Weightlessness usually causes disruption of the gut microbiota and impairs cognitive function. There is a close connection between gut microbiota and neurological diseases. Low-intensity pulsed ultrasound (LIPUS) has a beneficial effect on reducing intestinal inflammation. So we wondered if abdominal LIPUS stimulation can have a positive impact on weightlessness induced cognitive decline by reducing intestinal dysfunction. The findings revealed that the hind limb unloaded mice exhibited evident disruption in intestinal structure and gut microbial homeostasis, along with impairment in their learning and memory capabilities. However, 4-week abdominal LIPUS treatment improved intestinal function in hind limb unloaded mice, characterized by upregulation of tight junction proteins ZO-1 and Occludin expression in the colon, increased diversity and abundance of intestinal microbiota, decreased serum lipopolysaccharide (LPS), and increased short chain fatty acids in colon contents. The hind limb unloaded mice treated with LIPUS exhibited heightened activity levels, improved exploratory tendencies, and significantly enhanced learning and memory faculties, and elevated expression of neuroadaptation-related proteins such as PSD95, GAP43, P-CREB, BDNF, and its receptor TRKB in the hippocampus. Furthermore, the hind limb unloaded mice receiving fecal transplants from the mice whose abdomens were irradiated with LIPUS displayed enhanced cognitive abilities and improved intestinal structure, akin to the outcomes observed in hind limb unloaded mice who received LIPUS abdominal treatment directly. The above results indicate that LIPUS enhances intestinal structure and microbiota, which helps alleviate cognitive impairment caused by weightlessness. LIPUS could be a potential strategy to simultaneously improve gut dysfunction and cognitive decline in astronauts or bedridden patients.

Sepsis-associated encephalopathy (SAE) is a severe central nervous system complication that is secondary to sepsis and is characterized by a poor prognosis, high mortality, and multiple systemic manifestations. Although the specific etiology remains incompletely understood, SAE typically presents with varying degrees of neurological dysfunction. The complex mechanisms underlying SAE significantly influence patient outcomes. Recent studies have emphasized the roles of bloodbrain barrier (BBB) disruption, microglial activation, mitochondrial dysfunction, apoptosis, inflammatory responses, and oxidative stress in the development and progression of SAE. Dexmedetomidine, a highly selective α2-adrenergic receptor agonist initially employed as an anesthetic adjunct, has attracted increasing attention for its therapeutic potential in SAE. Its notable pharmacological properties include anti-inflammatory activity, modulation of microglial responses, regulation of immune function, stabilization of mitochondrial activity, inhibition of apoptosis, and maintenance of hemodynamic stability in patients with sepsis. In addition, dexmedetomidine supports gastrointestinal homeostasis and offers multiorgan protection. This review consolidates current findings regarding the protective mechanisms of dexmedetomidine in sepsis-induced brain injury and provides insight into its potential clinical applications in the management of SAE.

The oral microbiota is an essential microbial community within the human body, playing a vital role in maintaining health. In older adults, age-related changes in the oral microbiota are linked to both systemic and oral health impairments. The use of various medications for systemic diseases in the elderly can also contribute to the development of oral diseases. Oral microbiota dysbiosis refers to an imbalance in the composition of oral microbial communities. This imbalance, along with disruptions in the host immune response and prolonged inflammation, is closely associated with the onset and progression of several diseases. It contributes to oral conditions such as dental caries, periodontal disease, and halitosis. It is also linked to systemic diseases, including Alzheimer's disease, type 2 diabetes mellitus, rheumatoid arthritis, atherosclerotic cardiovascular disease, and aspiration pneumonia. This review aims to explore how oral microbiota influences specific health outcomes in older individuals, focusing on Alzheimer's disease, type 2 diabetes mellitus, rheumatoid arthritis, atherosclerotic cardiovascular disease, and aspiration pneumonia. The oral microbiota holds promise as a diagnostic tool, therapeutic target, and prognostic biomarker for managing cardiovascular disease, metabolic diseases, infectious diseases and autoimmune diseases. Emphasizing proper oral health care and instilling an understanding of how drugs prescribed for systemic disease impact the oral microbiome, is anticipated to emerge as a key strategy for promoting the general health of older adults.

COVID-19 has been associated with a wide range of systemic and neurological complications, known as long COVID or postacute sequelae of COVID-19 (PASC). Such sequelae can be observed among all infected individuals, even among those with a mild disease course. Dysbiosis, a common condition associated with low-grade inflammation, has been proposed as a potential mechanism of PASC by altering levels of circulating lipopolysaccharide (LPS) and the tryptophan pathway metabolites kynurenine and quinolinic acid, known to affect neurocognitive function. The authors evaluated the evolution of neurological, neurocognitive, and neuropsychiatric COVID-19 sequelae and their relationship with circulating LPS and kynurenine and quinolinic acid levels.

A prospective, longitudinal, and analytical study was conducted. Neurological, neurocognitive, and neuropsychiatric assessments of participants who had recovered from COVID-19 and did not require hospitalization during the acute stages of the infection were performed. Peripheral levels of LPS and tryptophan metabolites were measured 1, 3, 6, and 12 months after infection.

Of 95 participants recruited, 67 COVID-19-convalescent individuals and 20 COVID-19-free individuals were included. Significantly higher occurrences of asthenia, olfaction and taste alterations, headache, memory dysfunction, and systemic symptoms such as dyspnea, cough, and periodontal diseases were found among participants in the COVID-19-convalescent group compared with participants in the comparison group. A significant decrease in kynurenine levels, which correlated with cognitive impairment, was observed among PASC convalescents.

Significant neurocognitive and neuropsychiatric impairments were observed among COVID-19-convalescent individuals, along with decreased kynurenine levels, which recovered during a 12-month follow-up period.

Acute respiratory distress syndrome (ARDS) is characterized by diffuse lung injury and high mortality rates due to severe inflammation. Adipose tissue, functioning as both an endocrine and immune organ, plays a crucial role in immune regulation by secreting a variety of adipokines. Among these, adipose tissue-derived extracellular vesicles (EVs) have emerged as novel mediators of intercellular communication, capable of delivering bioactive molecules such as microRNAs to target cells. This study aimed to elucidate the immunomodulatory roles and underlying mechanisms of adipose tissue-derived EVs in the pathogenesis of ARDS.

Subcutaneous adipose tissue extracellular vesicles (SAT-EVs) were collected from the mice via ultracentrifugation. C57BL/6 mice were administered SAT-EVs (1×10^9 particles per mouse) via tail vein injection, followed by an intraperitoneal Lipopolysaccharide (LPS) injection three hours later to induce acute respiratory distress syndrome (ARDS). The mice were euthanized after 18 h to evaluate the permeability of the microvessels and level of inflammation in the lungs. For in vitro experiments, RAW 264.7 macrophages were stimulated with LPS, with or without SAT-EVs, as a control, to evaluate the inflammatory response of the macrophages.

