According to the "Old Friends" hypothesis, the increased prevalence of stress-associated disorders in urban concrete landscapes of high-income countries is at least in part due to a reduced exposure to immunoregulatory microorganisms. The latter is particularly impactful when occurring during early prenatal and postnatal life. Accordingly, our own preclinical studies demonstrate that non-pathogenic rapid-growing mycobacteria, including Mycobacterium (M.) vaccae NCTC 11659 and M. vaccae ATCC 15483T, have immunoregulatory and stress-protective effects when administered repeatedly prior to or during stressor exposure. Here, we advance these findings by showing that repeated intragastric (i.g.) administration of a heat-killed preparation of M. vaccae ATCC 15483T to female C57BL/6 N mice provides intergenerational stress protection. Their male offspring, despite never directly receiving administration of rapid-growing mycobacteria, were protected against multiple adverse consequences of chronic stress in adulthood. Moreover, correlational analyses implicate the fecal microbiome as a potential mediator of these effects, with M. vaccae ATCC 15483T intergenerationally facilitating α-diversity and increasing the relative abundance of bacterial taxa known to be potent short-chain fatty acid producers. Repeated intragastric (i.g.) administration of a heat-killed preparation of Mycobacterium (M.) vaccae ATCC 15483T (MvacATCC)vs. its vehicle borate-buffered saline (BBS) to adult nulliparous female C57BL/6N mice was intergenerationally protective against multiple negative physiological and immunological consequences of chronic subordinate colony housing (CSC; compared with respective single-housed control (SHC) mice), including adrenal hypertrophy, splenomegaly, thymus involution, and tibia growth reduction as well as increased splenic toll-like receptor (TLR) 2 and TLR4 protein concentrations and splenocyte ex vivo (re)activity, but also decreased splenic ex vivo glucocorticoid  sensitivity, regulatory T cell (Treg) counts and Treg suppression capacity in their male offspring. In contrast, CSC-induced increase in splenic myeloid cell counts as well as of neutrophilic chemotactic activity was not affected intergenerationally by MvacATCC. Moreover, fecal microbiome analyses before and after CSC showed that MvacATCC intergenerationally facilitated α-diversity and relative abundance of bacterial taxa known to be potent short-chain fatty acid (SCFA) producers. Of note, we abstained from showing respective data of female offspring in the graphical abstract (*), as the intergenerational resilience effects of MvacATCC on female offspring were difficult to interpret. The latter was due to the fact that chronic adult stressor exposure (i.e., social instability paradigm, SIP) per se did not affect any of the physiological and immunological readouts reported in females. The graphical abstract was created with Biorender.com.

Posttraumatic stress disorder (PTSD), depression, and anxiety disorders are prevalent and often overlapping mental health conditions with complex, multifactorial etiologies. Growing evidence implicates the gut microbiome in their pathophysiology through immune modulation, neurotransmitter regulation, and bidirectional gut-brain signaling. Findings remain fragmented and difficult to reconcile due to differences in study populations, clinical contexts, and analytic methods. This structured narrative review synthesizes current evidence on gut microbial alterations in PTSD, depression, and anxiety, while examining methodological sources of heterogeneity. We searched four databases: PubMed, Scopus, Web of Science, and PsycINFO, and identified 64 eligible studies assessing the gut microbiome composition in these disorders. Sample sizes ranged from small, exploratory cohorts (≈20 participants) to large population-based datasets (>1000 participants), with most studies conducted in China. Stool sampling and DNA extraction protocols varied widely, although 16S rRNA gene amplicon sequencing of the V3-V4 region on Illumina platforms predominated. Alpha-diversity results were inconsistent, whereas beta-diversity analyses distinguished cases from controls. Across these disorders, alterations in microbial composition was observed, including enrichment of proinflammatory and depletion of beneficial bacterial taxa. The current findings indicate that that the gut microbiome represents a promising avenue for biomarker discovery and therapeutic innovation.

