High-fat diet, microbiome-gut-brain axis signaling, and anxiety-like behavior in male rats.

Obesity, associated with the intake of a high-fat diet (HFD), and anxiety are common among those living in modern urban societies. Recent studies suggest a role of microbiome-gut-brain axis signaling, including a role for brain serotonergic systems in the relationship between HFD and anxiety. Evidence suggests the gut microbiome and the serotonergic brain system together may play an important role in this response. Here we conducted a nine-week HFD protocol in male rats, followed by an analysis of the gut microbiome diversity and community composition, brainstem serotonergic gene expression (tph2, htr1a, and slc6a4), and anxiety-related defensive behavioral responses. We show that HFD intake decreased alpha diversity and altered the community composition of the gut microbiome in association with obesity, increased brainstem tph2, htr1a and slc6a4 mRNA expression, including in the caudal part of the dorsomedial dorsal raphe nucleus (cDRD), a subregion previously associated with stress- and anxiety-related behavioral responses, and, finally, increased anxiety-related defensive behavioral responses. The HFD increased the Firmicutes/Bacteroidetes ratio relative to control diet, as well as higher relative abundances of Blautia, and decreases in Prevotella. We found that tph2, htr1a and slc6a4 mRNA expression were increased in subregions of the dorsal raphe nucleus in the HFD, relative to control diet. Specific bacterial taxa were associated with increased serotonergic gene expression in the cDRD. Thus, we propose that HFD-induced obesity is associated with altered microbiome-gut-serotonergic brain axis signaling, leading to increased anxiety-related defensive behavioral responses in rats.

Longitudinal Influence of Prescribed Antidepressants on Fecal and Oral Microbiomes Among Veterans With Major Depressive Disorder.

OBJECTIVE: The purpose of this study was to evaluate the influence of a new course of antidepressant monotherapy on gut and oral microbiomes and the relationship to depressive symptoms. METHODS: Longitudinal microbiome samples obtained from 10 U.S. veterans were analyzed. Baseline samples were taken before a new course of antidepressant monotherapy (either switching from a previous treatment or starting a new treatment). Targeted genomic sequencing of the microbiome samples was used to analyze changes in taxonomy and diversity across participants, medications, and medication class. Associations between these changes and Patient Health Questionnaire-9 (PHQ-9) scores were analyzed. RESULTS: Taxonomic variability was observed across participants, with the individual being the main microbial community driver. In terms of the fecal microbiome, antidepressants were associated with shifts toward Bacteroides being less abundant and Blautia, Pseudomonas, or Faecalibacterium being more abundant. Likewise, the composition of the oral microbiome was variable, with individual participants being the primary drivers of community composition. In the oral samples, the relative abundance of Haemophilus decreased after antidepressants were started. Increases in Blautia and decreases in Bacteroides were associated with lower PHQ-9 scores. CONCLUSIONS: Antidepressants were found to influence fecal and oral microbiomes such that a new course of antidepressant monotherapy was associated with taxonomic alterations toward healthier states in both fecal and oral microbiomes, which were associated with decreases in depressive symptoms. Additional longitudinal research is required to increase understanding of microbiomes and symptom-based changes, with a particular focus on potential differences between medication classes and underlying mechanisms.

Association of homelessness and diet on the gut microbiome: a United States-Veteran Microbiome Project (US-VMP) study.

