Mucosal-associated invariant T (MAIT) cells are innate-like T cells that rapidly produce cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-17 (IL-17) upon activation. The immune response is crucial in stroke-related injury. However, few studies have investigated the role of MAIT cells in ischemic brain injury. This study assessed the predictive value of circulating MAIT cells in acute ischemic stroke (AIS) and early neurological deterioration (END).

We prospectively and continuously enrolled AIS patients within 72 h of stroke onset and included controls. END was defined as a ≥ 2-point increase in the National Institutes of Health Stroke Scale score within the first 72 h. Receiver operating characteristic curves were used to evaluate the predictive value of MAIT cells for END.

This study included 188 AIS patients and 135 controls, with 50 (26.6 %) AIS patients experiencing END. After adjusting for all potential confounders, circulating MAIT cell frequencies were lower in AIS patients than in controls (odds ratio [OR]: 0.83, 95 % confidence interval [CI]: 0.70-0.97, P = 0.02). IL-17 and TNF-α levels were significantly higher in AIS patients and negatively correlated with MAIT cell frequencies (R = -0.26, P < 0.05; R = -0.19, P < 0.05). Multivariate logistic regression analysis revealed that MAIT cell frequencies were lower in patients with END compared to those without END (OR: 0.74, 95 % CI: 0.55-0.96, P = 0.03). The area under the curve for MAIT cells in END prediction was 0.641 (95 % CI: 0.548-0.725, P < 0.05).

MAIT cell frequency was reduced in AIS patients and may serve as a predictive marker for END. Modulating these cells could be a novel AIS treatment strategy.

Post-stroke depression (PSD) is one of the most common and devastating neuropsychiatric complications in stroke patients, affecting more than one-third of survivors of ischemic stroke (IS). Despite its high incidence, PSD is often overlooked or undertreated in clinical practice, and effective preventive measures and therapeutic interventions remain limited. Although the exact mechanisms of PSD are not fully understood, emerging evidence suggests that the gut microbiota plays a key role in regulating gut-brain communication. This has sparked great interest in the relationship between the microbiota-gut-brain axis (MGBA) and PSD, especially in the context of cerebral ischemia. In addition to the gut microbiota, another important factor is the gut barrier, which acts as a frontline sensor distinguishing between beneficial and harmful microbes, regulating inflammatory responses and immunomodulation. Based on this, this paper proposes a new approach, the microbiota-immune-barrier axis, which is not only closely related to the pathophysiology of IS but may also play a critical role in the occurrence and progression of PSD. This review aims to systematically analyze how the gut microbiota affects the integrity and function of the barrier after IS through inflammatory responses and immunomodulation, leading to the production or exacerbation of depressive symptoms in the context of cerebral ischemia. In addition, we will explore existing technologies that can assess the MGBA and potential therapeutic strategies for PSD, with the hope of providing new insights for future research and clinical interventions.

Stroke is one of the most devastating pathologies in terms of mortality, cause of dementia, major adult disability, and socioeconomic burden worldwide. Despite its severity, treatment options remain limited, with no pharmacological therapies available for hemorrhagic stroke (HS) and only fibrinolytic therapy or mechanical thrombectomy for ischemic stroke (IS). In the pathophysiology of stroke, after the acute phase, many patients develop systemic immunosuppression, which, combined with neurological dysfunction and hospital management, leads to the onset of stroke-associated infections (SAIs). These infections worsen prognosis and increase mortality. Recent evidence, particularly from experimental studies, has highlighted alterations in the microbiota-gut-brain axis (MGBA) following stroke, which ultimately disrupts the gut flora and increases intestinal permeability. These changes can result in bacterial translocation (BT) from the gut to sterile organs, further contributing to the development of SAIs. Given the novelty and significance of these processes, especially the role of BT in the development of SAIs, this review summarizes the latest advances in understanding these phenomena and discusses potential therapeutic strategies to mitigate them, ultimately reducing post-stroke complications and improving treatment outcomes.

The activation of the immune system is crucial for the fate of the ischemic brain tissue and neurological outcome in experimental stroke. Rapidly after stroke γδ (γδ17), T cells release IL-17A in the ischemic brain and thereby amplify the early detrimental immune response. Notably, IL-17A levels in γδ17 T cells are modulated by the intestinal microbiota which is, in turn, shaped by the diet. Importantly, besides their proinflammatory effects, meningeal γδ17 T cells have been recently implicated in regulating neuronal signaling, behavior, and cognition under homeostatic and pathological conditions at the brain-meningeal interface. Against this background, we propose that a dietary intervention represents a promising treatment option to improve poststroke outcomes by the modulation of the microbiota composition and IL-17A levels in γδ T cells.

