Metabolic features of adolescent major depressive disorder: A comparative study between treatment-resistant depression and first-episode drug-naive depression.

Major depressive disorder (MDD) is a psychiatric illness that can jeopardize the normal growth and development of adolescents. Approximately 40% of adolescent patients with MDD exhibit resistance to conventional antidepressants, leading to the development of Treatment-Resistant Depression (TRD). TRD is associated with severe impairments in social functioning and learning ability and an elevated risk of suicide, thereby imposing an additional societal burden. In this study, we conducted plasma metabolomic analysis on 53 adolescents diagnosed with first-episode drug-naïve MDD (FEDN-MDD), 53 adolescents with TRD, and 56 healthy controls (HCs) using hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS) and reversed-phase liquid chromatography-mass spectrometry (RPLC-MS). We established a diagnostic model by identifying differentially expressed metabolites and applying cluster analysis, metabolic pathway analysis, and multivariate linear support vector machine (SVM) algorithms. Our findings suggest that adolescent TRD shares similarities with FEDN-MDD in five amino acid metabolic pathways and exhibits distinct metabolic characteristics, particularly tyrosine and glycerophospholipid metabolism. Furthermore, through multivariate receiver operating characteristic (ROC) analysis, we optimized the area under the curve (AUC) and achieved the highest predictive accuracy, obtaining an AUC of 0.903 when comparing FEDN-MDD patients with HCs and an AUC of 0.968 when comparing TRD patients with HCs. This study provides new evidence for the identification of adolescent TRD and sheds light on different pathophysiologies by delineating the distinct plasma metabolic profiles of adolescent TRD and FEDN-MDD.

Dysregulations of amino acid metabolism and lipid metabolism in urine of children and adolescents with major depressive disorder: a case-control study.

RATIONALE: The mechanisms underlying major depressive disorder (MDD) in children and adolescents are unclear. Metabolomics has been utilized to capture metabolic signatures of various psychiatric disorders; however, urinary metabolic profile of MDD in children and adolescents has not been studied. OBJECTIVES: We analyzed urinary metabolites in children and adolescents with MDD to identify potential biomarkers and metabolic signatures. METHODS: Here, liquid chromatography-mass spectrometry was used to profile metabolites in urine samples from 192 subjects, comprising 80 individuals with antidepressant-naïve MDD (AN-MDD), 37 with antidepressant-treated MDD (AT-MDD) and 75 healthy controls (HC). We performed orthogonal partial least squares discriminant analysis to identify differential metabolites and employed logistic regression and receiver operating characteristic analysis to establish a diagnostic panel. RESULTS: In total, 143 and 71 differential metabolites were identified in AN-MDD and AT-MDD, respectively. These were primarily linked to lipid metabolism, molecular transport, and small molecule biochemistry. AN-MDD additionally exhibited dysregulated amino acid metabolism. Compared to HC, a diagnostic panel of seven metabolites displayed area under the receiver operating characteristic curves of 0.792 for AN-MDD, 0.828 for AT-MDD, and 0.799 for all MDD. Furthermore, the urinary metabolic profiles of children and adolescents with MDD significantly differed from those of adult MDD. CONCLUSIONS: Our research suggests dysregulated amino acid metabolism and lipid metabolism in the urine of children and adolescents with MDD, similar to results in plasma metabolomics studies. This contributes to the comprehension of mechanisms underlying children and adolescents with MDD.

Adolescent male rats show altered gut microbiota composition associated with depressive-like behavior after chronic unpredictable mild stress: Differences from adult rats.

