Brain, Behavior, & Immunity - Health

BackgroundPatients exposed to trauma often experience high rates of adverse post-traumatic neuropsychiatric sequelae (APNS). The biologic mechanisms promoting APNS are currently unknown, but the microbiota-gut-brain axis offers an avenue to understanding mechanisms as well as possibilities for intervention. Microbiome composition at the time of trauma exposure has been poorly examined regarding neuropsychiatric outcomes. We aimed to determine whether baseline the gut microbiomes of trauma-exposed emergency department patients who later develop APNS have dysfunctional gut microbiome profiles and discover potential associated mechanisms. MethodsWe performed metagenomic analysis on stool samples (n=51) from a subset of adults enrolled in the Advancing Understanding of RecOvery afteR traumA (AURORA) study. Twelve-week post-trauma outcomes for post-traumatic stress disorder (PTSD) (PTSD checklist for DSM-5), normalized depression scores (PROMIS Depression Short Form 8b) and somatic symptom counts were collected. Generalized linear models were created for each outcome using microbial abundances and relevant demographics. Mixed-effect random forest machine learning models were used to identify associations between APNS outcomes and microbial features and metabolic pathways. ResultsMicrobial species, including Flavonifactor plautti and Ruminococcus gnavus, which are associated with inflammation and poor health outcomes, were found to be important in predicting worse APNS outcomes. Notably, worse APNS outcomes were highly predicted by decreased L-arginine related pathway genes and increased citrulline and ornithine pathways. ConclusionsPro-inflammatory microbes that are enriched in individuals who develop APNS. More notably, we identified a biological mechanism through which the gut microbiome reduces global arginine bioavailability, which also has been demonstrated in patients with PTSD.

INTRODUCTIONMediterranean diets may be neuroprotective and prevent cognitive decline relative to Western diets, however the underlying biology is poorly understood. METHODSWe assessed the effects of Western vs. Mediterranean-like diets on RNAseq generated transcriptional profiles in temporal cortex and their relationships with changes in MRI neuroimaging phenotypes, circulating monocyte gene expression, and observations of social isolation and anxiety in 38 socially-housed, middle-aged female cynomolgus macaques. RESULTSDiet resulted in differential expression of seven transcripts (FDR<0.05). Cyclin dependent kinase 14 (CDK14), a proinflammatory regulator, was lower in the Mediterranean group. The remaining six transcripts [i.e., "lunatic fringe" (LFNG), mannose receptor C type 2 (MRC2), solute carrier family 3 member 2 (SLCA32), butyrophilin subfamily 2 member A1 (BTN2A1), katanin regulatory subunit B1 (KATNB1), and transmembrane protein 268 (TMEM268)] were higher in cortex of the Mediterranean group and generally associated with anti-inflammatory/neuroprotective pathways. KATNB1 encodes a subcomponent of katanin, important in maintaining microtubule homeostasis. BTN2A1 is involved in immunomodulation of {gamma}{delta} T-cells which have anti-neuroinflammatory and neuroprotective effects. CDK14, LFNG, MRC2, and SLCA32 are associated with inflammatory pathways. The latter four differentially expressed cortex transcripts were associated with monocyte transcript levels, changes in AD-relevant brain volumes determined by MRI over the course of the study, and social isolation and anxiety. CDK14 was positively correlated with monocyte inflammatory transcripts, changes in total brain, gray matter, cortical gray matter volumes, and time alone and anxious behavior, and negatively correlated with changes in total white matter and cerebrospinal fluid (CSF) volumes. In contrast, LFNG, MRC2, and SLCA32 were negatively correlated with monocyte inflammatory transcripts and changes in total gray matter volume, and positively correlated with CSF volume changes, and SLCA32 was negatively correlated with time alone. DISCUSSIONCollectively, our results suggest that relative to Western diets, Mediterranean diets confer protection against peripheral and central inflammation which is reflected in preserved brain structure and behavior.

