RESUMEN
Respiratory infections are one of the most common causes of illness and morbidity in neonates worldwide. In the acute phase infections are known to cause wide-spread peripheral inflammation. However, the inflammatory consequences to the critical neural control centres for respiration have not been explored. Utilising a well characterised model of neonatal respiratory infection, we investigated acute responses within the medulla oblongata which contains key respiratory regions. Neonatal mice were intranasally inoculated within 24 h of birth, with either Chlamydia muridarum or sham-infected, and tissue collected on postnatal day 15, the peak of peripheral inflammation. A key finding of this study is that, while the periphery appeared to show no sex-specific effects of a neonatal respiratory infection, sex had a significant impact on the inflammatory response of the medulla oblongata. There was a distinct sex-specific response in the medulla coincident with peak of peripheral inflammation, with females demonstrating an upregulation of anti-inflammatory cytokines and males showing very few changes. Microglia also demonstrated sex-specificity with the morphology of females and males differing based upon the nuclei. Astrocytes showed limited changes during the acute response to neonatal infection. These data highlight the strong sex-specific impact of a respiratory infection can have on the medulla in the acute inflammatory phase.
Asunto(s)
Animales Recién Nacidos , Infecciones por Chlamydia , Chlamydia muridarum , Animales , Ratones , Femenino , Infecciones por Chlamydia/microbiología , Infecciones por Chlamydia/patología , Masculino , Infecciones del Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/patología , Tronco Encefálico/patología , Enfermedades Neuroinflamatorias/microbiología , Enfermedades Neuroinflamatorias/patología , Enfermedades Neuroinflamatorias/inmunología , Caracteres Sexuales , Ratones Endogámicos C57BL , Citocinas/metabolismoRESUMEN
Importance: Research is beginning to elucidate the sophisticated mechanisms underlying the microbiota-gut-brain-immune interface, moving from primarily animal models to human studies. Findings support the dynamic relationships between the gut microbiota as an ecosystem (microbiome) within an ecosystem (host) and its intersection with the host immune and nervous systems. Adding this to the effects on epigenetic regulation of gene expression further complicates and strengthens the response. At the heart is inflammation, which manifests in a variety of pathologies including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Multiple Sclerosis (MS). Observations: Generally, the research to date is limited and has focused on bacteria, likely due to the simplicity and cost-effectiveness of 16s rRNA sequencing, despite its lower resolution and inability to determine functional ability/alterations. However, this omits all other microbiota including fungi, viruses, and phages, which are emerging as key members of the human microbiome. Much of the research has been done in pre-clinical models and/or in small human studies in more developed parts of the world. The relationships observed are promising but cannot be considered reliable or generalizable at this time. Specifically, causal relationships cannot be determined currently. More research has been done in Alzheimer's disease, followed by Parkinson's disease, and then little in MS. The data for MS is encouraging despite this. Conclusions and relevance: While the research is still nascent, the microbiota-gut-brain-immune interface may be a missing link, which has hampered our progress on understanding, let alone preventing, managing, or putting into remission neurodegenerative diseases. Relationships must first be established in humans, as animal models have been shown to poorly translate to complex human physiology and environments, especially when investigating the human gut microbiome and its relationships where animal models are often overly simplistic. Only then can robust research be conducted in humans and using mechanistic model systems.