Accumulating evidence reveals the metabolism and neurotransmitter systems are different in major depressive disorder (MDD) between adolescent and adult patients; however, much is still unknown from the gut microbiome perspective. To minimize confounding factors such as geographical location, ethnicity, diet, and drugs, we investigated the gut microbial differences between adolescent and adult male Sprague-Dawley rats. We exposed the adolescent rats to chronic unpredictable mild stress (CUMS) for 3 weeks and assessed their behavior using the sucrose preference test (SPT), open field test (OFT), and forced swimming test (FST). We collected and sequenced fecal samples after the behavioral tests and compared them with our previous data on adult rats. Both adolescent and adult CUMS rats exhibited reduced sucrose preference in SPT, reduced total distance in OFT, and increased immobility time in FST. Moreover, compared to their respective controls, the adolescent CUMS rats had distinct amplicon sequence variants (ASVs) mainly in the Muribaculaceae family, Bacteroidetes phylum, while the adult CUMS rats had those in the Lachnospiraceae family, Firmicutes phylum. In the adolescent group, the Muribaculaceae negatively correlated with FST and positively correlated with SPT and OFT. In the adult group, the different genera in the Lachnospiraceae showed opposite correlations with FST. Furthermore, the adolescent CUMS rats showed disrupted microbial functions, such as "Xenobiotics biodegradation and metabolism" and "Immune system", while the adult CUMS rats did not. These results confirmed the gut microbiota differences between adolescent and adult rats after CUMS modeling and provided new insight into the age-related influence on depression models.

Identifying plasma metabolic characteristics of major depressive disorder, bipolar disorder, and schizophrenia in adolescents.

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are classified as major mental disorders and together account for the second-highest global disease burden, and half of these patients experience symptom onset in adolescence. Several studies have reported both similar and unique features regarding the risk factors and clinical symptoms of these three disorders. However, it is still unclear whether these disorders have similar or unique metabolic characteristics in adolescents. We conducted a metabolomics analysis of plasma samples from adolescent healthy controls (HCs) and patients with MDD, BD, and SCZ. We identified differentially expressed metabolites between patients and HCs. Based on the differentially expressed metabolites, correlation analysis, metabolic pathway analysis, and potential diagnostic biomarker identification were conducted for disorders and HCs. Our results showed significant changes in plasma metabolism between patients with these mental disorders and HCs; the most distinct changes were observed in SCZ patients. Moreover, the metabolic differences in BD patients shared features with those in both MDD and SCZ, although the BD metabolic profile was closer to that of MDD than to SCZ. Additionally, we identified the metabolites responsible for the similar and unique metabolic characteristics in multiple metabolic pathways. The similar significant differences among the three disorders were found in fatty acid, steroid-hormone, purine, nicotinate, glutamate, tryptophan, arginine, and proline metabolism. Interestingly, we found unique characteristics of significantly altered glycolysis, glycerophospholipid, and sphingolipid metabolism in SCZ; lysine, cysteine, and methionine metabolism in MDD and BD; and phenylalanine, tyrosine, and aspartate metabolism in SCZ and BD. Finally, we identified five panels of potential diagnostic biomarkers for MDD-HC, BD-HC, SCZ-HC, MDD-SCZ, and BD-SCZ comparisons. Our findings suggest that metabolic characteristics in plasma vary across psychiatric disorders and that critical metabolites provide new clues regarding molecular mechanisms in these three psychiatric disorders.

AKT and MAPK signaling pathways in hippocampus reveals the pathogenesis of depression in four stress-induced models.

Major depressive disorder (MDD) is a highly heterogeneous psychiatric disorder. The pathogenesis of MDD remained unclear, and it may be associated with exposure to different stressors. Most previous studies have focused on molecular changes in a single stress-induced depression model, which limited the identification of the pathogenesis of MDD. The depressive-like behaviors were induced by four well-validated stress models in rats, including chronic unpredictable mild stress, learned helplessness stress, chronic restraint stress and social defeat stress. We applied proteomic and metabolomic to investigate molecular changes in the hippocampus of those four models and revealed 529 proteins and 98 metabolites. Ingenuity Pathways Analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified differentially regulated canonical pathways, and then we presented a schematic model that simulates AKT and MAPK signaling pathways network and their interactions and revealed the cascade reactions. Further, the western blot confirmed that p-AKT, p-ERK12, GluA1, p-MEK1, p-MEK2, p-P38, Syn1, and TrkB, which were changed in at least one depression model. Importantly, p-AKT, p-ERK12, p-MEK1 and p-P38 were identified as common alterations in four depression models. The molecular level changes caused by different stressors may be dramatically different, and even opposite, between four depression models. However, the different molecular alterations converge on a common AKT and MAPK molecular pathway. Further studies of these pathways could contribute to a better understanding of the pathogenesis of depression, with the ultimate goal of helping to develop or select more effective treatment strategies for MDD.

