The present study aimed to clarify the onset of traumatic brain injury (TBI) and identify mortality-related risk factors in patients with severe TBI, to enable the early identification of high-risk individuals and timely implementation of prevention and treatment strategies to minimize mortality rates. Comprehensive database searches were conducted across Web of Science, PubMed, CINAHL and EMBASE, covering publications from database inception until October 17, 2023. Search terms in English included 'head trauma', 'brain trauma', 'mortality', 'death' and 'risk factor'. In total, two independent researchers screened and extracted the data on mortality onset and associated risk factors in patients with severe TBI. Meta-analysis was performed using R 4.2.2. A total of 33 cohort studies, including 71,718 patients with severe TBI, were selected for meta-analysis. The data indicated an overall mortality rate of 27.8% (95%CI: 22.5-33.2%) from database inception until October 17, 2023. Subgroup analysis revealed a mortality rate of 25.2% (95%CI: 20.2-30.1%) in developed countries, compared with 38.0% (95%CI: 21.4-54.7%) in developing countries. Additionally, the mean age of deceased patients was significantly higher compared with that of survivors (41.53±16.47). Key risk factors found to be associated with mortality included anemia [relative risk (RR), 1.42; 95%CI, 1.04-1.93], diabetes mellitus (RR, 1.40; 95%CI, 1.00-1.96), coagulopathy (RR, 4.31; 95%CI, 2.31-8.05), shock (RR, 3.41; 95%CI, 2.31-5.04) and systolic blood pressure≤90 mmHg (RR, 2.32; 95%CI, 1.65-3.27). Furthermore, pre-hospital intubation (RR, 1.48; 95%CI, 1.13-1.92),hypotension (RR, 2.04; 95%CI: 1.58, 2.63), hypoxemia (RR, 1.42; 95%CI: 1.13, 1.79), subdural hemorrhage (RR, 1.99; 95%CI: 1.50, 2.62), subarachnoid hemorrhage (RR, 1.64; 95%CI: 1.09, 2.47) and subdural hematoma (SDH; RR, 1.50; 95%CI: 1.04, 2.17). was identified to be a significant risk factor during hospitalization treatment. These results suggest that various factors, such as age, anemia, diabetes, shock, hypotension, hypoxemia, trauma scores and brain injury types, can all contribute to mortality risk in patients with severe TBI. Addressing these risk factors will likely be important for reducing mortality in this patient population.

Necrotizing enterocolitis (NEC) and intracranial hemorrhage are severe emergencies in the neonatal period. The two do not appear to be correlated. However, our report suggests that parenchymal brain hemorrhage in full-term newborns may put patients at risk for NEC by altering intestinal function through the brain-gut axis.

We present a case of spontaneous parenchymal cerebral hemorrhage in a full-term newborn who developed early-stage NEC on Day 15.

It is possible to consider brain parenchymal hemorrhage as a risk factor for the appearance of NEC. Clinicians should be highly cautious about NEC in infants who have experienced parenchymal hemorrhage. This article is the first to discuss the relationship between parenchymal hemorrhage and NEC in full-term newborns.

Aim of the study: To examine the effect of controlled-cortical impact (CCI), a preclinical model of traumatic brain injury (TBI), on intestinal integrity using a binary classification model of machine learning (ML).Materials and methods: Adult, male C57BL/6 mice were subjected to CCI surgery using a stereotaxic impactor (Impact One™). The rotarod and hot-plate tests were performed to assess the neurological deficits.Results: Mice underwent CCI displayed a remarkable neurological deficit as noticed by decreased latency to fall and lesser paw withdrawal latency in rotarod and hot plate test, respectively. Animals were sacrificed 3 days post-injury (dpi). The colon sections were stained with hematoxylin and eosin (H&E) to integrate with machinery tool-based algorithms. Several stained colon images were captured to build a dataset for ML model to predict the impact of CCI vs sham procedure. The best results were obtained with VGG16 features with SVM RBF kernel and VGG16 features with stacked fully connected layers on top. We achieved a test accuracy of 84% and predicted the disrupted gut permeability and epithelium wall of colon in CCI group as compared to sham-operated mice.Conclusion: We suggest that ML may become an important tool in the development of preclinical TBI model and discovery of newer therapeutics.