Asunto(s)
Eje Cerebro-Intestino , Encéfalo , Microbioma Gastrointestinal , Enfermedades Neuroinflamatorias , Humanos , Microbioma Gastrointestinal/inmunología , Animales , Eje Cerebro-Intestino/inmunología , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/microbiología , Enfermedades Neuroinflamatorias/etiología , Encéfalo/inmunología , Encéfalo/microbiologíaRESUMEN
Short-chain fatty acids (SCFAs) are gut microbial metabolic derivatives produced during the fermentation of ingested complex carbohydrates. SCFAs have been widely regarded to have a potent anti-inflammatory and neuro-protective role and have implications in several disease conditions, such as, inflammatory bowel disease, type-2 diabetes, and neurodegenerative disorders. Japanese encephalitis virus (JEV), a neurotropic flavivirus, is associated with life threatening neuro-inflammation and neurological sequelae in infected hosts. In this study, we hypothesize that SCFAs have potential in mitigating JEV pathogenesis. Postnatal day 10 BALB/c mice were intraperitoneally injected with either a SCFA mixture (acetate, propionate, and butyrate) or PBS for a period of 7 days, followed by JEV infection. All mice were observed for onset and progression of symptoms. The brain tissue was collected upon reaching terminal illness for further analysis. SCFA-supplemented JEV-infected mice (SCFA + JEV) showed a delayed onset of symptoms, lower hindlimb clasping score, and decreased weight loss and increased survival by 3 days (p < 0.0001) upon infection as opposed to the PBS-treated JEV-infected animals (JEV). Significant downregulation of inflammatory cytokines TNF-α, MCP-1, IL-6, and IFN-Υ in the SCFA + JEV group relative to the JEV-infected control group was observed. Inflammatory mediators, phospho-NF-kB (P-NF-kB) and iba1, showed 2.08 ± 0.1 and 3.132 ± 0.43-fold upregulation in JEV versus 1.19 ± 0.11 and 1.31 ± 0.11-fold in the SCFA + JEV group, respectively. Tissue section analysis exhibited reduced glial activation (JEV groupâ42 ± 2.15 microglia/ROI; SCFA + JEV groupâ27.07 ± 1.8 microglia/ROI) in animals that received SCFA supplementation prior to infection as seen from the astrocytic and microglial morphometric analysis. Caspase-3 immunoblotting showed 4.08 ± 1.3-fold upregulation in JEV as compared to 1.03 ± 0.14-fold in the SCFA + JEV group and TUNEL assay showed a reduced cellular death post-JEV infection (JEV-6.4 ± 1.5 cells/ROI and SCFA + JEV-3.7 ± 0.73 cells/ROI). Our study critically contributes to the increasing evidence in support of SCFAs as an anti-inflammatory and neuro-protective agent, we further expand its scope as a potential supplementary intervention in JEV-mediated neuroinflammation.
Asunto(s)
Encefalitis Japonesa , Ácidos Grasos Volátiles , Microbioma Gastrointestinal , Enfermedades Neuroinflamatorias , Microbioma Gastrointestinal/fisiología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/microbiología , Microglía/efectos de los fármacos , Microglía/inmunología , Encefalitis Japonesa/tratamiento farmacológico , Encefalitis Japonesa/inmunología , Encefalitis Japonesa/microbiología , Encefalitis Japonesa/prevención & control , Encefalitis Japonesa/virología , Ácidos Grasos Volátiles/farmacología , Ácidos Grasos Volátiles/uso terapéutico , Virus de la Encefalitis Japonesa (Subgrupo)/efectos de los fármacos , Virus de la Encefalitis Japonesa (Subgrupo)/inmunología , Virus de la Encefalitis Japonesa (Subgrupo)/patogenicidad , Análisis de Supervivencia , Quimiocinas/inmunología , Quimiocinas/metabolismo , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/metabolismo , Síndrome de Liberación de Citoquinas/prevención & control , Humanos , Femenino , Animales , Ratones , Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/virología , Carga Viral/efectos de los fármacos , Factores de TiempoRESUMEN
Tau-mediated neurodegeneration is a hallmark of Alzheimer's disease. Primary tauopathies are characterized by pathological tau accumulation and neuronal and synaptic loss. Apolipoprotein E (ApoE)-mediated neuroinflammation is involved in the progression of tau-mediated neurodegeneration, and emerging evidence suggests that the gut microbiota regulates neuroinflammation in an APOE genotype-dependent manner. However, evidence of a causal link between the microbiota and tau-mediated neurodegeneration is lacking. In this study, we characterized a genetically engineered mouse model of tauopathy expressing human ApoE isoforms reared under germ-free conditions or after perturbation of their gut microbiota with antibiotics. Both of these manipulations reduced gliosis, tau pathology, and neurodegeneration in a sex- and ApoE isoform-dependent manner. The findings reveal mechanistic and translationally relevant interrelationships between the microbiota, neuroinflammation, and tau-mediated neurodegeneration.