Disturbances of purine and lipid metabolism in the microbiota-gut-brain axis in male adolescent nonhuman primates with depressive-like behaviors.

INTRODUCTION: Major depressive disorder (MDD) in adolescents is a widespread and growing global public health concern with unique characteristics and pathophysiological mechanisms that are distinct from MDD in adults. OBJECTIVE: The purpose of our work was to address this knowledge gap about the unique characteristics and pathophysiological mechanisms of adolescent depression from a microbiota-gut-brain (MGB) axis perspective. METHOD: Ten healthy male cynomolgus macaques (Macaca fascicularis) were paired into five pairs based on age and body weight, and two cynomolgus macaques from each pair were randomly allocated to chronic unpredictable mild stress group, or unstressed control group. At endpoint, microbe composition from cecum, ascending colon, transverse colon, and descending colon were analyzed by metagenome sequencing, and the metabolite profiles of MGB axis including central (prefrontal cortex, hippocampus and amygdala) and peripheral (plasma, gut and feces of cecum, ascending colon, transverse colon and descending colon) samples were analyzed by metabolomic profiling. Then, we compare the gut microbiome and metabolic signatures in MGB axis between adolescent and adult depressed macaques. RESULTS: The microbial composition and gut-brain metabolic signatures were widely divergent between adolescent and adult depressed macaques, though the phylum Firmicutes and lipid metabolism pathways were persistently altered in both populations. Purine and arginine biosynthesis metabolism were a specific hallmark of adolescent depressed macaques, while fatty acyl metabolism was specially altered in adult. These differential metabolic pathways in adolescent and adult depressed macaques were mainly mapped into the prefrontal cortex and hippocampus, respectively. Notably, the genus Clostridium and Haemophilus, characteristically disturbed in adolescent depressed macaques but not in adult, were also significantly associated with the majority of purine metabolites in MGB axis. CONCLUSION: These findings provide a new framework describing divergent pathophysiological mechanisms between adolescent and adult depression, and may open new windows for more effective treatment strategies of adolescent depression.

Biomarkers of intestinal permeability and blood-brain barrier permeability in adolescents with major depressive disorder.

BACKGROUND: The etiology in major depressive disorder (MDD) has not been fully understood. Accumulating evidence suggests an association between altered intestinal and blood-brain barrier (BBB) permeability and psychiatric disorders, while its changes in adolescent MDD populations have been received less attention. In this study, our aim was to explore the differences in plasma levels of intestinal and blood-brain barrier permeability markers in adolescents with MDD compared with healthy controls (HCs). METHODS: We enrolled MDD (n = 50), and HCs (n = 40) with the age of 13-18 years old. The plasma level of zonulin, I-FABP, LPS, and claudin-5 were quantified. The Hamilton Depression Scale 17 items (HAMD-17) and Hamilton Anxiety Scale 14 items (HAMA-14) were used for symptom assessments. RESULTS: The plasma levels of zonulin, I-FABP, LPS, and claudin-5 in the MDD group were significantly higher than those in the HCs. Plasma I-FABP levels in MDD with moderate to severe anxiety were significantly higher than those in MDD without moderate to severe anxiety and HCs. In addition, these four biomarkers (alone or combined) can be used as diagnostic markers for MDD in adolescents. LIMITATIONS: The key limitation of this study is the blood measurements at a single time point with a relatively small sample size. CONCLUSIONS: These findings advance our understanding of the pathophysiology of intestinal barrier injury, bacterial translocation, and blood-brain barrier injury involved in adolescents with MDD.