SAT-EVs treatment enhanced the survival rate of ARDS mice and reduced pulmonary vascular permeability. SAT-EVs were internalized by alveolar macrophages, leading to an attenuation of inflammation, as indicated by decreased levels of TNF-α, IL-1β, iNOS, PTGS2, and CCL2. Notably, SAT-EVs transferred miR-26a-5p to alveolar macrophages, which directly targeted conserved helix-loop-helix ubiquitous kinase (CHUK), a key regulator of the NF-κB pathway. This inhibition resulted in reduced transcription of inflammatory mediators (iNOS, PTGS2, and IL-1β). In vitro, SAT-EVs were internalized by RAW 264.7 macrophages, leading to the suppression of LPS-induced inflammation, as shown by decreased expression of TNF-α, IL-1β, iNOS, PTGS2, and CCL2. These findings suggest that miR-26a-5p plays a crucial role in the anti-inflammatory effects of SAT-EVs by suppressing CHUK and modulating the NF-κB pathway.

SAT-EVs significantly attenuated LPS-induced ARDS, potentially through the CHUK/NF-κB pathway mediated by miR-26a-5p, thereby exerting protective effects against inflammatory lung injury. These findings provide mechanistic insights into the role of SAT-EVs in immune modulation and suggest their potential as a therapeutic strategy for ARDS.

Typhoid fever, primarily caused by Salmonella Typhi, can result in severe life-threatening complications such as encephalopathy. Here we elucidate the mechanisms by which typhoid toxin, a unique virulence factor of S. Typhi, mediates the neuropathology associated with typhoid fever. Utilizing mice engineered to have specific tissues protected from toxin action and an in vitro model of the blood-brain barrier (BBB), we demonstrate that, rather than direct action on neuronal or glial cells, typhoid toxin causes neuropathology by disrupting the BBB. Intravenous tracer studies confirmed significant BBB permeability changes following toxin exposure, an effect we found to be mediated by typhoid toxin's CdtB catalytic subunit. We demonstrate that corticosteroids are effective at mitigating BBB disruption in vivo, supporting their use for managing typhoid fever neurological complications. Our data reveal mechanistic insight into how typhoid toxin causes encephalopathy and suggest targeted therapeutic interventions to alleviate the severe neurological manifestations of typhoid fever.

In recent years, with the increasing volume of related research, it has become apparent that the liver and gut play important roles in the pathogenesis of neurological disorders. Considering the interactions among the brain, liver, and gut, the brain-liver-gut axis has been proposed and gradually recognized. In this article, we summarized the complex network of interactions within the brain-liver-gut axis, encompassing the vagus nerve, barrier permeability, immunity and inflammation, the blood-brain barrier, gut microbial metabolites, the gut barrier, neurotoxic metabolites, and beta-amyloid (Aβ) metabolism. We also elaborated on the impact of the brain-liver-gut axis on various neurological disorders. Furthermore, we outline several therapies aimed at modulating the brain-liver-gut axis, including antibiotics, probiotics and prebiotics, fecal microbiota transplantation (FMT), vagus nerve stimulation (VNS), and dietary interventions. The focus is on elucidating possible mechanisms underlying neurological disorders pathogenesis and identifying effective treatments that are based on our understanding of the brain-liver-gut axis.

Neurodegenerative disorders such as Alzheimer's disease (AD), the most common form of dementia, represent a growing global health crisis, yet current treatment strategies remain primarily palliative. Recent studies have shown that neurodegeneration through complex interactions within the gut-brain axis largely depends on the gut microbiota and its metabolites. This review explores the intricate molecular mechanisms linking gut microbiota dysbiosis to cognitive decline, emphasizing the impact of microbial metabolites, including short-chain fatty acids (SCFAs), bile acids, and tryptophan metabolites, on neuroinflammation, blood-brain barrier (BBB) integrity, and amyloid-β and tau pathology. The paper highlights major microbiome signatures associated with Alzheimer's disease, detailing their metabolic pathways and inflammatory crosstalk. Dietary interventions have shown promise in modulating gut microbiota composition, potentially mitigating neurodegenerative processes. This review critically examines the influence of dietary patterns, such as the Mediterranean and Western diets, on microbiota-mediated neuroprotection. Bioactive compounds like prebiotics, omega-3 fatty acids, and polyphenols exhibit neuroprotective effects by modulating gut microbiota and reducing neuroinflammation. Furthermore, it discusses emerging microbiome-based therapeutic strategies, including probiotics, prebiotics, postbiotics, and fecal microbiota transplantation (FMT), as potential interventions for slowing Alzheimer's progression. Despite these advances, several knowledge gaps remain, including interindividual variability in microbiome responses to dietary interventions and the need for large-scale, longitudinal studies. The study proposes an integrative, precision medicine approach, incorporating microbiome science into Alzheimer's treatment paradigms. Ultimately, cognizance of the gut-brain axis at a mechanistic level could unlock novel therapeutic avenues, offering a non-invasive, diet-based strategy for managing neurodegeneration and improving cognitive health.

Gut microbiota plays an essential role in cognitive dysfunction during aging. The aim of this study was to investigate the dynamic alterations in the gut microbiota and screen for key gut bacterial taxa correlated with age-associated cognitive dysfunction during natural aging.

16S rRNA gene sequencing was performed to determine the composition of the gut microbiota in faecal samples from SAMR1 and SAMP8 mice, cognitively normal controls (NC), and patients with amnestic mild cognitive impairment (aMCI). Faecal microbiota transplantation (FMT) and GMrepo database were used to screen key gut microbiota associated with cognitive decline in aging mice and humans.

The composition of the gut microbiota dynamically changed during natural aging in SAMR1 and SAMP8 mice, as well as in healthy subjects of different ages extracted from the GMrepo database. FMT from SAMR1 to SAMP8 mice altered the gut microbiota composition and improved the cognitive impairment in SAMP8 mice. Key gut bacterial taxa, including Lactobacillus, Akkermansia, Clostridium, Oscillospira and Dorea, were screened and validated to correlate with aging-associated cognitive decline. The function of the key gut bacterial taxa predicted by PICRUSt2 indicated that the metabolic pathways related to short-chain fatty acids (SCFAs) and lipopolysaccharide (LPS) synthesis were involved in age-associated cognitive dysfunction during natural aging.

These results demonstrate that the composition of the gut microbiota changes dynamically during brain aging, with some key gut bacterial taxa playing critical roles in age-associated cognitive dysfunction through SCFAs and LPS synthesis metabolic pathways.

