients: a prospective randomized pilot study.” Critical care (London, England) vol. 15,6 (2011): R290. doi:10.1186/cc10579
Taraskina, Anastasiia et al. “Effects of Traumatic Brain Injury on the Gut Microbiota Composition and Serum Amino Acid Profile in Rats.” Cells vol. 11,9 1409. 21 Apr. 2022, doi:10.3390/cells11091409
Treangen, Todd J et al. “Traumatic Brain Injury in Mice Induces Acute Bacterial Dysbiosis Within the Fecal Microbiome.” Frontiers in immunology vol. 9 2757. 27 Nov. 2018, doi:10.3389/fimmu.2018.02757
Urban, Randall J et al. “Altered Fecal Microbiome Years after Traumatic Brain Injury.” Journal of neurotrauma vol. 37,8 (2020): 1037-1051. doi:10.1089/neu.2019.6688
Wan, Guohua et al. “Effects of probiotics combined with early enteral nutrition on endothelin-1 and C-reactive protein levels and prognosis in patients with severe traumatic brain injury.” The Journal of international medical research vol. 48,3 (2020): 300060519888112. doi:10.1177/0300060519888112
Zhao, Liang et al. “Bidirectional gut-brain-microbiota axis as a potential link between inflammatory bowel disease and ischemic stroke.” Journal of neuroinflammation vol. 15,1 339. 11 Dec. 2018, doi:10.1186/s12974-018-1382-3