Deciphering the 'gut-brain axis' through microbiome diversity.

Incentivised by breakthroughs and data generated by the high-throughput sequencing technology, this paper proposes a distance-based framework to fulfil the emerging needs in elucidating insights from the high-dimensional microbiome data in psychiatric studies. By shifting focus from traditional methods that focus on the observations from each subject to the between-subject attributes that aggregate two or more subjects' entire feature vectors, the described approach revolutionises the conventional prescription for high-dimensional observations via microbiome diversity. To this end, we enrich the classical generalised linear models to articulate the multivariable regression relationship between distance-based variables. We also discuss a robust and computationally feasible semiparametric inference technique. Benefitting from the latest advances in the semiparametric efficiency theory for such attributes, the proposed estimators enjoy robustness and good asymptotic properties that guarantee sensitivity in detecting signals between clinical outcomes and microbiome diversity. It offers a readily implementable and easily interpretable solution for deciphering the gut-brain axis in mental health research.

The Microbiome and Mental Health Across the Lifespan.

INTRODUCTION: The combined genetic material of the microorganisms in the human body, known as the microbiome, is being increasingly recognized as a major determinant of human health and disease. Although located predominantly on mucosal surfaces, these microorganisms have profound effects on brain functioning through the gut-brain axis. METHOD: The content of the chapter is based on a study group session at the annual meeting of the American College of Neuropsychopharmacology (ACNP). The objective was to discuss the emerging relationship between the human microbiome and mental health as relevant to ACNP's interests in developing and evaluating novel neuropsychiatric treatment strategies. The focus is on specific brain disorders, such as schizophrenia, substance use, and Alzheimer's disease, as well as on broader clinical issues such as suicidality, loneliness and wisdom in old age, and longevity. RESULTS: Studies of schizophrenia indicate that the microbiome of individuals with this disorder differs from that of non-psychiatric comparison groups in terms of diversity and composition. Differences are also found in microbial metabolic pathways. An early study in substance use disorders found that individuals with this disorder have lower levels of beta diversity in their oral microbiome than a comparison group. This measure, along with others, was used to distinguish individuals with substance use disorders from controls. In terms of suicidality, there is preliminary evidence that persons who have made a suicide attempt differ from psychiatric and non-psychiatric comparison groups in measures of beta diversity. Exploratory studies in Alzheimer's disease indicate that gut microbes may contribute to disease pathogenesis by regulating innate immunity and neuroinflammation and thus influencing brain function. In another study looking at the microbiome in older adults, positive associations were found between wisdom and alpha diversity and negative associations with subjective loneliness. In other studies of older adults, here with a focus on longevity, individuals with healthy aging and unusually long lives had an abundance of specific microorganisms which distinguished them from other individuals. DISCUSSION: Future studies would benefit from standardizing methods of sample collection, processing, and analysis. There is also a need for the standardized collection of relevant demographic and clinical data, including diet, medications, cigarette smoking, and other potentially confounding factors. While still in its infancy, research to date indicates a role for the microbiome in mental health disorders and conditions. Interventions are available which can modulate the microbiome and lead to clinical improvements. These include microbiome-altering medications as well as probiotic microorganisms capable of modulating the inflammation in the brain through the gut-brain axis. This research holds great promise in terms of developing new methods for the prevention and treatment of a range of human brain disorders.

Peripheral inflammation levels associated with degree of advanced brain aging in schizophrenia.