The gut serves as a vital immunological organ orchestrating immune responses and influencing distant mucosal sites, notably the respiratory mucosa. It is increasingly recognized as a central driver of critical illnesses, with intestinal hyperpermeability facilitating bacterial translocation, systemic inflammation, and organ damage. The "gut-lung" axis emerges as a pivotal pathway, where gut-derived injurious factors trigger acute lung injury (ALI) through the systemic circulation. Direct and indirect effects of gut microbiota significantly impact immune responses. Dysbiosis, particularly intestinal dysbiosis, termed as an imbalance of microbial species and a reduction in microbial diversity within certain bodily microbiomes, influences adaptive immune responses, including differentiating T regulatory cells (Tregs) and T helper 17 (Th17) cells, which are critical in various lung inflammatory conditions. Additionally, gut and bone marrow immune cells impact pulmonary immune activity, underscoring the complex gut-lung interplay. Moreover, lung microbiota alterations are implicated in diverse gut pathologies, affecting local and systemic immune landscapes. Notably, lung dysbiosis can reciprocally influence gut microbiota composition, indicating bidirectional gut-lung communication. In this review, we investigate the pathophysiology of ALI/acute respiratory distress syndrome (ARDS), elucidating the role of immune cells in the gut-lung axis based on recent experimental and clinical research. This exploration aims to enhance understanding of ALI/ARDS pathogenesis and to underscore the significance of gut-lung interactions in respiratory diseases.

The economic impact of gastrointestinal (GI) nematode infections on livestock production is well documented worldwide. Increasing evidence supports the hypothesis that parasite colonization induces significant changes in the GI tract environment and, therefore, in the landscape where the microbiota and parasites occur. Understanding the interactions between bacterial and parasite populations in the digestive tract of livestock may be useful to design parasite control strategies based on microbiota modification. The aims of this work were to investigate the impact of the oxytetracycline-mediated manipulation of the gut microbial community on the composition of GI nematode populations in naturally infected sheep and to explore changes in the GI microbial communities after nematode population treatment with the anthelmintic compound monepantel. Extensive manipulation of the GI microbiota with a therapeutic dose of the long-acting oxytetracycline formulation did not induce significant changes in the GI nematode burden. The gut microbiota of treated animals returned to control levels 17 days after treatment, suggesting strong resilience of the sheep microbial community to antibiotic-mediated microbiota perturbation. A significant decrease of the bacterial Mycoplasmataceae family (Log2FC = -4, Padj = 0.001) and a marked increase of the Methanobacteriaceae family (Log2FC = 2.9, Padj = 0.018) were observed in the abomasum of sheep receiving the monepantel treatment. While a comprehensive evaluation of the interactions among GI mycoplasma, methanobacteria and nematode populations deserves further assessment, the bacteria-nematode population interactions should be included in future control programs in livestock production. Understanding how bacteria and parasites may influence each other in the GI tract environment may substantially contribute to the knowledge of the role of microbiota composition in nematode parasite establishment and the role of the parasites in the microbiota composition.

Ischemic stroke (IS) is a serious central nervous system disease. Post-IS complications, such as post-stroke cognitive impairment (PSCI), post-stroke depression (PSD), hemorrhagic transformation (HT), gastrointestinal dysfunction, cardiovascular events, and post-stroke infection (PSI), result in neurological deficits. The microbiota-gut-brain axis (MGBA) facilitates bidirectional signal transduction and communication between the intestines and the brain. Recent studies have reported alterations in gut microbiota diversity post-IS, suggesting the involvement of gut microbiota in post-IS complications through various mechanisms such as bacterial translocation, immune regulation, and production of gut bacterial metabolites, thereby affecting disease prognosis. In this review, to provide insights into the prevention and treatment of post-IS complications and improvement of the long-term prognosis of IS, we summarize the interaction between the gut microbiota and IS, along with the effects of the gut microbiota on post-IS complications.

