Early depletion of gut microbiota shape oligodendrocyte response after traumatic brain injury.

White matter injury (WMI) is thought to be a major contributor to long-term cognitive dysfunctions after traumatic brain injury (TBI). This damage occurs partly due to apoptotic death of oligodendrocyte lineage cells (OLCs) after the injury, triggered directly by the trauma or in response to degenerating axons. Recent research suggests that the gut microbiota modulates the inflammatory response through the regulation of peripheral immune cell infiltration after TBI. Additionally, T-cells directly impact OLCs differentiation and proliferation. Therefore, we hypothesized that the gut microbiota plays a critical role in regulating the OLC response to WMI influencing T-cells differentiation and activation. Gut microbial depletion early after TBI chronically reduced re-myelination, acutely decreased OLCs proliferation, and was associated with increased myelin debris accumulation. Surprisingly, the absence of T-cells in gut microbiota depleted mice restored OLC proliferation and remyelination after TBI. OLCs co-cultured with T-cells derived from gut microbiota depleted mice resulted in impaired proliferation and increased expression of MHC-II compared with T cells from control-injured mice. Furthermore, MHC-II expression in OLCs appears to be linked to impaired proliferation under gut microbiota depletion and TBI conditions. Collectively our data indicates that depletion of the gut microbiota after TBI impaired remyelination, reduced OLCs proliferation with concomitantly increased OLC MHCII expression, and required the presence of T cells. This data suggests that T cells are an important mechanistic link by which the gut microbiota modulate the oligodendrocyte response and white matter recovery after TBI.

Modelling lung infection with Klebsiella pneumoniae after murine traumatic brain injury.

Pneumonia is a common comorbidity in patients with severe traumatic brain injury (TBI), and is associated with increased morbidity and mortality. In this study, we established a model of intratracheal Klebsiella pneumoniae administration in young adult male and female mice, at 4 days following an experimental TBI, to investigate how K. pneumoniae infection influences acute post-TBI outcomes. A dose-response curve determined the optimal dose of K. pneumoniae for inoculation (1 x 10^6 colony forming units), and administration at 4 days post-TBI resulted in transient body weight loss and sickness behaviors (hypoactivity and acute dyspnea). K. pneumoniae infection led to an increase in pro-inflammatory cytokines in serum and bronchoalveolar lavage fluid at 24 h post-infection, in both TBI and sham (uninjured) mice. By 7 days, when myeloperoxidase + neutrophil numbers had returned to baseline in all groups, lung histopathology was observed with an increase in airspace size in TBI + K. pneumoniae mice compared to TBI + vehicle mice. In the brain, increased neuroinflammatory gene expression was observed acutely in response to TBI, with an exacerbated increase in Ccl2 and Hmox1 in TBI + K. pneumoniae mice compared to either TBI or K. pneumoniae alone. However, the presence of neuroinflammatory immune cells in the injured brain, and the extent of damage to cortical and hippocampal brain tissue, was comparable between K. pneumoniae and vehicle-treated mice by 7 days. Examination of the fecal microbiome across a time course did not reveal any pronounced effects of either injury or K. pneumoniae on bacterial diversity or abundance. Together, these findings demonstrate that K. pneumoniae lung infection after TBI induces an acute and transient inflammatory response, primarily localized to the lungs with some systemic effects. However, this infection had minimal impact on secondary injury processes in the brain following TBI. Future studies are needed to evaluate the potential longer-term consequences of this dual-hit insult.

Oral administration of lysozyme protects against injury of ileum via modulating gut microbiota dysbiosis after severe traumatic brain injury.