Brain structural abnormalities have been demonstrated in schizophrenia (SZ); these resemble those seen in typical aging, but are seen at younger ages. Furthermore, SZ is associated with accelerated global brain aging, as measured by brain structure-based brain predicted age difference (Brain-PAD). High heterogeneity exists in the degree of brain abnormalities in SZ, and individual differences may be related to levels of peripheral inflammation and may relate to cognitive deficits and negative symptoms. The goal of our study was to investigate the relationship between brain aging, peripheral inflammation, and symptoms of SZ. We hypothesized older brain-PAD in SZ vs. healthy comparison (HC) participants, as well as positive relationships of brain-PAD with peripheral inflammation markers and symptoms in SZ. We analyzed data from two cross-sectional studies in SZ (n = 26; M/F: 21/5) and HC (n = 28; 20/8) (22-64 years). Brain-PAD was calculated using a previously validated Gaussian process regression model applied to raw T1-weighted MRI data. Plasma levels of inflammatory biomarkers (CRP, Eotaxin, Fractalkine, IP10, IL6, IL10, ICAM1, IFNγ, MCP1, MIP1ß, SAA, TNFα, VEGF, VCAM1) and cognitive and negative symptoms were assessed. We observed a higher brain-PAD in SZ vs. HC, and advanced brain age relative to chronological age was related to higher peripheral levels of TNFα in the overall group and in the SZ group; other inflammatory markers were not related to brain-PAD. Within the SZ group, we observed no association between cognitive or negative symptoms and brain-PAD. These results support our hypothesis of advanced brain aging in SZ. Furthermore, our findings on the relationship of the pro-inflammatory cytokine TNFα with higher brain-PAD of SZ are relevant to explain heterogeneity of brain ages in SZ, but we did not find strong evidence for cognitive or negative symptom relationships with brain-PAD.

Associations between inflammatory marker profiles and neurocognitive functioning in people with schizophrenia and non-psychiatric comparison subjects.

BACKGROUND: Cognitive dysfunction in schizophrenia is the key predictor of functional disability and drives economic burden. Inflammation has been increasingly implicated in the pathogenesis of schizophrenia, yet its role in cognitive decline has not been evaluated. This study explores the association between inflammation and cognitive functioning in persons with schizophrenia. METHODS: Participants included 143 persons with schizophrenia (PwS) and 139 non-psychiatric comparison subjects (NCs) from an ongoing study of aging. Cognitive assessments included validated measures for executive functioning, processing speed, and visuospatial skills. Plasma levels of nine biomarkers associated with inflammation (high sensitivity C-reactive protein, intercellular adhesion molecule 1, serum amyloid A, interleukin-6, interleukin-8, interferon gamma-induced protein-10, monocyte chemotactic protein-1, fractalkine, and brain-derived neurotrophic factor) were quantified using commercially available, enzyme-linked immunosorbent assays. Partial least squares regression was used to develop a composite "inflammatory profile" to maximize correlations with the cognitive outcomes. We then constructed a best-fit model using these composites and their interactions with diagnosis and sex as the predictors, controlling for covariates. RESULTS: The biomarker composite, which best correlated with scores on cognitive testing, included high sensitivity C-reactive protein, intercellular adhesion molecule 1, serum amyloid A, interleukin-6, and brain-derived neurotrophic factor, for a 5-biomarker "inflammatory profile." The best-fit model showed a significant biomarker composite by diagnosis by sex three-way interaction, for executive function and processing speed, but not visuospatial skill. CONCLUSIONS: This approach to building an "inflammatory profile" may provide insight into inflammatory pathways affecting brain function and potential targets for anti-inflammatory interventions to improve cognition in schizophrenia.

The Microbiota-Gut-Brain Axis in Alzheimer's Disease: A Review of Taxonomic Alterations and Potential Avenues for Interventions.

OBJECTIVE: The gut microbiome is a complex community of microorganisms that inhabit the gastrointestinal tract. The microbiota-gut-brain axis encompasses a bidirectional communication system that allows the gut to influence the brain via neural, endocrine, immune, and metabolic signaling. Differences in the gut microbiome have been associated with psychiatric and neurological disorders, including Alzheimer's Disease (ad). Understanding these ad-associated alterations may offer novel insight into the pathology and treatment of ad. METHOD: We conducted a narrative review of clinical studies investigating the gut microbiome in ad, organizing the results by phyla to understand the biological contributions of the gut microbial community to ad pathology and clinical features. We also reviewed randomized clinical trials of interventions targeting the microbiome to ameliorate ad symptoms and biomarkers. RESULTS: Alpha diversity is reduced in patients with ad. Within Firmicutes, taxa that produce beneficial metabolites are reduced in ad, including Clostridiaceae, Lachnospiraceae, Ruminococcus, and Eubacterium. Within Bacteroidetes, findings were mixed, with studies showing either reduced or increased abundance of Bacteroides in mild cognitive impairment or ad patients. Proteobacteria that produce toxins tend to be increased in ad patients, including Escherichia/Shigella. A Mediterranean-ketogenic dietary intervention significantly increased beneficial short-chain fatty acids and taxa that were inversely correlated with changes in ad pathological markers. Probiotic supplementation with Lactobacillus spp. and Bifidobacterium spp. improved cognitive function and reduced inflammatory and metabolic markers in patients with ad. CONCLUSIONS: The gut microbiome may provide insight into ad pathology and be a novel target for intervention. Potential therapeutics include probiotics and dietary intervention.

