Gut flora in multiple sclerosis: implications for pathogenesis and treatment.

ABSTRACT: Multiple sclerosis is an inflammatory disorder characterized by inflammation, demyelination, and neurodegeneration in the central nervous system. Although current first-line therapies can help manage symptoms and slow down disease progression, there is no cure for multiple sclerosis. The gut-brain axis refers to complex communications between the gut flora and the immune, nervous, and endocrine systems, which bridges the functions of the gut and the brain. Disruptions in the gut flora, termed dysbiosis, can lead to systemic inflammation, leaky gut syndrome, and increased susceptibility to infections. The pathogenesis of multiple sclerosis involves a combination of genetic and environmental factors, and gut flora may play a pivotal role in regulating immune responses related to multiple sclerosis. To develop more effective therapies for multiple sclerosis, we should further uncover the disease processes involved in multiple sclerosis and gain a better understanding of the gut-brain axis. This review provides an overview of the role of the gut flora in multiple sclerosis.

Causal relationships between susceptibility and severity of COVID-19 and neuromyelitis optica spectrum disorder (NMOSD) in European population: a bidirectional Mendelian randomized study.

Background: Neurological disorders can be caused by viral infections. The association between viral infections and neuromyelitis optica spectrum disorder (NMOSD) has been well-documented for a long time, and this connection has recently come to attention with the occurrence of SARS-CoV-2 infection. However, the precise nature of the causal connection between NMOSD and COVID-19 infection remains uncertain. Methods: To investigate the causal relationship between COVID-19 and NMOSD, we utilized a two-sample Mendelian randomization (MR) approach. This analysis was based on the most extensive and recent genome-wide association study (GWAS) that included SARS-CoV-2 infection data (122616 cases and 2475240 controls), hospitalized COVID-19 data (32519 cases and 2062805 controls), and data on severe respiratory confirmed COVID-19 cases (13769 cases and 1072442 controls). Additionally, we incorporated a GWAS meta-analysis comprising 132 cases of AQP4-IgG-seropositive NMOSD (NMO-IgG+), 83 cases of AQP4-IgG-seronegative NMOSD (NMO-IgG-), and 1244 controls. Results: The findings of our study indicate that the risk of developing NMO-IgG+ is elevated when there is a genetic predisposition to SARS-CoV-2 infection (OR = 5.512, 95% CI = 1.403-21.657, P = 0.014). Furthermore, patients with genetically predicted NMOSD did not exhibit any heightened susceptibility to SARS-CoV2 infection, COVID-19 hospitalization, or severity. Conclusion: our study using Mendelian randomization (MR) revealed, for the first time, that the presence of genetically predicted SARS-CoV2 infection was identified as a contributing factor for NMO-IgG+ relapses.

COVID-19 hospitalization increases the risk of developing glioblastoma: a bidirectional Mendelian-randomization study.

Background: As a result of the COVID-19 pandemic, patients with glioblastoma (GBM) are considered a highly vulnerable population. Despite this, the extent of the causative relationship between GBM and COVID-19 infection is uncertain. Methods: Genetic instruments for SARS-CoV-2 infection (38,984 cases and 1,644,784 control individuals), COVID-19 hospitalization (8,316 cases and 1,549,095 control individuals), and COVID-19 severity (4,792 cases and 1,054,664 control individuals) were obtained from a genome-wide association study (GWAS) from European populations. A total of 6,183 GBM cases and 18,169 controls from GWAS were enrolled in our study. Their associations were evaluated by applying Mendelian randomization (MR) including IVW meta-analysis, MR-Egger regression, and weighted-median analysis. To make the conclusions more robust and reliable, sensitivity analyses were performed. Results: Our results showed that genetically predicted COVID-19 hospitalization increases the risk of GBM (OR = 1.202, 95% CI = 1.035-1.395, p = 0.016). In addition, no increased risk of SARS-CoV-2 infection, COVID-19 hospitalization and severity were observed in patients with any type of genetically predicted GBM. Conclusion: Our MR study indicated for the first time that genetically predicted COVID-19 hospitalization was demonstrated as a risk factor for the development of GBM.