Objective: The current study sought to clarify the role of lysozyme-regulated gut microbiota and explored the potential therapeutic effects of lysozyme on ileum injury induced by severe traumatic brain injury (sTBI) and bacterial pneumonia in vivo and in vitro experiments. Methods: Male 6-8-week-old specific pathogen-free (SPF) C57BL/6 mice were randomly divided into Normal group (N), Sham group (S), sTBI group (T), sTBI + or Lysozyme-treated group (L), Normal + Lysozyme group (NL) and Sham group + Lysozyme group (SL). At the day 7 after establishment of the model, mice were anesthetized and the samples were collected. The microbiota in lungs and fresh contents of the ileocecum were analyzed. Lungs and distal ileum were used to detect the degree of injury. The number of Paneth cells and the expression level of lysozyme were assessed. The bacterial translocation was determined. Intestinal organoids culture and co-coculture system was used to test whether lysozyme remodels the intestinal barrier through the gut microbiota. Results: After oral administration of lysozyme, the intestinal microbiota is rebalanced, the composition of lung microbiota is restored, and translocation of intestinal bacteria is mitigated. Lysozyme administration reinstates lysozyme expression in Paneth cells, thereby reducing intestinal permeability, pathological score, apoptosis rate, and inflammation levels. The gut microbiota, including Oscillospira, Ruminococcus, Alistipes, Butyricicoccus, and Lactobacillus, play a crucial role in regulating and improving intestinal barrier damage and modulating Paneth cells in lysozyme-treated mice. A co-culture system comprising intestinal organoids and brain-derived proteins (BP), which demonstrated that the BP effectively downregulated the expression of lysozyme in intestinal organoids. However, supplementation of lysozyme to this co-culture system failed to restore its expression in intestinal organoids. Conclusion: The present study unveiled a virtuous cycle whereby oral administration of lysozyme restores Paneth cell's function, mitigates intestinal injury and bacterial translocation through the remodeling of gut microbiota.

Temporal shifts to the gut microbiome associated with cognitive dysfunction following high-fat diet consumption in a juvenile model of traumatic brain injury.

The gut-brain axis interconnects the central nervous system (CNS) and the commensal bacteria of the gastrointestinal tract. The composition of the diet consumed by the host influences the richness of the microbial populations. Traumatic brain injury (TBI) produces profound neurocognitive damage, but it is unknown how diet influences the microbiome following TBI. The present work investigates the impact of a chow diet versus a 60% fat diet (HFD) on fecal microbiome populations in juvenile rats following TBI. Twenty-day-old male rats were placed on one of two diets for 9 days before sustaining either a Sham or TBI via the Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA). Fecal samples were collected at both 1- and 9-days postinjury. Animals were cognitively assessed in the novel object recognition tests at 8 days postinjury. Fecal microbiota DNA was isolated and sequenced. Twenty days of HFD feeding did not alter body weight, but fat mass was elevated in HFD compared with Chow rats. TBI animals had a greater percentage of entries to the novel object quadrant than Sham counterparts, P < 0.05. The Firmicutes/Bacteroidetes ratio was significantly higher in TBI than in the Sham, P < 0.05. Microbiota of the Firmicutes lineage exhibited perturbations by both injury and diet that were sustained at both time points. Linear regression analyses were performed to associate bacteria with metabolic and neurocognitive endpoints. For example, counts of Lachnospiraceae were negatively associated with percent entries into the novel object quadrant. Taken together, these data suggest that both diet and injury produce robust shifts in microbiota, which may have long-term implications for chronic health.NEW & NOTEWORTHY Traumatic brain injury (TBI) produces memory and learning difficulties. Diet profoundly influences the populations of gut microbiota. Following traumatic brain injury in a pediatric model consuming either a healthy or high-fat diet (HFD), significant shifts in bacterial populations occur, of which, some are associated with diet, whereas others are associated with neurocognitive performance. More work is needed to determine whether these microbes can therapeutically improve learning following trauma to the brain.

Acute gut microbiome changes after traumatic brain injury are associated with chronic deficits in decision-making and impulsivity in male rats.

The mechanisms underlying chronic psychiatric-like impairments after traumatic brain injury (TBI) are currently unknown. The goal of the present study was to assess the role of diet and the gut microbiome in psychiatric symptoms after TBI. Rats were randomly assigned to receive a high-fat diet (HFD) or calorie-matched low-fat diet (LFD). After 2 weeks of free access, rats began training on the rodent gambling task (RGT), a measure of risky decision-making and motor impulsivity. After training, rats received a bilateral frontal TBI or a sham procedure and continued postinjury testing for 10 weeks. Fecal samples were collected before injury and 3-, 30-, and 60 days postinjury to evaluate the gut microbiome. HFD altered the microbiome, but ultimately had low-magnitude effects on behavior and did not modify functional outcomes after TBI. Injury-induced functional deficits were far more robust; TBI substantially decreased optimal choice and increased suboptimal choice and motor impulsivity on the RGT. TBI also affected the microbiome, and a model comparison approach revealed that bacterial diversity measured 3 days postinjury was predictive of chronic psychiatric-like deficits on the RGT. A functional metagenomic analysis identified changes to dopamine and serotonin synthesis pathways as a potential candidate mechanism. Thus, the gut may be a potential acute treatment target for psychiatric symptoms after TBI, as well as a biomarker for injury and deficit severity. However, further research will be needed to confirm and extend these findings. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

POSTINJURY FECAL MICROBIOME TRANSPLANT DECREASES LESION SIZE AND NEUROINFLAMMATION IN TRAUMATIC BRAIN INJURY.