BackgroundExposure to prenatal maternal inflammation (PNMI) has been linked to neurodevelopmental alterations in human offspring. Preclinical studies suggest that PNMI disrupts reward circuitry, particularly within mesolimbic circuits. However, the effects of PNMI on mesolimbic circuits (i.e, ventral tegmental area (VTA) projections to the hippocampus (VTA-H) and limbic striatum (VTA-LS)) in humans are not yet known. MethodsData for PNMI biomarkers [interleukin (IL)-6, IL-8, IL-1 receptor antagonist (IL-1ra), soluble TNF receptor-II (sTNF-RII)] from first trimester (T1) and second trimester (T2) maternal sera, and offspring MRI brain scans in late midlife (aged 57-63 years), were available for 89 mother-offspring dyads. Probabilistic tractography delineated bilateral VTA-H and VTA-LS tracts. Macrostructural tract measures were examined using hierarchical linear regressions. Microstructural integrity was assessed using neurite orientation dispersion and density imaging, and permutation-based cluster analyses. ResultsHigher T2 IL-1ra was associated with increased macrostructure (left VTA-H tract), whereas higher T2 sTNF-RII was associated with reduced macrostructure (right VTA-H and VTA-LS tracts) and higher T2 IL-8 (bilateral VTA-LS tracts). Microstructurally, higher T2 IL-6 was associated with increased neurite density (distal cluster, right VTA-H tract), while higher T1 IL-8 was associated with reduced neurite density (near the hippocampus in the left VTA-H tract, near the VTA in bilateral VTA-LS tracts). ConclusionsPNMI was associated with altered mesolimbic reward circuitry in offspring. This suggests that prenatal inflammation may contribute to affective and motivational disorders in offspring via alterations in mesolimbic circuitry.

IntroductionRodent studies have addressed the importance of early life gut microbiota in the development of emotional and social functioning. Studies in human infants are still scarce, but associations with cognition and temperament have been reported. Neuroimaging studies have linked the amygdala with fecal microbiota diversity in infants, but crucially these studies have not covered the neonatal period, and the current study addressed this gap. MethodsThe study population included 65 infants drawn from the ongoing, general population based FinnBrain Birth Cohort Study. Brain MRI was performed around the age of one month (mean age 25 days). Fecal microbiota profiles (mean 68 days) were assessed by 16s rRNA amplicon sequencing at the age of 2.5 months. ResultsWe found a negative association between infant left amygdala volume and alpha diversity (n=52, beta =-0.0043, p=0.034, adjusted for infant sex, breastfeeding, delivery mode, age during fecal sampling, age from conception during scan, and intracranial volume, Fig.1). Amygdala volumes were not associated with beta diversity (p=0.21), nor with the abundances of individual genera when adjusted for the same covariates and multiple testing. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/537273v1_fig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@bf1304org.highwire.dtl.DTLVardef@798edeorg.highwire.dtl.DTLVardef@92c040org.highwire.dtl.DTLVardef@8bc2a9_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure. 1.C_FLOATNO Gut microbiota alpha diversity associates negatively with left (A), but not with right (B) amygdala volume. The grey areas depict 95% confidence intervals. C_FIG ConclusionOur results provide first evidence for associations between the brain and fecal microbiota in human neonates. Although the reported data do not allow investigation of underlying mechanisms, i.e. about the directionality of the hypothesized gut-brain connection, the reported connection encourages for future investigations of manifestations of gut-brain axis in early life.

BackgroundSickness behavior comprises a coordinated constellation of motivational, cognitive, and social alterations that emerge during systemic inflammation. Although reductions in locomotion, feeding, and social engagement have been extensively characterized, how inflammation affects ultrasonic vocal communication--an ethologically relevant index of social motivation in rodents--remains insufficiently understood. Here, we investigated how systemic immune activation alters male-female social communication in mice by jointly assessing ultrasonic vocalizations (USVs) and approach behavior. MethodsSexually experienced male mice received an intraperitoneal injection of lipopolysaccharide (LPS), and their interactions with a novel estrous female were evaluated 24 h later by quantifying USVs and approach behavior. ResultsLPS administration robustly suppressed both the total number of USVs and the duration of male approach behavior, indicating a pronounced reduction in social motivation. Beyond this quantitative suppression, LPS also induced qualitative changes in vocal output, including shifts in the proportional use of specific USV subtypes and alterations in acoustic features such as sound pressure. ConclusionsThese findings demonstrate that USVs capture multiple dimensions of inflammation-induced disruption of social communication, reflecting not only diminished motivation to engage socially but also changes in the structure of communicative signals themselves. By revealing that systemic immune activation reshapes both social approach behavior and vocal communication patterns, this study establishes USV analysis as a sensitive and translationally relevant behavioral readout for probing neuroimmune mechanisms underlying the social and communicative disturbances characteristic of sickness behavior. More broadly, our results highlight the utility of vocal communication analyses for elucidating how inflammatory processes perturb social circuits and communicative function in health and disease.