Exploring the cortical habituation in migraine patients based on contingent negative variation.

Introduction: Cognitive dysfunction has frequently been found in patients with migraine. The so-called contingent negative variation (CNV) and EEG power spectral densities may be the best choices to explore the underlining pathophysiology, such as cortical inhibition and habituation. Methods: Thirty migraine patients without aura and healthy controls matched for sex, age, and education were recruited separately for CNV recording. The amplitudes, latencies, and squares of different CNV components, such as oCNV, iCNV, tCNV, and PINV, were selected and analyzed. Behavioral data, such as manual reaction time (RT), were analyzed. We used the Person correlation coefficient R to analyze different ERP components in relation to clinical characteristics. A multiple regression analysis was conducted for the migraine group. Spectral analysis of EEG data from all channels using the fast Fourier transform (FFT). Results: The migraine group had longer A-latency, C-latency, and iCNV-latency than the control group. The migraine group had higher iCNV-amplitude, oCNV-amplitude, and tCNV-amplitude than the control group, especially those located in the occipital area. The iCNV-square, oCNV-square, tCNV-square, or PINV-square in the migraine group was significantly larger than the control group. Different correlations were found between clinical characteristics and ERP components. The delta or theta activity in the migraine group was statistically lower than in the control group. Discussion: Our study has revealed that migraine attacks may influence responsivity, pre-activation, habituation, and cortical inhibition not only on the behavioral level but also on the electrophysiological level. Abnormal changes in cortical habituation and inhibition can be interpreted as CNV components. Additionally, analyses have revealed correlations between CNV components and various factors, including age, the clinical course of the condition, attack frequency, pain intensity, and duration. Thus, repetitive migraine attacks can lead to a reduction in cortical inhibition and subsequent impairment in executive function.

Assessment of the relationship between generalized convulsive epilepsy and systemic inflammatory regulators: a bidirectional Mendelian randomization study.

Background: Generalized convulsive epilepsy (GCE), an important subtype of epilepsy, is a syndrome of neuronal dysfunction characterized by diffuse abnormal discharge of neurons within the brain. Compounding evidence suggests a correlation between epilepsy and inflammatory factors, for instance, cyclooxygenase-2, interleukin-1ß, and interleukin-6. Elevated levels of inflammatory factors have been observed in patients with epilepsy and several animal models. Therefore, inflammation may be closely associated with the pathogenesis and progression of GCE. However, the cause-and-effect relationship between the two is difficult to determine because of small sample sizes and confounding factors. Methods: To test for causality of the 41 cytokines on GCE, we conducted a two-sample Mendelian randomization (MR) based on the largest and latest genome-wide association study (GWAS) involving 290 cases and 453,521 European controls and a GWAS meta-analysis consisting of 41 cytokines from 8,293 individuals. Results: R confirmed a bidirectional causal link between cytokines and GCE. Genetically predicted increased levels of hepatocyte growth factor and decreased levels of eotaxin and interleukin-18 are associated with an increased risk of GCE (OR = 1.904, 95% CI = 1.019-3.561, p = 0.044; OR = 0.641, 95% CI = 0.417-0.984, p = 0.042; OR = 0.482, 95% CI = 0.251-0.927, p = 0.046). Furthermore, the presence of GCE is related to an increase in levels of multiple cytokines, such as macrophage inflammatory protein-1α, interleukin-12p70, interleukin-17, interleukin-1 receptor antagonist, and basic fibroblast growth factor (OR = 1.038, 95% CI = 1.005-1.073, p = 0.024; OR = 1.031, 95% CI = 1.009-1.054, p = 0.006; OR = 1.027, 95% CI = 1.002-1.053, p = 0.037; OR = 1.037, 95% CI = 1.003-1.072, p = 0.032; OR = 1.032, 95% CI = 1.000-1.066, p = 0.048; OR = 1.025, 95% CI = 1.003-1.048, p = 0026). Conclusion: A bidirectional causal link existed between inflammation and GCE. Detecting significantly altered factor concentrations may be of great significance for screening GCE and predicting their occurrence. Moreover, available pharmacological treatments for GCE are focused primarily on suppressing seizures. In future, altering the concentration of these cytokines in the body through targeted anti-inflammatory therapy to modify the epileptogenic mechanism and prevent the recurrence and refractoriness of GCE may become the key to new treatments.