Military veterans account for 8% of homeless individuals living in the United States. To highlight associations between history of homelessness and the gut microbiome, we compared the gut microbiome of veterans who reported having a previous experience of homelessness to those from individuals who reported never having experienced a period of homelessness. Moreover, we examined the impact of the cumulative exposure of prior and current homelessness to understand possible associations between these experiences and the gut microbiome. Microbiome samples underwent genomic sequencing and were analyzed based on alpha diversity, beta diversity, and taxonomic differences. Additionally, demographic information, dietary data, and mental health history were collected. A lifetime history of homelessness was found to be associated with alcohol use disorder, substance use disorder, and healthy eating index compared to those without such a history. In terms of differences in gut microbiota, beta diversity was significantly different between veterans who had experienced homelessness and veterans who had never been homeless (P = 0.047, weighted UniFrac), while alpha diversity was similar. The microbial community differences were, in part, driven by a lower relative abundance of Akkermansia in veterans who had experienced homelessness (mean; range [in percentages], 1.07; 0-33.9) compared to veterans who had never been homeless (2.02; 0-36.8) (P = 0.014, ancom-bc2). Additional research is required to facilitate understanding regarding the complex associations between homelessness, the gut microbiome, and mental and physical health conditions, with a focus on increasing understanding regarding the longitudinal impact of housing instability throughout the lifespan.IMPORTANCEAlthough there are known stressors related to homelessness as well as chronic health conditions experienced by those without stable housing, there has been limited work evaluating the associations between microbial community composition and homelessness. We analyzed, for the first time, bacterial gut microbiome associations among those with experiences of homelessness on alpha diversity, beta diversity, and taxonomic differences. Additionally, we characterized the influences of diet, demographic characteristics, military service history, and mental health conditions on the microbiome of veterans with and without any lifetime history of homelessness. Future longitudinal research to evaluate the complex relationships between homelessness, the gut microbiome, and mental health outcomes is recommended. Ultimately, differences in the gut microbiome of individuals experiencing and not experiencing homelessness could assist in identification of treatment targets to improve health outcomes.

A cross-sectional study of correlations among blood-based biomarkers for intestinal permeability: A pilot study of United States veterans with posttraumatic stress disorder symptoms.

While many studies of intestinal permeability (IP) are focused on those with gastrointestinal (GI) disorders, there is a rising trend to analyze IP among individuals with mental health conditions including posttraumatic stress disorder (PTSD) with and without diagnosed GI conditions. This interest stems from the association between gut dysbiosis and chronic inflammation, which are mechanisms linked to stress-related somatic and mental health conditions. Efforts to date have resulted in the exploration of non-invasive and feasible measures to identify an IP biomarker that could also serve as a treatment target. Additionally, those conducting studies regarding IP often recruit individuals without health problems and compare levels of biomarkers of IP to those obtained from participants with conditions of interest. This study aimed to assess correlations between blood-based biomarkers of IP, as well as examine the association between blood-based biomarkers of IP and PTSD symptoms. Blood was sampled from seventeen United States military Veterans with variable severity of PTSD symptoms per the posttraumatic checklist for DSM-5 (PCL-5) (n = 6 with scores over 31 indicating clinically meaningful symptoms of PTSD; overall range 0-49, mean 20.8, standard deviation 15.7) and analyzed blood biomarkers of IP including citrulline, diamine oxidase, glucagon-like peptide-2, intestinal fatty-acid binding protein, lipopolysaccharide binding protein, lipopolysaccharide, and zonulin. Correlations between the IP blood-based biomarkers ranged from ρ of -0.31 to 0.35. None of the measured biomarkers were significantly correlated to PTSD symptom severity scores (ρ of -0.34 to 0.05). Although based on limited sample size, our results call into question the specificity of blood-based biomarkers of IP when: (1) studying persons with and without PTSD symptoms in whom clinical GI disorders are not necessarily the focus of the study; and (2) comparing IP results among individuals with well-defined disease states to those without the disease (e.g., controls). Further studies are needed to explore the role of external factors (e.g., nutrition, obesity, alcohol use) on IP and to determine if the biomarkers studied are appropriate for measuring IP in people with a range of symptoms related to PTSD.

Food desert residence has limited impact on veteran fecal microbiome composition: a U.S. Veteran Microbiome Project study.

IMPORTANCE: Social and economic inequities can have a profound impact on human health. The inequities could result in alterations to the gut microbiome, an important factor that may have profound abilities to alter health outcomes. Moreover, the strong correlations between social and economic inequities have been long understood. However, to date, limited research regarding the microbiome and mental health within the context of socioeconomic inequities exists. One particular inequity that may influence both mental health and the gut microbiome is living in a food desert. Persons living in food deserts may lack access to sufficient and/or nutritious food and often experience other inequities, such as increased exposure to air pollution and poor access to healthcare. Together, these factors may confer a unique risk for microbial perturbation. Indeed, external factors beyond a food desert might compound over time to have a lasting effect on an individual's gut microbiome. Therefore, adoption of a life-course approach is expected to increase the ecological validity of research related to social inequities, the gut microbiome, and physical and mental health.

Human microbiome transfer in the built environment differs based on occupants, objects, and buildings.