Antidepressants are among the most widely used neuropsychiatric drugs, yet their interactions with the gut microbiome remain mechanistically unresolved. Here, we synthesize evidence across microbial physiology, host metabolism, and in silico enzymatic predictions to delineate how selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) interface with bacterial systems. Although direct experimental confirmation of antidepressant biotransformation is lacking, convergent signals — induction of efflux pump genes, enhanced plasmid transfer, neurotransmitter modulation, transporter interference, and broad-spectrum duloxetine bioaccumulation — reveal multiple pathways through which these compounds reshape microbial function. Integrative enzyme analyses further identify a putative digallate acylhydrolase capable of biotransforming fluoxetine, providing the first mechanistically plausible candidate for SSRI metabolism by gut bacteria. We additionally map antidepressant-associated shifts in host tryptophan metabolites and systemic LPS levels, and identify bacterial taxa with functional potential across the indole, serotonin, and kynurenine pathways. Together, this review provides a unified mechanistic framework for antidepressant-microbiome interactions and outlines testable hypotheses toward microbiome-informed antidepressant strategies.

Depression is the leading cause of global disability according to the World Health Organization. Current pharmacologic interventions suffer from significant limitations and side effects, highlighting a need for novel therapeutic approaches. Whole-body hyperthermia (WBH) has been identified as a promising avenue of treatment of major depressive disorder (MDD); however, the mechanisms responsible for the antidepressant effects of WBH are not completely understood. In a previously published trial, we randomized adults with moderate to severe MDD (Hamilton Depression Rating Scale (HDRS) score >16) to one of two interventions (WBH or sham WBH). We collected whole blood 30 min post-intervention and followed participants for 6 weeks. In these analyses, we used a high-throughput RNA sequencing (RNA-seq) approach to compare the whole-blood transcriptomic response 30 min post-intervention. Differentially expressed gene (DEG) analysis with a Benjamini-Hochberg false discovery rate (FDR)-adjusted p-value (q-value) < 0.01 identified 17 upregulated DEGs including, as expected, multiple genes encoding heat-shock proteins belonging to the heat-shock protein (HSP) 70, HSP90, and HSP110 families, but also identified upregulated DEGs associated with immune response. Resulting log-fold changes and unadjusted p-values for all genes were used in Gene Set Enrichment Analysis (GSEA), which identified 88 enriched gene sets using a Benjamini-Hochberg FDR-adjusted p-value (q-value) of <0.05) representing biological processes (BPs) including those related to heat-shock responses and immune responses, including “interleukin 6 production”, which has been identified as a potential mediator of the antidepressant effects of WBH. These results are consistent with previous analyses identifying effects of WBH on heat shock response and interleukin (IL) 6 and, furthermore, identify novel genes and BPs that warrant further investigation as potential mediators of the antidepressant effects of WBH.