The human gastrointestinal tract (GIT) has a rich and pre-programmed microbiome. This microbiome is essential for physiological functions such as digestion, immunity, metabolism, and structural integrity, and of prime concern to us in conducting this study is the nervous system communication. This two-way communication between the GIT and central nervous system (CNS) is known as the gut-brain axis (GBA) and has implications for neurocritical disease. A change in any factor relating to this microbiome is known as gut dysbiosis; this can lead to aberrant communication through the GBA and in turn, can contribute to disease states. The primary objective of this study is to determine the cause-specific dysbiotic organisms in neuro-critically ill patients and their effects. We performed this study by searching published literature as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies that defined gastrointestinal dysbiosis in neuro-critically ill patients were retrieved using Boolean search from 2000 to 2023 via PubMed and Google Scholar and narrowed the results down to five prospective case-control studies. We performed their quality assessment. The results concluded that in neurocritical illnesses such as encephalitis, brain tumors, intracerebral hemorrhage, and ischemic stroke, fluctuations in specific microbiota correlated with disease severity and prognosis. Moreover, the inhabiting population of dysbiotic organisms in neuro-critically ill patients were different in different diseases and there were no similarities in the composition of gut microbiota in these diseases. Taking stroke patients as an example; increased Enterobacteriaceae and lower Lachnospiraceae microbiome levels were found in patients with a higher stroke dysbiosis index (SDI). Those patients who developed stroke-associated pneumonia (SAP) displayed higher levels of Enterococcus species. In conclusion, dysbiosis has a major effect on neuro-critically ill patients' disease states and dysbiotic organisms can be used as a biomarker for disease. Further prospective studies on this topic are warranted for potential neurological and prognostic correlations.

Acute ischaemic and haemorrhagic stroke account for significant disability and morbidity burdens worldwide. The myeloid arm of the peripheral innate immune system is critical in the immunological response to acute ischaemic and haemorrhagic stroke. Neutrophils, monocytes, and dendritic cells (DC) contribute to the evolution of pathogenic local and systemic inflammation, whilst maintaining a critical role in ongoing immunity protecting against secondary infections. This review aims to summarise the key alterations to myeloid immunity in acute ischaemic stroke, intracerebral haemorrhage (ICH), and subarachnoid haemorrhage (SAH). By integrating clinical and preclinical research, we discover how myeloid immunity is affected across multiple organ systems including the brain, blood, bone marrow, spleen, and lung, and evaluate how these perturbations associate with real-world outcomes including infection. These findings are placed in the context of the rapidly developing field of human immunology, which offers a wealth of opportunity for further research.

Cerebral stroke is a common neurological disease and often causes severe neurological deficits. With high morbidity, mortality, and disability rates, stroke threatens patients' life quality and brings a heavy economic burden on society. Ischemic cerebral lesions incur pathological changes as well as spontaneous nerve repair following stroke. Strategies such as drug therapy, physical therapy, and surgical treatment, can ameliorate blood and oxygen supply in the brain, hamper the inflammatory responses and maintain the structural and functional integrity of the brain. The gut microbiome, referred to as the "second genome" of the human body, participates in the regulation of multiple physiological functions including metabolism, digestion, inflammation, and immunity. The gut microbiome is not only inextricably associated with dangerous factors pertaining to stroke, including high blood pressure, diabetes, obesity, and atherosclerosis, but also influences stroke occurrence and prognosis. AMPK functions as a hub of metabolic control and is responsible for the regulation of metabolic events under physiological and pathological conditions. The AMPK mediators have been found to exert dual roles in regulating gut microbiota and neuroinflammation/neuronal apoptosis in stroke. In this study, we reviewed the role of the gut microbiome in cerebral stroke and the underlying mechanism of the AMPK signaling pathway in stroke. AMPK mediators in nerve repair and the regulation of intestinal microbial balance were also summarized.

Acute ischemic stroke (AIS) is associated with high rates of disability and mortality, exerting a substantial impact on overall survival and health-related quality of life. Treatment of AIS remains challenging given that the underlying pathologic mechanisms remain unclear. However, recent research has demonstrated that the immune system plays a key role in the development of AIS. Numerous studies have reported infiltration of T cells into ischemic brain tissue. While some types of T cells can promote the development of inflammatory responses and aggravate ischemic damage in patients with AIS, other T cells appear to exert neuroprotective effects via immunosuppression and other mechanisms. In this review, we discuss the recent findings regarding the infiltration of T cells into ischemic brain tissue, and the mechanisms governing how T cells can facilitate tissue injury or neuroprotection in AIS. Factors influencing the function of T cells, such as intestinal microflora and sex differences, are also discussed. We also explore the recent research on the effect of non-coding RNA on T cells after stroke, as well as the potential for specifically targeting T cells in the treatment of stroke patients.

Metabolites secreted by the gut microbiota may play an essential role in microbiota-gut-central nervous system crosstalk. In this study, we explored the changes occurring in the gut microbiota and their metabolites in patients with spinal cord injury (SCI) and analyzed the correlations among them.