Asunto(s)
Apolipoproteínas E , Microbioma Gastrointestinal , Enfermedades Neuroinflamatorias , Tauopatías , Animales , Humanos , Ratones , Antibacterianos/farmacología , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Modelos Animales de Enfermedad , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Ratones Transgénicos , Enfermedades Neuroinflamatorias/genética , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/microbiología , Proteínas tau/genética , Proteínas tau/metabolismo , Tauopatías/genética , Tauopatías/metabolismo , Tauopatías/microbiología , Factores SexualesRESUMEN
Microbiota mediate neuroinflammation in a genetic- and sex-specific manner in mice.
Asunto(s)
Microbioma Gastrointestinal , Enfermedades Neurodegenerativas , Enfermedades Neuroinflamatorias , Animales , Femenino , Masculino , Ratones , Enfermedades Neurodegenerativas/microbiología , Factores Sexuales , Enfermedades Neuroinflamatorias/microbiologíaRESUMEN
Alzheimer's disease (AD) is the most common type of dementia. Tau hyperphosphorylation and amyloid ß (Aß) deposition are the key pathological hallmarks of AD. Recent studies have shown that periodontitis is a significant risk factor for AD. The periodontal pathogen Porphyromonas gingivalis and its virulence factors have been shown to initiate and promote the hallmark pathologies and behavioral symptoms of AD. A possible link between Treponema denticola, another main periodontal pathogen, and AD has been reported. However, the role of T. denticola in AD pathogenesis is still unclear, and whether T. denticola and P. gingivalis exert a synergistic effect to promote AD development needs to be further studied. In this study, we investigated whether oral infection with T. denticola caused tau hyperphosphorylation in the hippocampi of mice and explored the underlying mechanisms. Orally administered T. denticola induced alveolar bone resorption, colonized brain tissues, and increased the activity of the phosphokinase GSK3ß by activating neuroinflammation in the hippocampus, thus promoting the hyperphosphorylation of the tau protein at Ser396, Thr181, and Thr231 in mice. An in vitro study with BV2 and N2a cell models of T. denticola invasion also verified the role of this pathogen in tau phosphorylation. T. denticola and P. gingivalis were not found to exert a synergistic effect on tau phosphorylation. In summary, these findings provide new insight into the important role of T. denticola in AD pathogenesis, providing biological connections between periodontal diseases and AD.
Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neuroinflamatorias , Infecciones por Treponema , Pérdida de Hueso Alveolar/microbiología , Enfermedad de Alzheimer/microbiología , Péptidos beta-Amiloides/metabolismo , Animales , Hipocampo/fisiopatología , Ratones , Enfermedades Neuroinflamatorias/microbiología , Porphyromonas gingivalis , Treponema denticola , Infecciones por Treponema/patología , Proteínas tau/metabolismoRESUMEN
Even after appropriate treatment, a proportion of Lyme disease patients suffer from a constellation of symptoms, collectively called Post-Treatment Lyme Disease Syndrome (PTLDS). Brain PET scan of patients with PTLDS have demonstrated likely glial activation indicating persistent neuroinflammatory processes. It is possible that unresolved bacterial remnants can continue to cause neuroinflammation. In previous studies, we have shown that non-viable Borrelia burgdorferi can induce neuroinflammation and apoptosis in an oligodendrocyte cell line. In this follow-up study, we analyze the effect of sonicated remnants of B. burgdorferi on primary rhesus frontal cortex (FC) and dorsal root ganglion (DRG) explants. Five FC and three DRG tissue fragments from rhesus macaques were exposed to sonicated B. burgdorferi and analyzed for 26 inflammatory mediators. Live bacteria and medium alone served as positive and negative control, respectively. Tissues were also analyzed for cell types mediating inflammation and overall apoptotic changes. Non-viable B. burgdorferi induced significant levels of several inflammatory mediators in both FC and DRG, similar to live bacteria. However, the levels induced by non-viable B. burgdorferi was often (several fold) higher than those induced by live ones, especially for IL-6, CXCL8 and CCL2. This effect was also more profound in the FC than in the DRG. Although the levels often differed, both live and dead fragments induced the same mediators, with