Background and AimsAccumulating evidence suggests the microbiota is a key factor in disorders of gut-brain interaction (DGBI), by affecting host immune and neural systems. However, the underlying mechanisms remain elusive due to their complexity and clinical heterogeneity of patients with DGBIs. We aimed to identify neuroimmune pathways that are critical in microbiota-gut-brain communication during de novo gut colonization. MethodsWe employed a combination of gnotobiotic and state-of-the-art microbial tools, behavioral analysis, immune and pharmacological approaches. Germ-free wild type, MyD88-/- Ticam1-/- and SCID mice were studied before and after colonization with specific pathogen-free microbiota, Altered Schaedler Flora, E. coli or S. typhimurium (permanent or transient colonizers). TLR agonists and antagonists, CCR7 antagonist or immunomodulators were used to study immune pathways. We assessed brain c-Fos, brain-derived neurotrophic factor, and dendritic and glial cells by immunofluorescence, expression of neuroimmune genes by NanoString and performed brain proteomics. ResultsBacterial monocolonization, conventionalization or administration of microbial products to germ-free mice altered mouse behavior similarly, acting through Toll-like receptor or nucleotide-binding oligomerization domain signaling. The process required CD11b+CD11c+CD103+ cell activation and migration into the brain. The change in behavior did not require the continued presence of bacteria and was associated with activation of multiple neuro-immune networks in the gut and the brain. ConclusionsChanges in neural plasticity occur rapidly upon initial gut microbial colonization and involve innate immune signaling to the brain, mediated by CD11b+CD11c+CD103+ cell migration. The results identify a new target with therapeutic potential for DGBIs developing in context of increased gut and blood-brain barrier permeability. HighlightsO_LIMicrobiota impairment is a key factor in disorders of gut-brain interaction (DGBI) C_LIO_LIMicrobial colonization induces changes in brain and behavior via innate immunity C_LIO_LIMicrobial colonization activates multiple neuro-immune networks in gut and brain C_LIO_LIBehavioral change is mediated by CD11b+CD11c+CD103+ cells migration to the brain C_LI

ObjectiveThis study aims to investigate how neuroinflammation alters gliogenic regulatory pathways and glial cell fate decisions, with a focus on identifying clinically relevant mechanisms that may increase susceptibility to glial-derived brain tumors. By linking inflammatory signaling to early disruptions in gliogenesis, this study seeks to inform future strategies for risk assessment, early detection, and potential therapeutic intervention in inflammation-associated neuro-oncology. BackgroundNeuroinflammation alters gliogenic signaling by disrupting key regulatory pathways such as FGFR3, JAK-STAT, STAT3, and others. This dysregulation affects glial cell differentiation and lineage decisions, contributing to impaired neurodevelopment and increased susceptibility to glial-derived brain tumors, particularly gliomas. Understanding these inflammatory mechanisms is essential for identifying early biomarkers, evaluating long-term tumor risk, and developing strategies to prevent or mitigate neuro-oncological outcomes in individuals with acute or chronic CNS inflammation. MethodsDatabases, including PubMed, MEDLINE, Google Scholar, and both open-access and subscription-based journals, were searched without date restrictions to investigate the brain inflammation induced disruption of gliogenic regulators (FGFR3, JAK-STAT, STAT3, S100, Hey1, HES1, DTX, IL-6, NF-{kappa}B, Neuregulin-1, MAPK/MEK, E2F/TCFL2, NFIX/Ephrins/Netrins) resulting in glial cell fate dysregulations and Its contribution to brain tumor risk. Studies meeting the criteria outlined in the methods section were systematically reviewed to address the research question. This study adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. ResultsNeuroinflammation significantly alters gliogenic regulators, including FGFR3, JAK-STAT, STAT3, S100, IL-6, and NF-{kappa}B, disrupting normal glial maturation, migration, and lineage commitment. This leads to aberrant cell fate decisions, sustained proliferation, and genomic instability, conditions favorable for glioma initiation. Pro-inflammatory pathways, notably IL-6 and NF-{kappa}B, drive oxidative stress and cellular dysfunction, reinforcing the tumor-permissive environment. These insights point to the clinical relevance of inflammation-driven glial dysregulation in brain tumor pathogenesis. ConclusionDisruption of gliogenic regulators by neuroinflammation alters glial fate specification, promotes proliferative stress, and contributes to oncogenic transformation within the CNS. These findings emphasize the need to clinically monitor individuals with significant or recurrent brain inflammation for long-term neuro-oncological risks. Early recognition of these disturbances may guide risk stratification, surveillance, and development of anti-inflammatory or gliogenesis-targeted interventions to prevent glial-origin brain tumors.