The blood-brain barrier, recently reintroduced as the blood-brain border (BBB), is a dynamic interface between the central nervous system (CNS) and the bloodstream. Disruption of the BBB exposes the CNS to peripheral pathogens and harmful substances, causing or worsening various CNS diseases. While traditional views attribute BBB failure to tight junction disruption or increased transcytosis, recent studies highlight the critical role of gasdermin D (GSDMD) pore formation in brain endothelial cells (bECs) during BBB disruption by lipopolysaccharide (LPS) or bacterial infections. This mechanism may also be involved in neurological complications like the 'brain fog' seen in long COVID. Pore formation in bECs may represent a prevalent mechanism causing BBB leakage. Investigating membrane-permeabilizing pores or channels and their effects on BBB integrity is a growing area of research. Further exploration of molecular processes that maintain, disrupt, and restore bEC membrane integrity will advance our understanding of brain vasculature and aid in developing new therapies for BBB-related diseases.

This study aimed to investigate the effects of MCC950 in a rat model of sepsis-associated encephalopathy (SAE). Adult male rats were randomly assigned to 12 groups according to the surgery or treatment received and evaluation times. The SAE model was established using the cecal ligation and puncture (CLP) method. Intraperitoneal injections of normal saline (10 mL/kg) or MCC950 (10 mg/kg) were administered 30 min pre-surgery and daily post-surgery. Changes in survival rates, weight loss, and heart rate were assessed at four time points, and neurobehavioral changes were evaluated using the composite neural reflex function scores, light/dark box test, and open-field test (OFT). Compared with the SAE group, the SAE + MCC950 group had significantly higher survival rates (P < 0.05), lower postoperative weight loss rates (P < 0.05), and higher neurological function scores (P < 0.05); the SAE + MCC950 group also traveled further and crossed the central area more frequently in the OFT (P < 0.05), spent more time in the light compartment at different time points (P < 0.05), and exhibited a lower heart rate at different time points (P < 0.05). MCC950 treatment significantly improved cognitive function and related indices in the SAE rats.

Sepsis-associated encephalopathy (SAE) is a severe neurological syndrome marked by widespread brain dysfunctions due to sepsis. Despite increasing data supporting the hypothesis of neuronal damage, the exact mechanism of sepsis-related cognitive disorders and therapeutic strategies remain unclear and need further investigation. In this study, a sepsis model was established in C57 mice using lipopolysaccharide (LPS). The findings demonstrated that LPS exposure induced neuronal loss, synaptic and cognitive deficits accompanied by mitochondrial damage. Bioinformatics and western blot analyses demonstrated a significant increase in Lipocalin-2 (LCN2) during sepsis as a key hub gene involved in immune and neurological inflammation. Interestingly, the recombinant LCN2 protein exhibited similar effects on synaptic dysfunction and cognitive deficits in C57 mice. Conversely, downregulating LCN2 effectively nullified the impact of LPS, leading to the amelioration of synaptic and cognitive deficits, neuronal loss, and reactive oxygen species (ROS)-associated mitochondrial damage. These findings suggest a novel etiopathogenic mechanism of SAE, which is initiated by the increased LCN2, leading to neuronal loss and cognitive deficit. Inhibition of LCN2 could be therapeutically beneficial in treating sepsis-induced synaptic and cognitive impairments.

Alpiniae oxyphyllae fructus (AOF) has been widely used for the treatment of central nervous system (CNS) diseases. Flavonoids, namely, baicalein, wogonin, and pinocembrin, are bioactive components with neuroprotective effects against AOF. Herein, a lipopolysaccharide (LPS)-induced in vitro inflammatory blood-brain barrier (BBB) model of a co-culture of hCMEC/D3 and HA1800 cells was constructed to investigate the permeability of flavonoids. The values of transmembrane resistance (TEER), apparent permeability (Papp) of sodium fluorescein (Na-F), and levels of TNF-α and IL-1β confirmed the construction of the in vitro inflammatory BBB model. An ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) was established to quantify the permeability of the three flavonoids. The average coefficients (R2) of the calibration curves were better than 0.99. The intraday and interday accuracies ranged from -13.75 % to 6.37 % and -14.28 % to 11.80 %, respectively. The recoveries and matrix effects were higher than 88.00 % and 92.42 %, respectively. These results indicated that the methodology was reliable. Compared with the normal BBB model, the permeability and efflux ratios of the three flavonoids significantly increased using the inflammatory BBB model. Papp BL→AP of wogonin and pinocembrin increased by approximately 1.3 and 5.5 times, respectively, thereby increasing the efflux ratios by 48 % and 76 %, respectively. The efflux ratios of the three flavonoids in the AOF were all < 2, demonstrating that they passed through the BBB in a passive diffusion way. This study investigated flavonoid transport from the AOF using the in vitro inflammatory BBB model, providing a material basis for neuroprotection as a potential drug for treating CNS diseases.

The aim of the present study was to characterize the antimicrobial and anti-inflammatory activities of postbiotics from lactic acid bacteria against Porphyromonas gingivalis.

The anti-P. gingivalis activity of postbiotics from the CERELA culture collection was assessed by measuring changes in the expression of key host proteins by ELISA and qPCR, the proteolytic activity by a fluorescence and a spectrophotometric method and virulence factors from P. gingivalis by qPCR.

Even though Lacticaseibacillus (L.) rhamnosus CRL1522 and Lactiplantibacillus (L.) plantarum CRL1363 exhibit only a discrete antibacterial activity against P. gingivalis, the cell-free supernatants of these strains significantly reduced P. gingivalis-induced secretion of interleukins IL-6 and IL-8 by keratinocytes and TNF-α and IL-6 by U937 macrophage-like cells. More importantly, P. gingivalis arginine-gingipain (Rgp) protease activity was markedly reduced by both lactic acid bacteria (LAB) strains. This finding is particularly interesting because it means that both LAB might prevent the ulterior citrullination of peptides and the consequent generation of autoantibodies. The expression of COX2 and TLR2 was also significantly downregulated in macrophages.

Postbiotics from L. rhamnosus CRL1522 and L. plantarum CRL1363 rise as suitable candidates for antagonizing the periodontopathogen P. gingivalis, since they were able to reduce the expression of proinflammatory cytokines and the protein degradation induced by this pathogen. We propose that postbiotics from these LAB could potentially halt the progression of periodontitis based on this in vitro study.