Compared to microbiomes on other skin sites, the bacterial microbiome of the human hand has been found to have greater variability across time. To increase understanding regarding the longitudinal transfer of the hand microbiome to objects in the built environment, and vice versa, 22 participants provided skin microbiome samples from their dominant hands, as well as from frequently and infrequently touched objects in their office environments. Additional longitudinal samples from home environments were obtained from a subset of 11 participants. We observed stability of the microbiomes of both the hand and built environments within the office and home settings; however, differences in the microbial communities were detected across the two built environments. Occupants' frequency of touching an object correlated to that object having a higher relative abundance of human microbes, yet the percent of shared microbes was variable by participants. Finally, objects that were horizontal surfaces in the built environment had higher microbial diversity as compared to objects and the occupants' hands. This study adds to the existing knowledge of microbiomes of the built environment, enables more detailed studies of indoor microbial transfer, and contributes to future models and building interventions to reduce negative outcomes and improve health and well-being.

Effects of Mycobacterium vaccae NCTC 11659 and Lipopolysaccharide Challenge on Polarization of Murine BV-2 Microglial Cells.

Previous studies have shown that the in vivo administration of soil-derived bacteria with anti-inflammatory and immunoregulatory properties, such as Mycobacterium vaccae NCTC 11659, can prevent a stress-induced shift toward an inflammatory M1 microglial immunophenotype and microglial priming in the central nervous system (CNS). It remains unclear whether M. vaccae NCTC 11659 can act directly on microglia to mediate these effects. This study was designed to determine the effects of M. vaccae NCTC 11659 on the polarization of naïve BV-2 cells, a murine microglial cell line, and BV-2 cells subsequently challenged with lipopolysaccharide (LPS). Briefly, murine BV-2 cells were exposed to 100 µg/mL whole-cell, heat-killed M. vaccae NCTC 11659 or sterile borate-buffered saline (BBS) vehicle, followed, 24 h later, by exposure to 0.250 µg/mL LPS (Escherichia coli 0111: B4; n = 3) in cell culture media vehicle (CMV) or a CMV control condition. Twenty-four hours after the LPS or CMV challenge, cells were harvested to isolate total RNA. An analysis using the NanoString platform revealed that, by itself, M. vaccae NCTC 11659 had an "adjuvant-like" effect, while exposure to LPS increased the expression of mRNAs encoding proinflammatory cytokines, chemokine ligands, the C3 component of complement, and components of inflammasome signaling such as Nlrp3. Among LPS-challenged cells, M. vaccae NCTC 11659 had limited effects on differential gene expression using a threshold of 1.5-fold change. A subset of genes was assessed using real-time reverse transcription polymerase chain reaction (real-time RT-PCR), including Arg1, Ccl2, Il1b, Il6, Nlrp3, and Tnf. Based on the analysis using real-time RT-PCR, M. vaccae NCTC 11659 by itself again induced "adjuvant-like" effects, increasing the expression of Il1b, Il6, and Tnf while decreasing the expression of Arg1. LPS by itself increased the expression of Ccl2, Il1b, Il6, Nlrp3, and Tnf while decreasing the expression of Arg1. Among LPS-challenged cells, M. vaccae NCTC 11659 enhanced LPS-induced increases in the expression of Nlrp3 and Tnf, consistent with microglial priming. In contrast, among LPS-challenged cells, although M. vaccae NCTC 11659 did not fully prevent the effects of LPS relative to vehicle-treated control conditions, it increased Arg1 mRNA expression, suggesting that M. vaccae NCTC 11659 induces an atypical microglial phenotype. Thus, M. vaccae NCTC 11659 acutely (within 48 h) induced immune-activating and microglial-priming effects when applied directly to murine BV-2 microglial cells, in contrast to its long-term anti-inflammatory and immunoregulatory effects observed on the CNS when whole-cell, heat-killed preparations of M. vaccae NCTC 11659 were given peripherally in vivo.

Rationale, design, and methods: A randomized placebo-controlled trial of an immunomodulatory probiotic intervention for Veterans with PTSD.