Background and ObjectivesObesity aggravates disease severity in multiple sclerosis (MS). Altered neural processing of food motivation and cognitive control, and the sensitivity of these processes to stress have been recognized as key obesity mechanisms but never been investigated in MS. MethodsIn this cross-sectional observational study, we evaluated the link between body mass and neural, endocrine and immunological stress parameters in persons with MS (PwMS). We conducted an Arterial-Spin-Labeling MRI task comprising a rest and stress stage (mental arithmetic plus evaluative feedback) in 57 PwMS (37 female, 46.4 {+/-} 10.6 years) covering the full spectrum of the Body Mass Index (BMI [kg/m2]; 6 obese, 19 over-, 28 normal-, 4 underweight). We tested whether BMI in MS links to (i) functional connectivity (FC) between stress-reactive brain regions (showing activity differences for stress vs. rest) computed separately for the tasks rest and stress stage, (ii) T cell glucocorticoid sensitivity and (iii) salivary cortisol secretion. ResultsBMI correlated positively with MS relapse rate (t = 3.23, p = 0.003 = pFamily-Wise-Error [FWE]-corrected = 0.012, and f2 = 0.22) and rest stage FC between right anterior insula and supramarginal gyrus (t = 4.02, p = 2.5 {middle dot} 10-4 = pFWE = 0.034, f2 = 0.51) and negatively with stress stage FC between right superior parietal lobule and cerebellum exterior (t = -3.67, p = 3.3 {middle dot} 10-4 = pFWE = 0.045, f2 = 0.30). Further, BMI was negatively associated with the expression of the co-chaperone FKBP4 on CD8+ T cells (t = -2.96, p = 0.003 = pFWE = 0.024, f2 = 0.13) and positively with that of FKBP5 (t = 1.83, p = 0.003 = pFWE = 0.024, f2 = 0.38). ConclusionOur study shows that higher BMI in MS is linked to increased FC between key food motivation and stimulus salience regions and to reduced FC between regions critically involved in cognitive control and generation of stressful states. We further report on correlations between BMI and co-chaperones modulating immune system stress responsivity. Taken together, these results demonstrate that BMI in MS is tied to stress processing across different biological systems.

BackgroundThe causal relationship between Multiple Sclerosis (MS) and Gastric Cancer (GC) remains unclear despite reports suggesting that MS, an autoimmune disease, may contribute to the development of various tumors. MethodsMendelian Randomization (MR) analysis was employed to explore the potential causal relationship between MS and GC. Subsequently, the GEO database was utilized to identify differentially expressed genes (DEGs) that are commonly associated with both MS and GC, thereby revealing the shared molecular mechanisms underlying these two diseases. ResultsThe MR analysis indicated that MS significantly increased the risk of GC, demonstrating a positive causal effect. However, reverse analysis from GC to MS did not reveal any significant causal relationships. The sensitivity analysis supported the evidence of a positive causal effect of MS on GC. Transcriptomic data analysis identified shared DEGs between MS and GC, particularly those involved in immune regulation, stromal formation, and cell migration, suggesting that these genes operate through similar biological pathways in both diseases. ConclusionThese findings underscore the intricate interplay between autoimmune disorders and gastrointestinal malignancies, offering potential molecular targets for the personalized management of MS and GC prevention.