ObjectivePrior studies have reported that higher body temperature correlates with greater depressive symptoms, but did not adjust for potential confounders.MethodsWe used linear regression models and linear mixed models to assess associations between self-reported depressive symptoms and body temperature (once-daily self-reported temperature from a thermometer and minute-level distal temperature from a commercially available wearable device, worn on the finger). Adjusted models covaried for biological sex, age, daylight length, ambient temperature, and number of medical conditions. Distal body temperature metrics included awake and asleep temperatures, the asleep–awake temperature difference, and the diurnal temperature amplitude. Distal body temperature models also covaried for daylight length and ambient temperature over time. Finally, we used adjusted logistic regression models to assess associations between all body temperature metrics and four categories of depressive symptom severity.ResultsIn an adjusted linear regression model, the positive association between depressive symptoms and self-reported body temperature remained significant (b = 0.940, 95% CI [0.686, 1.193], p = 1.7 × 10–12). Adjusted associations with awake distal body temperature (b = 0.300, 95% CI [0.229, 0.371], p = 1.2 × 10–15), diurnal distal body temperature amplitude (b = -0.204, 95% CI [-0.248, -0.159], p = 6.1 × 10–18), and asleep-awake distal body temperature difference (b = -0.308, 95% CI [-0.375, -0.240], p = 6.1 × 10–18) were stronger than in unadjusted models. Standardized effect estimates from the adjusted linear regression models indicated that the magnitude of these associations was robust but small in magnitude, with standardized coefficients ranging from -0.067 to 0.061 and partial R² values ranging from 0.0006 to 0.0041. Adjusted linear mixed models using repeated measurements showed similar significant associations between distal body temperature metrics and depressive symptom severity. Adjusted logistic regression models showed that increases in self-reported body temperature and awake distal body temperature conferred significantly higher odds of a more severe depressive symptom category; increases in diurnal distal body temperature amplitude and asleep-awake temperature difference conferred significantly lower odds.ConclusionHigher body temperature was associated with increased depressive symptoms, and this association was robust to adjustment for potential confounders. These findings support body temperature as a physiological correlate of depressive symptom severity and motivate further investigation of thermoregulatory measures as part of multimodal approaches for monitoring depressive symptoms.

Major traumatic life events are risk factors for stress-related neuropsychiatric disorders, often accompanied by systemic inflammation, neuroinflammation, and microglial priming. As systemic inflammation, neuroinflammation, and microglial priming are considered risk factors for developing stress-related psychiatric disorders, one novel therapeutic strategy is to identify interventions that mitigate these responses. In this study, we investigated the effects of a novel soil-derived Mycolicibacterium, Mycolicibacterium sp. strain KGA-10, on in vitro immunoregulatory potential in murine bone marrow-derived dendritic cells (BMDCs) and on biomarkers of systemic inflammation, biomarkers of hippocampal neuroinflammation and microglial priming, and anxiety-like defensive behavioral responses in adult male rats exposed to inescapable tail-shock stress (IS). In Experiments 1 and 2, BMDCs were exposed to the type strain, Mycolicibacterium vaccae ATCC 15483 (0, 10, 30, 100, 300 µg/mL; Experiment 1) or M. sp. strain KGA-10 (100 µg/mL; Experiment 2) or sterile borate-buffered saline (BBS) vehicle followed, 24 h later, by exposure to lipopolysaccharide (LPS; 250 ng/mL) or a cell culture media vehicle, then, 24 h later, assessed for Il10, Il12a, and Il12b mRNA expression. Exposure of murine BMDCs to M. vaccae ATCC 15483 or M. sp. strain KGA-10 induced an immunoregulatory phenotype, characterized by increased ratios of Il10:Il12a and Il10:Il12b mRNA expression in both naïve and lipopolysaccharide- (LPS; 250 ng/mL) challenged conditions. In Experiment 3, adult male rats received weekly injections of heat-killed M. sp. strain KGA-10 (0.1 mg/0.1 mL, s.c.) or sterile BBS vehicle over three weeks prior to IS. Anxiety-like defensive behavioral responses were assessed 24 h following IS or home cage control conditions using the juvenile social exploration (JSE) test, while biomarkers of hippocampal neuroinflammation and microglial priming were assessed using real-time reverse transcription - polymerase chain reaction (real-time RT-PCR). M. sp. strain KGA-10 treatment promoted an anti-inflammatory immunophenotype, evidenced by decreased hippocampal Il12a, and decreased biomarkers of microglial priming, Nfkbia and Nlrp3 mRNA expression among rats exposed to IS, in association with prevention of IS-induced increases in anxiety-like defensive responses in the JSE test. These findings suggest that M. sp. strain KGA-10 is a promising candidate for a novel intervention for promotion of stress resilience and prevention of stress-related psychiatric disorders.

