Andrew J. Hoisington

The Microbiota, Immunoregulation, and Mental Health: Implications for Public Health

The hygiene or “Old Friends” hypothesis proposes that the epidemic of inflammatory disease in modern urban societies stems at least in part from reduced exposure to microbes that normally prime mammalian immunoregulatory circuits and suppress inappropriate inflammation. Such diseases include but are not limited to allergies and asthma; we and others have proposed that the markedly reduced exposure to these Old Friends in modern urban societies may also increase vulnerability to neurodevelopmental disorders and stress-related psychiatric disorders, such as anxiety and affective disorders, where data are emerging in support of inflammation as a risk factor. Here, we review recent advances in our understanding of the potential for Old Friends, including environmental microbial inputs, to modify risk for inflammatory disease, with a focus on neurodevelopmental and psychiatric conditions. We highlight potential mechanisms, involving bacterially derived metabolites, bacterial antigens, and helminthic antigens, through which these inputs promote immunoregulation. Though findings are encouraging, significant human subjects’ research is required to evaluate the potential impact of Old Friends, including environmental microbial inputs, on biological signatures and clinically meaningful mental health prevention and intervention outcomes.

The microbiome of the built environment and mental health

The microbiome of the built environment (MoBE) is a relatively new area of study. While some knowledge has been gained regarding impacts of the MoBE on the human microbiome and disease vulnerability, there is little knowledge of the impacts of the MoBE on mental health. Depending on the specific microbial species involved, the transfer of microorganisms from the built environment to occupant’s cutaneous or mucosal membranes has the potential to increase or disrupt immunoregulation and/or exaggerate or suppress inflammation. Preclinical evidence highlighting the influence of the microbiota on systemic inflammation supports the assertion that microorganisms, including those originating from the built environment, have the potential to either increase or decrease the risk of inflammation-induced psychiatric conditions and their symptom severity. With advanced understanding of both the ecology of the built environment, and its influence on the human microbiome, it may be possible to develop bioinformed strategies for management of the built environment to promote mental health. Here we present a brief summary of microbiome research in both areas and highlight two interdependencies including the following: (1) effects of the MoBE on the human microbiome and (2) potential opportunities for manipulation of the MoBE in order to improve mental health. In addition, we propose future research directions including strategies for assessment of changes in the microbiome of common areas of built environments shared by multiple human occupants, and associated cohort-level changes in the mental health of those who spend time in the buildings. Overall, our understanding of the fields of both the MoBE and influence of host-associated microorganisms on mental health are advancing at a rapid pace and, if linked, could offer considerable benefit to health and wellness.

Characterizing the Bacterial Communities in Retail Stores in the United States

The microorganisms present in retail environments have not been studied in detail despite the fact that these environments represent a potentially important location for exposure. In this study, HVAC filter dust samples in 13 US retail stores were collected and analyzed via pyrosequencing to characterize the indoor bacterial communities and to explore potential relationships between these communities and building and environmental parameters. Although retail stores contained a diverse bacterial community of 788 unique genera, over half of the nearly 118K sequences were attributed to the Proteobacteria phylum. Streptophyta, Bacillus, Corynebacterium, Pseudomonas, and Acinetobacter were the most prevalent genera detected. The recovered indoor airborne microbial community was statistically associated with both human oral and skin microbiota, indicating occupants are important contributors, despite a relatively low occupant density per unit volume in retail stores. Bacteria generally associated with outdoor environments were present in the indoor communities with no obvious association with air exchange rate, even when considering relative abundance. No significant association was observed between the indoor bacterial community recovered and store location, store type, or season. However, predictive functional gene profiling showed significant associations between the indoor community and season. The microbiome recovered from multiple samples collected months apart from the same building varied significantly indicating that caution is warranted when trying to characterize the bacterial community with a single sampling event.

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, &agr;-diversity, and &bgr;-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 &agr;- or &bgr;-diversity measures (e.g., &agr;-diversity: Shannon index, t = 0.386, p = .70; &bgr;-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.

Kynurenine and Tryptophan Levels in Patients with Schizophrenia and Elevated Antigliadin Immunoglobulin G Antibodies