ABSTRACT: Background: Traumatic brain injury (TBI) is an underrecognized public health threat. The constitutive activation of microglia after TBI has been linked to long-term neurocognitive deficits and the progression of neurodegenerative disease. Evolving evidence indicates a critical role for the gut-brain axis in this process. Specifically, TBI has been shown to induce the depletion of commensal gut bacteria. The resulting gut dysbiosis is associated with neuroinflammation and disease. Hypothesis: We hypothesized that fecal microbiota transplantation would attenuate microglial activation and improve neuropathology after TBI. Methods: C57Bl/6 mice were subjected to severe TBI (n = 10) or sham injury (n = 10) via an open-head controlled cortical impact. The mice underwent fecal microbiota transplantation (FMT) or vehicle alone via oral gavage once weekly for 4 weeks after injury. At 59 days after TBI, mice underwent three-dimensional, contrast-enhanced magnetic resonance imaging. Following imaging, mice were killed, brains harvested at 60 DPI, and CD45+ cells isolated via florescence-activated cell sorting. cDNA libraries were prepared using the 10x Genomics Chromium Single Cell 3' Reagent kit followed by sequencing on a HiSeq4000 instrument, and computational analysis was performed. Results: Fecal microbiota transplantation resulted in a >marked reduction of ventriculomegaly (P < 0.002) and preservation of white matter connectivity at 59 days after TBI (P < 0.0001). In addition, microglia from FMT-treated mice significantly reduced inflammatory gene expression and enriched pathways involving the heat-shock response compared with mice treated with vehicle alone. Conclusions: We hypothesized that restoring gut microbial community structure via FMT would attenuate microglial activation and reduce neuropathology after TBI. Our data demonstrated significant preservation of cortical volume and white matter connectivity after an injury compared with mice treated with vehicle alone. This preservation of neuroanatomy after TBI was associated with a marked reduction in inflammatory gene expression within the microglia of FMT-treated mice. Microglia from FMT-treated mice enriched pathways in the heat-shock response, which is known to play a neuroprotective role in TBI and other neurodegenerative disease processes.

Traumatic Brain Injury Induces Gastrointestinal Dysfunction and Dysbiosis of Gut Microbiota Accompanied by Alterations of Bile Acid Profile.

Gastrointestinal dysfunction is a common peripheral organ complication after traumatic brain injury (TBI), yet the underlying mechanism remains unknown. TBI has been demonstrated to cause gut microbiota dysbiosis in animal models, although the impacts of gut microbiota dysbiosis on gastrointestinal dysfunction were not examined. Bile acids are key metabolites between gut microbiota and host interactions. Therefore, the aim of this study was to investigate the mechanistic links between them by detecting the alterations of gut microbiota and bile acid profile after TBI. For that, we established TBI in mice using a lateral fluid percussion injury model. Gut microbiota was examined by 16S rRNA sequencing, and bile acids were profiled by ultra-performance liquid chromatography-tandem mass spectrometry. Our results showed that TBI caused intestinal inflammation and gut barrier impairment. Alterations of gut microbiota and bile acid profile were observed. The diversity of gut microbiota experienced a time dependent change from 1 h to 7 days post-injury. Levels of bile acids in feces and plasma were decreased after TBI, and the decrease was more significant in secondary bile acids, which may contribute to intestinal inflammation. Specific bacterial taxa such as Staphylococcus and Lachnospiraceae that may contribute to the bile acid metabolic changes were identifed. In conclusion, our study suggested that TBI-induced gut microbiota dysbiosis may contribute to gastrointestinal dysfunction via altering bile acid profile. Gut microbiota may be a potential treatment target for TBI-induced gastrointestinal dysfunction.

Brain-gut axis dysfunction in the pathogenesis of traumatic brain injury.