AbstractPrenatal stress, a risk factor for neurodevelopmental disorders (NDDs), leads to immune alterations, including offspring neuroimmune cells. Differences in offspring outcomes may arise from whether the extent of prenatal stress crosses "thresholds" for effects on specific outcomes. Therefore, we sought to determine offspring outcomes using models with different extents of prenatal stress. We focused on striatal outcomes, because of their relevance for NDDs. Pregnant CD1 mice were assigned to four groups (each: N=6): no stress ("NoS") or one of the following stressors administered three times daily: i.p. saline injections (low prenatal stress, LoS), Interleukin-6 injections as a component of prenatal stress (immune prenatal stress; ImS), or restraint stress + saline injections (high prenatal stress, HiS), embryonic day 12-18. In adult offspring, HiS altered striatal-dependent behavior across males and females, while ImS induced fewer behavioral changes, and LoS did not affect behavior. Adult striatal microglia morphologies were mostly unchanged across groups, with only HiS leading to altered striatal density of minimally ramified cells. However, embryonic striatal microglia were affected by all models of stress, albeit in distinct ways. The HiS model, and to a lesser extent LoS, also influenced immune components of the maternal-fetal interface: placental macrophages. In conclusion, high and immune stress affected adult striatal-dependent behavior, exceeding the threshold necessary for persistent impacts, but all stress models affected embryonic microglia, suggesting that early neuroimmune outcomes had a lower threshold for impacts. Distinct severities and aspects of prenatal stress may therefore underlie different outcomes relevant to NDDs.

Increased production of cytokines in the in the brain during illness or injury modulates physiological processes, behavior, and cognitive function. It is likely that the pattern of cytokines, rather than the activation of any individual cytokine, determines the functional outcome of neuroimmune signaling. Cytokine networks may thus be particularly useful for understanding sex differences in immune and neuroimmune activation and outcomes. In this project, we aimed to determine the activation and resolution of hippocampal cytokine networks in both male and female mice. We measured 32 cytokines in the hippocampus and periphery of male and female mice at rest, 2, 6, 24, 48, and 168 hours after an acute systemic injection of lipopolysaccharide (LPS; 250g/kg). We hypothesized that males and females would exhibit both differences in individual cytokine levels and differences in network dynamics of hippocampal cytokines. Cytokines with sex-specific activation by LPS included male-specific elevations of IFN{gamma}, CSF1, CSF2, and IL-10; and female-specific activation of the IL-2 family and IL-4. We also observed differences in time course, where females showed more rapid elevations, and faster resolution of cytokine activity compared with males. Network analysis using ARACNE and Cytoscape demonstrated markedly different hippocampal cytokine networks across sex even at baseline, and sex differences in cytokine network activation states in response to LPS. Analysis of global shifts in cytokine concentrations further identified a period of cytokine and chemokine downregulation at 48 hours that was more pronounced in females compared with males. Together, these findings demonstrate that sex differences in neuroimmune responses include both differences in intensity of the cytokine response, and importantly differences in cytokine networks activated. Such sex differences in cytokine networks in the brain are likely critical for short and long-term functional outcomes associated with neuroimmune activation.

Post-traumatic stress disorder (PTSD) has been linked to various alterations within the immune system, yet the metabolic programming of immune cells remains unexplored. In the current cross-sectional study, we interrogated immunometabolic function by applying cell-specific metabolic flow cytometry, serum biomarker profiling, and targeted gene expression analysis in peripheral blood mononuclear cells from patients with PTSD (N=34) compared with healthy controls (N=32). PTSD was associated with higher glycolysis- and oxidative pentose phosphate pathway-related markers across adaptive and innate immune cell subsets, as well as elevated circulating interleukin-6. Expression of inflammatory- and stress-related genes was largely comparable between groups. Together, these data provide preliminary evidence for immunometabolic alterations in PTSD at both cellular and systemic levels. These results could contribute to understanding potential pathophysiological mechanisms and support further investigation of immunometabolism in PTSD.