Stress has been implicated in the onset of mental disorders such as depression, with the prefrontal cortex (PFC) playing a crucial role. However, the underlying mechanisms remain to be fully elucidated. Metabolites secreted by intestinal flora can enter the bloodstream and exert regulatory effects on the body. Consequently, this study aims to investigate the molecular mechanisms by which gut flora influences ferroptosis in PFC neurons, thereby affecting depression-like behavioral changes in mice subjected to acute stress. Initially, we established a mouse model of acute restraint stress (3-day duration) and verified that stress-induced ferroptosis of PFC neurons contributed to depression-like behavioral alterations in mice, as evidenced by morphological, behavioral, and molecular biology assessments. Subsequently, through fecal microbiota transplantation (FMT) experiments, we established a significant correlation between gut microbiota and ferroptosis of PFC neurons in acute stress-exposed mice. 16S rDNA sequencing identified butyric acid-producing bacteria, specifically g_Butyricimonas and its primary metabolite, butyric acid, as critical regulators of ferroptosis in PFC neurons in acutely stressed mice. Furthermore, the intervention of butyrate demonstrated its potential to ameliorate damage to the intestinal and blood-brain barriers in these mice. This intervention also mitigated depression-like behaviors induced by ferroptosis of PFC neurons by alleviating systemic inflammatory responses. The findings of this study indicate that acute stress-induced ferroptosis of PFC neurons plays a critical role in depression-like behavioral changes in mice. Additionally, the gut microbiota metabolite butyrate can modulate ferroptosis and depression-like behavioral changes through the gut-brain axis.

Changes in population demographics indicate that the elderly population will reach 2.1 billion worldwide by 2050. In parallel, there will be an increase in neurodegenerative diseases such as Alzheimer's and Parkinson's. This review explores dysbiosis occurring in these pathologies and how virulence factors contribute to the worsening or development of clinical conditions, and it summarizes existing and potential ways to combat microorganisms related to these diseases. Microbiota imbalances can contribute to the progression of neurodegenerative diseases by increasing intestinal permeability, exchanging information through innervation, and even acting as a Trojan horse affecting immune cells. The microorganisms of the microbiota produce virulence factors to protect themselves from host defenses, many of which contribute to neurodegenerative diseases. These virulence factors are expressed according to the genetic composition of each microorganism, leading to a wide range of factors to be considered. Among the main virulence factors are LPS, urease, curli proteins, amyloidogenic proteins, VacA, and CagA. These factors can also be packed into bacterial outer membrane vesicles, which transport proteins, RNA, and DNA, enabling distal communication that impacts various diseases, including Alzheimer's and Parkinson's.

This study evaluated the effects of Rubus sp. extract on behavioral and neurochemical parameters in female mice submitted to experimental model of depression induced by lipopolysaccharide (LPS). The results indicated that Rubus sp. extract protected against depressive-like behavior induced by LPS. Moreover, the administration of Rubus sp. extract was effective in preventing the increase in reactive species and nitrites levels, as well as the decrease in catalase activity induced by LPS in the cerebral cortex. In the serum, the Rubus sp. extract was effective in preventing the decrease in catalase activity induced by LPS. Treatment with Rubus sp. extract attenuated the increase in acetylcholinesterase activity induced by LPS in the cerebral cortex. Finally, blackberry extract also downregulated IL-1β levels in cerebral cortex. In conclusion, our findings demonstrated that treatment with Rubus sp. exerted antidepressant, antioxidant, anticholinesterase and anti-inflammatory effects in a model of depressive - like behavior induced by LPS in female mice. This highlights Rubus sp. as a potential therapeutic agent for individuals with major depressive disorder.

Alzheimer's disease (AD) is a progressive, degenerative disorder of the central nervous system. Despite extensive research conducted on this disorder, its precise pathogenesis remains unclear. In recent years, the microbiota-gut-brain axis has attracted considerable attention within the field of AD. The gut microbiota communicates bidirectionally with the central nervous system through the gut-brain axis, and alterations in its structure and function can influence the progression of AD. Consequently, regulating the gut microbiota to mitigate the progression of AD has emerged as a novel therapeutic approach. Currently, numerous studies concentrate on the intrinsic relationship between the microbiota-gut-brain axis and AD. In this paper, we summarize the multifaceted role of the gut microbiota in AD and present detailed therapeutic strategies targeting the gut microbiota, including the treatment of AD with Traditional Chinese Medicine (TCM), which has garnered increasing attention in recent years. Finally, we discuss potential therapeutic strategies for modulating the gut microbiota to alleviate the progression of AD, the current challenges in this area of research, and provide an outlook on future research directions in this field.

Sepsis-associated encephalopathy (SAE) is a severe and frequent septic complication, characterized by neuronal damage as key pathological features. The astrocyte-microglia crosstalk in the central nervous system (CNS) plays important roles in various neurological diseases. However, how astrocytes interact with microglia to regulate neuronal injury in SAE is poorly defined. In this study, we aim to investigate the molecular basis of the astrocyte-microglia crosstalk underlying SAE pathogenesis and also to explore the new therapeutic strategies targeting this crosstalk in this devastating disease. We established a human astrocyte/microglia coculture system on a microfluidic device, which allows real-time and high-resolution recording of glial responses to inflammatory stimuli. Based on this microfluidic system, we can test the responses of astrocytes and microglia to lipopolysaccharide (LPS) treatment, and identify the molecular cues that mediate the astrocyte-microglia crosstalk underlying the pathological condition. In addition, the SAE mouse model was utilized to determine the state of glial cells and evaluate the therapeutic effect of drugs targeting the astrocyte-microglia crosstalk in vivo. Here, we found that activated astrocytes and microglia exhibited close spatial interaction in the SAE mouse model. Upon LPS exposure for astrocytes, we detected that more microglia migrated to the central astrocyte culture compartment on the microfluidic device, accompanied by M1 polarization and increased cell motility in microglia. Cytokine array analysis revealed that less interleukin 11 (IL11) was secreted by astrocytes following LPS treatment, which further promoted reprogramming of microglia to pro-inflammatory M1 phenotype via the nuclear factor-κB (NF-κB) signaling pathway. Intriguingly, we found that IL11 addition markedly rescued LPS-induced neuronal injuries on the microfluidic system and brain injury in the SAE mouse model. This study defines an unknown crosstalk of astrocyte-microglia mediated by IL11, which contributed to the neuropathogenesis of SAE, and suggested a potential therapeutic value of IL11 in the devastating disease.

Recent developments in microbiome research suggest that the gut microbiome may remotely modulate central and peripheral neuronal processes, ranging from early brain development to age-related changes. Dysbiotic microbiome configurations have been increasingly associated with neurological disorders, such as neurodegeneration, but causal understanding of these associations remains limited. Most mechanisms explaining how the microbiome may induce such remote neuronal effects involve microbially modulated metabolites that influx into the 'sterile' host. Some metabolites are able to cross the blood-brain barrier (BBB) to reach the central nervous system, where they can impact a variety of cells and processes. Alternatively, metabolites may directly signal to peripheral nerves to act as neurotransmitters or exert modulatory functions, or impact immune responses, which, in turn, modulate neuronal function and associated disease propensity. Herein, we review the current knowledge highlighting microbiome-modulated metabolite impacts on neuronal disease, while discussing unknowns, controversies and prospects impacting this rapidly evolving research field.