The prevalence of obesity is increasing in modern urban societies, resulting in a significant burden on public health systems globally. The current review explores research supporting the premise that chronic consumption of a Western diet alters the diversity and community composition of the gut microbiome, promotes “leaky gut”, systemic low-grade inflammation, and neuroinflammation, enhancing risk for obesity and stress-related psychiatric disorders. Specifically, consumption of a Western diet promotes metabolic endotoxemia by altering the gut microbiome, disrupting the mucus layer, and increasing permeability of the mucosal barrier. Specifically, increased permeability of the mucosal barrier leads to translocation of gut contents, including bacteria and bacterial metabolites, across the mucosal barrier. Translocation of gram-negative bacteria or lipopolysaccharide (LPS) can promote metabolic endotoxemia, heightened inflammation, and disruption of physiological function, leading to metabolic diseases. The review explores a novel approach to counteracting the metabolic effects of the Western diet by utilizing “Old Friends”, i.e., anti-inflammatory, immunoregulatory microbes that humans co-evolved with, but are reduced or absent in modern urban societies. Particularly, Mycobacterium vaccae ATCC 15483, one of these “Old Friends”, has showcased promising results by protecting against Western diet-induced systemic inflammation, obesity, and anxiety-like defensive behavioral responses associated with stress-related psychiatric disorders. Furthermore, M. vaccae ATCC 15483 decreases biomarkers of hippocampal microglial priming, suggesting a potential mechanism underlying stress resilience effects. While more research is warranted, harnessing the therapeutic potential of “Old Friends” like Mycobacterium vaccae ATCC 15483 may offer a novel strategy to combat modern diseases associated with consumption of a Western diet.

Posttraumatic stress disorder (PTSD) is a mental health condition that can develop following exposure to a traumatic event, often with persistent anxiety and depressive symptoms. Recent research suggests the microbiome-gut-brain axis may play an important role in the etiology and pathophysiology of PTSD. At the same time, retreats incorporating psychedelic-assisted therapies have gained increasing attention as potential treatments for PTSD. However, little is known about how participation in these retreats may affect the gut microbiome. Therefore, we conducted a preliminary observational single-arm pre-post study investigating the diversity and community composition of the gut microbiome pre/post participation in a retreat involving ceremonial ayahuasca use, as well as associations between microbiome features, PTSD symptoms, and personality traits. Participants included U.S. Veterans and non-Veterans with varied PTSD symptoms (N = 22). The international retreat took place over one week and included three ayahuasca ceremonies. PTSD Checklist for the DSM-5 (PCL-5) scores, Five-Factor Model (FFM) personality measures, and fecal samples were collected from participants pre/post retreat. Fecal samples were analyzed using 16S rRNA gene amplicon sequencing to assess gut microbiome diversity and community composition. PCL-5 scores decreased following the retreat, relative to baseline. Openness, Conscientiousness, Extraversion, and Agreeableness increased, while Neuroticism decreased. Measures of gut microbiome alpha diversity did not change. However, beta diversity analyses revealed a within-subjects shift in microbial community composition at the end of the retreat relative to baseline. Post retreat there was an increase in the relative abundances of several short-chain fatty acid-producing bacteria associated with gut health, including Lachnospiraceae UCG-004, Colidextribacter, Oscillospira, and Blautia. Although the study design has limitations and does not establish causality, it highlights within-subjects effects of participation in an ayahuasca retreat on the gut microbiome, effects that should be evaluated further in future large randomized double-blind, placebo-controlled clinical trials.