Background: United States military Veterans from recent conflicts are experiencing symptoms related to posttraumatic stress disorder (PTSD). Many Veterans are resistant to conventional health and mental health interventions (e.g., medication, psychotherapy). Alternative treatment approaches are needed. An underlying feature of PTSD is exaggerated inflammation, both peripherally and in the central nervous system. This inflammation is thought to play an important role in the vulnerability to, aggravation of, and persistence of PTSD symptoms. Therefore, an innovative intervention strategy would be the use of immunoregulatory/anti-inflammatory probiotics to reduce inflammation. Here we describe the rationale, design, and methods of a randomized placebo-controlled trial (RCT) of Lactobacillus rhamnosus GG (LGG; ATCC 53103) for posttraumatic stress disorder (PTSD). Methods: This is a Phase IIa trial of LGG for United States military Veterans with PTSD, using a longitudinal, double-blind, randomized placebo-controlled design. The primary outcome measure is plasma concentration of high-sensitivity C-reactive protein. Conclusion: Despite the fact that symptoms associated with PTSD can be disabling, individuals living with this trauma-related disorder have limited options in terms of evidence-based interventions. Recent research efforts aimed at highlighting the biological mechanisms of PTSD suggest that increased inflammation and altered autonomic nervous system activity may be treatment targets, and that immunoregulatory probiotics, such as LGG, have the potential to decrease trauma-induced inflammatory responses, as well as associated symptoms. This manuscript describes the best powered human subjects Phase IIa trial, to date, of a probiotic intervention for those living with PTSD.

Effects of paternal high-fat diet and maternal rearing environment on the gut microbiota and behavior.

Exposing a male rat to an obesogenic high-fat diet (HFD) influences attractiveness to potential female mates, the subsequent interaction of female mates with infant offspring, and the development of stress-related behavioral and neural responses in offspring. To examine the stomach and fecal microbiome's potential roles, fecal samples from 44 offspring and stomach samples from offspring and their fathers were collected and bacterial community composition was studied by 16 small subunit ribosomal RNA (16S rRNA) gene sequencing. Paternal diet (control, high-fat), maternal housing conditions (standard or semi-naturalistic housing), and maternal care (quality of nursing and other maternal behaviors) affected the within-subjects alpha-diversity of the offspring stomach and fecal microbiomes. We provide evidence from beta-diversity analyses that paternal diet and maternal behavior induced community-wide shifts to the adult offspring gut microbiome. Additionally, we show that paternal HFD significantly altered the adult offspring Firmicutes to Bacteroidetes ratio, an indicator of obesogenic potential in the gut microbiome. Additional machine-learning analyses indicated that microbial species driving these differences converged on Bifidobacterium pseudolongum. These results suggest that differences in early-life care induced by paternal diet and maternal care significantly influence the microbiota composition of offspring through the microbiota-gut-brain axis, having implications for adult stress reactivity.

Evaluation of the gut microbiome in association with biological signatures of inflammation in murine polytrauma and shock.

Severe injuries are frequently accompanied by hemorrhagic shock and harbor an increased risk for complications. Local or systemic inflammation after trauma/hemorrhage may lead to a leaky intestinal epithelial barrier and subsequent translocation of gut microbiota, potentially worsening outcomes. To evaluate the extent with which trauma affects the gut microbiota composition, we performed a post hoc analysis of a murine model of polytrauma and hemorrhage. Four hours after injury, organs and plasma samples were collected, and the diversity and composition of the cecal microbiome were evaluated using 16S rRNA gene sequencing. Although cecal microbial alpha diversity and microbial community composition were not found to be different between experimental groups, norepinephrine support in shock animals resulted in increased alpha diversity, as indicated by higher numbers of distinct microbial features. We observed that the concentrations of proinflammatory mediators in plasma and intestinal tissue were associated with measures of microbial alpha and beta diversity and the presence of specific microbial drivers of inflammation, suggesting that the composition of the gut microbiome at the time of trauma, or shortly after trauma exposure, may play an important role in determining physiological outcomes. In conclusion, we found associations between measures of gut microbial alpha and beta diversity and the severity of systemic and local gut inflammation. Furthermore, our data suggest that four hours following injury is too early for development of global changes in the alpha diversity or community composition of the intestinal microbiome. Future investigations with increased temporal-spatial resolution are needed in order to fully elucidate the effects of trauma and shock on the gut microbiome, biological signatures of inflammation, and proximal and distal outcomes.

Characterization of the gut microbiota among Veterans with unique military-related exposures and high prevalence of chronic health conditions: A United States-Veteran Microbiome Project (US-VMP) study.