Effect of antidepressants on functioning and quality of life outcomes in children and adolescents with major depressive disorder: a systematic review and meta-analysis.

Functioning and quality of life (QOL) are typical outcomes assessed in children and adolescents with major depressive disorder (MDD); however, meta-analytical evidence remains scarce. The aim of this meta-analysis was to assess functioning and QOL antidepressant outcomes in this population. Eight electronic databases (PubMed, Cochrane Library, Web of Science, Embase, CINAHL, PsycINFO, LILACS, and ProQuest Dissertation Abstracts) were searched for double-blind randomized controlled trials (RCTs) up to July 31, 2020. RCTs that compared antidepressants with placebo for treating functioning and QOL in children and adolescents with MDD were included. Primary outcomes were mean change scores of functioning and QOL scales from baseline to post-treatment. Subgroup and sensitivity analyses were conducted to examine whether results were affected by moderator variables (e.g., medication type, age, sample size, and treatment duration). From 7284 publications, we included 17 RCTs (all 17 assessed functioning and 4 assessed QOL outcomes) including 2537 participants. Antidepressants showed significant positive effects on functioning (standardized mean difference [SMD] = 0.17, 95% confidence interval [CI] = 0.09-0.25, p < 0.0001) but not on QOL (SMD = 0.11, 95% CI = -0.02 to 0.24, p = 0.093), with no significant heterogeneity. The subgroup analysis showed that second-generation antidepressants (especially fluoxetine, escitalopram, and nefazodone), but not first-generation antidepressants, led to significant improvements in functioning. Antidepressants (especially second generation) improve functioning but not QOL in children and adolescents with MDD. However, well-designed clinical studies using large samples are needed to confirm these findings.

A diathesis-stress rat model induced suicide-implicated endophenotypes and prefrontal cortex abnormalities in the PKA and GABA receptor signaling pathways.

Suicide is one of the leading causes of death and represents a significant public health problem worldwide; however, the underlying mechanism of suicide remains unclear, and there is no animal model with suicide-implicated endophenotypes for investigating the etiology, course and potential treatment targets of suicide. Thus, we generated a diathesis-stress rat model to simulate suicide-implicated endophenotypes. First, two hundred rats were screened in two rounds of learned helplessness (LH) tests and selected as learned helplessness-sensitive (LHS) rats (n = 37) and learned helplessness-resistant (LHR) rats (n = 39). Then, all LHS rats and half of the rats (randomly selected) in the LHR group were exposed to four weeks of social defeat stress (SDS) (LHS + SDS group, n = 37 and LHR + SDS group, n = 20, respectively). The remainder of the LHR rats were handled as controls (LHR + CON group, n = 19). The LHS + SDS group showed significantly more suicide-implicated endophenotypes than the LHR + CON group, including longer immobile times in the forced swim test (hopelessness), higher scores in the irritability test (irritability), shorter latencies to attack (impulsivity), longer total attack times in the resident-intruder test (aggression), and lower sucrose preference indices (anhedonia). Proteomic analyses revealed that the canonical pathways that were the most common between the LHS + SDS and LHR + CON groups were the PKA and GABA receptor pathways in the prefrontal cortex. A diathesis-stress paradigm would be a useful way to establish a rat model with suicide-implicated endophenotypes, providing novel perspectives for revealing the potential mechanism of suicide.

Biogeography of the large intestinal mucosal and luminal microbiome in cynomolgus macaques with depressive-like behavior.