Objective:To assess the acceptability of a randomized single-blind trial of cognitive behavioral therapy (CBT) and whole-body hyperthermia (WBH) treatment for major depressive disorder (MDD). Methods:All participants (N = 30) with MDD received CBT for depression and were randomized to also receive either: (1) WBH that raised core body temperature using an infrared sauna device, or (2) sham WBH of a similar duration that did not significantly raise core body temperature. Results:Study acceptability was the primary outcome: of participants who completed the final assessment (n = 29; 96.7%), 22 (75.9%) reported that they would recommend participation to a friend or family member with MDD. Twenty-five (86.2%) participants reported that they would be likely or extremely likely to enroll in this study, given the experience they had in the study. All participants randomized to WBH correctly believed they received WBH, and 6 (43%) of participants randomized to sham WBH correctly believed they received sham WBH. Both arms achieved clinically meaningful and statistically significant reductions in depression symptoms. The average decreases in the Beck Depression Inventory-II (BDI-II) were -19.07 (SE = 2.69, P < 0.0001) in the WBH arm (80.0% no longer meeting DSM-5 criteria, 60.0% achieving 50% or greater reduction in BDI-II) and -21.10 (SE = 2.41, P<0.0001) in the sham WBH arm (92.9% no longer meeting DSM-5 criteria, 78.6% achieving 50% or greater reduction in BDI-II). Conclusions:Study procedures were acceptable. Participants in the WBH and sham WBH groups had substantial reductions in depressive symptoms that were greater than typically seen with CBT alone. The sham WBH arm was not fully credible and may have exerted antidepressant effects, thus raising concerns about its use in future trials. Further research to test whether adding WBH to CBT results in additional antidepressant effects is warranted.

BACKGROUND:Periodontal disease (PD) is a common oral infection that is often exacerbated during pregnancy. Porphyromonas gingivalis (P. gingivalis), a keystone PD pathogen, promotes systemic inflammation, depressive-like behavior in animals, and can translocate to the brain and genital tract. Its capsular antigens (K1-K7) are key virulence factors. We hypothesized that seropositivity to specific P. gingivalis capsular K serotypes is associated with depressive symptoms and systemic inflammation during pregnancy. METHODS:In a prospective cohort of pregnant women (N = 114), depressive symptoms were assessed in each trimester of pregnancy using the Edinburgh Postnatal Depression Rating Scale (EPDS, ≥13 denoting moderate-to-severe depression symptoms). Plasma IgG antibodies against P. gingivalis K1-K7 serotypes and proinflammatory cytokines were measured. Statistical analyses included Firth's bias-reduced logistic regression and mixed-effects linear models. RESULTS:Approximately 25 % of participants were seropositive for at least one K serotype. IgG seropositivity to P. gingivalis K1 serotype was significantly associated with moderate-to-severe depressive symptoms during the first trimester (EPDS≥13; P = 0.035). Additionally, aggregated K seropositivity was significantly associated with elevated plasma IL-10 levels during the first trimester (P < 0.05, adjusted for multiple comparisons). Other cytokines were unrelated to P. gingivalis K seropositivity. LIMITATIONS:We did not assess clinical or radiological manifestations of PD, antibodies to non-capsular P. gingivalis antigens, or the presence of other PD pathogens. CONCLUSION:These results suggest the importance of integrating IgG K seropositivity (which, in addition to local oral pathogens, may also reflect their distal translocation) with clinical, bacteriological and radiological measures when studying associations between PD and affective dysregulation in pregnancy.

The gut microbiota, the dynamic orchestrator of physiological and neuroimmune processes, influences mental health via the bidirectional microbiota–gut–brain axis. Although distinct microbial signatures are linked with psychiatric disorders such as depression, anxiety, post-traumatic stress disorder and schizophrenia, whether this relationship is causative, correlative or represents a complex interplay remains unresolved. This Review examines this trichotomy, highlighting key mechanistic pathways including microbial metabolites, immune modulation and neural signaling, alongside challenges in disentangling causation from correlation. Clarifying this distinction elevates the gut microbiota from a curiosity to a cornerstone of personalized medicine. Furthermore, emphasis is placed on advancing methodological frameworks, fostering interdisciplinary collaboration and addressing research disparities that bias insights toward specific populations. Clearer understanding of the microbiota’s role in mental health could yield new therapies and predictive biomarkers, ultimately charting paths toward more equitable and evidence-based approaches. This work outlines the transformative potential of clarifying the microbiota–gut–brain axis in addressing global mental health burden. This Review provides a critical assessment of current mechanistic and clinical evidence on the interaction between the gut microbiota and mental health to differentiate causative, correlative and bidirectional roles of the gut microbiota in psychiatric disorders. It highlights current priority questions and provides recommendations for the standardization of future studies.