Partial least squares regression and principal component analysis: similarity and differences between two popular variable reduction approaches.

In many statistical applications, composite variables are constructed to reduce the number of variables and improve the performances of statistical analyses of these variables, especially when some of the variables are highly correlated. Principal component analysis (PCA) and factor analysis (FA) are generally used for such purposes. If the variables are used as explanatory or independent variables in linear regression analysis, partial least squares (PLS) regression is a better alternative. Unlike PCA and FA, PLS creates composite variables by also taking into account the response, or dependent variable, so that they have higher correlations with the response than composites from their PCA and FA counterparts. In this report, we provide an introduction to this useful approach and illustrate it with data from a real study.

Physical and Mental Health Characteristics of 2,962 Adults With Subjective Cognitive Complaints.

We investigated subjective cognitive complaints (SCCs), as well as physical and mental health factors, in adults and older adults. U.S. residents (N = 2,962) were recruited via the Amazon Mechanical Turk platform and completed a 90-item survey. Overall, 493/1930 (25.5%) of younger adults and 278/1032 (26.9%) of older adults endorsed SCCs. Analyses revealed worse physical and mental health characteristics in the SCC+ compared to the SCC- group, with primarily medium (Cohen's d = 0.50) to large (0.80) effect sizes. Age did not moderate relationships between SCCs and physical/mental health. Results suggest that SCCs are associated with a diverse set of negative health characteristics such as poor sleep and high body mass index, and lower levels of positive factors, including happiness and wisdom. Effect sizes of psychological correlates were at least as large as those of physical correlates, indicating that mental health is critical to consider when evaluating SCCs.

Rates of Cognitive and Functional Impairments in Older Adults Residing in a Continuing Care Senior Housing Community.

OBJECTIVE: The current cross-sectional study examined cognition and performance-based functional abilities in a continuing care senior housing community (CCSHC) that is comparable to other CCSHCs in the US with respect to residents' demographic characteristics. METHOD: Participants were 110 older adult residents of the independent living unit. We assessed sociodemographics, mental health, neurocognitive functioning, and functional capacity. RESULTS: Compared to normative samples, participants performed at or above expectations in terms of premorbid functioning, attention span and working memory, processing speed, timed set-shifting, inhibitory control, and confrontation naming. They performed below expectation in verbal fluency and verbal and visual learning and memory, with impairment rates [31.4% (>1 SD below the mean) and 18.49% (>1.5 SD below the mean)] well above the general population (16% and 7%, respectively). Within the cognitive test battery, two tests of delayed memory were most predictive of a global deficit score. Most cognitive test scores correlated with performance-based functional capacity. CONCLUSIONS: Overall, results suggest that a subset of older adults in the independent living sector of CCSHCs are cognitively and functionally impaired and are at risk for future dementia. Results also argue for the inclusion of memory tests in abbreviated screening batteries in this population. We suggest that CCSHCs implement regular cognitive screening procedures to identify and triage those older adults who could benefit from interventions and, potentially, a transition to a higher level of care.

Multi-omics of human plasma reveals molecular features of dysregulated inflammation and accelerated aging in schizophrenia.

Schizophrenia is a devastating psychiatric illness that detrimentally affects a significant portion of the worldwide population. Aging of schizophrenia patients is associated with reduced longevity, but the potential biological factors associated with aging in this population have not yet been investigated in a global manner. To address this gap in knowledge, the present study assesses proteomics and metabolomics profiles in the plasma of subjects afflicted with schizophrenia compared to non-psychiatric control patients over six decades of life. Global, unbiased analyses of circulating blood plasma can provide knowledge of prominently dysregulated molecular pathways and their association with schizophrenia, as well as features of aging and gender in this disease. The resulting data compiled in this study represent a compendium of molecular changes associated with schizophrenia over the human lifetime. Supporting the clinical finding of schizophrenia's association with more rapid aging, both schizophrenia diagnosis and age significantly influenced the plasma proteome in subjects assayed. Schizophrenia was broadly associated with prominent dysregulation of inflammatory and metabolic system components. Proteome changes demonstrated increased abundance of biomarkers for risk of physiologic comorbidities of schizophrenia, especially in younger individuals. These findings advance our understanding of the molecular etiology of schizophrenia and its associated comorbidities throughout the aging process.