significant overlap between FC and DRG. In the FC, immunohistochemical staining for several inflammatory mediators showed the presence of multiple mediators in astrocytes, followed by microglia and oligodendrocytes, in response to bacterial remnants. Staining was also seen in endothelial cells. In the DRG, chemokine/cytokine staining was predominantly seen in S100 positive (glial) cells. B. burgdorferi remnants also induced significant levels of apoptosis in both the FC and DRG. Apoptosis was confined to S100 + cells in the DRG while distinct neuronal apoptosis was also detected in most FC tissues in response to sonicated bacteria. Non-viable B. burgdorferi can continue to be neuropathogenic to both CNS and PNS tissues with effects likely more profound in the former. Persistence of remnant-induced neuroinflammatory processes can lead to long term health consequences.
Asunto(s)
Borrelia burgdorferi/patogenicidad , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/microbiología , Animales , Apoptosis , Quimiocina CCL2/metabolismo , Femenino , Técnicas In Vitro , Mediadores de Inflamación/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Enfermedad de Lyme/metabolismo , Enfermedad de Lyme/patología , Macaca mulatta , MasculinoRESUMEN
Gastrointestinal (GI) problems and microbiota alterations have been frequently reported in autism spectrum disorders (ASD). In addition, abnormal perinatal trace metal levels have been found in ASD. Accordingly, mice exposed to prenatal zinc deficiency display features of ASD-like behavior. Here, we model GI development using 3D intestinal organoids grown under zinc-restricted conditions. We found significant morphological alterations. Using proteomic approaches, we identified biological processes affected by zinc deficiency that regulate barrier permeability and pro-inflammatory pathways. We confirmed our results in vivo through proteomics studies and investigating GI development in zinc-deficient mice. These show altered GI physiology and pro-inflammatory signaling, resulting in chronic systemic and neuroinflammation, and gut microbiota composition similar to that reported in human ASD cases. Thus, low zinc status during development is sufficient to compromise intestinal barrier integrity and activate pro-inflammatory signaling, resulting in changes in microbiota composition that may aggravate inflammation, altogether mimicking the co-morbidities frequently observed in ASD.
Asunto(s)
Trastorno del Espectro Autista , Enfermedades Gastrointestinales , Enfermedades Neuroinflamatorias , Zinc/deficiencia , Animales , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/microbiología , Femenino , Enfermedades Gastrointestinales/metabolismo , Enfermedades Gastrointestinales/microbiología , Microbioma Gastrointestinal , Tracto Gastrointestinal/crecimiento & desarrollo , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/microbiología , Organoides , ProteómicaRESUMEN
BACKGROUND: Atrial natriuretic peptide (ANP) secreted from atrial myocytes is shown to possess anti-inflammatory, anti-oxidant and immunomodulatory effects. The aim of this study is to assess the effect of ANP on bacterial lipopolysaccharide (LPS)-induced endotoxemia-derived neuroinflammation and cognitive impairment. METHODS: LPS (5 mg/kg) was given intraperitoneally to mice. Recombinant human ANP (rhANP) (1.0 mg/kg) was injected intravenously 24 h before and/or 10 min after LPS injection. Subdiaphragmatic vagotomy (SDV) was performed 14 days before LPS injection or 28 days before fecal microbiota transplantation (FMT). ANA-12 (0.5 mg/kg) was administrated intraperitoneally 30 min prior to rhANP treatment. RESULTS: LPS (5.0 mg/kg) induced remarkable splenomegaly and an increase in the plasma cytokines at 24 h after LPS injection. There were positive correlations between spleen weight and plasma cytokines levels. LPS also led to increased protein levels of ionized calcium-binding adaptor molecule (iba)-1, cytokines and inducible nitric oxide synthase (iNOS) in the hippocampus. LPS impaired the natural and learned behavior, as demonstrated by an increase in the latency to eat the food in the buried food test and a decrease in the number of entries and duration in the novel arm in the Y maze test. Combined prophylactic and therapeutic treatment with rhANP reversed LPS-induced splenomegaly, hippocampal and peripheral inflammation as well as cognitive impairment. However, rhANP could not further enhance the protective