Identification of novel endoplasmic reticulum-related genes and their association with immune cell infiltration in major depressive disorder.

BACKGROUND: Several lines of evidence point to an interaction between genetic predisposition and environmental factors in the onset of major depressive disorder (MDD). This study is aimed to investigate the pathogenesis of MDD by identifying key biomarkers, associated immune infiltration using bioinformatic analysis and human postmortem sample. METHODS: The Gene Expression Omnibus (GEO) database of GSE98793 was adopted to identify hub genes linked to endoplasmic reticulum (ER) stress-related genes (ERGs) in MDD. Another GEO database of GSE76826 was employed to validate the novel target associated with ERGs and immune infiltration in MDD. Moreover, human postmortem sample from MDD patients was utilized to confirm the differential expression analysis of hub genes. RESULTS: We discovered 12 ER stress-related differentially expressed genes (ERDEGs). A LASSO Cox regression analysis helped construct a diagnostic model for these ERDEGs, incorporating immune infiltration analysis revealed that three hub genes (ERLIN1, SEC61B, and USP13) show the significant and consistent expression differences between the two groups. Western blot analysis of postmortem brain samples indicated notably higher expression levels of ERLIN1 and SEC61B in the MDD group, with USP13 also tending to increase compared to control group. LIMITATIONS: The utilization of the MDD gene chip in this analysis was sourced from the GEO database, which possesses a restricted number of pertinent gene chip samples. CONCLUSIONS: These findings indicate that ERDEGs especially including ERLIN1, SEC61B, and USP13 associated the infiltration of immune cells may be potential diagnostic indicators for MDD.

Ketamine and its enantiomers for depression: a bibliometric analysis from 2000 to 2023.

Ketamine has demonstrated rapid and sustained antidepressant effects, marking its emergence as an innovative treatment of depression. Despite the growing number of preclinical and clinical studies exploring the antidepressant effects of ketamine and its enantiomers, a comprehensive bibliometric analysis in this field has yet to be conducted. This study employs bibliometric methods and visualization tools to examine the literature and identify key topics related to the antidepressant effects of ketamine and its enantiomers. We sourced publications on the antidepressant effects of ketamine and its enantiomers from the Web of Science Core Collection (WOSCC) database, covering the period from 2000 to 2023. Tools such as VOSviewer, CiteSpace and the R package "bibliometrix" were utilized for visual analysis. The study included 4,274 publications, with a notable increase in publications peaking in 2022. Co-occurrence analysis highlighted two primary research focal points: the efficacy and safety of ketamine and its enantiomers in treating depression, and the mechanisms behind their antidepressant effects. In conclusion, this analysis revealed a significant increase in research on the antidepressant effects of ketamine and its enantiomers over the past two decades, leading to the approval of esketamine nasal spray for treatment-resistant depression. The rapid antidepressant effects of ketamine have spurred further studies into its mechanisms of action and the search for new antidepressants with fewer side effects.

Viewpoints Sigma-1 receptor agonist fluvoxamine for multiple sclerosis.

Accumulating evidence suggests that the Epstein-Barr virus (EBV) plays a key role in the development of multiple sclerosis (MS). Additionally, depressive symptoms often precede the onset of MS. Given the role of the XBP1-sigma-1 receptor complex in the endoplasmic reticulum during EBV reactivation, the author proposes that fluvoxamine, an antidepressant with sigma-1 receptor agonism, could be a suitable therapeutic drug for MS.

Efficacy and safety of esketamine for perioperative depression in patients undergoing elective surgery: A meta-analysis of randomized controlled trials.