Oily fish and raw vegetable consumption can decrease the risk of AQP4-positive neuromyelitis optica spectrum disorders: a Mendelian-randomization study.

Neuromyelitis optica spectrum disorders (NMOSD) are severe inflammatory disorders of the central nervous system targeting aquaporin-4 (AQP4). The risk factors for NMOSD remain to be determined, though they may be related to diet and nutrition. This study aimed to explore the possibility of a causal relationship between specific food intake and AQP4-positive NMOSD risk. The study followed a two-sample Mendelian randomization (MR) design. Genetic instruments and self-reported information on the intake of 29 types of food were obtained from a genome-wide association study (GWAS) on 445,779 UK Biobank participants. A total of 132 individuals with AQP4-positive NMOSD and 784 controls from this GWAS were included in our study. The associations were evaluated using inverse-variance-weighted meta-analysis, weighted-median analysis, and MR-Egger regression. A high consumption of oily fish and raw vegetables was associated with a decreased risk of AQP4-positive NMOSD (odds ratio [OR] = 1.78 × 10-16, 95% confidence interval [CI] = 2.60 × 10-25-1.22 × 10-7, p = 0.001; OR = 5.28 × 10-6, 95% CI = 4.67 × 10-11-0.598, p = 0.041, respectively). The results were consistent in the sensitivity analyses, and no evidence of directional pleiotropy was observed. Our study provides useful implications for the development of AQP4-positive NMOSD prevention strategies. Further research is needed to determine the exact causal relationship and mechanisms underlying the association between specific food intake and AQP4-positive NMOSD.

Cerebrospinal fluid protein levels are elevated 100 times in a Leptomeningeal metastasis patient: a case report and literature review.

Leptomeningeal metastasis (LM) has a high degree of malignancy and high mortality. We describe a patient admitted to hospital with acute lower extremity weakness, dysuria, and high intracranial pressure. Enhanced magnetic resonance imaging (MRI) showed extensive enhancement of the leptomeningeal and spinal meninges with multiple nodular changes and extensive fusion. His cerebrospinal fluid (CSF) was yellow and cloudy, the Pandy test was strongly positive (++++), the protein was 46 g/L (normal range 0.15-0.45 g/L), which attracted our attention. Initially, miliary TB with associated tuberculous meningitis (TBM) was diagnosed, and neurosarcoidosis cannot be ruled out. After poor therapeutic effect of standard antituberculosis (anti-TB) therapy, further inspection found that malignant cells were detected by cerebrospinal fluid (CSF) cytology. PET/CT suggested the diagnosis of LM. The purpose of this paper is to describe the characteristics of atypical diffuse LM. In conclusion, when patient with unexplained high levels of CSF protein, it is necessary to be alert to the diagnosis of LM. Multiple examinations of fresh CSF are helpful to increase the positive detection rate of tumor cells. Early diagnosis and active treatment are conducive to improving survival rate.

Systemic inflammatory regulators and risk of acute-on-chronic liver failure: A bidirectional mendelian-randomization study.

Inflammation plays a role in the pathogenesis of acute-on-chronic liver failure (ACLF), however, whether there is a causal relationship between inflammation and ACLF remains unclear. A two-sample Mendelian randomization (MR) approach was used to investigate the causal relationship between systemic inflammatory regulators and ACLF. The study analyzed 41 cytokines and growth factors from 8,293 individuals extracted from a genome-wide association study (GWAS) meta-analysis database involving 253 ACLF cases and 456,095 controls. Our results showed that lower stem cell factor (SCF) levels, lower basic fibroblast growth factor (bFGF) levels and higher Interleukin-13 (IL-13) levels were associated with an increased risk of ACLF (OR = 0.486, 95% CI = 0.264-0.892, p = 0.020; OR = 0.323, 95% CI = 0.107-0.972, p = 0.044; OR = 1.492, 95% CI = 1.111-2.004, p = 0.008, respectively). In addition, genetically predicted ACLF did not affect the expression of systemic inflammatory regulators. Our results indicate that cytokines play a crucial role in the pathogenesis of ACLF. Further studies are needed to determine whether these biomarkers can be used to prevent and treat ACLF.