Most previous studies in the pathophysiology of major depressive disorder (MDD) focused on fecal samples, which limit the identification of the gut mucosal and luminal microbiome in depression. Here, we address this knowledge gap. Male cynomolgus macaques (Macaca fascicularis) were randomly assigned to a chronic unpredictable mild stress (CUMS) group, or to an unstressed control group. Behavioral tests were completed in both groups. At endpoint, microbe composition of paired mucosal and luminal samples from cecum, ascending, transverse, and descending colons were determined by 16S ribosomal RNA gene sequencing. The levels of 34 metabolites involved in carbohydrate or energy metabolism in luminal samples were measured by targeted metabolomics profiling. CUMS macaques demonstrated significantly more depressive-like behaviors than controls. We found differences in mucosal and luminal microbial composition between the two groups, which were characterized by Firmicutes and Bacteriodetes at the phylum level, as well as Prevotellaceae and Lachnospiraceae at the family level. The majority of discriminative microbes correlated with the depressive-like behavioral phenotype. In addition, we found 27 significantly different microbiome community functions between the two groups in mucosa, and one in lumen, which were mainly involved in carbohydrate and energy metabolism. A total of nine metabolites involved in these pathways were depleted in CUMS animals. Together, CUMS macaques with depressive-like behaviors associated with distinct alterations of covarying microbiota, carbohydrate and energy metabolism in mucosa and lumen. Further studies should focus on the mucosal and luminal microbiome to provide a deeper spatiotemporal perspective of microbial alterations in the pathogenesis of MDD.

Chronic unpredictable mild stress produces depressive-like behavior, hypercortisolemia, and metabolic dysfunction in adolescent cynomolgus monkeys.

Adolescent depression is a common and serious mental disorder with unique characteristics that are distinct from adult depression. The adult non-human primate stress-induced model of depressive-like behavior is an excellent model for the study of mechanisms; however, an adolescent nonhuman primate model is still lacking. Ten male adolescent cynomolgus monkeys were divided into a chronic unpredictable mild stress (CUMS, n = 5) group and a control (CON, n = 5) group by age and weight-matched pairs. The CUMS group was exposed to multiple unpredictable mild stressors for five cycles over 55 days. At baseline, there were no differences between CUMS and CON groups. At endpoint, the CUMS group demonstrated significantly higher depressive-like behavior (huddle posture), and significantly lower locomotion compared with the CON group. Furthermore, depressive-like behavior increased from baseline to endpoint in the CUMS group, but not changed in the CON group. In the attempt for apple test, the CUMS group made significantly fewer attempts for the apple than the CON group. In the human intruder test, the CUMS group showed significantly higher anxiety-like behaviors in the stare phase than the CON group. Hair cortisol level was significantly higher in the CUMS group than the CON group at endpoint, and was also elevated from baseline to endpoint. Metabolic profiling of plasma at endpoint identified alterations in metabolite pathways which overlapped with those of adolescent depression patients. CUMS can induce depressive-like and anxiety-like behaviors, hypercortisolemia, and metabolic perturbations in adolescent cynomolgus monkeys. This is a promising model to study the mechanisms underlying adolescent depression.

Efficacy and acceptability of parent-only group cognitive behavioral intervention for treatment of anxiety disorder in children and adolescents: a meta-analysis of randomized controlled trials.