Ammonia-N, as the most toxic nitrogenous waste, has high toxicity to marine animals. However, the interplay between ammonia-induced neuroendocrine toxicity and intestinal immune homeostasis has been largely overlooked. Here, a significant concordance of metabolome and transcriptome-based "cholinergic synapse" supports that plasma metabolites acetylcholine (ACh) plays an important role during NH4Cl exposure. After blocking the ACh signal transduction, the release of dopamine (DA) and 5-hydroxytryptamine (5-HT) in the cerebral ganglia increased, while the release of NPF in the thoracic ganglia and NE in the abdominal ganglia, and crustacean hyperglycemic hormone (CHH) and neuropeptide F (NPF) in the eyestalk decreased, finally the intestinal immunity was enhanced. After bilateral eyestalk ablation, the neuroendocrine system of shrimp was disturbed, more neuroendocrine factors, such as corticotropin releasing hormone (CRH), adrenocorticotropic-hormone (ACTH), ACh, DA, 5-HT, and norepinephrine (NE) were released into the plasma, and further decreased intestinal immunity. Subsequently, these neuroendocrine factors reach the intestine through endocrine or neural pathways and bind to their receptors to affect downstream signaling pathway factors to regulate intestinal immune homeostasis. Combined with different doses of ammonia-N exposure experiment, these findings suggest that NH4Cl may exert intestinal toxicity on shrimp by disrupting the cerebral ganglion-eyestalk axis and the cerebral ganglion-thoracic ganglion-abdominal ganglion axis, thereby damaging intestinal barrier function and inducing inflammatory response.

Traumatic brain injury (TBI) is a chronic and debilitating disease, associated with a high risk of psychiatric and neurodegenerative diseases. Despite significant advancements in improving outcomes, the lack of effective treatments underscore the urgent need for innovative therapeutic strategies. The brain-gut axis has emerged as a crucial bidirectional pathway connecting the brain and the gastrointestinal (GI) system through an intricate network of neuronal, hormonal, and immunological pathways. Four main pathways are primarily implicated in this crosstalk, including the systemic immune system, autonomic and enteric nervous systems, neuroendocrine system, and microbiome. TBI induces profound changes in the gut, initiating an unrestrained vicious cycle that exacerbates brain injury through the brain-gut axis. Alterations in the gut include mucosal damage associated with the malabsorption of nutrients/electrolytes, disintegration of the intestinal barrier, increased infiltration of systemic immune cells, dysmotility, dysbiosis, enteroendocrine cell (EEC) dysfunction and disruption in the enteric nervous system (ENS) and autonomic nervous system (ANS). Collectively, these changes further contribute to brain neuroinflammation and neurodegeneration via the gut-brain axis. In this review article, we elucidate the roles of various anti-inflammatory pharmacotherapies capable of attenuating the dysregulated inflammatory response along the brain-gut axis in TBI. These agents include hormones such as serotonin, ghrelin, and progesterone, ANS regulators such as beta-blockers, lipid-lowering drugs like statins, and intestinal flora modulators such as probiotics and antibiotics. They attenuate neuroinflammation by targeting distinct inflammatory pathways in both the brain and the gut post-TBI. These therapeutic agents exhibit promising potential in mitigating inflammation along the brain-gut axis and enhancing neurocognitive outcomes for TBI patients.

This study aimed to investigate how gut microbiota dysbiosis impacts the repair of the blood-brain barrier and neurological deficits following traumatic brain injury (TBI). Through 16S rRNA sequencing analysis, we compared the gut microbiota of TBI rats and normal controls, discovering significant differences in abundance, species composition, and ecological function, potentially linked to Ghrelin-mediated brain-gut axis functionality. Further, in vivo experiments showed that fecal microbiota transplantation or Ghrelin injection could block the intracerebral TNF signaling pathway, enhance GLP-1 expression, significantly reduce brain edema post-TBI, promote the repair of the blood-brain barrier, and improve neurological deficits. However, the TNF signaling pathway activation could reverse these beneficial effects. In summary, our research suggests that by restoring the balance of gut microbiota, the levels of Ghrelin can be elevated, leading to the blockade of intracerebral TNF signaling pathway and enhanced GLP-1 expression, thereby mitigating post-TBI blood-brain barrier disruption and neurological injuries.

Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide, particularly among individuals under the age of 45. It is a complex, and heterogeneous disease with a multifaceted pathophysiology that remains to be elucidated. Metabolomics has the potential to identify metabolic pathways and unique biochemical profiles associated with TBI. Herein, we employed a longitudinal metabolomics approach to study TBI in a weight drop mouse model to reveal metabolic changes associated with TBI pathogenesis, severity, and secondary injury. Using proton nuclear magnetic resonance (1H NMR) spectroscopy, we biochemically profiled post-mortem brain from mice that suffered mild TBI (N = 25; 13 male and 12 female), severe TBI (N = 24; 11 male and 13 female) and sham controls (N = 16; 11 male and 5 female) at baseline, day 1 and day 7 following the injury. 1H NMR-based metabolomics, in combination with bioinformatic analyses, highlights a few significant metabolites associated with TBI severity and perturbed metabolism related to the injury. We report that the concentrations of taurine, creatinine, adenine, dimethylamine, histidine, N-Acetyl aspartate, and glucose 1-phosphate are all associated with TBI severity. Longitudinal metabolic observation of brain tissue revealed that mild TBI and severe TBI lead distinct metabolic profile changes. A multi-class model was able to classify the severity of injury as well as time after TBI with estimated 86% accuracy. Further, we identified a high degree of correlation between respective hemisphere metabolic profiles (r > 0.84, p < 0.05, Pearson correlation). This study highlights the metabolic changes associated with underlying TBI severity and secondary injury. While comprehensive, future studies should investigate whether: (a) the biochemical pathways highlighted here are recapitulated in the brain of TBI sufferers and (b) if the panel of biomarkers are also as effective in less invasively harvested biomatrices, for objective and rapid identification of TBI severity and prognosis.

Traumatic brain injury (TBI) is one of the most serious types of trauma and imposes a heavy social and economic burden on healthcare systems worldwide. The development of emerging biotechnologies is uncovering the relationship between TBI and gut flora, and gut flora as a potential intervention target is of increasing interest to researchers. Nevertheless, there is a paucity of research employing bibliometric methodologies to scrutinize the interrelation between these two. Therefore, this study visualized the relationship between TBI and gut flora based on bibliometric methods to reveal research trends and hotspots in the field. The ultimate objective is to catalyze progress in the preclinical and clinical evolution of strategies for treating and managing TBI.

Terms related to TBI and gut microbiota were combined to search the Scopus database for relevant documents from inception to February 2023. Visual analysis was performed using CiteSpace and VOSviewer.

From September 1972 to February 2023, 2,957 documents published from 98 countries or regions were analyzed. The number of published studies on the relationship between TBI and gut flora has risen exponentially, with the United States, China, and the United Kingdom being representative of countries publishing in related fields. Research has formed strong collaborations around highly productive authors, but there is a relative lack of international cooperation. Research in this area is mainly published in high-impact journals in the field of neurology. The "intestinal microbiota and its metabolites," "interventions," "mechanism of action" and "other diseases associated with traumatic brain injury" are the most promising and valuable research sites. Targeting the gut flora to elucidate the mechanisms for the development of the course of TBI and to develop precisely targeted interventions and clinical management of TBI comorbidities are of great significant research direction and of interest to researchers.

The findings suggest that close attention should be paid to the relationship between gut microbiota and TBI, especially the interaction, potential mechanisms, development of emerging interventions, and treatment of TBI comorbidities. Further investigation is needed to understand the causal relationship between gut flora and TBI and its specific mechanisms, especially the "brain-gut microbial axis."

The mitochondrial electron transport chain (mETC) contains molecular targets of volatile general anesthetics (VGAs), which places carriers of mutations at risk for anesthetic complications. The ND-23⁶⁰¹¹⁴ and mt:ND2^del1 lines of fruit flies (Drosophila melanogaster) that carry mutations in core subunits of Complex I of the mETC replicate numerous characteristics of Leigh syndrome (LS) caused by orthologous mutations in mammals and serve as models of LS. ND-23⁶⁰¹¹⁴ flies are behaviorally hypersensitive to volatile anesthetic ethers and develop an age- and oxygen-dependent anesthetic-induced neurotoxicity (AiN) phenotype after exposure to isoflurane but not to the related anesthetic sevoflurane. The goal of this paper was to investigate whether the alkane volatile anesthetic halothane and other mutations in Complex I and in Complexes II-V of the mETC cause AiN. We found that (i) ND-23⁶⁰¹¹⁴ and mt:ND2^del1 were susceptible to toxicity from halothane; (ii) in wild-type flies, halothane was toxic under anoxic conditions; (iii) alleles of accessory subunits of Complex I predisposed to AiN; and (iv) mutations in Complexes II-V did not result in an AiN phenotype. We conclude that AiN is neither limited to ether anesthetics nor exclusive to mutations in core subunits of Complex I.