BackgroundThe inflammatory markers C-reactive protein (CRP), interleukin-1 receptor antagonist (IL1-Ra), and interleukin-6 (IL-6) have been associated with depression risk in observational studies. The causal nature of these associations is unclear as conventional observational designs are susceptible to reverse causation and residual confounding. Bidirectional Mendelian randomization (MR) analysis uses genetic variants to proxy for risk factors to help elucidate the presence, magnitude, and direction of causal relationships between traits. MethodsWe performed bidirectional two-sample MR to examine causal associations between circulating CRP, IL1-Ra, and IL-6 and major depressive disorder (MDD) in 135,458 cases and 344,901 controls in the Psychiatric Genetics Consortium. Genetic instruments to proxy inflammatory markers and liability to MDD were constructed by obtaining single-nucleotide polymorphisms (SNPs) associated with these phenotypes in genome-wide association study meta-analyses. Wald ratios and inverse-variance weighted random-effects models were employed to generate causal effect estimates and various sensitivity analyses were performed to examine violations of MR assumptions. ResultsThere was evidence supporting a causal effect of circulating IL-6 on risk of MDD (per natural-log increase: OR 0.85, 95% CI: 0.75-0.96, P=0.007). Higher circulating levels of IL-6 as influenced by variants in the IL6R gene region represent lower cellular binding of IL-6 to its receptor and therefore the present results suggest that IL-6 increases the risk of MDD. We found limited evidence supporting a causal effect of CRP (1.06, 95% CI 0.93-1.22; P=0.36) or IL1-Ra (OR 0.95, 95% CI: 0.87-1.03, P=0.20) on risk of MDD. Reverse direction MR analyses suggested limited evidence for a causal effect of genetic liability to MDD on any of the inflammatory markers examined. ConclusionsThese findings support a causal role of IL-6-related pathways in development of major depressive disorder and suggest the possible efficacy of interleukin-6 inhibition as a therapeutic target for depression.

ObjectiveIraq and Afghanistan war-era (OEF/OIF/OND) Veterans are at elevated risk for physical injuries and psychiatric illnesses, in particular comorbid mild traumatic brain injury (mTBI), posttraumatic stress disorder (PTSD), and chronic pain. The gut microbiome has been implicated in modulation of critical processes such as digestion, immune system functioning, and stress responsivity, and may be an important factor in understanding physical and mental health outcomes following deployment and trauma exposure, yet minimal research to date has sought to characterize gut microbiome composition in this population. Methods26 male OEF/OIF/OND Veterans aged 18 to 65 who previously completed a VA Comprehensive TBI Evaluation were enrolled in this study. Participants completed self-report measures of PTSD symptom severity, pain intensity and interference, fatigue, cognitive symptoms, substance use, and sleep quality. Participants submitted fecal samples, and metagenomic sequencing was used to calculate alpha- and beta-diversity and taxonomic microbial composition. Associations between microbiome data and clinical variables was then examined. ResultsAlpha and beta diversity measures were not significantly correlated with clinical outcomes. Fatigue, post-concussive symptoms, executive function symptoms, and cannabis use were associated with differences in gut microbial composition, specifically Verrucomicrobiota. ConclusionThis exploratory study demonstrated that altered gut microbiome composition is associated with psychiatric and cognitive symptoms in OEF/OIF/OND Veterans and highlights a potential new therapeutic target of interest. Future research is needed to examine whether probiotic treatment is effective for reducing symptoms common in this clinical population.

Maes et al. (2008) published the first paper demonstrating that major depressive disorder (MDD) is accompanied by abnormalities in the microbiota-gut-brain axis, as evidenced by elevated serum IgM/IgA to lipopolysaccharides (LPS) of Gram-negative bacteria, such as Morganella morganii and Klebsiella Pneumoniae. The latter aberrations, which point to increased gut permeability (leaky gut), are linked to activated neuro-immune and oxidative pathways in MDD. To delineate the profile and composition of the gut microbiome in Thai patients with MDD, we examined fecal samples of 32 MDD patients and 37 controls using 16S rDNA sequencing and analyzed -(Chao and Shannon indices) and {beta}-diversity (Bray-Curtis dissimilarity) and conducted Linear discriminant analysis (LDA) Effect Size (LEfSe) analysis. Neither -nor {beta}-diversity differed significantly between MDD and controls. Rhodospirillaceae, Hungatella, Clostridium bolteae, Hungatella hathewayi, and Clostridium propionicum were significantly enriched in MDD, while Gracillibacteraceae family, Lutispora, and Ruminococcus genus, Ruminococcus callidus, Desulfovibrio piger, Coprococcus comes, and Gemmiger, were enriched in controls. Contradictory results have been reported for all these taxa, with the exception of Ruminococcus which is depleted in 6 different MDD studies (one study showed increased abundance), many medical disorders that show comorbidities with MDD, and animal MDD models. Our results may suggest a specific profile of compositional gut dysbiosis in Thai MDD patients with increases in some pathobionts and depletion of some beneficial microbiota. The results suggest that depletion of Ruminococcus may be a more universal biomarker of MDD that maybe contributes to increased enteral LPS load, LPS translocation, and gut-brain axis abnormalities.