Objective Several studies have reported an association between nonceliac gluten sensitivity and schizophrenia. Immune and kynurenine (KYN) pathways have also been implicated in the pathophysiology of schizophrenia, and certain proinflammatory immune mediators may increase KYN and reduce tryptophan (TRP) levels. Methods We measured serum antigliadin immunoglobulin G (IgG), KYN, and TRP in 950 patients with schizophrenia. Patients with antibody level at the 90th percentile or higher of control participants (21.9% of all patients) were classified as having elevated antigliadin IgG. Independent t tests and linear regression models were used to compare TRP, KYN, and KYN-TRP ratio (indicator of TRP metabolism) between patients with and those without elevated antigliadin IgG. The correlation between antigliadin IgG and TRP, KYN, and the ratio was also evaluated in the patients. Results KYN and KYN-TRP ratio were higher in patients with elevated antigliadin IgG (geometric mean [standard deviation {SD}] = 2.65 [0.25] µmol/L versus 2.25 [0.23] µmol/L [p < .001] and 0.05 [0.26] versus 0.04 [0.25; p = .001] respectively), findings robust to adjustment for potential demographic and clinical confounders. Antigliadin IgG positively correlated with KYN and KYN-TRP ratio (r = 0.12, p < .001; r = 0.11, p = .002). TRP did not differ between the two groups and did not correlate with antigliadin IgG. Conclusions Our results connect nonceliac gluten sensitivity with the KYN pathway of TRP metabolism in psychotic illness and hint toward potential individualized treatment targets.

Exploring the microbiome of the built environment: A primer on four biological methods available to building professionals

Building professionals are increasingly being called upon to conduct indoor microbial investigations as they remediate moisture-damaged buildings and design new, healthy, sustainable buildings. Characterizing the indoor microbial community present in the built environment is challenging and complicated by the vast array of biological methods available to building professionals. Furthermore, the particular biological technique employed to study an indoor environment can have a significant impact on the results obtained. This study evaluates the advantages and disadvantages of four biological methods suitable for indoor microbial investigations: culturing, quantitative polymerase chain reaction (qPCR), Sanger sequencing, and pyrosequencing. The results obtained from a study of four buildings are used to evaluate the merits of each bioanalytical approach. In each of the four study sites, the microbial-laden dust recovered on HVAC filters was used to provide a passive, long-term sample of the indoor air. Culturing of the microorganisms recovered from the dust was the least expensive method tested but provided a limited characterization of the microbial community present. qPCR provided the most specific information about the presence and quantity of target microorganisms but this method requires a priori knowledge of the species of interest and specifically designed primers that may not enumerate unanticipated species. Sanger sequencing provided microbial identification at the species level but lacked coverage to fully describe the microbial community present. Pyrosequencing provided in-depth sequence coverage of the microbial community present (to the genus level) but the vast dataset generated required increased computational analysis and data storage. Nevertheless, pyrosequencing when coupled with qPCR for target species quantification represents a viable approach that should become more accessible to building professionals as user-friendly software for analyzing sequencing results becomes available and more commercial laboratories offer these services.

Mental Health in Allergic Rhinitis: Depression and Suicidal Behavior

Opinion statementA high proportion of suicides visit their medical provider in the month prior to death, but depression, suicidal thoughts, and substance use are seldom addressed. For the clinicians routinely treating a substantial patient population with allergic diseases, there are additional concerns, as allergy has been linked with both depression and suicidal behavior. While psychotropic medications may affect diagnosis of allergies, medications used to treat allergies impact mood and behavior. Thus, we present an overview of the overlap of allergic rhinitis with depression and suicidal behavior in adults, based on clinical and epidemiological data, and our research and clinical experience. In summary, we suggest: (1) inquiring among patients with allergies about personal and family history of depression, substance use disorders, suicidal ideation, and attempts; (2) increased mindfulness regarding the potential effects of allergy medications on mood and behavior; and (3) for people identified with certain types of depression or increased suicide risk, a systematic multilevel collaborative approach. While, for practical reasons the majority of patients with depression will continue to be treated by general or family practitioners, the allergy-treating provider should always consider integrated care for bipolar, psychotic, or suicidal depression and incomplete remission, or relapsing and highly recurrent course. While awaiting results of a much needed basic and clinical research to guide the clinical approach to patients with comorbid allergic rhinitis and depression, the simple steps recommended here are expected to lead to improved clinical outcomes in depression, and, perhaps, contributing to lowering the highly resilient suicide mortality.Learning objectives: a) Present overlaps between allergy, allergen exposure, depression, and suicidal behavior in adults and b) Familiarize allergists with the principles of diagnosis and treatment of depression in adults and importance to monitor suicide risk.

Heritability of plasma neopterin levels in the Old Order Amish

BACKGROUND We examined the heritability of neopterin, a biomarker for cell-mediated immunity and oxidative stress, and potentially for psychiatric disorders, in the Old Order Amish. METHODS Plasma neopterin levels were determined in 2015 Old Order Amish adults. Quantitative genetic procedures were used to estimate heritability of neopterin. RESULTS Heritability of log-neopterin was estimated at 0.07 after adjusting for age, gender, and household (p=0.03). The shared household effect was 0.06 (p<0.02). CONCLUSIONS We found a low heritability of neopterin and small household effect, suggesting that non-household environmental factors are more important determinants of variance of neopterin levels in the Amish.

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.