Clinical characteristics of late-onset neuromyelitis optica spectrum disorder.

BACKGROUND: Anti-aquaporin-4 (AQP-4) immunoglobulin G (IgG) is a major autoimmune antibody that contributes to the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD). NMOSD often presents as disability, severe sensory impairment, and sleep disorders, which can cause anxiety and depression and further affect the quality of life. The age of onset is a key factor influencing the prognosis of NMOSD. However, this result was based on studies involving only anti-aquaporin-4 (AQP4) immunoglobulin G (IgG)-seropositive NMOSD patients or studies using the 2006 NMOSD diagnosis criteria. Therefore, further study of the age of onset of NMOSD is valuable. This study aimed to describe the clinical and magnetic resonance imaging (MRI) differences between early-onset neuromyelitis optica spectrum disorder (EO-NMOSD) and late-onset (LO)-NMOSD patients. METHODS: Fifty patients were enrolled, their anti-AQP4-IgG titers were measured, and brain and spinal cord MRIs were obtained. Additionally, several questionnaires related to disease severity, anxiety, depression, cognition, sleep, pain, and fatigue were collected. RESULTS: Higher AQP4-IgG seropositivity, higher AQP4-IgG titer, frequency of thoracic myelitis, and white matter hyperintensities (WMH), as well as greater severity of disability, greater severity of sleep disorders, higher anxiety, poorer cognitive function, and higher clinical dementia rating (CDR)-community affairs scores were observed in late-onset (LO)-NMOSD patients than those in early-onset (EO)-NMOSD. AQP4-IgG titer positively correlated with age, annual relapse rate, Expanded Disability Status Scale (EDSS) sensory scores, Activity of Daily Living Scale (ADL) scores, and Pittsburgh Sleep Quality Index (PSQI) scores. The EDSS-sensory scores positively correlated with age, relapse time, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, PSQI, ADL, and CDR. WMH was positively correlated with age, EDSS-sensory scores, PSQI scores, and CDR scores and negatively correlated with the California Verbal Learning Test scores. CONCLUSION: LO-NMOSD patients have worse prognoses than those of EO-NMOSD patients. Higher AQP4-IgG titers, more WMHs, thoracic myelitis, and severe sensory symptoms are associated with cognition, depression, anxiety, and sleep disorders.

Acetylcholine receptor binding antibody-associated myasthenia gravis, myocarditis, and rhabdomyolysis induced by tislelizumab in a patient with colon cancer: A case report and literature review.

Despite the intriguing therapeutic prospects offered by immune checkpoint inhibitors (ICIs), immune-related adverse events (irAEs) become an increasingly important safety issue. Herein, we report a patient with locally advanced colorectal cancer (LACRC) who received anti-programmed cell death protein 1 (PD-1) (tislelizumab) therapy, then developed weakness of the limbs and drooping eyelids. He experienced sequential irAEs including severe myasthenia gravis, myocarditis, and rhabdomyolysis. Although many irAEs caused by tislelizumab have been reported, the cooccurrence of severe myasthenia gravis, myocarditis, and rhabdomyolysis caused by tislelizumab has not been described. The patient responded well to methylprednisolone and intravenous immunoglobulin therapy. This case illustrates the severe toxicity caused by ICIs, highlighting the importance of early prevention, early diagnosis, and appropriate management of irAEs. Multidisciplinary discussions should be held to improve the prognosis of patients.

Milder symptoms and shorter course in patients with re-positive COVID-19: A cohort of 180 patients from Northeast China.