The gut microbiome is impacted by environmental exposures and has been implicated in many physical and mental health conditions, including anxiety disorders, affective disorders, and trauma- and stressor-related disorders such as posttraumatic stress disorder (PTSD). United States (US) military Veterans are a unique population in that their military-related exposures can have consequences for both physical and mental health, but the gut microbiome of this population has been understudied. In this publication, we describe exposures, health conditions, and medication use of Veterans in the US Veteran Microbiome Project (US-VMP) and examine the associations between these characteristics and the gut microbiota. This cohort included 331 US Veterans seeking healthcare with the Veterans Health Administration who were 83% male with an average (±SD) age of 47.6 â€‹± â€‹13.4 years. The cohort displayed a high prevalence of PTSD (49.8%) and history of traumatic brain injuries (76.1%), and high current use of prescription medications (74.9%) to treat various acute and chronic conditions. We observed significant associations between the gut microbiota composition and gastroenteritis, peripheral vascular disease (PVD), bipolar disorders, symptoms of severe depression based on the Beck Depression Inventory, stimulant and opioid use disorders, beta-blockers, serotonin and norepinephrine reuptake inhibitor antidepressants, diabetes medications, and proton pump inhibitors. Many of the Veteran characteristics examined were associated with altered relative abundances of specific taxa. We found that PVD and cardiovascular disease were associated with lower microbiota diversity in the gut (i.e., α-diversity), while supplemental vitamin use was associated with higher α-diversity. Our study contributes novel insights as to whether the unique exposures of Veterans in this cohort correlate with gut microbiota characteristics and, in line with previous findings with other population-level studies of the microbiome, confirms associations between numerous health conditions and medications with the gut microbiome.

Evaluation of an Immunomodulatory Probiotic Intervention for Veterans With Co-occurring Mild Traumatic Brain Injury and Posttraumatic Stress Disorder: A Pilot Study.

Background: US military Veterans returned from Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) with symptoms associated with mild traumatic brain injury [mTBI; i.e., persistent post-concussive (PPC) symptoms] and posttraumatic stress disorder (PTSD). Interventions aimed at addressing symptoms associated with both physical and psychological stressors (e.g., PPC and PTSD symptoms) are needed. This study was conducted to assess the feasibility, acceptability, and safety of a probiotic intervention, as well as to begin the process of evaluating potential biological outcomes. Methods: A pilot randomized controlled trial was implemented among US military Veterans from recent conflicts in Iraq and Afghanistan. Those enrolled had clinically significant PPC and PTSD symptoms. Participants were randomized to intervention (Lactobacillus reuteri DSM 17938) or placebo supplementation (daily for 8 weeks +/- 2 weeks) at a 1:1 ratio, stratified by irritable bowel syndrome status. Thirty-one Veterans were enrolled and randomized (15 to the placebo condition and 16 to the probiotic condition). Results: Thresholds for feasibility, acceptability, and safety were met. Probiotic supplementation resulted in a decrease in plasma C-reactive protein (CRP) concentrations relative to the placebo group that approached statistical significance (p = 0.056). Although during the Trier Social Stress Test (TSST; administered post-supplementation) no between-group differences were found on a subjective measure of stress responsivity (Visual Analog Scale), there was a significantly larger increase in mean heart beats per minute between baseline and the math task for the placebo group as compared with the probiotic group (estimated mean change, probiotic 5.3 [95% Confidence Interval: -0.55, 11.0], placebo 16.9 [11.0, 22.7], p = 0.006). Conclusions: Findings from this trial support the feasibility, acceptability, and safety of supplementation with an anti-inflammatory/immunoregulatory probiotic, L. reuteri DSM 17938, among Veterans with PPC and PTSD symptoms. Moreover, results suggest that CRP may be a viable inflammatory marker of interest. A larger randomized controlled trial aimed at measuring both biological and clinical outcomes is indicated. Clinical Trial Registration: ClinicalTrials.gov, Identifier NCT02723344.

Microbial Diversity and Community Structures Among Those With Moderate to Severe TBI: A United States-Veteran Microbiome Project Study.