BACKGROUND: Anxiety disorder is the most prevalent mental disorder among children and adolescents, causing significant psychosocial problems and physical health conditions. Cognitive behavioral therapy (CBT) is an effective treatment for anxiety disorder in children and adolescents. And parent-only CBT is an alternative treatment for childhood anxiety disorder, which includes psychologists and parents rather than children in the treatment. As a new type of CBT, parent-only CBT has some advantages. However, it remains unclear whether parent-only CBT interventions are effective for treating children and adolescents with anxiety disorder. METHODS: In this study, we evaluated the efficacy (the mean change scores of the anxiety rating scale from baseline to post-treatment, standardized mean difference SMD) and acceptability (the proportion of patients in the treatment group who withdrew from treatment early for any reason, risk ratios RRs) of parent-only cognitive behavioral therapy (CBT) for children and adolescents with anxiety disorder. We searched electronic databases, including PubMed, Cochrane Library, Embase, Web of Science, ProQuest, and PsycINFO from inception to June 2019. We included randomized controlled trials (RCTs) comparing parent-only CBT either with waitlist (WL), or CBT with parents in children and adolescents with anxiety disorder. RESULTS: Finally, six RCTs with 407 participants were included in the meta-analyses. In terms of efficacy, pooled analyses indicated that parent-only CBT was significantly more effective than WL for reducing anxiety symptoms with SMD of - 0.72 (95% CI - 1.41 to - 0.03, p = 0.04), and more remission rate with RR of 4.33 (37.96% vs. 6.85, 95% CI 1.82 to 10.27, p = 0.0009) at post-treatment. And our analyses showed no evidence that parent-only CBT had significantly greater efficacy than CBT with parents with SMD of 0.21 (95% CI - 0.09 to 0.50, p = 0.17). Acceptability in the parent-only CBT group was not significantly different to the WL group with RR of 0.92 (95% CI 0.52 to 1.62, p = 0.77), and was significantly worse than in the CBT with parents group with RR of 1.93 (95% CI 1.05 to 3.57, p = 0.03). CONCLUSIONS: Current evidence indicates that parent-only CBT can be an alternative and acceptable intervention for treating children and adolescents with anxiety disorder.

The gut microbiome modulates gut-brain axis glycerophospholipid metabolism in a region-specific manner in a nonhuman primate model of depression.

Emerging research demonstrates that microbiota-gut-brain (MGB) axis changes are associated with depression onset, but the mechanisms underlying this observation remain largely unknown. The gut microbiome of nonhuman primates is highly similar to that of humans, and some subordinate monkeys naturally display depressive-like behaviors, making them an ideal model for studying these phenomena. Here, we characterized microbial composition and function, and gut-brain metabolic signatures, in female cynomolgus macaque (Macaca fascicularis) displaying naturally occurring depressive-like behaviors. We found that both microbial and metabolic signatures of depressive-like macaques were significantly different from those of controls. The depressive-like monkeys had characteristic disturbances of the phylum Firmicutes. In addition, the depressive-like macaques were characterized by changes in three microbial and four metabolic weighted gene correlation network analysis (WGCNA) clusters of the MGB axis, which were consistently enriched in fatty acyl, sphingolipid, and glycerophospholipid metabolism. These microbial and metabolic modules were significantly correlated with various depressive-like behaviors, thus reinforcing MGB axis perturbations as potential mediators of depression onset. These differential brain metabolites were mainly mapped into the hippocampal glycerophospholipid metabolism in a region-specific manner. Together, these findings provide new microbial and metabolic frameworks for understanding the MGB axis' role in depression, and suggesting that the gut microbiome may participate in the onset of depressive-like behaviors by modulating peripheral and central glycerophospholipid metabolism.

Landscapes of bacterial and metabolic signatures and their interaction in major depressive disorders.

Gut microbiome disturbances have been implicated in major depressive disorder (MDD). However, little is known about how the gut virome, microbiome, and fecal metabolome change, and how they interact in MDD. Here, using whole-genome shotgun metagenomic and untargeted metabolomic methods, we identified 3 bacteriophages, 47 bacterial species, and 50 fecal metabolites showing notable differences in abundance between MDD patients and healthy controls (HCs). Patients with MDD were mainly characterized by increased abundance of the genus Bacteroides and decreased abundance of the genera Blautia and Eubacterium These multilevel omics alterations generated a characteristic MDD coexpression network. Disturbed microbial genes and fecal metabolites were consistently mapped to amino acid (γ-aminobutyrate, phenylalanine, and tryptophan) metabolism. Furthermore, we identified a combinatorial marker panel that robustly discriminated MDD from HC individuals in both the discovery and validation sets. Our findings provide a deep insight into understanding of the roles of disturbed gut ecosystem in MDD.

Differential Gut Microbiota and Fecal Metabolites Related With the Clinical Subtypes of Myasthenia Gravis.