China experienced another widespread Coronavirus disease 2019 (COVID-19) outbreak recently caused by the Omicron variant, which is less severe but far more contagious than the other COVID-19 variants, leading local governments to focus efforts on eliminating the spread of the disease. Previous studies showed that after "recovering" from the virus, some patients could re-test positive for COVID-19 with nucleic acid tests, challenging the control of disease spread. In this study, we aimed to analyze the clinical and laboratory characteristics of re-positive COVID-19 patients in Northeast China. We retrospectively analyzed data from confirmed reverse transcription polymerase chain reaction (RT-PCR) re-positive COVID-19 patients who were admitted to the First Hospital of Jilin University, Jilin Province, China, from March to June 2022. Detailed clinical symptoms, medical history, anti-Corona Virus (CoV) IgG and IgM levels, and CoV nucleic acid cycle threshold (Ct) values during the re-positive period were collected and analyzed. A total of 180 patients were included in this study, including 62 asymptomatic cases and 118 mild cases. The cohort included 113 men and 67 women, with an average age of 45.73 years. The median time between recovery from the virus and re-positivity was 13 days. Our results showed that the proportion of re-positive patients with symptoms was lower, and the nucleic acid test-positive duration was shorter during the re-positive period. Furthermore, in patients with underlying disease, the proportion of patients with symptoms was higher, anti-CoV IgG levels were lower, and the total disease duration was longer. In conclusion, during the re-positive period, the symptoms were milder, and the CoV nucleic acid test-positive course was shorter. The concomitant underlying disease is an important factor associated with clinical symptoms, and the overall course of COVID-19 re-positive patients may be associated with lower anti-CoV IgG levels. Large-scale and multicenter studies are recommended to better understand the pathophysiology of recurrence in patients with COVID-19.

Case Report: A Case of Adult Methylmalonic Acidemia With Bilateral Cerebellar Lesions Caused by a New Mutation in MMACHC Gene.

Methylmalonic acidemia is a severe heterogeneous disorder of methylmalonate and cobalamin (Cbl; vitamin B12) metabolism with poor prognosis. Around 90% of reported patients with methylmalonic acidemia (MMA) are severe infantile early onset, while cases with late-onset MMA have been rarely reported. Few reported late-onset MMA patients presented with atypical clinical symptoms, therefore, often misdiagnosed if without family history. Herein, we report a 29-year-old female who was admitted to our hospital due to symptoms manifested as encephalitis. The brain MRI showed symmetrical bilateral cerebellar lesions with Gd enhancement. Laboratory tests showed significantly elevated levels of homocysteine and methylmalonic acid. A genetic analysis identified a novel homozygous mutation (c.484G>A; p.Gly162 Arg) in the MMACHC gene. The patient was diagnosed with MMA, and her symptoms improved dramatically with intramuscular adenosine cobalamin treatment. In conclusion, for patients with symmetrical lesions in the brain, the possibility of metabolic diseases should be considered, detailed medical and family history should be collected, and metabolic screening tests as well as gene tests are necessary for correct diagnosis. The mutation diversity in MMACHC gene is an important factor leading to the heterogeneity of clinical manifestations of patients with MMA.

Comparisons of clinical phenotype, radiological and laboratory features, and therapy of neuromyelitis optica spectrum disorder by regions: update and challenges.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease of the central nervous system (CNS) associated with autoantibody (ab) to aquaporin-4 (AQP4). There is obvious variation between regions and countries in the epidemiology, clinical features and management in NMOSD. Based on published population-based observation and cohort studies, the different clinical pattern of NMOSD has been seen in several geographical regions and some of these patients with NMOSD-like features do not fully meet the current diagnostic criteria, which is needed to consider the value of recently revised diagnostic criteria. At present, all treatments applied in NMOSD have made great progress, however, these treatments failed in AQP4 ab negative and refractory patients. Therefore, it is necessary to turn into an innovative idea and to open a new era of NMOSD treatment to develop novel and diverse targets and effective therapeutic drugs in NMOSD and to conduct the trails in large clinical samples and case-control studies to confirm their therapeutic effects on NMOSD in the future, which still remain a challenge.