Traumatic brain injury (TBI) is a chronic and progressive disease, and management requires an understanding of both the primary neurological injury and the secondary sequelae that affect peripheral organs, including the gastrointestinal (GI) tract. The brain-gut axis is composed of bidirectional pathways through which TBI-induced neuroinflammation and neurodegeneration impact gut function. The resulting TBI-induced dysautonomia and systemic inflammation contribute to the secondary GI events, including dysmotility and increased mucosal permeability. These effects shape, and are shaped by, changes in microbiota composition and activation of resident and recruited immune cells. Microbial products and immune cell mediators in turn modulate brain-gut activity. Importantly, secondary enteric inflammatory challenges prolong systemic inflammation and worsen TBI-induced neuropathology and neurobehavioral deficits. The importance of brain-gut communication in maintaining GI homeostasis highlights it as a viable therapeutic target for TBI. Currently, treatments directed toward dysautonomia, dysbiosis, and/or systemic inflammation offer the most promise.

Fecal Microbiota Transplantation Is a Promising Method to Restore Gut Microbiota Dysbiosis and Relieve Neurological Deficits after Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI) can induce persistent fluctuation in the gut microbiota makeup and abundance. The present study is aimed at determining whether fecal microbiota transplantation (FMT) can rescue microbiota changes and ameliorate neurological deficits after TBI in rats. METHODS: A controlled cortical impact (CCI) model was used to simulate TBI in male Sprague-Dawley rats, and FMT was performed for 7 consecutive days. 16S ribosomal RNA (rRNA) sequencing of fecal samples was performed to analyze the effects of FMT on gut microbiota. Modified neurological severity score and Morris water maze were used to evaluate neurobehavioral functions. Metabolomics was used to screen differential metabolites from the rat serum and ipsilateral brains. The oxidative stress indices were measured in the brain. RESULTS: TBI induced significance changes in the gut microbiome, including the alpha- and beta-bacterial diversity, as well as the microbiome composition at 8 days after TBI. On the other hand, FMT could rescue these changes and relieve neurological deficits after TBI. Metabolomics results showed that the level of trimethylamine (TMA) in feces and the level of trimethylamine N-oxide (TMAO) in the ipsilateral brain and serum was increased after TBI, while FMT decreased TMA levels in the feces, and TMAO levels in the ipsilateral brain and serum. Antioxidant enzyme methionine sulfoxide reductase A (MsrA) in the ipsilateral hippocampus was decreased after TBI but increased after FMT. In addition, FMT elevated SOD and CAT activities and GSH/GSSG ratio and diminished ROS, GSSG, and MDA levels in the ipsilateral hippocampus after TBI. CONCLUSIONS: FMT can restore gut microbiota dysbiosis and relieve neurological deficits possibly through the TMA-TMAO-MsrA signaling pathway after TBI.

Gut Microbiota and Acute Central Nervous System Injury: A New Target for Therapeutic Intervention.

Acute central nervous system (CNS) injuries, including stroke, traumatic brain injury (TBI), and spinal cord injury (SCI), are the common causes of death or lifelong disabilities. Research into the role of the gut microbiota in modulating CNS function has been rapidly increasing in the past few decades, particularly in animal models. Growing preclinical and clinical evidence suggests that gut microbiota is involved in the modulation of multiple cellular and molecular mechanisms fundamental to the progression of acute CNS injury-induced pathophysiological processes. The altered composition of gut microbiota after acute CNS injury damages the equilibrium of the bidirectional gut-brain axis, aggravating secondary brain injury, cognitive impairments, and motor dysfunctions, which leads to poor prognosis by triggering pro-inflammatory responses in both peripheral circulation and CNS. This review summarizes the studies concerning gut microbiota and acute CNS injuries. Experimental models identify a bidirectional communication between the gut and CNS in post-injury gut dysbiosis, intestinal lymphatic tissue-mediated neuroinflammation, and bacterial-metabolite-associated neurotransmission. Additionally, fecal microbiota transplantation, probiotics, and prebiotics manipulating the gut microbiota can be used as effective therapeutic agents to alleviate secondary brain injury and facilitate functional outcomes. The role of gut microbiota in acute CNS injury would be an exciting frontier in clinical and experimental medicine.

Microbial Diversity and Community Structures Among Those With Moderate to Severe TBI: A United States-Veteran Microbiome Project Study.