Xixin Decoction (XXD) is a classical formula that has been used to effectively treat dementia for over 300 years. Modern clinical studies have demonstrated its significant therapeutic effects in treating Alzheimer's disease (AD) without notable adverse reactions. Nevertheless, the specific mechanisms underlying its efficacy remain to be elucidated. This investigation sought to elucidate XXD's impact on various aspects of AD pathology, including blood-brain barrier (BBB) impairment, neuroinflammatory processes, and amyloid-β (Aβ) deposition, as well as the molecular pathways involved in these effects.

In vitro experiments were conducted using hCMEC/D3 and HBVP cell coculture to establish an in vitro blood-brain barrier (BBB) model. BBB damage was induced in this model by 24-h exposure to 1 μg/mL lipopolysaccharide (LPS). After 24, 48, and 72 h of treatment with 10% XXD-medicated serum, the effects of XXD were assessed through Western blotting, RT-PCR, and immunofluorescence techniques. In vivo, SAMP8 mice were administered various doses of XXD via gavage for 8 weeks, including high-dose XXD group (H-XXD) at 5.07 g kg-1·d-1, medium-dose XXD group (M-XXD) at 2.535 g kg-1·d-1, and low-dose XXD group (L-XXD) at 1.2675 g kg-1·d-1. Cognitive function was subsequently evaluated using the Morris water maze test. BBB integrity was evaluated using Evans blue staining, and protein expression levels were analyzed via ELISA, Western blotting, and immunofluorescence.

In vitro experiments revealed that XXD-containing serum, when cultured for 24, 48, and 72 h, could upregulate the expression of P-gp mRNA and protein, downregulate CB1 protein expression, and upregulate CB2 and Mfsd2a protein expression. In vivo studies demonstrated that XXD improved spatial learning and memory abilities in SAMP8 mice, reduced the amount of Evans blue extravasation in brain tissues, modulated the BBB-associated P-gp/ECS axis, RAGE/LRP1 receptor system, as well as MRP2 and Mfsd2a proteins, and decreased the accumulation of Aβ in the brains of SAMP8 mice. Additionally, XXD upregulated the expression of TREM2, downregulated IBA1, TLR1, TLR2, and CMPK2 expression, and reduced the levels of pro-inflammatory factors NLRP3, NF-κB p65, COX-2, TNF-α, and IL-1β in the hippocampal tissues.

XXD may exert its effects by regulating the P-gp/ECS axis, the RAGE/LRP1 receptor system, and the expression of MRP2 and Mfsd2a proteins, thereby modulating the transport function of the BBB to expedite the clearance of Aβ, reduce cerebral Aβ accumulation, and consequently inhibit the activation of microglia induced by Aβ aggregation. This process may suppress the activation of the CMPK2/NLRP3 and TLRs/NF-κB pathways, diminish the production of inflammatory cytokines and chemokines, alleviate neuroinflammation associated with microglia in the brain of AD, and ultimately improve AD pathology.

Remimazolam, a novel benzodiazepine, is widely used as an anesthetic in endoscopic procedures; however, its effects on cognitive function remain unclear, limiting its broader application in general anaesthesia. Neuroinflammation is a well-established key factor in the etiology and progression of cognitive dysfunction, including conditions such as Alzheimer's disease, Parkinson's disease, postoperative delirium, and postoperative cognitive dysfunction. Preclinical studies have demonstrated that remimazolam exerts anti-inflammatory and neuroprotective effects, and clinical reports indicate a reduced incidence of postoperative delirium in patients treated with remimazolam. Nevertheless, whether remimazolam improves cognitive function through its anti-inflammatory properties remains uncertain. This study aimed to investigate the neuroprotective effects of remimazolam and its underlying mechanism in a lipopolysaccharide (LPS)-induced model of neuroinflammation, neuronal injury, and cognitive dysfunction METHODS: C57BL/6 J male mice were administered LPS intraperitoneally to establish a model of neuroinflammation-induced cognitive impairment. A subset of mice received remimazolam via intraperitoneal injection 30 minutes prior to LPS administration. Cognitive performance was evaluated using behavioural tests, including the Morris Water Maze (MWM), Novel Object Recognition (NOR) test, and Open Field Test (OFT). Hippocampal tissues were analyzed by haematoxylin-eosin (HE) staining to assess structural changes. Inflammatory markers, including Interleukin (IL)-6, IL-1β, and tumor necrosis factor-α, were quantified using enzyme-linked immunosorbent assay (ELISA) and real-time quantitative PCR. Immunofluorescence was used to detect translocator protein (TSPO) and markers of microglia activation (IBA-1, CD16/32, and CD206).

(1) Remimazolam reversed LPS-induced cognitive deficits, as evidenced by shorter spatial exploration latency and increased platform crossings in the MWM, and an elevated recognition index in the NOR test. (2) Remimazolam improved hippocampal morphology, reducing LPS-induced neuronal damage. (3) Remimazolam significantly decreased levels of hippocampal inflammatory cytokines, inhibited microglial activation, promoted M2-type microglia polarization, and increased TSPO expression.

Remimazolam demonstrated neuroprotective and anti-neuroinflammatory effects in a mouse model of LPS-induced cognitive impairment. These effects are likely mediated through the regulation of TSPO, which inhibits microglial activation and promotes the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) widely used for depression, but its potential effects on gut microbiota regulation and vagus nerve-mediated serotonin receptor expression have not been well studied. We investigated changes in the gut microbiome regulated by fluoxetine and vagus nerve-mediated expression of several serotonin (5-HT) receptor types associated with anxiety and depression. Oral administration of fluoxetine alleviated lipopolysaccharide (LPS)-induced depressive and anxiety behaviors, increased 5-HT1A, 2 C, and melanocortin 4 (MC4) receptor expression, and the composition of Lactobacillus in mice's gut microbiome. In contrast, in the vagotomized group, fluoxetine did not modulate behaviors and receptor expression. Increased Lactobacillus composition was found to correlate significantly with behavioral test results. The importance of Lactobacillus growth to the efficacy of fluoxetine was confirmed by the effectiveness of fluoxetine, which was reduced by co-administering antibiotics. To determine the additional impact of the gut microbiome, we isolated Limosilactobacillus reuteri and Ligilactobacillus murinus, which were increased in the fluoxetine-treated group and administrated. The results showed that administration of each strain improved anxious or depressive behavior, as did fluoxetine, and vagotomy eliminated these effects. These results suggest that fluoxetine administration increases the proportion of Lactobacillus in the gut, which modulates 5-HT1A, 2 C, and MC4 receptor expression through the enteric nervous system and improves depression.

