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Additional file 1 Figure S1. The alpha-diversity comparison of faeces between two groups, A Chao, B Ace, C Shannon and D Simpson index were present microbial community abundance and diversity. NS: None significantly differences. Figure S2. PCoA analysis: PC1 coordinates represent the main coordinate component that caused the largest difference in the sample, and PC2 represents the second coordinate component. Figure S3. Heatmap of Weighted UniFrac analysis. On top, the cluster tree presented sample phylogenetic relationships, the change of diversity ratio along with colour from blue to red.

Myasthenia gravis (MG) is a devastating acquired autoimmune disease. Emerging evidence indicates that the gut microbiome plays a key role in maintaining immune system homeostasis. This work reports that MG is characterized by decreased α‐phylogenetic diversity, and significantly disturbed gut microbiome and fecal metabolome. The altered gut microbial composition is associated with fecal metabolome changes, with 38.75% of altered bacterial operational taxonomic units showing significant correlations with a range of metabolite biomarkers. Some microbes are particularly linked with MG severity. Moreover, a combination of microbial makers and their correlated metabolites enable discriminating MG from healthy controls (HCs) with 100% accuracy. To investigate whether disturbed gut mcirobiome might contribute to the onset of MG, germ‐free (GF) mice are initially colonized with MG microbiota (MMb) or healthy microbiota (HMb), and then immunized in a classic mouse model of MG. The MMb mice demonstrate substantially impaired locomotion ability compared with the HMb mice. This effect could be reversed by cocolonizing GF mice with both MMb and HMb. The MMb mice also exhibit similar disturbances of fecal metabolic pathways as found in MG. Together these data demonstrate disturbances in microbiome composition and activity that are likely to be relevant to the pathogenesis of MG.

// Pengfei Cheng 1, 2, 3, 4, * , Junxi Pan 2, 3, 5, * , Jinjun Xia 2, 3, 5, * , Fengli Deng 2, 3, * , Wen Huang 6 , Shunjie Bai 2, 3, 5 , Xiaofeng Zhu 7 , Weihua Shao 8 , Haiyang Wang 2, 3 and Peng Xie 1, 2, 3 1 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China 2 Chongqing Key Laboratory of Neurobiology, Chongqing, 400016, China 3 Institute of Neuroscience and The Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, 400016, China 4 Department of Neurology, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang Province, 154002, China 5 The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China 6 Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China 7 Institute of Neuroscience, Jiamusi University, Jiamusi, Heilongjiang Province, 154002, China 8 Department of Respiratory Medicine, The First Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China * These authors contributed equally to this work Correspondence to: Peng Xie, email: xiepeng58@21cn.com Keywords: diet; cholesterol; stroke; cerebrovascular accident; meta-analysis Received: May 13, 2017 Accepted: November 03, 2017 Epub: January 04, 2018 Published: May 22, 2018 ABSTRACT Background/Objectives : The association between dietary cholesterol and stroke risk has remained controversial over the past two decades. The aim of this meta-analysis was to assess the relationship between dietary cholesterol and stroke risk. Results : Seven prospective studies including 269,777 non-overlapping individuals (4,604 strokes) were included. The combined RR of stroke for higher cholesterol intake (> 300 mg/day) was 0.98 (95% CI, 0.90–1.07), and the combined RR of stroke for higher cholesterol intake (> 300 mg/day) in females (age of ≥ 60 years or body mass index of ≥ 24 kg/m 2 ) was 1.18 (95% CI, 1.02–1.36). Materials and Methods : The PubMed, Medline, Embase, Web of Knowledge, and Google Scholar databases were searched. Relevant studies were identified by searching these online databases through September 2017. The relative risk (RR) and 95% confidence interval (CI) were used to investigate the strength of the association. Conclusions : Higher cholesterol intake has no association with the overall stroke risk. Age and body mass index affect the relationship between dietary cholesterol intake and stroke risk. However, the association between higher dietary cholesterol and stroke risk in males remains unclear.