BACKGROUND: Depression is a prevalent mood disorder during the perioperative period, with both preoperative concurrent depression and new-onset postoperative depression impacting postoperative recovery. Recent studies have indicated that the dissociative anesthetic esketamine may alleviate perioperative depressive symptoms. OBJECTIVE: This meta-analysis aimed to assess the efficacy and safety of esketamine in treating perioperative depression. METHODS: We selected randomized controlled trials comparing esketamine to placebo in terms of postoperative depressive symptoms. The primary outcome was postoperative depression scores, with secondary outcomes including the prevalence of postoperative depression, pain scores using the Visual Analogue Scale or Numeric Rating Scale, and incidences of adverse reactions such as nausea/vomiting, dizziness, dreams/nightmares, hallucinations. RESULTS: We enrolled a total of 17 studies involving 2462 patients. The esketamine group demonstrated a significant reduction in postoperative depression scores within one week after surgery (SMD -0.47, 95% CI (-0.66, -0.27), P < 0.001) and over the long term (SMD -0.44, 95% CI (-0.79, -0.09), P = 0.01). Furthermore, esketamine significantly decreased the prevalence of postoperative depression both within one week (RR 0.46, 95% CI (0.33, 0.63), P < 0.001) and over the long term (RR 0.50, 95% CI (0.36, 0.70), P < 0.001). Additionally, esketamine effectively relieved pain on the first postoperative day compared to control. However, it also increased the risks of dizziness and hallucinations for a short time. CONCLUSION: This meta-analysis suggests that the intraoperative or postoperative application of esketamine could be a potentially effective treatment for perioperative depression, although the increased risk of adverse reactions should be considered.

Are "mystical experiences" essential for antidepressant actions of ketamine and the classic psychedelics?

The growing interest in the rapid and sustained antidepressant effects of the dissociative anesthetic ketamine and classic psychedelics, such as psilocybin, is remarkable. However, both ketamine and psychedelics are known to induce acute mystical experiences; ketamine can cause dissociative symptoms such as out-of-body experience, while psychedelics typically bring about hallucinogenic experiences, like a profound sense of unity with the universe or nature. The role of these mystical experiences in enhancing the antidepressant outcomes for patients with depression is currently an area of ongoing investigation and debate. Clinical studies have shown that the dissociative symptoms following the administration of ketamine or (S)-ketamine (esketamine) are not directly linked to their antidepressant properties. In contrast, the antidepressant potential of (R)-ketamine (arketamine), thought to lack dissociative side effects, has yet to be conclusively proven in large-scale clinical trials. Moreover, although the activation of the serotonin 5-HT2A receptor is crucial for the hallucinogenic effects of psychedelics in humans, its precise role in their antidepressant action is still under discussion. This article explores the importance of mystical experiences in enhancing the antidepressant efficacy of both ketamine and classic psychedelics.

Depression-like phenotypes in mice following common bile duct ligation: Insights into the gut-liver-brain axis via the vagus nerve.

Depression frequently occurs in patients with liver cirrhosis, yet the reasons for this correlation are not fully understood. Dysbiosis of gut microbiota has been implicated in depression through the gut-brain axis via the vagus nerve. This study explored the potential role of the gut-liver-brain axis via the vagus nerve in depression-like phenotypes in mice with liver cirrhosis. These mice underwent common bile duct ligation (CBDL), a method used to stimulate liver cirrhosis. To assess depression-like behaviors, behavioral tests were conducted 10 days following either sham or CBDL surgeries. The mice with CBDL displayed symptoms such as splenomegaly, elevated plasma levels of interleukin-6 and tumor necrosis factor-α, depression-like behaviors, decreased levels of synaptic proteins in the prefrontal cortex (PFC), disrupted gut microbiota balance, and changes in blood metabolites (or lipids). Additionally, there were positive or negative correlations between the relative abundance of microbiome and behavioral data or blood metabolites (or lipids). Significantly, these changes were reversed in CBDL mice by performing a subdiaphragmatic vagotomy. Intriguingly, depression-like phenotypes in mice with CBDL were improved after a single injection of arketamine, a new antidepressant. These results suggest that CBDL-induced depression-like phenotypes in mice are mediated through the gut-liver-brain axis via the subdiaphragmatic vagus nerve, and that arketamine might offer a new treatment approach for depression in liver cirrhosis patients.

A role of gut-brain axis on prophylactic actions of arketamine in male mice exposed to chronic restrain stress.