OBJECTIVE: To evaluate the association between distal moderate/severe traumatic brain injury (TBI) history and the human gut microbiome. SETTING: Veterans Affairs Medical Center. PARTICIPANTS: Veterans from the United States-Veteran Microbiome Project (US-VMP). Veterans with moderate/severe TBI (n = 34) were compared with (1) Veterans with a history of no TBI (n = 79) and (2) Veterans with a history of no TBI or mild TBI only (n = 297). DESIGN: Microbiome analyses from 16S rRNA gene sequencing with gut microbiota function inferred using PICRUSt2. MAIN MEASURES: α-Diversity and ß-diversity of the gut microbiome, as well as taxonomic and functional signatures associated with moderate/severe TBI. RESULTS: There were no significant differences in gut bacterial α- and ß-diversity associated with moderate/severe TBI status. No differentially abundant taxa were identified when comparing samples from moderate/severe TBI to those with no TBI or no TBI/mild TBI. CONCLUSION: Results suggest that moderate/severe TBI-related changes to the gut microbiome do not persist for years postinjury.

Depletion of gut microbiota is associated with improved neurologic outcome following traumatic brain injury.

Signaling between intestinal microbiota and the brain influences neurologic outcome in multiple forms of brain injury. The impact of gut microbiota following traumatic brain injury (TBI) has not been well established. Our objective was to compare TBI outcomes in specific pathogen-free mice with or without depletion of intestinal bacteria. Adult male C57BL6/J SPF mice (n = 6/group) were randomized to standard drinking water or ampicillin (1 g/L), metronidazole (1 g/L), neomycin (1 g/L), and vancomycin (0.5 g/L) (AMNV) containing drinking water 14 days prior to controlled cortical impact (CCI) model of TBI. 16S rRNA gene sequencing of fecal pellets was performed and alpha and beta diversity determined. Hippocampal neuronal density and microglial activation was assessed 72 h post-injury by immunohistochemistry. In addition, mice (n = 8-12/group) were randomized to AMNV or no treatment initiated immediately after CCI and memory acquisition (fear conditioning) and lesion volume assessed. Mice receiving AMNV had significantly reduced alpha diversity (p < 0.05) and altered microbiota community composition compared to untreated mice (PERMANOVA: p < 0.01). Mice receiving AMNV prior to TBI had increased CA1 hippocampal neuronal density (15.2 ± 1.4 vs. 8.8 ± 2.1 cells/0.1 mm; p < 0.05) and a 26.6 ± 6.6% reduction in Iba-1 positive cells (p < 0.05) at 72 h. Mice randomized to AMNV immediately after CCI had attenuated associative learning deficit on fear conditioning test (%freeze Cue: 63.7 ± 2.7% vs. 41.0 ± 5.1%, p < 0.05) and decreased lesion volume (27.2 ± 0.8 vs. 24.6 ± 0.7 mm3, p < 0.05). In conclusion, depletion of intestinal microbiota was consistent with a neuroprotective effect whether initiated before or after injury in a murine model of TBI. Further investigations of the role of gut microbiota in TBI are warranted.

Catastrophic consequences: can the feline parasite Toxoplasma gondii prompt the purrfect neuroinflammatory storm following traumatic brain injury?

Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality worldwide; however, treatment development is hindered by the heterogenous nature of TBI presentation and pathophysiology. In particular, the degree of neuroinflammation after TBI varies between individuals and may be modified by other factors such as infection. Toxoplasma gondii, a parasite that infects approximately one-third of the world's population, has a tropism for brain tissue and can persist as a life-long infection. Importantly, there is notable overlap in the pathophysiology between TBI and T. gondii infection, including neuroinflammation. This paper will review current understandings of the clinical problems, pathophysiological mechanisms, and functional outcomes of TBI and T. gondii, before considering the potential synergy between the two conditions. In particular, the discussion will focus on neuroinflammatory processes such as microglial activation, inflammatory cytokines, and peripheral immune cell recruitment that occur during T. gondii infection and after TBI. We will present the notion that these overlapping pathologies in TBI individuals with a chronic T. gondii infection have the strong potential to exacerbate neuroinflammation and related brain damage, leading to amplified functional deficits. The impact of chronic T. gondii infection on TBI should therefore be investigated in both preclinical and clinical studies as the possible interplay could influence treatment strategies.