Enterobacteriaceae are often found in the lungs of patients with severe Traumatic Brain Injury (sTBI). However, it is unknown whether these bacteria come from the gut microbiota. To investigate this hypothesis, the mice model of sTBI was used in this study. After sTBI, Chao1 and Simpson index peaking at 7 d in the lungs (p < 0.05). The relative abundance of Acinetobacter in the lungs increased to 16.26% at 7 d after sTBI. The chao1 index of gut microbiota increased after sTBI and peaked at 7 d (p < 0.05). Three hours after sTBI, the conditional pathogens such as Lachnoclostridium, Acinetobacter, Bacteroides and Streptococcus grew significantly. At 7 d and 14 d, the histology scores in the sTBI group were significantly higher than the control group (p < 0.05). The myeloperoxidase (MPO) activity increased at all-time points after sTBI and peaked at 7 d (p < 0.05). The LBP and sCD14 peaking 7 d after sTBI (p < 0.05). The Zonulin increased significantly at 3 d after sTBI and maintained the high level (p < 0.05). SourceTracker identified that the lung tissue microbiota reflects 49.69% gut source at 7 d after sTBI. In the small intestine, sTBI induced gastrointestinal dysfunction with increased apoptosis and decreasing antimicrobial peptides. There was a negative correlation between gut conditional pathogens and the expression level of antimicrobial peptides in Paneth cells. Our data indicate that gut bacteria translocated to the lungs after sTBI, and Paneth cells may regulate gut microbiota stability and translocation.

For centuries, the study of traumatic brain injury (TBI) has been centred on historical observation and analyses of personal, social, and environmental processes, which have been examined separately. Today, computation implementation and vast patient data repositories can enable a concurrent analysis of personal, social, and environmental processes, providing insight into changes in health status transitions over time. We applied computational and data visualization techniques to categorize decade-long health records of 235,003 patients with TBI in Canada, from preceding injury to the injury event itself. Our results highlighted that health status transition patterns in TBI emerged along with the projection of comorbidity where many disorders, social and environmental adversities preceding injury are reflected in external causes of injury and injury severity. The strongest associations between health status preceding TBI and health status at the injury event were between multiple body system pathology and advanced age-related brain pathology networks. The interwoven aspects of health status on a time continuum can influence post-injury trajectories and should be considered in TBI risk analysis to improve prevention, diagnosis, and care.

Traumatic brain injury (TBI) can be considered a "silent epidemic", causing morbidity, disability, and mortality in all age cohorts. Therefore, a greater understanding of the underlying pathophysiological intricate mechanisms and interactions with other organs and systems is necessary to intervene not only in the treatment but also in the prevention of complications. In this complex of reciprocal interactions, the complex brain-gut axis has captured a growing interest.

The purpose of this manuscript is to examine and systematize existing evidence regarding the pathophysiological processes that occur following TBI and the influences exerted on these by the brain-gut axis.

A systematic review of the literature was conducted according to the PRISMA methodology. On the 8th of October 2021, two independent databases were searched: PubMed and Scopus. Following the inclusion and exclusion criteria selected, 24 (12 from PubMed and 12 from Scopus) eligible manuscripts were included in the present review. Moreover, references from the selected articles were also updated following the criteria mentioned above, yielding 91 included manuscripts.

Published evidence suggests that the brain and gut are mutually influenced through four main pathways: microbiota, inflammatory, nervous, and endocrine.

These pathways are bidirectional and interact with each other. However, the studies conducted so far mainly involve animals. An autopsy methodological approach to corpses affected by traumatic brain injury or intestinal pathology could represent the keystone for future studies to clarify the complex pathophysiological processes underlying the interaction between these two main systems.