OBJECTIVE: To evaluate the association between distal moderate/severe traumatic brain injury (TBI) history and the human gut microbiome. SETTING: Veterans Affairs Medical Center. PARTICIPANTS: Veterans from the United States-Veteran Microbiome Project (US-VMP). Veterans with moderate/severe TBI (n = 34) were compared with (1) Veterans with a history of no TBI (n = 79) and (2) Veterans with a history of no TBI or mild TBI only (n = 297). DESIGN: Microbiome analyses from 16S rRNA gene sequencing with gut microbiota function inferred using PICRUSt2. MAIN MEASURES: α-Diversity and ß-diversity of the gut microbiome, as well as taxonomic and functional signatures associated with moderate/severe TBI. RESULTS: There were no significant differences in gut bacterial α- and ß-diversity associated with moderate/severe TBI status. No differentially abundant taxa were identified when comparing samples from moderate/severe TBI to those with no TBI or no TBI/mild TBI. CONCLUSION: Results suggest that moderate/severe TBI-related changes to the gut microbiome do not persist for years postinjury.

Association of the Salivary Microbiome With Animal Contact During Early Life and Stress-Induced Immune Activation in Healthy Participants.

The prevalence of stress-associated somatic and psychiatric disorders is increased in environments offering a narrow relative to a wide range of microbial exposure. Moreover, different animal and human studies suggest that an overreactive immune system not only accompanies stress-associated disorders, but might even be causally involved in their pathogenesis. In support of this hypothesis, we recently showed that urban upbringing in the absence of daily contact with pets, compared to rural upbringing in the presence of daily contact with farm animals, is associated with a more pronounced immune activation following acute psychosocial stressor exposure induced by the Trier Social Stress Test (TSST). Here we employed 16S rRNA gene sequencing to test whether this difference in TSST-induced immune activation between urban upbringing in the absence of daily contact with pets (n = 20) compared with rural upbringing in the presence of daily contact with farm animals (n = 20) is associated with differences in the composition of the salivary microbiome. Although we did not detect any differences in alpha or beta diversity measures of the salivary microbiome between the two experimental groups, statistical analysis revealed that the salivary microbial beta diversity was significantly higher in participants with absolutely no animal contact (n = 5, urban participants) until the age of 15 compared to all other participants (n = 35) reporting either daily contact with farm animals (n = 20, rural participants) or occasional pet contact (n = 15, urban participants). Interestingly, when comparing these urban participants with absolutely no pet contact to the remaining urban participants with occasional pet contact, the former also displayed a significantly higher immune, but not hypothalamic-pituitary-adrenal (HPA) axis or sympathetic nervous system (SNS) activation, following TSST exposure. In summary, we conclude that only urban upbringing with absolutely no animal contact had long-lasting effects on the composition of the salivary microbiome and potentiates the negative consequences of urban upbringing on stress-induced immune activation.

Effects of Immunization With the Soil-Derived Bacterium Mycobacterium vaccae on Stress Coping Behaviors and Cognitive Performance in a "Two Hit" Stressor Model.

Previous studies demonstrate that Mycobacterium vaccae NCTC 11659 (M. vaccae), a soil-derived bacterium with anti-inflammatory and immunoregulatory properties, is a potentially useful countermeasure against negative outcomes to stressors. Here we used male C57BL/6NCrl mice to determine if repeated immunization with M. vaccae is an effective countermeasure in a "two hit" stress exposure model of chronic disruption of rhythms (CDR) followed by acute social defeat (SD). On day -28, mice received implants of biotelemetric recording devices to monitor 24-h rhythms of locomotor activity. Mice were subsequently treated with a heat-killed preparation of M. vaccae (0.1 mg, administered subcutaneously on days -21, -14, -7, and 27) or borate-buffered saline vehicle. Mice were then exposed to 8 consecutive weeks of either stable normal 12:12 h light:dark (LD) conditions or CDR, consisting of 12-h reversals of the LD cycle every 7 days (days 0-56). Finally, mice were exposed to either a 10-min SD or a home cage control condition on day 54. All mice were exposed to object location memory testing 24 h following SD. The gut microbiome and metabolome were assessed in fecal samples collected on days -1, 48, and 62 using 16S rRNA gene sequence and LC-MS/MS spectral data, respectively; the plasma metabolome was additionally measured on day 64. Among mice exposed to normal LD conditions, immunization with M. vaccae induced a shift toward a more proactive behavioral coping response to SD as measured by increases in scouting and avoiding an approaching male CD-1 aggressor, and decreases in submissive upright defensive postures. In the object location memory test, exposure to SD increased cognitive function in CDR mice previously immunized with M. vaccae. Immunization with M. vaccae stabilized the gut microbiome, attenuating CDR-induced reductions in alpha diversity and decreasing within-group measures of beta diversity. Immunization with M. vaccae also increased the relative abundance of 1-heptadecanoyl-sn-glycero-3-phosphocholine, a lysophospholipid, in plasma. Together, these data support the hypothesis that immunization with M. vaccae stabilizes the gut microbiome, induces a shift toward a more proactive response to stress exposure, and promotes stress resilience.