Alterations of the GH/IGF-I Axis and Gut Microbiome after Traumatic Brain Injury: A New Clinical Syndrome?

CONTEXT: Pituitary dysfunction with abnormal growth hormone (GH) secretion and neurocognitive deficits are common consequences of traumatic brain injury (TBI). Recognizing the comorbidity of these symptoms is of clinical importance; however, efficacious treatment is currently lacking. EVIDENCE ACQUISITION: A review of studies in PubMed published between January 1980 to March 2020 and ongoing clinical trials was conducted using the search terms "growth hormone," "traumatic brain injury," and "gut microbiome." EVIDENCE SYNTHESIS: Increasing evidence has implicated the effects of TBI in promoting an interplay of ischemia, cytotoxicity, and inflammation that renders a subset of patients to develop postinjury hypopituitarism, severe fatigue, and impaired cognition and behavioral processes. Recent data have suggested an association between abnormal GH secretion and altered gut microbiome in TBI patients, thus prompting the description of a hypothesized new clinical syndrome called "brain injury associated fatigue and altered cognition." Notably, these patients demonstrate distinct characteristics from those with GH deficiency from other non-TBI causes in that their symptom complex improves significantly with recombinant human GH treatment, but does not reverse the underlying mechanistic cause as symptoms typically recur upon treatment cessation. CONCLUSION: The reviewed data describe the importance of alterations of the GH/insulin-like growth factor I axis and gut microbiome after brain injury and its influence in promoting neurocognitive and behavioral deficits in a bidirectional relationship, and highlight a new clinical syndrome that may exist in a subset of TBI patients in whom recombinant human GH therapy could significantly improve symptomatology. More studies are needed to further characterize this clinical syndrome.

Rapidly fatal pneumococcal meningitis following non-penetrating traumatic brain injury.

A previously healthy young man presented to hospital with severe traumatic brain injury following a motor vehicle collision. Within 24 hours of admission, and despite antibiotic coverage, he developed a fever. On the second day, the source of infection was discovered to be purulent pneumococcal meningitis. At 48 hours post-accident, he developed brain-stem death without evidence of raised intracranial pressure or trans-tentorial herniation. Initial CT scans of the head were essentially normal, but early repeat scans revealed evidence of pneumocephalus and possible frontal bone fracture. Current recommendations do not make room for targeted antibiotic prophylaxis in traumatic brain injury patients with traumatic skull fracture. We argue that our case demonstrates the need for aggressive targeted antibiotic prophylaxis in the presence of certain features such as frontal or sphenoid bone fracture and pneumocephalus.

Altered Fecal Microbiome Years after Traumatic Brain Injury.

Patients with chronic traumatic brain injury (TBI) requiring long-term, permanent care suffer a myriad of clinical symptoms (i.e., impaired cognition, fatigue, and other conditions) that persist for years beyond the acute brain injury. In addition to these comorbid clinical symptoms, chronic TBI patients exhibit altered amino acid and hormonal profiles with distinct cytokine patterns suggesting chronic inflammation. This metabolic link suggests a role of the gut-brain axis in chronic TBI. Thus, we utilized a two-site trial to investigate the role of the gut-brain axis in comorbidities of chronic TBI. The fecal microbiome profile of 22 moderate/severe TBI patients residing in permanent care facilities in Texas and California was compared to 18 healthy age-matched control subjects working within the participating facilities. Each fecal microbiome was characterized by 16S(V4) ribosomal RNA (rRNA) gene sequencing and metagenomic genome sequencing approaches followed by confirmatory full 16S rRNA gene sequencing or focused tuf gene speciation and specific quantitative polymerase chain reaction evaluation of selected genera or species. The average chronic TBI patient fecal microbiome structure was significantly different compared to the control cohort, and these differences persisted after group stratification analysis to identify any unexpected confounders. Notably, the fecal microbiome of the chronic TBI cohort had absent or reduced Prevotella spp. and Bacteroidies spp. Conversely, bacteria in the Ruminococcaceae family were higher in abundance in TBI compared to control profiles. Previously reported hypoaminoacidemia, including significantly reduced levels of l-tryptophan, l-sarcosine, ß-alanine, and alanine, positively correlated with the reduced levels of Prevotella spp. in the TBI cohort samples compared to controls. Although the sequelae of gut-brain axis disruption after TBI is not fully understood, characterizing TBI-related alterations in the fecal microbiome may provide biomarkers and therapeutic targets to address patient morbidity.