Objectives Recombinant tissue plasminogen activator (rtPA) is widely used for patients with thromboembolic disease, and increasing evidence indicates that it can directly induce neurotoxicity independent of its thrombolysis property. Here, we aimed to confirm the long-term effect of rtPA on animal's behavior, and investigate the underlying pathogenesis. Methods and results Male Sprague-Dawley rats randomly received a dose of rtPA (10 mg/kg) or sterile saline. Three months later, the animals receiving rtPA displayed anxiety-like behaviors in the open field and novelty-suppressed feeding tests. To investigate the possible pathogenesis, gas chromatography-mass spectrometry-based metabolomics analysis was performed, with 18 differential metabolites identified in the hippocampus 24 h after the treatments. Based upon these differential metabolites, a metabolite-protein integrated network was generated, which indicated that ERK1/2-glutamic acid decarboxylase (GAD) 1-γ aminobutyric acid (GABA) cascade may be related to long-term anxiety-like behaviors. The GABA levels in hippocampus were decreased 24 h post-treatment and three months later, confirmed by a high performance liquid chromatography method. We also examined the expression of GAD1 and GAD2 using western blotting or immunohistochemical staining. Levels of GAD1 were persistently decreased after treatment, while GAD2 levels, GAD1-immunoreactive, and GAD2-immunoreactive neurons showed no significant differences. The underlying pathogenesis also involved activation of ERK1/2, confirmed by increased phospho-ERK1/2 24 h post-treatment. Conclusions RtPA can induce long-term anxiety-like behaviors after a clinical injected dose. The underlying pathogenesis involves the ERK1/2-GAD1-GABA cascade in the hippocampus. This pharmacological side effect of rtPA may further exacerbate post-stroke anxiety disorder for stroke patients.

Feng-Li Deng,1–4,* Jun-Xi Pan,2,3,5,* Peng Zheng,2,3,6Jin-Jun Xia,2,3 Bang-Min Yin,1–3 Wei-Wei Liang,1–3 Yi-Fan Li,2,3,6Jing Wu,2,3 Fan Xu,2,3 Qing-Yuan Wu,2,3,7Chao-Hua Qu,2,3 Wei Li,2,3 Hai-Yang Wang,2,3Peng Xie1–31Department of Neurology, Yongchuan Hospital, Chongqing Medical University, Chongqing 402460, People’s Republic of China; 2Chongqing Key Laboratory of Neurobiology, Chongqing 400016, People’s Republic of China; 3Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing 400016, People’s Republic of China; 4School of Public Health and Management, Chongqing Medical University, Chongqing 400016, People’s Republic of China; 5The First Affiliated Hospital of Kunming Medical University, Kunming 650032, People’s Republic of China; 6Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People’s Republic of China; 7Department of Neurology, Three Gorges Central Hospital, Chongqing Medical University, Chongqing 400016, People’s Republic of China *These authors contributed equally to this work Purpose: Depression is a complex psychiatric disorder. Various depressive rodent models are usually constructed based on different pathogenesis hypotheses.Materials and methods: Herein, using our previously established naturally occurring depressive (NOD) model in a non-human primate (cynomolgus monkey, Macaca fascularis), we performed metabolomics analysis of cerebrospinal fluid (CSF) from NOD female macaques (N=10) and age- and gender-matched healthy controls (HCs) (N=12). Multivariate statistical analysis was used to identify the differentially expressed metabolites between the two groups. Ingenuity Pathways Analysis and MetaboAnalyst were applied for predicted pathways and biological functions analysis.Results: Totally, 37 metabolites responsible for discriminating the two groups were identified. The NOD macaques were mainly characterized by perturbations of fatty acid biosynthesis, ABC transport system, and amino acid metabolism (eg, aspartate, glycine, serine, and threonine metabolism). Interestingly, we found that eight altered CSF metabolites belonging to short-chain fatty acids and amino acids were also observed in the serum of NOD macaques (N=13 per group).Conclusion: Our findings suggest that peripheral and central short-chain fatty acids and amino acids are implicated in the onset of depression.Keywords: naturally occurring depressive, depression, non-human primate, metabonomics, cerebrospinal fluid, short-chain fatty acid