Longitudinal homogenization of the microbiome between both occupants and the built environment in a cohort of United States Air Force Cadets.

BACKGROUND: The microbiome of the built environment has important implications for human health and wellbeing; however, bidirectional exchange of microbes between occupants and surfaces can be confounded by lifestyle, architecture, and external environmental exposures. Here, we present a longitudinal study of United States Air Force Academy cadets (n = 34), which have substantial homogeneity in lifestyle, diet, and age, all factors that influence the human microbiome. We characterized bacterial communities associated with (1) skin and gut samples from roommate pairs, (2) four built environment sample locations inside the pairs' dormitory rooms, (3) four built environment sample locations within shared spaces in the dormitory, and (4) room-matched outdoor samples from the window ledge of their rooms. RESULTS: We analyzed 2,170 samples, which generated 21,866 unique amplicon sequence variants. Linear convergence of microbial composition and structure was observed between an occupants' skin and the dormitory surfaces that were only used by that occupant (i.e., desk). Conversely, bacterial community beta diversity (weighted Unifrac) convergence between the skin of both roommates and the shared dormitory floor between the two cadet's beds was not seen across the entire study population. The sampling period included two semester breaks in which the occupants vacated their rooms; upon their return, the beta diversity similarity between their skin and the surfaces had significantly decreased compared to before the break (p < 0.05). There was no apparent convergence between the gut and building microbiota, with the exception of communal bathroom door-handles, which suggests that neither co-occupancy, diet, or lifestyle homogenization had a significant impact on gut microbiome similarity between these cadets over the observed time frame. As a result, predictive classifier models were able to identify an individual more accurately based on the gut microbiota (74%) compared to skin (51%). CONCLUSIONS: To the best of our knowledge, this is the first study to show an increase in skin microbial similarity of two individuals who start living together for the first time and who are not genetically related or romantically involved. Cohabitation was significantly associated with increased skin microbiota similarity but did not significantly influence the gut microbiota. Following a departure from the occupied space of several weeks, the skin microbiota, but not the gut microbiota, showed a significant reduction in similarity relative to the building. Overall, longitudinal observation of these dynamics enables us to dissect the influence of occupation, diet, and lifestyle factors on occupant and built environment microbial ecology.

Military-Related Exposures, Social Determinants of Health, and Dysbiosis: The United States-Veteran Microbiome Project (US-VMP).

Significant effort has been put forth to increase understanding regarding the role of the human microbiome in health- and disease-related processes. In turn, the United States (US) Veteran Microbiome Project (US-VMP) was conceptualized as a means by which to serially collect microbiome and health-related data from those seeking care within the Veterans Health Administration (VHA). In this manuscript, exposures related to military experiences, as well as conditions and health-related factors among patients seen in VHA clinical settings are discussed in relation to common psychological and physical outcomes. Upon enrollment in the study, Veterans complete psychometrically sound (i.e., reliable and valid) measures regarding their past and current medical history. Participants also provide skin, oral, and gut microbiome samples, and permission to track their health status via the VHA electronic medical record. To date, data collection efforts have been cross-diagnostic. Within this manuscript, we describe current data collection practices and procedures, as well as highlight demographic, military, and psychiatric characteristics of the first 188 Veterans enrolled in the study. Based on these findings, we assert that this cohort is unique as compared to those enrolled in recent large-scale studies of the microbiome. To increase understanding regarding disease and health among diverse cohorts, efforts such as the US-VMP are vital. Ongoing barriers and facilitators to data collection are discussed, as well as future research directions, with an emphasis on the importance of shifting current thinking regarding the microbiome from a focus on normalcy and dysbiosis to health promotion and disease prevention.

Exploring service dogs for rehabilitation of veterans with PTSD: A microbiome perspective.