Penetration of antimicrobial treatments into the cerebrospinal fluid is essential to successfully treat infections of the central nervous system. This penetration is hindered by different barriers, including the blood-brain barrier, which is the most impermeable. However, inflammation may lead to structural alterations of these barriers, modifying their permeability. The impact of blood-brain barrier disruption on linezolid and tedizolid (antibiotics that may be alternatives to treat nosocomial meningitis) penetration in cerebrospinal fluid (CSF) remains unknown. The aim of this study is to evaluate the impact of blood brain barrier disruption on CSF penetration of linezolid and tedizolid. Female C57BI/6 J mice were used. Blood-brain barrier disruption was induced by an intraperitoneal administration of lipopolysaccharide. Linezolid (40 mg/kg) or tedizolid-phosphate (20 mg/kg) were injected intraperitoneally. All the plasma and CSF samples were analyzed with a validated UPLC-MS/MS method. Pharmacokinetic parameters were calculated using a non-compartmental approach based on the free drug concentration. The penetration ratio from the plasma into the CSF was calculated by the AUC0-8h (Area Under Curve) ratio (AUC0-8hCSF/AUC0-8hplasma). Linezolid penetration ratio was 46.5% in control group and 46.1% in lipopolysaccharide group. Concerning tedizolid, penetration ratio was 5.5% in control group and 15.5% in lipopolysaccharide group. In conclusion, CSF penetration of linezolid is not impacted by blood-brain barrier disruption, unlike tedizolid, whose penetration ratio increased.

Forecasting the progression of the disease in the early inflammatory stage of the most prevalent type of multiple sclerosis (MS), referred to as relapsing-remitting multiple sclerosis (RRMS), is essential for making prompt treatment modifications, aimed to reduce clinical relapses and disability. In total, 58 patients with RRMS, having an Expanded Disability Status Scale (EDSS) score less than 4, were included in this study. Baseline magnetic resonance imaging (MRI) was performed, and brain and spinal cord lesions were evaluated. The disability of the patients was evaluated using EDSS at baseline and follow-up; enzyme-linked immunosorbent assays (ELISAs) were also used to determine the level of blood-based inflammation markers in plasma at baseline. The main results demonstrated that the baseline level of LBP was correlated with an increase in EDSS in a short (8-10 months) follow-up period. Furthermore, the prognostic significance of LBP was only observed in patients who received disease-modifying treatment (DMT) before the study. Our results suggest that the baseline level of LBP may be among the predictors of disability progression in RRMS over short follow-up periods, particularly in those receiving treatment. It highlights the effect of endotoxins in the pathogenesis of RRMS.

Sepsis-associated encephalopathy (SAE) is common in septic patients, characterized by acute and long-term cognitive impairment, and is associated with higher mortality. This study aimed to identify SAE-related biomarkers and evaluate their diagnostic potential. We analyzed three SAE-related sequencing datasets, using two as training sets and one as a validation set. Weighted Gene Co-expression Network Analysis and four machine learning methods-Elastic Net regression, LASSO, random forest, and XGBoost-were employed, dentifying 18 biomarkers with significant expression changes. External validation and in vitro experiments confirmed the differential expression of these biomarkers. These findings provide insights into SAE pathogenesis and suggest potential therapeutic targets.

Pediatric obstructive sleep apnea (OSA) is a prevalent sleep-related breathing disorder associated with significant neurocognitive and behavioral impairments. Recent studies have highlighted the role of gut microbiota and the microbiota-gut-brain axis (MGBA) in influencing cognitive health in children with OSA. This narrative review aims to summarize current knowledge on the relationship between gut microbiota, MGBA, and cognitive function in pediatric OSA. It also explores the potential of artificial intelligence and machine learning in advancing this field and identifying novel therapeutic strategies. Pediatric OSA is associated with gut dysbiosis, reduced microbial diversity, and metabolic disruptions. MGBA mechanisms, such as endocrine, immune, and neural pathways, link gut microbiota to cognitive outcomes. Artificial intelligence and machine learning methodologies offer promising tools to uncover microbial markers and mechanisms associated with cognitive deficits in OSA. Future research should focus on validating these findings through clinical trials and developing personalized therapeutic approaches targeting the gut microbiota.

Anxiety disorders, prevalent mental health conditions, receive significant attention globally due to their intricate etiology and the suboptimal effectiveness of existing therapies. Research is increasingly recognizing that the genesis of anxiety involves not only neurochemical brain alterations but also changes in gut microbiota. The microbiota-gut-brain axis (MGBA), serving as a bidirectional communication pathway between the gut microbiota and the central nervous system (CNS), is at the forefront of novel approaches to deciphering the complex pathophysiology of anxiety disorders. This review scrutinizes the role and recent advancements in the MGBA concerning anxiety disorders through a review of the literature, emphasizing mechanisms via neural signals, endocrine pathways, and immune responses. The evidence robustly supports the critical influence of MGBA in both the development and progression of these disorders. Furthermore, this discussion explores potential therapeutic avenues stemming from these insights, alongside the challenges and issues present in this realm. Collectively, our findings aim to enhance understanding of the pathological mechanisms and foster improved preventative and therapeutic strategies for anxiety disorders.

In sepsis-associated encephalopathy (SAE), the activation of microglial cells and ensuing neuroinflammation are important in the underlying pathological mechanisms. Increasing evidence suggests that the protein Piezo1 functions as a significant regulator of neuroinflammation. However, the influence of Piezo1 on microglial cells in the context of SAE has not yet been determined. This study aims to investigate the role of Piezo1 in microglial cells in the context of SAE.

By inducing cecal ligation and puncture (CLP), a mouse model of SAE was established, while the control group underwent a sham surgery in which the cecum was exposed without ligation and puncture. Piezo1 knockout mice were employed in this study. Morris water maze tests were conducted between Days 14 and 18 postop to assess both the motor activity and cognitive function. A proteomic analysis was conducted to assess the SAE-related pathways, whereas a Mendelian randomization analysis was conducted to identify the pathways associated with cognitive impairment. Dual-label immunofluorescence and flow cytometry were used to assess the secretion of inflammatory factors, microglial status, and oligodendrocyte development. Electron microscopy was used to evaluate axonal myelination. A western blot analysis was conducted to evaluate the influence of Piezo1 on oligodendrocyte ferroptosis.

The results of the bioinformatics analysis have revealed the significant involvement of CCL25 in the onset and progression of SAE-induced cognitive impairment. SAE leads to cognitive dysfunction by activating the microglial cells. The release of CCL25 by the activated microglia initiates the demyelination of oligodendrocytes in the hippocampus, resulting in ferroptosis and the disruption of hippocampal functional connectivity. Of note, the genetic knockout of the Piezo1 gene mitigates these changes. The treatment with siRNA targeting Piezo1 effectively reduces the secretion of inflammatory mediators CCL25 and IL-18 by inhibiting the p38 pathway, thus preventing the ferroptosis of oligodendrocytes through the modulation of the CCL25/GPR78 axis.