New findings suggest that schizophrenia may be linked to gut bacteria., Schizophrenia (SCZ) is a devastating mental disorder with poorly defined underlying molecular mechanisms. The gut microbiome can modulate brain function and behaviors through the microbiota-gut-brain axis. Here, we found that unmedicated and medicated patients with SCZ had a decreased microbiome α-diversity index and marked disturbances of gut microbial composition versus healthy controls (HCs). Several unique bacterial taxa (e.g., Veillonellaceae and Lachnospiraceae) were associated with SCZ severity. A specific microbial panel (Aerococcaceae, Bifidobacteriaceae, Brucellaceae, Pasteurellaceae, and Rikenellaceae) enabled discriminating patients with SCZ from HCs with 0.769 area under the curve. Compared to HCs, germ-free mice receiving SCZ microbiome fecal transplants had lower glutamate and higher glutamine and GABA in the hippocampus and displayed SCZ-relevant behaviors similar to other mouse models of SCZ involving glutamatergic hypofunction. Together, our findings suggest that the SCZ microbiome itself can alter neurochemistry and neurologic function in ways that may be relevant to SCZ pathology.

The gut microbiome is composed of an enormous number of microorganisms, generally regarded as commensal bacteria. Resident gut bacteria are an important contributor to health and significant evidence suggests that the presence of healthy and diverse gut microbiota is important for normal cognitive and emotional processing. Here we measured the expression of monoamine neurotransmitter-related genes in the hippocampus of germ-free (GF) mice and specific-pathogen-free (SPF) mice to explore the effect of gut microbiota on hippocampal monoamine functioning. In total, 19 differential expressed genes (Htr7, Htr1f, Htr3b, Drd3, Ddc, Maob, Tdo2, Fos, Creb1, Akt1, Gsk3a, Pik3ca, Pla2g5, Cyp2d22, Grk6, Ephb1, Slc18a1, Nr4a1, Gdnf) that could discriminate between the two groups were identified. Interestingly, GF mice displayed anxiolytic-like behavior compared to SPF mice, which were not reversed by colonization with gut microbiota from SPF mice. Besides, colonization of adolescent GF mice by gut microbiota was not sufficient to reverse the altered gene expression associated with their GF status. Taking these findings together, the absence of commensal microbiota during early life markedly affects hippocampal monoamine gene-regulation, which was associated with anxiolytic behaviors and monoamine neurological signs.

Major depressive disorder (MDD) is a debilitating psychiatric illness. However, there is currently no objective laboratory-based diagnostic tests for this disorder. Although, perturbations in multiple neurotransmitter systems have been implicated in MDD, the biochemical changes underlying the disorder remain unclear, and a comprehensive global evaluation of neurotransmitters in MDD has not yet been performed. Here, using a GC-MS coupled with LC-MS/MS-based targeted metabolomics approach, we simultaneously quantified the levels of 19 plasma metabolites involved in GABAergic, catecholaminergic, and serotonergic neurotransmitter systems in 50 first-episode, antidepressant drug-naïve MDD subjects and 50 healthy controls to identify potential metabolite biomarkers for MDD (training set). Moreover, an independent sample cohort comprising 49 MDD patients, 30 bipolar disorder (BD) patients and 40 healthy controls (testing set) was further used to validate diagnostic generalizability and specificity of these candidate biomarkers. Among the 19 plasma neurotransmitter metabolites examined, nine were significantly changed in MDD subjects. These metabolites were mainly involved in GABAergic, catecholaminergic and serotonergic systems. The GABAergic and catecholaminergic had better diagnostic value than serotonergic pathway. A panel of four candidate plasma metabolite biomarkers (GABA, dopamine, tyramine, kynurenine) could distinguish MDD subjects from health controls with an AUC of 0.968 and 0.953 in the training and testing set, respectively. Furthermore, this panel distinguished MDD subjects from BD subjects with high accuracy. This study is the first to globally evaluate multiple neurotransmitters in MDD plasma. The altered plasma neurotransmitter metabolite profile has potential differential diagnostic value for MDD.