Mental health disorders and neurodegenerative diseases place a heavy burden on patients and societies, and, although great strides have been made to understand the pathophysiology of these conditions, advancement in drug development is lagging. The importance of gastrointestinal health in maintaining overall health and preventing disease is not a new concept. Hundreds of years ago, healers from various cultures and civilizations recognized the crucial role of the gut in sustaining health. More than a century ago, scientists began exploring the restorative effects of probiotics, marking the early recognition of the importance of gut microbes. The omics era brought more enlightenment and enabled researchers to identify the complexity of the microbial ecosystems we harbour, encompassing bacteria, eukaryotes (including fungi), archaea, viruses, and other microorganisms. The extensive genetic capacity of the microbiota is dynamic and influenced by the environment. The microbiota therefore serves as a significant entity within us, with evolutionarily preserved functions in host metabolism, immunity, development, and behavior. The significant role of the bacterial gut microbiome in mental health and neurodegenerative disorders has been realized and described within the framework of the microbiota-gut-brain axis. However, the bacterial members do not function unaccompanied, but rather in concert, and there is a substantial knowledge gap regarding the involvement of non-bacterial microbiome members in these disorders. In this review, we will explore the current literature that implicates a role for the entire metagenomic ensemble, and how their complex interkingdom relationships could influence CNS functioning in mental health disorders and neurodegenerative diseases.

Markers of chronic infection Toxoplasma gondii (Nicolle et Manceaux, 1908) have been associated with suicidal self-directed violence (SSDV). We present the results of the first study relating T. gondii IgG serology with suicide attempts and suicidal ideation in United States Veterans, known to have higher suicide rates than members of the general population. We also related T. gondii serology to SSDV risk factors, including valid and reliable measures of trait impulsivity, aggression, self-reported depression, and sleep disturbance. We recruited 407 Veterans enrolled at three Veterans Affairs Medical Centers with mean ( S.D. ) age = 45.6 (11.6) years; 304 men (74.7%); 203 with a history of SSDV and 204 with no history of any self-directed violence (SDV). Seropositivity and serointensity, categorised as high (top quartile) or low (lower three quartiles), were analysed in relationship to SSDV, suicidal ideation and clinical risk factors using age and gender-adjusted linear and logistic methods, after transformations and nonparametric tests when appropriate. Associations between seropositivity and SSDV and its risk factors were not significant in all groups. High serointensity, while not associated with SSDV or repeat suicide attempts, was positively associated with suicidal ideation, depression, impulsivity, and daytime dysfunction due to sleepiness (p < 0.05), but only in Veterans with a history of SSDV. In Veterans without a history of SDV, no associations were significant. These associations remained significant after adjustment for certain socioeconomic factors (i.e., income, homelessness, military rank). Including education in the model downgraded the statistical significance of suicidal ideation and depression to statistical trends, but the significance of associations with impulsivity and daytime dysfunction due to sleepiness remained. Major limitations include the cross-sectional design, overall low seropositivity within the sample, and potentially spurious results due to multiple comparisons. Thus, the results of this report need to be replicated in larger samples, ideally longitudinally.