Piezo1 is involved in the activation of microglia and demyelinating oligodendrocytes in the animal models of SAE, resulting in cognitive impairment. Consequently, targeting Piezo1 suppression can be a promising approach for therapeutic interventions aimed at addressing cognitive dysfunction associated with SAE.

Parkinson's Disease (PD) is a prevalent and escalating neurodegenerative disorder with significant societal implications. Despite being considered a proteinopathy, in which the aggregation of α-synuclein is the main pathological change, the intricacies of PD initiation remain elusive. Recent evidence suggests a potential link between gut microbiota and PD initiation, emphasizing the need to explore the effects of microbiota-derived molecules on neuronal cells. In this study, we exposed dopaminergic-differentiated SH-SY5Y cells to microbial molecules such as lipopolysaccharide (LPS), rhamnolipid, curli CsgA and phenol soluble modulin α-1 (PSMα1). We assessed cellular viability, cytotoxicity, growth curves and α-synuclein levels by performing MTS, LDH, real-time impedance readings, qRT-PCR and Western Blot assays respectively. Statistical analysis revealed that rhamnolipid exhibited concentration-dependent effects, reducing viability and inducing cytotoxicity at higher concentrations, increasing α-synuclein mRNA and protein levels with negative effects on cell morphology and adhesion. Furthermore, LPS exposure also increased α-synuclein levels. Curli CsgA and PSMα-1 showed minimal or no changes. Our findings suggest that microbiota-derived molecules, particularly rhamnolipid and LPS, impact dopaminergic neurons by increasing α-synuclein levels. This study highlights the potential involvement of gut microbiota in initiating the upregulation of α-synuclein that may further initiate PD, indicating the complex interplay between microbiota and neuronal cells.

Oxycodone, a widely used opioid analgesic, has an unbound brain-to-plasma concentration ratio (Kp,uu) greater than unity, indicating active uptake across brain barriers associated with the putative proton-coupled organic cation (H+/OC) antiporter system. With this study, we aimed to elucidate oxycodone's CNS disposition during lipopolysaccharide (LPS)-induced systemic inflammation in Sprague-Dawley rats.

Using brain microdialysis, we dynamically and simultaneously monitored unbound oxycodone concentrations in blood, striatum, lateral ventricle, and cisterna magna following intravenous administration of oxycodone post-LPS challenge.

Our results indicated a reduced, sex-independent brain net uptake of oxycodone across the blood-brain barrier (BBB) measured in the striatum. Notably, the LPS challenge has significantly altered the systemic pharmacokinetics (PK) of oxycodone, in a sex-specific manner, leading to lower clearance and higher blood concentrations in females compared to LPS-treated males and healthy rats of both sexes. Proteomic analysis using Olink Target 96 Mouse Exploratory assay confirmed the induction of systemic inflammation and neuroinflammation. The inflammation led to an increased paracellular transport, measured using 4 kDa dextran, while preserving net active uptake of oxycodone across both BBB and the blood-cerebrospinal fluid barrier (BCSFB), with Kp,uu values of 2.7 and 2.5, respectively. The extent of uptake was 1.6-fold lower (p < 0.0001) at the BBB and unchanged at the BCSFB after the LPS challenge compared to that in healthy rats. However, the mean exposure of unbound oxycodone in the brain following LPS was similar to that in healthy rats, primarily due to the LPS-induced changes in systemic exposure.

These findings highlight the dissimilar responses at blood-brain interfaces during LPS-induced inflammation. Advancing the knowledge of neuropharmacokinetic mechanisms, specifically those involving the H+/OC antiporter system, will enable the development of more effective therapeutic strategies during inflammation conditions.

This study investigated the protective role of Annexin A1 (ANXA1) in sepsis-associated encephalopathy (SAE) by examining its effects on brain vascular endothelium and blood-brain barrier (BBB) integrity.

Mice were divided into four groups: wild type (WT), cecal ligation and puncture (CLP), ANXA1 knockout (ANXA1[-/-]), and ANXA1(-/-) with CLP. Neurobehavioral changes were assessed using the Y-maze test, while BBB integrity was evaluated through Evans blue dye (EBD) staining and permeability tests with fluorescein isothiocyanate (FITC)-dextran.

Results showed that ANXA1 levels were reduced in septic mice, and its deficiency exacerbated cognitive impairment and survival rate reduction. ANXA1 deficiency also upregulated proinflammatory cytokines and adhesion molecules, worsened BBB impairment, and altered expression of tight junction proteins and VEGF-A/VEGF-R2. In vitro, ANXA1 Ac2-26 prevented LPS-induced increased permeability in bEnd.3 cells by restoring tight junction proteins and reducing VEGF-A/VEGF-R2 expression. Notably, VEGF-A negated the protective effects of ANXA1 Ac2-26.

The study concludes that ANXA1 reduces BBB permeability to protect against sepsis-induced brain dysfunction via VEGF-A/VEGF-R2 regulation of tight junction proteins, suggesting ANXA1 as a potential therapeutic for SAE.

Microplastics (MPs) have been detected in the atmospheric and the human respiratory system, indicating that the respiratory tract is a significant exposure route for MPs. However, the effect of inhaled MPs on cognitive function has not been adequately studied. Here, a C57BL/6 J mouse model of inhalation exposure to polystyrene MPs (PS-MPs, 5 µm, 60 d) is established by intratracheal instillation. Interestingly, in vivo fluorescence imaging and transmission electron microscopy reveal that PS-MPs do not accumulate in the brain. However, behavioral experiments shows that cognitive function of mice is impaired, accompanied by histopathological damage of lung and brain tissue. Transcriptomic studies in hippocampal and lung tissue have demonstrated key neuroplasticity factors as well as cognitive deficits linked to lung injury, respectively. Mechanistically, the lung-brain axis plays a central role in PS-MPs-induced neurological damage, as demonstrated by pulmonary flora transplantation, lipopolysaccharide (LPS) intervention, and cell co-culture experiments. Together, inhalation of PS-MPs reduces cognitive function by altering the composition of pulmonary flora to produce more LPS and promoting M1 polarization of microglia, which provides new insights into the mechanism of nerve damage caused by inhaled MPs and also sheds new light on the prevention of neurotoxicity of environmental pollutants.