The gut-brain axis, which includes gut microbiota and microbiome-derived metabolites, might be implicated in depression. We reported the sustained prophylactic effects of a new antidepressant arketamine in chronic restrain stress (CRS) model of depression. In this study, we investigated the role of gut-brain axis on the prophylactic effects of arketamine in the CRS (7 days) model. Pretreatment with arketamine (10 mg/kg, 1 day prior to the CRS onset) significantly prevented CRS-induced body weight loss, increased immobility time of forced swimming test, decreased sucrose preference of sucrose preference test, and reduced expressions of synaptic proteins (GluA1 and PSD-95) in the prefrontal cortex (PFC) in the male mice. Gut microbiota analysis showed that pretreatment with arketamine might restore altered abundance of gut microbiota in CRS-exposed mice. An untargeted metabolomics analysis revealed four metabolites (e.g., L-leucine, N-acetyl-l-glutamine, 2-(2,4-dichlorophenyl)-3-[4-(dimethylamino)phenyl]acrylonitrile, L-threonine amide) that were altered between control and CRS group; however, there were found to be altered between the saline + CRS group and the arketamine + CRS group. Network analysis demonstrated correlations among synaptic proteins in the PFC and certain microbiota, and blood metabolites. These findings suggest that gut-brain axis, including its metabolites, might partially contribute to the persistent prophylactic effects of arketamine in the CRS model.

Autophagy-related gene model as a novel risk factor for schizophrenia.

Autophagy, a cellular process where cells degrade and recycle their own components, has garnered attention for its potential role in psychiatric disorders, including schizophrenia (SCZ). This study aimed to construct and validate a new autophagy-related gene (ARG) risk model for SCZ. First, we analyzed differential expressions in the GSE38484 training set, identifying 4,754 differentially expressed genes (DEGs) between SCZ and control groups. Using the Human Autophagy Database (HADb) database, we cataloged 232 ARGs and pinpointed 80 autophagy-related DEGs (AR-DEGs) after intersecting them with DEGs. Subsequent analyses, including metascape gene annotation, pathway and process enrichment, and protein-protein interaction enrichment, were performed on the 80 AR-DEGs to delve deeper into their biological roles and associated molecular pathways. From this, we identified 34 candidate risk AR-DEGs (RAR-DEGs) and honed this list to final RAR-DEGs via a constructed and optimized logistic regression model. These genes include VAMP7, PTEN, WIPI2, PARP1, DNAJB9, SH3GLB1, ATF4, EIF4G1, EGFR, CDKN1A, CFLAR, FAS, BCL2L1 and BNIP3. Using these findings, we crafted a nomogram to predict SCZ risk for individual samples. In summary, our study offers deeper insights into SCZ's molecular pathogenesis and paves the way for innovative approaches in risk prediction, gene-targeted diagnosis, and community-based SCZ treatments.

Repeated (S)-ketamine administration ameliorates the spatial working memory impairment in mice with chronic pain: role of the gut microbiota-brain axis.

Chronic pain is commonly linked with diminished working memory. This study explores the impact of the anesthetic (S)-ketamine on spatial working memory in a chronic constriction injury (CCI) mouse model, focusing on gut microbiome. We found that multiple doses of (S)-ketamine, unlike a single dose, counteracted the reduced spontaneous alteration percentage (%SA) in the Y-maze spatial working memory test, without affecting mechanical or thermal pain sensitivity. Additionally, repeated (S)-ketamine treatments improved the abnormal composition of the gut microbiome (ß-diversity), as indicated by fecal 16S rRNA analysis, and increased levels of butyrate, a key gut - brain axis mediator. Protein analysis showed that these treatments also corrected the upregulated histone deacetylase 2 (HDAC2) and downregulated brain-derived neurotrophic factor (BDNF) in the hippocampi of CCI mice. Remarkably, fecal microbiota transplantation from mice treated repeatedly with (S)-ketamine to CCI mice restored %SA and hippocampal BDNF levels in CCI mice. Butyrate supplementation alone also improved %SA, BDNF, and HDAC2 levels in CCI mice. Furthermore, the TrkB receptor antagonist ANA-12 negated the beneficial effects of repeated (S)-ketamine on spatial working memory impairment in CCI mice. These results indicate that repeated (S)-ketamine administration ameliorates spatial working memory impairment in CCI mice, mediated by a gut microbiota - brain axis, primarily through the enhancement of hippocampal BDNF - TrkB signaling by butyrate.

(R)-ketamine restores anterior insular cortex activity and cognitive deficits in social isolation-reared mice.

Chronic social isolation increases the risk of mental health problems, including cognitive impairments and depression. While subanesthetic ketamine is considered effective for cognitive impairments in patients with depression, the neural mechanisms underlying its effects are not well understood. Here we identified unique activation of the anterior insular cortex (aIC) as a characteristic feature in brain-wide regions of mice reared in social isolation and treated with (R)-ketamine, a ketamine enantiomer. Using fiber photometry recording on freely moving mice, we found that social isolation attenuates aIC neuronal activation upon social contact and that (R)-ketamine, but not (S)-ketamine, is able to counteracts this reduction. (R)-ketamine facilitated social cognition in social isolation-reared mice during the social memory test. aIC inactivation offset the effect of (R)-ketamine on social memory. Our results suggest that (R)-ketamine has promising potential as an effective intervention for social cognitive deficits by restoring aIC function.