effects of SDV on hippocampal and peripheral inflammation. We further found that PGF mice transplanted with fecal bacteria from rhANP-treated endotoxemia mice alleviated the decreased protein levels of hippocampal polyclonal phosphorylated tyrosine kinase receptor B (p-TrkB), brain-derived neurotrophic factor (BDNF) and cognitive impairment, which was abolished by SDV. Moreover, TrkB/BDNF signaling inhibitor ANA-12 abolished the improving effects of rhANP on LPS-induced cognitive impairment. CONCLUSIONS: Our results suggest that rhANP could mitigate LPS-induced hippocampal inflammation and cognitive dysfunction through subdiaphragmatic vagus nerve-mediated gut microbiota-brain axis.
Asunto(s)
Factor Natriurético Atrial/farmacología , Eje Cerebro-Intestino/efectos de los fármacos , Disfunción Cognitiva/inducido químicamente , Endotoxinas/antagonistas & inhibidores , Microbioma Gastrointestinal/efectos de los fármacos , Nervio Vago/microbiología , Animales , Disfunción Cognitiva/psicología , Endotoxinas/toxicidad , Heces/microbiología , Mediadores de Inflamación , Inyecciones Intraperitoneales , Lipopolisacáridos/antagonistas & inhibidores , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias/microbiología , Proteínas Recombinantes , VagotomíaRESUMEN
Regulatory T cells (Tregs) are the major determinant of peripheral immune tolerance. Many Treg subsets have been described, however thymus-derived and peripherally induced Tregs remain the most important subpopulations. In multiple sclerosis, a prototypical autoimmune disorder of the central nervous system, Treg dysfunction is a pathogenic hallmark. In contrast, induction of Treg proliferation and enhancement of their function are central immune evasion mechanisms of infectious pathogens. In accordance, Treg expansion is compartmentalized to tissues with high viral replication and prolonged in chronic infections. In friend retrovirus infection, Treg expansion is mainly based on excessive interleukin-2 production by infected effector T cells. Moreover, pathogens seem also to enhance Treg functions as shown in human immunodeficiency virus infection, where Tregs express higher levels of effector molecules such as cytotoxic T-lymphocyte-associated protein 4, CD39 and cAMP and show increased suppressive capacity. Thus, insights into the molecular mechanisms by which intracellular pathogens alter Treg functions might aid to find new therapeutic approaches to target central nervous system autoimmunity. In this review, we summarize the current knowledge of the role of pathogens for Treg function in the context of autoimmune neuroinflammation. We discuss the mechanistic implications for future therapies and provide an outlook for new research directions.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/microbiología , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/microbiología , Linfocitos T Reguladores/inmunología , Animales , Humanos , Infección Persistente/inmunologíaRESUMEN
Neuroinflammation can severely affect brain homeostasis and adult hippocampal neurogenesis with detrimental effects on cognitive processes. Brain and gut are intimately connected via the "gut-brain axis", a bidirectional communication system, and the administration of live bacteria (probiotics) has been shown to represent an intriguing approach for the prevention or even the cure of several diseases. In the present study we evaluated the putative neuroprotective effect of 15-days consumption of a multi-strain probiotic formulation based on food-associated strains and human gut bacteria at the dose of 109 CFU/mouse/day in a mouse model of acute inflammation, induced by an intraperitoneal single injection of LPS (0.1 mg/kg) at the end of probiotic administration. The results indicate that the prolonged administration of the multi-strain probiotic formulation not only prevents the LPS-dependent increase of pro-inflammatory cytokines in specific regions of the brain (hippocampus and cortex) and in the gastrointestinal district but also triggers a potent proneurogenic response capable of enhancing hippocampal neurogenesis. This effect is accompanied by a potentiation of intestinal barrier, as documented by the increased epithelial junction expression in the colon. Our hypothesis is that pre-treatment with the multi-strain probiotic formulation helps to create a systemic protection able to counteract or alleviate the effects of LPS-dependent acute pro-inflammatory responses.