Neurological diseases are the primary cause of disability and death and impose substantial financial burdens. However, existing treatments only relieve symptoms and may cause many adverse effects. Natural products are a promising source of neurological therapeutic agents due to their excellent neuroprotective effect and safety. The gut microbiota has an essential impact on maintaining brain homeostasis via the gut-brain axis. Multiple investigations show that natural products offer neuroprotective effects by regulating gut microbiota-driven signaling networks.

This review aims to provide a systematic review of how natural products promote neurological health by harnessing the power of gut microbiota.

The pre-January 1, 2024 literature was gathered from several databases, including Scopus, PubMed, Google Scholar, and Web of Science, utilizing appropriate keywords. The gathered publications underwent a review process and were classified based on their study content, specifically focusing on the impact of natural products on gut microbiota and neurological health.

Here, we review how natural products promote neurological health by regulating the gut microbiota-brain axis. Specifically, we focus on the following areas. (1) Altering microorganism community structure, including increasing α-diversity and altering β-diversity. (2) Regulating the population of certain bacteria, including enriching beneficial microorganisms Akkermansia and Bifidobacterium, and inhibiting potentially hazardous microorganisms Bilophila, Klebsiella, and Helicobacter. (3) Regulating microbial neuroactive metabolites levels, including short-chain fatty acids, tryptophan and its derivatives, trimethylamine N-oxide, dopa/dopamine, γ-aminobutyric acid, and lipopolysaccharide. Furthermore, we review how natural products promote neurological health by regulating intestinal barrier homeostasis.

Natural products promote neurological health by harnessing the power of gut microbiota. This review will contribute to understanding how natural products promote neurological health by orchestrating the gut microbiota-brain axis.

Growing evidence has proved that alterations in the gut microbiota have been linked to neurological disorders including stroke. Structural and functional disruption of the blood-brain barrier (BBB) is observed after stroke. In this context, there is pioneering evidence supporting that gut microbiota may be involved in the pathogenesis of stroke by regulating the BBB function. However, only a few experimental studies have been performed on stroke models to observe the BBB by altering the structure of gut microbiota, which warrant further exploration. Therefore, in order to provide a novel mechanism for stroke and highlight new insights into BBB modification as a stroke intervention, this review summarizes existing evidence of the relationship between gut microbiota and BBB integrity and discusses the mechanisms of gut microbiota on BBB dysfunction and its role in stroke.

Gut dysbiosis leading to increased intestinal barrier permeability and translocation of lipopolysaccharide (LPS) in the circulation has been demonstrated in patients with acute myocardial infarction and pulmonary embolism.

We investigated changes in circulating LPS concentrations in acute ischemic stroke (AIS) and their consequences, including prognosis.

We studied 98 AIS patients, aged 74 ± 12 years, including 74 (75.5%) thrombolysed individuals. We determined serum LPS and zonulin, a marker of gut permeability, along with protein carbonyl (PC), fibrin clot properties, and thrombin generation on admission, at 24 hours and 3 months. Stroke severity was assessed using the National Institutes of Health Stroke Scale. Stroke functional outcome using modified Rankin scale and stroke-related mortality were evaluated at 3 months.

Serum LPS and zonulin levels on admission were associated with time since symptom onset (r = 0.57; P < .0001; and r = 0.40; P < .0001). Baseline LPS levels correlated with PC (r = 0.51; P < .0001) but not with coagulation and fibrinolysis markers. LPS levels increased at 24 hours in thrombolysed patients (P < .001) and correlated with the National Institutes of Health Stroke Scale score (r = 0.31; P = .002) and PC (r = 0.32; P = .0057). Both LPS and zonulin levels measured at 24 hours increased the odds of having unfavorable modified Rankin scale scores (odds ratio [OR], 1.22; 95% CI, 1.04-1.42; and OR, 2.36; 95% CI, 1.24-4.49 per unit). Elevated LPS level, but not zonulin, was associated with stroke-related mortality (OR, 1.26; 95% CI, 1.02-1.55 per unit).

In AIS patients intestinal permeability is mainly driven by increasing time since the symptom onset. Our findings suggest that LPS, with a trend toward its further rise following thrombolysis, adversely affects neurologic functional outcomes and 3-month mortality.

The gut-brain axis may mediate mood changes due to strenuous exercise. Therefore, probiotic supplementation may mitigate mood worsening.

The present study aims to evaluate the effect of probiotic supplementation on mood and immunometabolic parameters after a marathon.

Fourteen marathon runners were selected and divided into placebo and probiotic groups that were supplemented for 30 days. Before and after the marathon, mood (POMS) was assessed, and blood was collected for analysis of immunometabolic parameters. Statistical analysis was performed, and p < 0.05 was considered to determine statistically differences.

Tension decreased after the marathon in both groups. Vigor decreased only in the placebo group. Fatigue increased after the marathon in both groups. TMD increased after the marathon in placebo. The IL2/IL-4 ratio decreased in the probiotic group after the marathon compared to before and increased compared to the placebo group. The IL-10 increased after the marathon in placebo. TNF-α increased after the marathon in probiotics. The TNF-α/IL-10 ratio decreased after the marathon in both groups. LPS decreased in the probiotic group after the marathon compared to before and in the placebo group.

Thirty days of probiotic supplementation attenuated the impact of marathons on mood worsening. The decrease in LPS in the probiotic group mediated the change in the pro/anti-inflammatory balance, indicating an immunometabolic mechanism by which the gut-brain axis impacts mood after strenuous exercise.

Sepsis-related systemic inflammation is a deadly condition with high rates of morbidity and mortality. There is evidence that sepsis affects the brain, and the most frequent organ dysfunction linked to sepsis is sepsis-associated encephalopathy. Sepsis-related brain damage can drastically reduce a patient's chances of survival. However, a specific treatment for sepsis-associated encephalopathy is not currently available. Consequently, to treat the brain damage caused by sepsis, investigating novel therapeutic strategies is imperative. After establishing the CLP-induced mouse SAE model, we treated the mice with Gyp-XLIX and evaluated apoptosis, neuroinflammation, brain damage, and oxidative stress in the brain tissue of each group of mice. Furthermore, the protective effects of Gyp-XLIX on LPS-treated BV-2 cells were assessed. We discovered that Gyp-XLIX treatment increased the survival rate of CLP-treated mice, alleviated SAE-related cerebral nerve abnormalities, and decreased blood-brain barrier breakdown, all of which could better preserve brain tissue in vivo. Furthermore, we identified associated proteins and found that Gyp-XLIX may reduce oxidative stress, cell apoptosis, and inflammation in the brain tissues of SAE mice. This observation was further validated in vitro. We established that Gyp-XLIX alleviates SAE by targeting PPAR-α. These findings may be important for the clinical applicability of Gyp-XLIX in SAE treatment. We found that Gyp-XLIX can alleviate brain injury in SAE by targeting PPAR-α and is a potential protective agent for SAE.