The structure and composition of the gut microbiota derived from fecal samples collected from patients with SCI (n = 11) and matched control individuals (n = 10) were evaluated using 16S rRNA gene sequencing. Additionally, an untargeted metabolomics approach was used to compare the serum metabolite profiles of both groups. Meanwhile, the association among serum metabolites, the gut microbiota, and clinical parameters (including injury duration and neurological grade) was also analyzed. Finally, metabolites with the potential for use in the treatment of SCI were identified based on the differential metabolite abundance analysis.

The composition of the gut microbiota was different between patients with SCI and healthy controls. At the genus level, compared with the control group, the abundance of UBA1819, Anaerostignum, Eggerthella, and Enterococcus was significantly increased in the SCI group, whereas that of Faecalibacterium, Blautia, Escherichia-Shigella, Agathobacter, Collinsella, Dorea, Ruminococcus, Fusicatenibacter, and Eubacterium was decreased. Forty-one named metabolites displayed significant differential abundance between SCI patients and healthy controls, including 18 that were upregulated and 23 that were downregulated. Correlation analysis further indicated that the variation in gut microbiota abundance was associated with changes in serum metabolite levels, suggesting that gut dysbiosis is an important cause of metabolic disorders in SCI. Finally, gut dysbiosis and serum metabolite dysregulation was found to be associated with injury duration and severity of motor dysfunction after SCI.

We present a comprehensive landscape of the gut microbiota and metabolite profiles in patients with SCI and provide evidence that their interaction plays a role in the pathogenesis of SCI. Furthermore, our findings suggested that uridine, hypoxanthine, PC(18:2/0:0), and kojic acid may be important therapeutic targets for the treatment of this condition.

In humans, the gut microbiota (GM) are known to play a significant role in the metabolism of nutrients and drugs, immunomodulation, and pathogen defense by inhabiting the gastrointestinal tract (GIT). The role of the GM in the gut-brain axis (GBA) has been documented for different regulatory mechanisms and associated pathways and it shows different behaviors with individualized bacteria. In addition, the GM are known as susceptibility factor for neurological disorders in the central nervous system (CNS), regulating disease progression and being amenable to intervention. Bidirectional transmission between the brain and the GM occurs in the GBA, implying that it performs a significant role in neurocrine, endocrine, and immune-mediated signaling pathways. The GM regulates multiple neurological disorders by supplementing them with prebiotics, probiotics, postbiotics, synbiotics, fecal transplantations, and/or antibiotics. A well-balanced diet is critically important for establishing healthy GM, which can alter the enteric nervous system (ENS) and regulate multiple neurological disorders. Here, we have discussed the function of the GM in the GBA from the gut to the brain and the brain to the gut, the pathways associated with neurology that interacts with the GM, and the various neurological disorders associated with the GM. Furthermore, we have highlighted the recent advances and future prospects of the GBA, which may require addressing research concerns about GM and associated neurological disorders.

Ischaemic stroke is a leading cause of disability and death for which no acute treatments exist beyond recanalization. The development of novel therapies has been repeatedly hindered by translational failures that have changed the way we think about tissue damage after stroke. What was initially a neuron-centric view has been replaced with the concept of the neurovascular unit (NVU), which encompasses neuronal, glial and vascular compartments, and the biphasic nature of neural-glial-vascular signalling. However, it is now clear that the brain is not the private niche it was traditionally thought to be and that the NVU interacts bidirectionally with systemic biology, such as systemic metabolism, the peripheral immune system and the gut microbiota. Furthermore, these interactions are profoundly modified by internal and external factors, such as ageing, temperature and day-night cycles. In this Review, we propose an extension of the concept of the NVU to include its dynamic interactions with systemic biology. We anticipate that this integrated view will lead to the identification of novel mechanisms of stroke pathophysiology, potentially explain previous translational failures, and improve stroke care by identifying new biomarkers of and treatment targets in stroke.

Stroke leads to gut bacterial dysbiosis that impacts the post-stroke outcome. The gut microbiome also contains a high abundance of viruses which might play a crucial role in disease progression and recovery by modulating the metabolism of both host and host's gut bacteria. We presently analyzed the virome composition (viruses and phages) by shotgun metagenomics in the fecal samples obtained at 1 day of reperfusion following transient focal ischemia in adult mice. Viral genomes, viral auxiliary metabolic genes, and viral protein networks were compared between stroke and sham conditions (stroke vs sham, exclusive to sham and exclusive to stroke). Following focal ischemia, abundances of 2 viral taxa decreased, and 5 viral taxa increased compared with the sham. Furthermore, the abundance of Clostridia-like phages and Erysipelatoclostridiaceae-like phages were altered in the stroke compared with the sham cohorts. This is the first report to show that the gut virome responds acutely to stroke.