Role of Gut Microbiota in Multiple Sclerosis and Potential Therapeutic Implications.

The role of gut microbiota in health and diseases has been receiving increased attention recently. Emerging evidence from previous studies on gut-microbiota-brain axis highlighted the importance of gut microbiota in neurological disorders. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) resulting from T-cell-driven, myelin-directed autoimmunity. The dysbiosis of gut microbiota in MS patients has been reported in published research studies, indicating that gut microbiota plays an important role in the pathogenesis of MS. Gut microbiota have also been reported to influence the initiation of disease and severity of experimental autoimmune encephalomyelitis, which is the animal model of MS. However, the underlying mechanisms of gut microbiota involvement in the pathogenesis of MS remain unclear. Therefore, in this review, we summerized the potential mechanisms for gut microbiota involvement in the pathogenesis of MS, including increasing the permeability of the intestinal barrier, initiating an autoimmune response, disrupting the blood-brain barrier integrity, and contributing to chronic inflammation. The possibility for gut microbiota as a target for MS therapy has also been discussed. This review provides new insight into understanding the role of gut microbiota in neurological and inflammatory diseases.

New natural compound inhibitors of PDGFRA (platelet-derived growth factor receptor α) based on computational study for high-grade glioma therapy.

Background: High-grade glioma (HGG) is a malignant brain tumor that is common and aggressive in children and adults. In the current medical paradigm, surgery and radiotherapy are the standard treatments for HGG patients. Despite this, the overall prognosis is still very bleak. Studies have shown that platelet-derived growth factor receptor α (PDGFRA) is an essential target to treat tumors and inhibiting the activity of PDGFRA can improve the prognosis of HGG. Thus, PDGFRA inhibitors are critical to developing drugs and cancer treatment. Objective: The purpose of this study was to screen lead compounds and candidate drugs with potential inhibitors against platelet-derived growth factor receptor α (PDGFRA) from the drug library (ZINC database) in order to improve the prognosis of patients with high-grade glioma (HGG). Materials and methods: In our study, we selected Imatinib as the reference drug. A series of computer-aided technologies, such as Discovery Studio 2019 and Schrodinger, were used to screen and assess potential inhibitors of PDGFRA. The first step was to calculate the LibDock scores and then analyze the pharmacological and toxicological properties. Following this, we docked the small molecules selected in the previous steps with PDGFRA to study their docking mechanism and affinity. In addition, molecular dynamics simulation was used to determine whether the ligand-PDGFRA complex was stable in nature. Results: Two novel natural compounds 1 and 2 (ZINC000008829785 and ZINC000013377891) from the ZINC database were found binding to PDGFRA with more favorable interaction energy. Also, they were predicted with less Ames mutagenicity, rodent carcinogenicity, non-developmental toxic potential, and tolerant with cytochrome P450 2D6 (CYP2D6). The dynamic simulation analysis demonstrated that ZINC000008829785-PDGFRA and ZINC000013377891-PDGFRA dimer complex had more favorable potential energy compared with Imatinib, and they can exist in natural environments stably. Conclusion: ZINC000008829785 and ZINC000013377891 might provide a solid foundation for drugs that inhibit PDGFRA in HGG. In addition to being safe drug candidates, these compounds had important implications for improving drugs targeting PDGFRA.

Bow Hunter's syndrome with clicking sounds: A rare etiology of transient loss of consciousness with tonic-clonic seizure.