T-cell activation may be contributing to severe psychiatric disorders. Soluble CD27 (sCD27) - a marker for T-cell activation and disease activity in several autoimmune diseases - was evaluated as a tool for distinguishing T-cell activity in selected patients with severe psychiatric disorders, multiple sclerosis (MS), and controls. We hypothesise that elevated sCD27 levels will be associated with comorbid autoimmune disease (AID). sCD27 was measured in cerebrospinal fluid (CSF) and blood from a population enriched for suspected immunological comorbidity: the Immunopsychiatry Cohort (IP; n=115) and patients with MS (n=37), where levels in both groups were higher when compared with age matched controls undergoing surgery (n=154). Positive sCD27 (sCD27+), was defined as values >97.5% of controls. In IP, 23% were CSF sCD27+ and 15% blood sCD27+, compared to patients with MS where 88% were CSF sCD27+ and 22% were blood sCD27+. CSF-sCD27+ was confirmed as a sensitive marker for MS. In IP, CSF-sCD27+ was associated with comorbid AID (X2=4.847, p =0.028;) and AID disease activity (OR=5.14, p=0.029). Associations with AID were stronger when CSF and/or blood sCD27+ were combined (X2=8.559, p=0.003). CSF-sCD27+ in IP was also associated with pleocytosis, CSF-Total-tau, and CSF-NfL. In patients with severe psychiatric disorders, the sCD27+ cases were more likely to have comorbid AID and established markers for neuroinflammation in CSF. Combining analyses of CSF and blood improved sensitivity and specificity for AID suggesting compartmentalized T-cell activation. Psychiatric symptoms may precede somatic symptoms - or be the prominent symptom - of AID and sCD27 is a candidate marker for identification of this subgroup.

ObjectivesRates of adolescent depression are rising, especially among girls, with children of depressed parents facing a three times higher risk. Emerging evidence suggests a link between gut microbiota, neural function, and depression risk, possibly through pathways that involve brain-body interactions, including the vagus nerve. During adolescence, sex-specific changes in the microbiota align with pubertal development, although their connection to depression vulnerability remains unclear. We compared gut microbiota in adolescents at high and low familial risk for depression and explored whether differences are affected by vagal activity and pubertal stage. MethodsWe collected clinical assessments, physiological data, and stool samples from 52 adolescents (aged 9-15, including 31 females), consisting of 27 high-risk and 25 low-risk individuals. We used 16S rRNA marker gene sequencing to analyze the diversity, structure, composition, and predicted function of the microbial community. A laboratory stressor task was employed to examine changes in vagally mediated heart rate variability (stress reactivity). Regressions were used to assess the relationship between depression risk, gut microbiota, and cardiovascular stress reactivity indices. Exploratory analyses investigated the effects of sex, age, and pubertal stage (adrenarche and gonarche). ResultsHigh-risk adolescents exhibited a distinct gut microbiota profile compared to low-risk adolescents, with this effect primarily driven by female participants. This profile was characterized by a higher abundance of Prevotella, which was 2-fold higher in high-risk females, and lower levels of other beneficial genera. High-risk females were also significantly more advanced in adrenarcheal development; the link between depression risk and adrenarcheal development was mediated by gut microbiota in females. Cardiovascular stress reactivity did not differ between groups and was not linked to gut microbiota. ConclusionsOur results reveal sex-specific links between depression risk, adrenarcheal development, and gut microbiota in adolescence. The increase of Prevotella in high-risk females suggests inflammation-related pathways may connect familial vulnerability to mood disorders. Future long-term studies examining hormones, microbiota, and mood during pubertal changes are essential to determine causality and develop targeted treatments.

BackgroundSuicidal thoughts and behavior (STB) in children are a growing health concern, and more data is needed regarding their biological underpinnings. Immune processes such as inflammation have been associated with STB, primarily in adults. Asthma is a common chronic inflammatory disorder in children and has been associated with STB in adolescent and adult populations, but data in children is lacking. We wished to study associations of asthma with childhood STB given asthmas potential as a clinically relevant model for childhood chronic immune dysregulation. MethodsUsing data from the Adolescent Brain Cognitive Development (ABCD) Study (N=11,878, 52% males, mean age 9.9 years at baseline assessment and 10.9 years at 1-year follow up), we assessed associations between asthma and STB at both baseline and 1-year follow up. ResultsWe found that asthma at baseline assessment (n=2,214, 18.6%) is associated with STB, controlling for multiple confounders including demographics, socioeconomic factors and environmental confounders such as air pollution (odds ratio (OR)=1.2, 95%CI 1.01-1.42, P=0.039). Indicators of recently active asthma were not significantly associated with suicidality at baseline assessment (currently taking asthma medication: OR=1.22, 95%CI 0.93-1.60, P=0.146), or at 1-year follow up (past year asthma-related clinical visit: OR=1.13, 95%CI 0.87-1.47, P=0.357). Proxy-measures of asthma severity (number of asthma medications or clinical visits) did not reveal a significant dose response relationship with STB. ConclusionsFindings suggest an association between history of asthma and STB in children, which may not be related to asthma disease state. Further research is needed to investigate mechanisms underlying this relationship.