Homeostasis of gut microbiota is crucial in maintaining human health. Alterations, or "dysbiosis," are increasingly implicated in human diseases, such as cancer, inflammatory bowel diseases, and, more recently, neurological disorders. In ischemic stroke patients, gut microbial profiles are markedly different compared to healthy controls, whereas manipulation of microbiota in animal models of stroke modulates outcome, further implicating microbiota in stroke pathobiology. Despite this, evidence for the involvement of specific microbes or microbial products and microbial signatures have yet to be identified, likely owing to differences in methodology, data analysis, and confounding variables between different studies. Here, we provide a set of guidelines to enable researchers to conduct high-quality, reproducible, and transparent microbiota studies, focusing on 16S rRNA sequencing in the emerging subfield of the stroke-microbiota. In doing so, we aim to facilitate novel and reproducible associations between the microbiota and brain diseases, including stroke, and translation into clinical practice.

Communication between the enteric nervous system (ENS) of the gastrointestinal (GI) tract and the central nervous system (CNS) is vital for maintaining systemic homeostasis. Intrinsic and extrinsic neurological inputs of the gut regulate blood flow, peristalsis, hormone release, and immunological function. The health of the gut microbiome plays a vital role in regulating the overall function and well-being of the individual. Microbes release short-chain fatty acids (SCFAs) that regulate G-protein-coupled receptors to mediate hormone release, neurotransmitter release (i.e., serotonin, dopamine, noradrenaline, γ-aminobutyric acid (GABA), acetylcholine, and histamine), and regulate inflammation and mood. Further gaseous factors (i.e., nitric oxide) are important in regulating inflammation and have a response in injury. Neurologic injuries such as ischemic stroke, spinal cord injury, traumatic brain injury, and hemorrhagic cerebrovascular lesions can all lead to gut dysbiosis. Additionally, unfavorable alterations in the composition of the microbiota may be associated with increased risk for these neurologic injuries due to increased proinflammatory molecules and clotting factors. Interventions such as probiotics, fecal microbiota transplantation, and oral SCFAs have been shown to stabilize and improve the composition of the microbiome. However, the effect this has on neurologic injury prevention and recovery has not been studied extensively. The purpose of this review is to elaborate on the complex relationship between the nervous system and the microbiome and to report how neurologic injury modulates the status of the microbiome. Finally, we will propose various interventions that may be beneficial in the recovery from neurologic injury.

The gut microbiota is one of the great innovations of modern medicine. In the modern microbiota revolution era, more comprehensive and in-depth studies have been performed regarding the microbial gut communities and their impact on acute and chronic diseases, including those of the nervous system as acute neurological diseases. The microbiota has changed our knowledge of medical conditions; in particular, considering stroke (both ischemic and hemorrhagic), literature studies, experimental and clinical researches indicate that the individual's risk and outcomes are substantially impacted by the gut microbiota. The aim of our review article is to investigate and discuss the recent insights into the emerging role of this complex "gut microbiota-brain axis" in affecting some acute neurological diseases, such as stroke, responsible for a significant number of deaths worldwide. We performed electronic research on PubMed® and collected articles published in the last ten years, finding that changes in the gut microbiota composition could affect various aspects of stroke pathophysiology and individual predisposition, risk, and outcomes. Our review article suggests that there is a strong connection between the gut microbiota and the brain, both in health and in acute neurological diseases such as stroke. Investigating and exploring this relationship can be a challenge useful to learn more about this disabling/deadly condition, and it can be a useful tool to identify novel potential therapeutic approaches, improving an individual's outcomes and life.

The gut microbiome has been implicated as a key regulator of brain function in health and disease. But the impact of gut microbiota on functional brain connectivity is unknown. We used resting-state functional magnetic resonance imaging in germ-free and normally colonized mice under naive conditions and after ischemic stroke. We observed a strong, brain-wide increase of functional connectivity in germ-free animals. Graph theoretical analysis revealed significant higher values in germ-free animals, indicating a stronger and denser global network but with less structural organization. Breakdown of network function after stroke equally affected germ-free and colonized mice. Results from histological analyses showed changes in dendritic spine densities, as well as an immature microglial phenotype, indicating impaired microglia-neuron interaction in germ-free mice as potential cause of this phenomenon. These results demonstrate the substantial impact of bacterial colonization on brain-wide function and extend our so far mainly (sub) cellular understanding of the gut-brain axis.