Bipolar disorder (BD) is a common psychiatric mood disorder affecting more than 1-2% of the general population of different European countries. Unfortunately, there is no objective laboratory-based test to aid BD diagnosis or monitor its progression, and little is known about the molecular basis of BD. Here, we performed a comparative proteomic study to identify differentially expressed plasma proteins in various BD mood states (depressed BD, manic BD, and euthymic BD) relative to healthy controls. A total of 10 euthymic BD, 20 depressed BD, 15 manic BD, and 20 demographically matched healthy control subjects were recruited. Seven high-abundance proteins were immunodepleted in plasma samples from the 4 experimental groups, which were then subjected to proteome-wide expression profiling by two-dimensional electrophoresis and matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight tandem mass spectrometry. Proteomic results were validated by immunoblotting and bioinformatically analyzed using MetaCore. From a total of 32 proteins identified with 1.5-fold changes in expression compared with healthy controls, 16 proteins were perturbed in BD independent of mood state, while 16 proteins were specifically associated with particular BD mood states. Two mood-independent differential proteins, apolipoprotein (Apo) A1 and Apo L1, suggest that BD pathophysiology may be associated with early perturbations in lipid metabolism. Moreover, down-regulation of one mood-dependent protein, carbonic anhydrase 1 (CA-1), suggests it may be involved in the pathophysiology of depressive episodes in BD. Thus, BD pathophysiology may be associated with early perturbations in lipid metabolism that are independent of mood state, while CA-1 may be involved in the pathophysiology of depressive episodes.

The role of A1 adenosine receptors (A1ARs) in the white matter under chronic cerebral ischemic conditions remains unclear. Here, we used right unilateral common carotid artery occlusion (rUCCAO) to construct a chronic cerebral ischemic mouse model. A1AR expression and proteolipid protein (PLP, a marker of white matter myelination) in the corpus callosum were observed by immunoreaction and immunohistochemistry, respectively. Pro-inflammatory interleukin-1β (IL-1β) and anti-inflammatory interleukin-10 (IL-10) levels were determined by ELISA. The Morris water maze test was employed to detect cognitive impairment. A1AR expression significantly decreased in the rUCCAO group as compared with the sham control group on weeks 2, 4, and 6, respectively. IL-10 levels in the rUCCAO group significantly declined on week 6, while there was no significant change in IL-1β expression. PLP expression significantly decreased in the rUCCAO group on weeks 2, 4, and 6. Moreover, latency time for the Morris water maze test significantly increased in the rUCCAO group on weeks 4 and 6, while the number of platform location crossing significantly decreased in the rUCCAO group on weeks 2, 4, and 6. In conclusion, this study provides the first evidence that chronic cerebral ischemia appears to induce A1AR downregulation and inhibition of IL-10 production, which may play key roles in the neuropathological mechanisms of ischemic white matter lesions. These data will facilitate future studies in formulating effective therapeutic strategies for ischemic white matter lesions.