Asunto(s)
Antiinflamatorios/uso terapéutico , Eje Cerebro-Intestino , Enfermedades Neuroinflamatorias/prevención & control , Fármacos Neuroprotectores/uso terapéutico , Probióticos , Animales , Ansiedad , Encéfalo/citología , Cadherinas/metabolismo , Colon/metabolismo , Citocinas/genética , Modelos Animales de Enfermedad , Conducta Exploratoria , Conducta de Enfermedad , Lipopolisacáridos , Masculino , Ratones Endogámicos C57BL , Neurogénesis , Enfermedades Neuroinflamatorias/genética , Enfermedades Neuroinflamatorias/microbiología , Ocludina/metabolismoRESUMEN
Staphylococcus aureus induced brain abscess is a critical health concern throughout the developing world. The conventional surgical intervention could not regulate the abscess-induced brain inflammation. Thus further study over the alternative therapeutic strategy for treating a brain abscess is of high priority. The resident glial cells recognize the invading S. aureus by their cell surface Toll-like receptor-2 (TLR-2). Glucocorticoid receptor (GR) was known for its immunosuppressive effects. In this study, an attempt had been taken to utilize the functional relationship or cross-talking between TLR-2 and GR during the pathogenesis of brain abscesses. Here, the combination of an antibiotic (i.e. ciprofloxacin) and dexamethasone was used to regulate the brain inflammation either in TLR-2 or GR blocking condition. We were also interested to figure out the possible impact of alternative therapy on behavioral impairments. The results indicated that combination treatment during TLR-2 blockade significantly reduced the bacterial burden and abscess area score in the infected brain. However, marked improvements were observed in anxiety, depression-like behavior, and motor co-ordination. The combination treatment after TLR-2 blocking effectively scavenged free radicals (H2O2, superoxide anion, and NO) through modulating antioxidant enzyme activities that ultimately control S. aureus induced glial reactivity possibly via up-regulating GR expression. The exogenous dexamethasone might regulate the GR expression in the brain by increasing the corticosterone concentration and the GC-GR mediated signaling. Therefore, this in-vivo study demonstrates the possible regulatory mechanism of bacterial brain abscess that involved TLR-2 and GR as a part of neuroendocrine-immune interaction.
Asunto(s)
Absceso Encefálico/tratamiento farmacológico , Ciprofloxacina/farmacología , Dexametasona/farmacología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Infecciones Estafilocócicas/tratamiento farmacológico , Animales , Conducta Animal/efectos de los fármacos , Absceso Encefálico/complicaciones , Absceso Encefálico/inmunología , Absceso Encefálico/microbiología , Ciprofloxacina/uso terapéutico , Dexametasona/uso terapéutico , Modelos Animales de Enfermedad , Quimioterapia Combinada , Humanos , Masculino , Ratones , Enfermedades Neuroinflamatorias/diagnóstico , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/microbiología , Sistemas Neurosecretores/efectos de los fármacos , Sistemas Neurosecretores/inmunología , Receptores de Glucocorticoides/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Infecciones Estafilocócicas/complicaciones , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/inmunología , Receptor Toll-Like 2/metabolismoRESUMEN
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.