Rapid propagation of Ca2+ waves and electrical signals in a liverwort Marchantia polymorpha.

In response to both biotic and abiotic stresses, vascular plants transmit long-distance Ca2+ and electrical signals from localized stress sites to distant tissues through their vasculature. Various models have been proposed for the mechanisms underlying the long-distance signaling, primarily centered around the presence of vascular bundles. We here demonstrate that the non-vascular liverwort Marchantia polymorpha possesses a mechanism for propagating Ca2+ waves and electrical signals in response to wounding. The propagation velocity of these signals was approximately 1-2 mm/s, equivalent to that observed in vascular plants. Both Ca2+ waves and electrical signals were inhibited by La3+ as well as tetraethylammonium chloride, suggesting crucial importance of both Ca2+ channel(s) and K+ channel(s) in wound-induced membrane depolarization as well as the subsequent long-distance signal propagation. Simultaneous recordings of Ca2+ and electrical signals indicated a tight coupling between the dynamics of these two signaling modalities. Furthermore, molecular genetic studies revealed that a GLUTAMATE RECEPTOR-LIKE (GLR) channel plays a central role in the propagation of both Ca2+ waves and electrical signals. Conversely, none of the three two-pore channels (TPCs) were implicated in either signal propagation. These findings shed light on the evolutionary conservation of rapid long-distance Ca2+ wave and electrical signal propagation involving GLRs in land plants, even in the absence of vascular tissue.

Clemastine-induced enhancement of hippocampal myelination alleviates memory impairment in mice with chronic pain.

Patients with chronic pain often experience memory impairment, but the underlying mechanisms remain elusive. The myelin sheath is crucial for rapid and accurate action potential conduction, playing a pivotal role in the development of cognitive abilities in the central nervous system. The study reveals that myelin degradation occurs in the hippocampus of chronic constriction injury (CCI) mice, which display both chronic pain and memory impairment. Using fiber photometry, we observed diminished task-related neuronal activity in the hippocampus of CCI mice. Interestingly, the repeated administration with clemastine, which promotes myelination, counteracts the CCI-induced myelin loss and reduced neuronal activity. Notably, clemastine specifically ameliorates the impaired memory without affecting chronic pain in CCI mice. Overall, our findings highlight the significant role of myelin abnormalities in CCI-induced memory impairment, suggesting a potential therapeutic approach for treating memory impairments associated with neuropathic pain.

The role of CD38 in inflammation-induced depression-like behavior and the antidepressant effect of (R)-ketamine.

CD38 is involved in immune responses, cell proliferation, and has been identified in the brain, where it is implicated in inflammation processes and psychiatric disorders. We hypothesized that dysfunctional CD38 activity in the brain may contribute to the pathogenesis of depression. To investigate the underlying mechanisms, we used a lipopolysaccharide (LPS)-induced depression-like model and conducted behavioral tests, molecular and morphological methods, along with optogenetic techniques. We microinjected adeno-associated virus into the hippocampal CA3 region with stereotaxic instrumentation. Our results showed a marked increase in CD38 expression in both the hippocampus and cortex of LPS-treated mice. Additionally, pharmacological inhibition and genetic knockout of CD38 effectively alleviated neuroinflammation, microglia activation, synaptic defects, and Sirt1/STAT3 signaling, subsequently improving depression-like behaviors. Moreover, optogenetic activation of glutamatergic neurons of hippocampal CA3 reduced the susceptibility of mice to depression-like behaviors, accompanied by reduced CD38 expression. We also found that (R)-ketamine, which displayed antidepressant effects, was linked to its anti-inflammatory properties by suppressing increased CD38 expression and reversing synaptic defects. In conclusion, hippocampal CD38 is closely linked to depression-like behaviors in an inflammation model, highlighting its potential as a therapeutic target for antidepressant development.

Enhanced Ca2+ binding to EF-hands through phosphorylation of conserved serine residues activates MpRBOHB and chitin-triggered ROS production.