Previous studies have shown that corticosterone rapidly alters extracellular serotonin (5-hydroxytryptamine; 5-HT) concentrations in the dorsomedial hypothalamus (DMH) of adult male rats, suggesting a role for corticosterone actions in the DMH in regulation of physiological and behavioral responses. Whether or not corticosterone also rapidly alters extracellular serotonin concentrations in the DMH of female rats, and the dependence of this effect on ovarian hormones, is not known. To determine the effects of 17β-estradiol (E2), progesterone (P), and corticosterone on extracellular concentrations of serotonin in the DMH, corticosterone and/or P were delivered into the DMH of ovariectomized rats via reverse microdialysis in E2-primed rats. Combined, but not separate, delivery of corticosterone and P into the DMH rapidly and transiently increased extracellular 5-HT concentrations, a result that was dependent upon circulating E2. This effect of corticosterone on DMH 5-HT was replicated by local perfusion of the organic cation transporter 3 (OCT3) competitive inhibitor normetanephrine. Intra-DMH infusions of either corticosterone or normetanephrine also reversibly suppressed lordosis responses in E2 + P-primed females. These results suggest that ovarian hormones in combination with corticosterone modulate OCT3-mediated 5-HT clearance in the DMH, potentially representing an adaptive mechanism that allows sexually receptive females to respond rapidly to acute stressors.

Stress-protective effects have been reported for M. vaccae NCTC 11659 and M. vaccae ATCC 15483T. However, it remains to be investigated whether also closely related rapidly growing environmental saprophytic non-tuberculous mycobacteria (NTM) species have protective effects against the negative consequences of chronic psychosocial stress. Therefore, the aim of the current study was to assess whether repeated i.g. administrations of a heat-inactivated preparation of Mycobacterium aurum DSM 33539 prior to 19 days of chronic subordinate colony housing (CSC) are able to ameliorate the negative effects of this preclinically validated mouse model for chronic psychosocial stress on subsequent dextran sulfate sodium (DSS) colitis in male C57BL/6N mice. The results of the present study show that repeated i.g. administrations of M. aurum DSM 33539 have stabilizing effects on the composition of the gut microbiome, indicated by the findings that M. aurum DSM 33539 prevented CSC-induced increases in the relative abundances of the colitogenic phyla Desulfobacterota and Deferribacterota. Indeed, the relative abundance of Deferribacterota on day 19 was strongly correlated with histological damage to the colon. In line with the latter, M. aurum DSM 33539 was further protective against the aggravating effects of stress on subsequent DSS colitis. Collectively, our findings confirm and extend previous findings from our group and suggest that the stress-protective effects reported for M. vaccae NCTC 11659 and M. vaccae ATCC 15483T are generalizable also to other NTM species.

Long-term exposure to fluoxetine and other selective serotonin reuptake inhibitors alters social and anxiety-related behaviours, including social withdrawal, which is a symptom of several neuropsychiatric disorders. Adaptive changes in serotonergic neurotransmission likely mediate this delayed effect, although the exact mechanisms are still unclear. Here we investigated the functional circuitry underlying the biphasic effects of fluoxetine on social approach-avoidance behaviour and explored the place of serotonergic dorsal raphe nucleus (DR) ensembles in this network, using c-Fos-immunoreactivity as a correlate of activity. Graph theory-based network analysis revealed changes in patterns of functional connectivity and identified neuronal populations in the insular cortex (IC) and serotonergic populations in the DR as central targets to the prosocial effects of chronic fluoxetine. To determine the role of serotonergic projections to the IC, a retrograde tracer was micro-injected in the IC prior to fluoxetine treatment and social behaviour testing. Chronic fluoxetine increased c-Fos immunoreactivity in insula-projecting neurons of the rostral, ventral part of the DR (DRV). Using a virally delivered Tet-Off platform for temporally-controlled marking of neuronal activation, we observed that chronic fluoxetine may affect social behaviour by influencing independent but interconnected populations of serotonergic DR ensembles. These findings suggest that sustained fluoxetine exposure causes adaptive changes in functional connectivity due to altered serotonergic neurotransmission in DR projection targets, and the increased serotonergic signalling to the IC likely mediates some of the therapeutic effects of fluoxetine on social behaviour.

