Major depressive disorder (MDD) is the result of complex gene-environment interactions. According to the World Health Organization, MDD is the leading cause of disability worldwide, and it is a major contributor to the overall global burden of disease. However, the definitive environmental mechanisms underlying the pathophysiology of MDD remain elusive. The gut microbiome is an increasingly recognized environmental factor that can shape the brain through the microbiota-gut-brain axis. We show here that the absence of gut microbiota in germ-free (GF) mice resulted in decreased immobility time in the forced swimming test relative to conventionally raised healthy control mice. Moreover, from clinical sampling, the gut microbiotic compositions of MDD patients and healthy controls were significantly different with MDD patients characterized by significant changes in the relative abundance of Firmicutes, Actinobacteria and Bacteroidetes. Fecal microbiota transplantation of GF mice with 'depression microbiota' derived from MDD patients resulted in depression-like behaviors compared with colonization with 'healthy microbiota' derived from healthy control individuals. Mice harboring 'depression microbiota' primarily exhibited disturbances of microbial genes and host metabolites involved in carbohydrate and amino acid metabolism. This study demonstrates that dysbiosis of the gut microbiome may have a causal role in the development of depressive-like behaviors, in a pathway that is mediated through the host's metabolism.

IMPORTANCE Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options.OBJECTIVE To evaluate the efficacy and safety of oral fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC. DESIGN, SETTING, AND PARTICIPANTS FRESCO (Fruquintinib Efficacy and Safety in 3+ LineColorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017.INTERVENTIONS Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n = 278) or placebo (n = 138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal. MAIN OUTCOMES AND MEASURESThe primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objective response rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stable disease recorded Ն8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events. RESULTSOf the 416 randomized patients (mean age, 54.6 years; 161 [38.7%] women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months [95% CI, 8.2-10.5] vs 6.6 months [95% CI, 5.9-8.1]); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; P < .001). Median progression-free survival was also significantly increased with fruquintinib (3.7 months [95% CI, 3.7-4.6] vs 1.8 months [95% CI, 1.8-1.8] months); HR for progression or death, 0.26 (95% CI, 0.21 to 0.34; P < .001). Grades 3 and 4 treatment-emergent adverse events occurred in 61.2% (170) of patients who received fruquintinib and 19.7% ( 27) who received placebo. Serious adverse events were reported by 15.5% (43) of patients in the fruquintinib group and 5.8% (8) in the placebo group, with 14.4% (40) of fruquintinib-treated and 5.1% (7) of placebo-treated patients requiring hospitalization.CONCLUSIONS AND RELEVANCE Among Chinese patients with metastatic CRC who had tumor progression following at least 2 prior chemotherapy regimens, oral fruquintinib compared with placebo resulted in a statistically significant increase in overall survival. Further research is needed to assess efficacy outside of China.

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Bipolar disorder (BD) is a debilitating mental disorder that cannot be diagnosed by objective laboratory-based modalities. Our previous studies have independently used nuclear magnetic resonance (NMR)-based and gas chromatography-mass spectrometry (GC-MS)-based metabonomic methods to characterize the urinary metabolic profiles of BD subjects and healthy controls (HC). However, the combined application of NMR spectroscopy and GC-MS may identify a more comprehensive metabolite panel than any single metabonomic platform alone. Therefore, here we applied a dual platform (NMR spectroscopy and GC-MS) that generated a panel of five metabolite biomarkers for BD-four GC-MS-derived metabolites and one NMR-derived metabolite. This composite biomarker panel could effectively discriminate BD subjects from HC, achieving an area under receiver operating characteristic curve (AUC) values of 0.974 in a training set and 0.964 in a test set. Moreover, the diagnostic performance of this panel was significantly superior to the previous single platform-derived metabolite panels. Thus, the urinary biomarker panel identified here shows promise as an effective diagnostic tool for BD. These findings also demonstrate the complementary nature of NMR spectroscopy and GC-MS for metabonomic analysis, suggesting that the combination of NMR spectroscopy and GC-MS can identify a more comprehensive metabolite panel than applying each platform in isolation.

Depression is a debilitating psychiatric disorder and a growing global public health issue. However, the relationships between microbial infections and depression remains uncertain. A computerized literature search of Medline, ISI Web of Knowledge, PsycINFO, and the Cochrane Library was conducted up to May 2013, and 6362 studies were initially identified for screening. Case-control studies detected biomarker of microorganism were included. Based on inclusion and exclusion criteria, 28 studies were finally included to compare the detection of 16 infectious agents in unipolar depressed patients and healthy controls with a positive incident being defined as a positive biochemical marker of microbial infection. A customized form was used for data extraction. Pooled analysis revealed that the majority of the 16 infectious agents were not significantly associated with depression. However, there were statistically significant associations between depression and infection with Borna disease virus, herpes simplex virus-1, varicella zoster virus, Epstein-Barr virus, and Chlamydophila trachomatis.

Major depressive disorder (MDD) is a highly prevalent, debilitating mental illness of importance for global health. However, its molecular pathophysiology remains poorly understood. Combined proteomics and metabolomics approaches should provide a comprehensive understanding of MDD's etiology. The present study reports novel ''-omics'' insights from a rodent model of MDD. Cerebellar samples from chronic mild stressed (CMS)-treated depressed rats and controls were compared with a focus on the differentially expressed proteins and metabolites using isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics and gas chromotography/mass spectrometry (GC-MS) metabolomics techniques, respectively. The combined analyses found significant alterations associated with cerebellar energy metabolism, as indicated by (1) abnormal amino acid metabolism accompanied by corresponding metabolic enzymatic alterations and disturbed protein turnover, (2) increased glycolytic and tricarboxylic acid (TCA) cycle enzyme levels paralleled by changes in the concentrations of associated metabolites, and (3) perturbation of ATP biosynthesis through adenosine accompanied by perturbation of the mitochondrial respiratory chain. To the best of our knowledge, this study is the first to integrate proteomics and metabolomics analyses to examine the pathophysiological mechanism(s) underlying MDD in a CMS rodent model of depression. These results can offer important insights into the pathogenesis of MDD.

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