NADPH oxidases/RBOHs catalyze apoplastic ROS production and act as key signaling nodes, integrating multiple signal transduction pathways regulating plant development and stress responses. Although RBOHs have been suggested to be activated by Ca2+ binding and phosphorylation by various protein kinases, a mechanism linking Ca2+ binding and phosphorylation in the activity regulation remained elusive. Chitin-triggered ROS production required cytosolic Ca2+ elevation and Ca2+ binding to MpRBOHB in a liverwort Marchantia polymorpha. Heterologous expression analysis of truncated variants revealed that a segment of the N-terminal cytosolic region highly conserved among land plant RBOHs encompassing the two EF-hand motifs is essential for the activation of MpRBOHB. Within the conserved regulatory domain, we have identified two Ser residues whose phosphorylation is critical for the activation in planta. Isothermal titration calorimetry analyses revealed that phosphorylation of the two Ser residues increased the Ca2+ binding affinity of MpRBOHB, while Ca2+ binding is indispensable for the activation, even if the two Ser residues are phosphorylated. Our findings shed light on a mechanism through which phosphorylation potentiates the Ca2+ -dependent activation of MpRBOHB, emphasizing the pivotal role of Ca2+ binding in mediating the Ca2+ and phosphorylation-driven activation of MpRBOHB, which is likely to represent a fundamental mechanism conserved among land plant RBOHs.

Role of the gut-brain axis via the subdiaphragmatic vagus nerve in stress resilience of 3,4-methylenedioxymethamphetamine in mice exposed to chronic restrain stress.

3,4-Methylenedioxymethamphetamine (MDMA) is the most widely used illicit substance worldwide. Nevertheless, recent observational studies demonstrated that lifetime MDMA use among U.S. adults was associated with a lower risk of depression and suicide thoughts. We recently reported that the gut-brain axis may contribute to MDMA-induced stress resilience in mice. To further explore this, we investigated the effects of subdiaphragmatic vagotomy (SDV) in modulating the stress resilience effects of MDMA in mice subjected to chronic restrain stress (CRS). Pretreatment with MDMA (10 mg/kg/day for 14 days) blocked anhedonia-like behavior and reduced expression of synaptic proteins and brain-derived neurotrophic factor in the prefrontal cortex (PFC) of CRS-exposed mice. Interestingly, SDV blocked the beneficial effects of MDMA on these alterations in CRS-exposed mice. Analysis of gut microbiome revealed alterations in four measures of α-diversity between the sham + MDMA + CRS group and the SDV + MDMA + CRS group. Moreover, specific microbes differed between the vehicle + CRS group and the MDMA + CRS group, and further differences in microbial composition were observed among all four groups. Untargeted metabolomics analysis showed that SDV prevented the increase in plasma levels of three compounds [lactic acid, 1-(2-hydroxyethyl)-2,2,6-tetramethyl-4-piperidinol, 8-acetyl-7-hydroxyvumaline] observed in the sham + MDMA + CRS group. Interestingly, positive correlations were found between the plasma levels of two of these compounds and the abundance of several microbes across all groups. In conclusion, our data suggest that the gut-brain axis via the subdiaphragmatic vagus nerve might contribute to the stress resilience of MDMA.

Role of soluble epoxide hydrolase in the abnormal activation of fibroblast-like synoviocytes from patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by enigmatic pathogenesis. Polyunsaturated fatty acids (PUFAs) are implicated in RA's development and progression, yet their exact mechanisms of influence are not fully understood. Soluble epoxide hydrolase (sEH) is an enzyme that metabolizes anti-inflammatory epoxy fatty acids (EpFAs), derivatives of PUFAs. In this study, we report elevated sEH expression in the joints of CIA (collagen-induced arthritis) rats, concomitant with diminished levels of two significant EpFAs. Additionally, increased sEH expression was detected in both the synovium of CIA rats and in the synovium and fibroblast-like synoviocytes (FLS) of RA patients. The sEH inhibitor TPPU attenuated the migration and invasion capabilities of FLS derived from RA patients and to reduce the secretion of inflammatory factors by these cells. Our findings indicate a pivotal role for sEH in RA pathogenesis and suggest that sEH inhibitors offer a promising new therapeutic strategy for managing RA.

Myelin-associated oligodendrocytic basic protein-dependent myelin repair confers the long-lasting antidepressant effect of ketamine.