Myasthenia gravis (MG) is a devastating acquired autoimmune disease. Previous studies have observed that disturbances of gut microbiome may attribute to the development of MG through fecal metabolomic signatures in humans. However, whether there were differential gut microbial and fecal metabolomic phenotypes in different subtypes of MG remains unclear. Here, our objective was to explore whether the microbial and metabolic signatures of ocular (OMG) and generalized myasthenia gravis (GMG) were different, and further identify the shared and distinct markers for patients with OMG and GMG. In this study, 16S ribosomal RNA (rRNA) gene sequencing and gas chromatography-mass spectrometry (GC/MS) were performed to capture the microbial and metabolic signatures of OMG and GMG, respectively. Random forest (RF) classifiers was used to identify the discriminative markers for OMG and GMG. Compared with healthy control (HC) group, GMG group, but not OMG group, showed a significant decrease in α-phylogenetic diversity. Both OMG and GMG groups, however, displayed significant gut microbial and metabolic disorders. Totally, we identified 20 OTUs and 9 metabolites specific to OMG group, and 23 OTUs and 7 metabolites specific to GMG group. Moreover, combinatorial biomarkers containing 15 discriminative OTUs and 2 differential metabolites were capable of discriminating OMG and GMG from each other, as well as from HCs, with AUC values ranging from 0.934 to 0.990. In conclusion, different subtypes of MG harbored differential gut microbiota, which generated discriminative fecal metabolism.

Erratum: Perturbed Microbial Ecology in Myasthenia Gravis: Evidence from the Gut Microbiome and Fecal Metabolome.

[This corrects the article DOI: 10.1002/advs.201901441.].

Gut Microbial Signatures Can Discriminate Unipolar from Bipolar Depression.

Discriminating depressive episodes of bipolar disorder (BD) from major depressive disorder (MDD) is a major clinical challenge. Recently, gut microbiome alterations are implicated in these two mood disorders; however, little is known about the shared and distinct microbial characteristics in MDD versus BD. Here, using 16S ribosomal RNA (rRNA) gene sequencing, the microbial compositions of 165 subjects with MDD are compared with 217 BD, and 217 healthy controls (HCs). It is found that the microbial compositions are different between the three groups. Compared to HCs, MDD is characterized by altered covarying operational taxonomic units (OTUs) assigned to the Bacteroidaceae family, and BD shows disturbed covarying OTUs belonging to Lachnospiraceae, Prevotellaceae, and Ruminococcaceae families. Furthermore, a signature of 26 OTUs is identified that can distinguish patients with MDD from those with BD or HCs, with area under the curve (AUC) values ranging from 0.961 to 0.986 in discovery sets, and 0.702 to 0.741 in validation sets. Moreover, 4 of 26 microbial markers correlate with disease severity in MDD or BD. Together, distinct gut microbial compositions are identified in MDD compared to BD and HCs, and a novel marker panel is provided for distinguishing MDD from BD based on gut microbiome signatures.

Age-related changes in microbial composition and function in cynomolgus macaques.

Age can significantly affect human physiology and disease risk. Recent studies have shown that age may affect the composition and function of the gut microbiota, but the underlying mechanisms remain largely unknown. Non-human primates are an ideal model for uncovering how age shapes the gut microbiota, as their microbial composition is highly similar to that of humans and is not easily affected by confounding factors. Here, using the 16S rRNA and metagenomic sequencing methods, we characterized the microbial phenotypes of 16 female cynomolgus macaques from three age groups (young, adult and old). Our findings revealed significant differences in microbial composition among the three groups. With increased age, the relative abundances of Veillonellaceae, Coriobacteriaceae and Succinivibrionaceae were significantly increased, Ruminococcaceae and Rikenellaceae were significantly decreased at the family level. Functional enrichment showed that genes that differed among the three groups were mainly involved in arginine biosynthesis, purine metabolism and microbial polysaccharides metabolism. Moreover, CAZymes corresponding to polysaccharide degrading activities were also observed among the three groups. In conclusion, we characterized the composition and function of the gut microbiota at different ages, and our findings provide a new entry point for understanding the effects of age on the human body.