PURPOSE/OBJECTIVE: Recently, there has been an increase in the use of therapy animals, often dogs, to assist individuals with challenges associated with managing stressful social situations (i.e., psychological rehabilitation). Potential applications are wide-ranging from elementary schools to airports to hospitals. Here we present an overview of the present knowledge and provide recommendations for future research aimed at exploring the impact of therapy dogs on the rehabilitation of Veterans with posttraumatic stress disorder (PTSD) with a focus on the microbiome. Research Method/Design: In this review we searched the literature for studies that were conducted involving Veterans and service dogs. Because of the limited number of studies, we conducted a nonsystematic review to include the topics of the microbiome and psychological mechanisms that may play a role in rehabilitation of Veterans with dogs. RESULTS: Whether dogs can be used as an intervention to increase function among those with PTSD remains a question. Nonetheless, it has been suggested that dog ownership may improve mental health outcomes via multiple mechanisms, such as decreasing social isolation and increasing physical activity and exposure to green spaces. The presence of a dog in the home may alter the human inhabitants' microbiomes, thereby, potentially providing an additional mechanism through which service dogs may influence human health and well-being. CONCLUSIONS/IMPLICATIONS: Theoretically, the use of service dogs for rehabilitation of Veterans with PTSD could improve mental health outcomes. To the best of our knowledge the impact that therapy dogs have on the microbiome of the owners, as well as their built environments, has yet to be explored. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Differential anxiety-like responses in NOD/ShiLtJ and C57BL/6J mice following experimental autoimmune encephalomyelitis induction and oral gavage.

Oral gavage is commonly used in pre-clinical drug evaluation, but is potentially aversive and may induce behavioral effects independent of compounds under investigation. This study examined the combined effects of repeated oral gavage and disease induction on anxiety-like behavior in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. The C57BL/6J and NOD/ShiLtJ EAE variants were exposed to sham-EAE induction or untreated control conditions, and either daily oral gavage or home cage conditions. Anxiety-like behavior was subsequently assessed in the elevated plus maze. C57BL/6J mice exhibited increased anxiety-like behavior, relative to NOD/ShiLtJ mice, in response to repeated gavage, whereas sham-EAE induction and repeated gavage were associated with increased anxiety-like behavior in NOD/ShiLtJ mice. Thus, exposure to the induction procedure and repeated gavage differentially altered subsequent anxiety-like behavior in the two EAE variants. Future pre-clinical studies should rely on prior evaluation of parameters of the experimental design using sham-EAE mice. Additionally, less aversive administration routes should be utilized wherever possible to ensure that procedures do not distort effects of the therapeutic under investigation.

The Microbiome in Posttraumatic Stress Disorder and Trauma-Exposed Controls: An Exploratory Study.

OBJECTIVE: Inadequate immunoregulation and elevated inflammation may be risk factors for posttraumatic stress disorder (PTSD), and microbial inputs are important determinants of immunoregulation; however, the association between the gut microbiota and PTSD is unknown. This study investigated the gut microbiome in a South African sample of PTSD-affected individuals and trauma-exposed (TE) controls to identify potential differences in microbial diversity or microbial community structure. METHODS: The Clinician-Administered PTSD Scale for DSM-5 was used to diagnose PTSD according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Microbial DNA was extracted from stool samples obtained from 18 individuals with PTSD and 12 TE control participants. Bacterial 16S ribosomal RNA gene V3/V4 amplicons were generated and sequenced. Microbial community structure, α-diversity, and ß-diversity were analyzed; random forest analysis was used to identify associations between bacterial taxa and PTSD. RESULTS: There were no differences between PTSD and TE control groups in α- or ß-diversity measures (e.g., α-diversity: Shannon index, t = 0.386, p = .70; ß-diversity, on the basis of analysis of similarities: Bray-Curtis test statistic = -0.033, p = .70); however, random forest analysis highlighted three phyla as important to distinguish PTSD status: Actinobacteria, Lentisphaerae, and Verrucomicrobia. Decreased total abundance of these taxa was associated with higher Clinician-Administered PTSD Scale scores (r = -0.387, p = .035). CONCLUSIONS: In this exploratory study, measures of overall microbial diversity were similar among individuals with PTSD and TE controls; however, decreased total abundance of Actinobacteria, Lentisphaerae, and Verrucomicrobia was associated with PTSD status.