Ketamine exhibits rapid and sustained antidepressant effects. As decreased myelination has been linked to depression pathology, changes in myelination may be a pivotal mechanism underlying ketamine's long-lasting antidepressant effects. Although ketamine has a long-lasting facilitating effect on myelination, the precise roles of myelination in ketamine's sustained antidepressant effects remain unknown. In this study, we employed spatial transcriptomics (ST) to examine ketamine's lasting effects in the medial prefrontal cortex (mPFC) and hippocampus of mice subjected to chronic social defeat stress and identified several differentially expressed myelin-related genes. Ketamine's ability to restore impaired myelination in the brain by promoting the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes was demonstrated. Moreover, we showed that inhibiting the expression of myelin-associated oligodendrocytic basic protein (Mobp) blocked ketamine's long-lasting antidepressant effects. We also illustrated that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) signaling mediated ketamine's facilitation on myelination. In addition, we found that the (R)-stereoisomer of ketamine showed stronger effects on myelination than (S)-ketamine, which may explain its longer-lasting antidepressant effects. These findings reveal novel mechanisms underlying the sustained antidepressant effects of ketamine and the differences in antidepressant effects between (R)-ketamine and (S)-ketamine, providing new insights into the role of myelination in antidepressant mechanisms.

Prophylactic effects of arketamine, but not hallucinogenic psychedelic DOI nor non-hallucinogenic psychedelic analog lisuride, in lipopolysaccharide-treated mice and mice exposed to chronic restrain stress.

Anesthetic ketamine and classical psychedelics that act as 5-hydroxytryptamine-2A receptor (5-HT2AR) agonists demonstrated rapid and sustained antidepressant actions in patients with treatment-resistant depression. The new antidepressant arketamine is reported to cause long-lasting prophylactic effects in lipopolysaccharide (LPS)-treated mice and mice exposed to chronic restrain stress (CRS). However, no study has compared the prophylactic effects of DOI (2,5-dimethoxy-4-iodoamphetamine: a hallucinogenic psychedelic drug with potent 5-HT2AR agonism), lisuride (non-hallucinogenic psychedelic analog with 5-HT2AR and 5-HT1AR agonism), and arketamine on depression-like behaviors in mice. Saline (10 ml/kg), DOI (2.0 or 4.0 mg/kg), lisuride (1.0 or 2.0 mg/kg), or arketamine (10 mg/kg) was administered intraperitoneally (i.p.) to male mice 6 days before administration of LPS (1.0 mg/kg). Pretreatment with aketamine, but not DOI and lisuride, significantly ameliorated body weight loss, splenomegaly, the increased immobility time of forced swimming test (FST), and the decreased expression of PSD-95 in the prefrontal cortex (PFC) of LPS-treated mice. In another test, male mice received the same treatment one day before CRS (7 days). Pretreatment with aketamine, but not DOI and lisuride, significantly ameliorated the increased FST immobility time, the reduced sucrose preference in the sucrose preference test, and the decreased expression of PSD-95 in the PFC of CRS-exposed mice. These findings suggest that, unlike to arketamine, both DOI and lisuride did not exhibit long-lasting prophylactic effects in mouse models of depression.

Emerging role of the host microbiome in neuropsychiatric disorders: overview and future directions.

The human body harbors a diverse ecosystem of microorganisms, including bacteria, viruses, and fungi, collectively known as the microbiota. Current research is increasingly focusing on the potential association between the microbiota and various neuropsychiatric disorders. The microbiota resides in various parts of the body, such as the oral cavity, nasal passages, lungs, gut, skin, bladder, and vagina. The gut microbiota in the gastrointestinal tract has received particular attention due to its high abundance and its potential role in psychiatric and neurodegenerative disorders. However, the microbiota presents in other body tissues, though less abundant, also plays crucial role in immune system and human homeostasis, thus influencing the development and progression of neuropsychiatric disorders. For example, oral microbiota imbalance and associated periodontitis might increase the risk for neuropsychiatric disorders. Additionally, studies using the postmortem brain samples have detected the widespread presence of oral bacteria in the brains of patients with Alzheimer's disease. This article provides an overview of the emerging role of the host microbiota in neuropsychiatric disorders and discusses future directions, such as underlying biological mechanisms, reliable biomarkers associated with the host microbiota, and microbiota-targeted interventions, for research in this field.