Parkinson’s disease (PD), a progressive and age-related neurodegenerative condition, is a common neurodegenerative disorder. However, no validated biomarkers for PD have been identified to date. Accumulating evidence supports the role of proNGF-p75NTR-sortilin signaling in the neurodegeneration and pathogenesis of PD. The aim of our study was to investigate alterations in serum proNGF concentrations in PD patients and related anxiety. Seventy-seven consecutive PD patients and 39 healthy controls were enrolled, and clinical data were collected. Modified Hoehn-Yahr Staging Scale, Unified Parkinson’s Disease Rating Scale (UPDRS), and Hamilton Anxiety (HAMA) Scale scores were assessed upon admission. Serum proNGF concentration was compared between that of PD patients and healthy controls. Pearson correlation coefficients were determined to explore the relationship between proNGF concentration and UPDRS, Hoehn-Yahr, and HAMA scores. Received operating characteristic (ROC) curves and proNGF optimal cutoff point were used to distinguish PD and related anxiety. The median concentration of proNGF was significantly lower (p = 0.000) in PD patients (94.91 ng/L, range 85.92–118.06 ng/L) compared with that of healthy controls (106.67 ng/L, range 102.39–122.06 ng/L). The optimal proNGF cutoff point for distinguishing PD patients was 102.29 ng/L, and the sensitivity and specificity values were 87.0 and 100%, respectively. proNGF concentration positively correlated with UPDRS (r = 0.281, p = 0.013), Hoehn-Yahr (r = 0.260, p = 0.023), and HAMA (r = 0.276, p = 0.015) scores. Our results indicate that serum proNGF concentration may represent a biomarker for PD and its role in the pathogenesis of PD thus warrants further investigation.

Aims To measure the effectiveness of antidepressants for adolescents and young adults with co-occurring depression and substance use disorder. Design, Setting and Participants Meta-analysis of randomized controlled clinical trials. A comprehensive literature search of PubMed, Cochrane, Embase, Web of Science and PsychINFO was conducted (from 1970 to 2013). Prospective, parallel groups, double-blind, controlled trials with random assignment to an antidepressant or placebo on young patients (age ≤ 25 years) who met diagnostic criteria of both substance use and unipolar depressive disorder were included. Five trials were selected for this analysis and included 290 patients. Measurements Our efficacy outcome measures were depression outcomes (dichotomous and continuous measures) and substance-use outcomes (change of frequency or quantity of substance-use). Secondary analysis was conducted to access the tolerability of antidepressant treatment. Findings For dichotomous depression outcome, antidepressants group was significantly more effective than placebo group [risk ratio (RR) = 1.21; 95% confidence interval (CI) 1.01–1.45], with low heterogeneity (I2 = 0%). Although no statistically significant effects for continuous depression outcome [standardized mean differences (SMD) = −0.13; 95% CI, −0.55 to 0.30] were found with moderate heterogeneity (I2 = 63%), subgroup analysis showed that the medicine group with a sample size of more than 50 showed statistically significant efficacy compared with the placebo group (SMD −0.53, 95% CI −0.82 to −0.25). Moreover, there was no significant difference for substance-use outcomes and tolerability outcomes between the medication and placebo groups. Conclusions Antidepressant medication has a small overall effect in reducing depression in young patients with combined depressive and substance-use disorders, but does not appear to improve substance use outcomes.

Background/Objectives The association between dietary cholesterol and stroke risk has remained controversial over the past two decades. The aim of this meta-analysis was to assess the relationship between dietary cholesterol and stroke risk. Results Seven prospective studies including 269,777 non-overlapping individuals (4,604 strokes) were included. The combined RR of stroke for higher cholesterol intake (> 300 mg/day) was 0.98 (95% CI, 0.90–1.07), and the combined RR of stroke for higher cholesterol intake (> 300 mg/day) in females (age of ≥ 60 years or body mass index of ≥ 24 kg/m2) was 1.18 (95% CI, 1.02–1.36). Materials and Methods The PubMed, Medline, Embase, Web of Knowledge, and Google Scholar databases were searched. Relevant studies were identified by searching these online databases through September 2017. The relative risk (RR) and 95% confidence interval (CI) were used to investigate the strength of the association. Conclusions Higher cholesterol intake has no association with the overall stroke risk. Age and body mass index affect the relationship between dietary cholesterol intake and stroke risk. However, the association between higher dietary cholesterol and stroke risk in males remains unclear.