BackgroundGrowing evidence indicates a significant correlation between the gut microbiota, immune system, and psychiatric disorders. Nevertheless, the impacts and interactions of the gut microbiota and immunophenotypes on psychiatric disorders remain unclear. MethodsWe utilized a bidirectional Mendelian randomization (MR) study to evaluate the causal associations among the gut microbiota, immunophenotypes, and psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), posttraumatic stress disorder (PTSD), schizophrenia (SCZ), and Tourettes syndrome (TS). The primary analysis was conducted using the inverse variance weighted (IVW) method, with several complementary sensitivity analyses being performed to ensure the reliability of the results. ResultsOur study reveals significant causal relationships between 22 immunophenotypes, 15 types of gut microbiota, and various psychiatric disorders. We further sought to ascertain whether immunophenotypes act as intermediaries in the pathway from gut microbiota to psychiatric disorders. In particular, three immunophenotypes were identified that mediate the causal effects of different gut microbiota on ADHD. Additionally, one immunophenotype was detected to mediate the causal effects of gut microbiota on PTSD. ConclusionsOur study indicates that immunophenotypes partially mediate the pathway from the gut microbiota to psychiatric disorders.

BackgroundEarly-life adversity (ELA) is a significant risk factor for emotional disorders like depression, likely by provoking changes in stress-related circuit development. We have previously shown that ELA increases the number of excitatory synapses onto corticotropin-releasing hormone (CRH)-expressing neurons in the paraventricular nucleus (PVN) by decreasing microglial synapse engulfment. Here, we hypothesize that ELA induces microglial dysfunction via inhibition of the microglial phagocytic receptor, MerTK, thus resulting in the observed changes in synapses and stress-related behavior. MethodsTo determine whether deleting MerTK in microglia phenocopies the effects of ELA, microglia-specific (m)MerTK-KO (CX3CR1-Cre+::MerTKfl/fl) mice were crossed with wild-type (CX3CR1-Cre-::MerTKfl/fl) mice and their litters were reared in either a control or ELA (induced by limited bedding and nesting paradigm) environment, from postnatal days (P)2-10. Excitatory synapses in the PVN were assessed at P10, and adult offspring were tested in a behavioral battery to measure threat-response (known to be dependent on PVN-CRH+neurons) and anxiety-like behavior, followed by acute restraint stress to measure the neuroendocrine stress response. ResultsFollowing ELA at P10, excitatory, but not inhibitory, synapses in the PVN were increased in males, which was mimicked by mMerTK-KO in control males, but caused no further increase in ELA males. However, females already had higher numbers of excitatory synapses at baseline, and showed no further increase with ELA or mMerTK-KO. Remarkably, the pattern of threat-response behavior in males closely matched the excitatory synapses, with mMerTK-KO control males escaping more from the simulated predator threat in the looming-shadow threat task, similar to ELA males. Again, females did not show any significant changes due to ELA or mMerTK-KO in the threat-response, although they did show ELA-induced changes in anxiety-like behavior. ELA provoked a greater corticosterone response to acute stress in males, but not females, although females were again higher at baseline. ConclusionsOur results demonstrate that ELA provokes increased excitatory synapses in the PVN, leading to an increased active response to threat in the looming-shadow test in males only. Deleting MerTK specifically from microglia recapitulates both the synaptic and behavioral effects in control males, but does not have an effect in ELA males or control females, suggesting that the MerTK pathway is already inhibited by ELA in males and less active in females at baseline. Our work is the first to elucidate the mechanisms underlying the male-biased microglial dysfunction caused by ELA, with promise for the development of better preventative and therapeutic strategies for at-risk children.