Taxa level associations of the human gut microbiota have been reported in relation to sleep health; however, which taxa are associated with good sleep has yet to be determined. Many study methodologies rely on self-reported sleep metrics, 16S rRNA gene-amplicon sequencing or statistical methodologies not designed for gut microbiome assessments, which have limitations. We examined the association between sleep measures assessed by actigraphy followed by one night of in-laboratory polysomnography (PSG) and whole genome sequencing (WGS) gut microbiome taxa. Fifteen healthy participants aged 26±4.0(SD) were instructed to maintain a consistent 8h sleep schedule for fourteen days at home. Wrist actigraphy and time stamped call-ins were assessed for adherence. Following fourteen days of monitoring, participants underwent 8h overnight in-laboratory PSG. Fecal microbiome samples were collected at PSG visit. WGS at the operational genomic unit (OGU) were then referenced against Web of Life 2 for taxonomic assignment. Differential abundance testing (ANCOM-BC) was performed to detect the OGUs associated with individuals with high (≥85%) or low (< 85%) sleep efficiency (SE) assessed via actigraphy. Following, linear regression associations between SE, sleep onset latency (SOL) and wake after sleep onset (WASO) from PSG were tested against these differentially abundant OGUs to determine: 1) whether these associations were maintained with PSG SE and; 2) whether these taxa were associated with SOL or WASO. ANCOM-BC determined Bifidobacterium breve and Bifidobacterium saguini species were increased in the high SE wrist actigraphy group (log fold change 2.2, q=0.002 and log fold change 2.0, q=0.006, respectively). Linear regression indicated increased breve and saguini were associated with higher PSG SE (β=0.0003, p=0.03, R²=0.18 and β=0.0013, p=0.02, R²=0.46, respectively). Further investigation into PSG SOL and WASO indicated that the higher SE was due to these strains being associated with decreased WASO, specifically (β=–0.09, p=0.04, R²=0.38 and β=–0.58, p=0.04, R²=0.40, respectively). We find that higher SE, specifically by decreased WASO, is associated with higher levels of two Bifidobacterium species, breve and saguini. Bifidobacterium, commonly found in probiotics, may improve subjective sleep quality. Therefore, Bifidobacterium breve and saguini may be specific targets for improving human sleep. ONR N00014-15-1-2809, NIH-T32-HL149646, NIH/NCATS Colorado CTSA-UL1TR002535.

BACKGROUND:Individuals raised in an urban environment (URBANs) show an exaggerated inflammatory response to the Trier Social Stress Test (TSST) compared with individuals raised in a rural environment (RURALs). The underlying mechanisms are unclear but may relate to childhood animal contact. As an exaggerated immune (re)activity plays a causal role in the pathogenesis of stress-associated disorders, these findings might explain the higher prevalence of stress-associated disorders in urban vs. rural areas. METHODS:We recruited physically and emotionally healthy male URBANs, raised in a city with more than 40,000 residents either in the absence (noPETs) or presence (PETs) of household pets. Participants were individually exposed to the TSST, and before and after the TSST, blood and saliva were collected for assessment of different stress-related parameters. An additional saliva sample before the TSST was collected for salivary microbiome analysis. Heart rate (HR) and HR variability (HRV) were recorded continuously. Mental and physical health status, early-life and perceived life stress, current animal contact, and subjective strain induced by TSST exposure were assessed using validated questionnaires. RESULTS:Here we show that adult healthy male noPETs vs. PETs still reported less animal contact during adulthood and were characterized by deficits in their immunoregulatory and intestinal barrier function, which under basal conditions did not translate into a chronic low-grade inflammatory state. This was different under acute psychosocial stress conditions. Exposure to the TSST resulted in a facilitated mobilization of particularly neutrophil granulocytes in noPETs vs. PETs, accompanied by an enhanced pro- and compromised anti-inflammatory systemic stress response. CONCLUSION:Together, the presence of pets seems to reduce the risk for URBANs to develop stress-associated disorders later in life (i.e., primary prevention) by facilitating immunoregulatory and barrier functions, in turn preventing an overshooting immune activation in response to acute stressors and chronic low-grade inflammation in response to repeated/chronic stressors.