We present the case of a young male patient experiencing a transient loss of consciousness and manifesting a seizure when he tilted his head backward. Transcranial Doppler ultrasound (TCD) and carotid artery ultrasound (CAU) examination were normal when the patient's neck was in the neutral position. However, the CAU revealed vertebral artery (VA) transient occlusion during neck rotation or backward movement. Electroencephalogram (EEG) monitoring was performed with multiple neck rotation-induced tests. The patient developed dizziness, which was the same as the prodromal symptoms of the first seizure, and the EEG showed a large number of spinal slow waves and sharp slow waves in the frontal-to-frontal midline area, with an occasional generalization trend. CT angiography revealed occipitalization of the atlas and the lack of contrast agent filling in the local area of the VA when the patient's head was turned contralaterally. Thus, the patient was diagnosed with Bow Hunter's syndrome (BHS) and treated conservatively with neck immobilization. No recurrence occurred at 3 and 6 months of follow-up. Therefore, this case alerts neurologists to suspect BHS on observing seizure manifestations during neck rotation, and CAU may be a recommended dynamic screening method for BHS. This report is accompanied by a discussion of the phenomenon and diagnosis in the context of the existing literature.

Gut Microbial Metabolites in Parkinson's Disease: Implications of Mitochondrial Dysfunction in the Pathogenesis and Treatment.

The search for therapeutic targets for Parkinson's disease (PD) is hindered by the incomplete understanding of the pathophysiology of the disease. Mitochondrial dysfunction is an area with high potential. The neurobiological signaling connections between the gut microbiome and the central nervous system are incompletely understood. Multiple lines of evidence suggest that the gut microbiota participates in the pathogenesis of PD. Gut microbial dysbiosis may contribute to the loss of dopaminergic neurons through mitochondrial dysfunction. The intervention of gut microbial metabolites via the microbiota-gut-brain axis may serve as a promising therapeutic strategy for PD. In this narrative review, we summarize the potential roles of gut microbial dysbiosis in PD, with emphasis on microbial metabolites and mitochondrial function. We then review the possible ways in which microbial metabolites affect the central nervous system, as well as the impact of microbial metabolites on mitochondrial dysfunction. We finally discuss the possibility of gut microbiota as a therapeutic target for PD.

Axonal variants of Guillain-Barré syndrome: an update.

Axonal variants of Guillain-Barré syndrome (GBS) mainly include acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, and pharyngeal-cervical-brachial weakness. Molecular mimicry of human gangliosides by a pathogen's lipooligosaccharides is a well-established mechanism for Campylobacter jejuni-associated GBS. New triggers of the axonal variants of GBS (axonal GBS), such as Zika virus, hepatitis viruses, intravenous administration of ganglioside, vaccination, and surgery, are being identified. However, the pathogenetic mechanisms of axonal GBS related to antecedent bacterial or viral infections other than Campylobacter jejuni remain unknown. Currently, autoantibody classification and serial electrophysiology are cardinal approaches to differentiate axonal GBS from the prototype of GBS, acute inflammatory demyelinating polyneuropathy. Newly developed technologies, including metabolite analysis, peripheral nerve ultrasound, and feature selection via artificial intelligence are facilitating more accurate diagnosis of axonal GBS. Nevertheless, some key issues, such as genetic susceptibilities, remain unanswered and moreover, current therapies bear limitations. Although several therapies have shown considerable benefits to experimental animals, randomized controlled trials are still needed to validate their efficacy.

Case Report: Innate Immune System Challenge Unleashes Paraneoplastic Neurological Autoimmunity.

Paraneoplastic autoimmune neurological disorders reflect tumor-initiated immune responses against onconeural antigens. Symptoms and signs can affect the central and/or peripheral nervous systems, neuromuscular junction or muscle, and typically evolve subacutely before an underlying neoplasm is discovered. We describe four patients whose neurological symptoms were precipitated by potent innate immune system challenges: bladder instillation of BCG, tick bite and an "alternative cancer therapy" with bacterial extracts and TNF-α. We hypothesize that a tumor-initiated autoimmune response (evidenced by autoantibody profiles), pre-dating the immune system challenge, was unmasked or amplified in these patients by cytokines released systemically from innate immune cells activated by microbial pathogen-associated molecular patterns (PAMPs). The resultant upregulation of cognate onconeural peptides as MHC1 protein complexes on neural cell surfaces would render those cells susceptible to killing by CD8+ T cells, thus precipitating the patient's neurological symptoms.