Repeated mild traumatic brain injury affects microbial diversity in rat jejunum.

Traumatic brain injuries (TBI) manifest into post-traumatic stress disorders such as anxiety comorbid with gut ailments. The perturbations in gut microbial communities are often linked to intestinal and neuropsychological disorders. We have previously reported anxiety and abnormalities in gut function in mild TBI (MTBI)-exposed rats. The current study demonstrates the changes in gut microbiome of MTBI-exposed animals and discusses its implications in intestinal health and behaviours. The rats were subjected to repeated MTBI (rMTBI) and microbial composition in jejunum was examined after 6 h, 48 h and 30 days of rMTBI. Significant reduction in bacterial diversity was observed in the rMTBI-exposed animals at all the time points. Principal coordinate analysis based on weighted UniFrac distances indicated substantial differences in gut microbial diversity and abundances in rMTBI-exposed animals as compared to that in healthy controls. The abundance of Proteobacteria increased dramatically with reciprocal decrease in Firmicutes after rMTBI. At the genus level, Helicobacter, Lactobacillus, Campylobacter, and Streptococcus were found to be differentially abundant in the jejunum of rMTBI-exposed rats as compared to sham controls indicating profound dysbiosis from the healthy state. Furthermore, substantial depletion in butyrate-producing bacterial communities was observed in rMTBI-exposed animals. These results suggest that the traumatic stress alters the gut microbiome with possible implications in gut health and neuropsychopathology.

Investigating Alterations in Caecum Microbiota After Traumatic Brain Injury in Mice.

Increasing evidence shows that the microbiota-gut-brain axis plays an important role in the pathogenesis of brain diseases. Several studies also demonstrate that traumatic brain injuries cause changes to the gut microbiota. However, mechanisms underlying the bidirectional regulation of the brain-gut axis remain unknown. Currently, few models exist for studying the changes in gut microbiota after traumatic brain injury. Therefore, the presented study combines protocols for inducing traumatic brain injury using a lateral fluid percussion device and analysis of caecum samples following injury for investigating alterations in the gut microbiome. Alterations of the gut microbiota composition after traumatic brain injury are determined using 16S-rDNA sequencing. This protocol provides an effective method for studying the relationships between enteric microorganisms and traumatic brain injury.

The Beehive Theory: Role of microorganisms in late sequelae of traumatic brain injury and chronic traumatic encephalopathy.

Traumatic brain injury and chronic traumatic encephalopathy are both major health problems, well-publicized for the severe delayed effects attributed to them, including cognitive decline, psychiatric disorders, seizures, impaired motor function, and personality changes. For convenience, the two afflictions are considered together under the rubric traumatic brain injury. Despite the need for neuroprotective agents, no substances have shown efficacy in clinical studies. Thus, a deeper understanding of the neuropathological mechanism of such injury is still needed. Proposed here is a theory that microorganisms from within the brain and elsewhere in the body contribute to the long-term neurological deterioration characteristic of traumatic brain injury. The label, "The Beehive Theory", is drawn from the well-known fact that disturbing a tranquil beehive with a blow can cause a swarm of angry bees to exit their dwelling place and attack nearby humans. Similarly, an impact to the head can initiate dislocations and disruptions in the microbiota present in the brain and body. First, since the normal human brain is not sterile, but is host to a variety of microorganisms, blows to the skull may dislodge them from their accustomed local environments, in which they have been living in quiet equilibrium with neighboring brain cells. Deleterious substances may be released by the displaced microbes, including metabolic products and antigens. Second, upon impact commensal microbes already resident on surfaces of the nose, mouth, and eyes, and potentially harmful organisms from the environment, may gain access to the brain through the distal ends of the olfactory and optic nerves or even a disrupted blood-brain barrier. Third, microbes dwelling in more distant parts of the body may be propelled through the walls of local blood vessels into the bloodstream, and then leak out into damaged areas of the brain that have increased blood-brain barrier permeability. Fourth, the impact may cause dysbiosis in the gastrointestinal microbiome, thereby disrupting signaling via the gut-brain axis. Possible preventatives or therapeutics that would address the adverse contributions of microbes to the late sequelae of traumatic brain injury include anti-inflammatories, antibacterials, antivirals, and probiotics.