The Fecal Microbiome and Metabolome of Pitt Hopkins Syndrome, a Severe Autism Spectrum Disorder.

Alterations to the gut microbiome have been reported between children with autism spectrum disorders (ASDs) and typically developing (TD) children. Characterizing these differences has led to the proposal of new treatments for ASD, such as probiotic interventions and fecal matter transplants. However, no study to date has characterized the gut microbiome or metabolome in Pitt Hopkins syndrome (PTHS), a severe ASD with a high incidence of gastrointestinal (GI) disturbances such as constipation. Here, we surveyed the gut microbiome and metabolome in a cohort of PTHS individuals and their unaffected parents. We focused our analysis on Clostridium bolteae, a microbe previously associated with ASD known to chemically modify bile acids in the gut. PTHS individuals carry a higher load of C. bolteae than their parents as well as both ASD and non-ASD individuals from the American Gut Project cohort. Specific metabolites were associated with PTHS, including bile acids and sphingosines. With a metadata reanalysis tool, we found that PTHS-associated metabolites have previously been identified in inflammatory bowel disease and obesity patients. These results suggest microbial involvement in PTHS, but further research must be performed to clarify the exact mechanisms through which microbes may act. Furthermore, new associations between PTHS-specific metabolites and other conditions may lead to additional therapeutic options for PTHS individuals. IMPORTANCE GI disturbances in ASD such as severe constipation can be medically significant and often require medication. This is especially true for individuals with PTHS, suggesting that the gut microbiome may be involved in PTHS's pathology. Revealing associations between specific gut microbes and PTHS may allow the development of new therapeutics or the application of existing therapeutics to ease day-to-day challenges encountered by PTHS individuals. In this study, we characterized an association between C. bolteae and PTHS, in addition to metabolites linked to both PTHS and C. bolteae. We also identified other microbiome-involved medical conditions where PTHS-associated metabolites have been isolated. Utilizing common metabolites to identify conditions with similar phenotypes may suggest new therapeutic options for GI-related symptoms.

Ageism: The Brain Strikes Back.

Our authors, who study successful aging and mental illnesses at the University of California, San Diego, address the often debated, complicated question that many of us have long wondered about: Does the brain improve with age?

Neurobiology of loneliness: a systematic review.

Loneliness is associated with increased morbidity and mortality. Deeper understanding of neurobiological mechanisms underlying loneliness is needed to identify potential intervention targets. We did not find any systematic review of neurobiology of loneliness. Using MEDLINE and PsycINFO online databases, we conducted a search for peer-reviewed publications examining loneliness and neurobiology. We identified 41 studies (n = 16,771 participants) that had employed various methods including computer tomography (CT), structural magnetic resonance imaging (MRI), functional MRI (fMRI), electroencephalography (EEG), diffusion tensor imaging (DTI), single-photon emission computed tomography (SPECT), positron emission tomography (PET), and post-mortem brain tissue RNA analysis or pathological analysis. Our synthesis of the published findings shows abnormal structure (gray matter volume or white matter integrity) and/or activity (response to pleasant versus stressful images in social versus nonsocial contexts) in the prefrontal cortex (especially medial and dorsolateral), insula (particularly anterior), amygdala, hippocampus, and posterior superior temporal cortex. The findings related to ventral striatum and cerebellum were mixed. fMRI studies reported links between loneliness and differential activation of attentional networks, visual networks, and default mode network. Loneliness was also related to biological markers associated with Alzheimer's disease (e.g., amyloid and tau burden). Although the published investigations have limitations, this review suggests relationships of loneliness with altered structure and function in specific brain regions and networks. We found a notable overlap in the regions involved in loneliness and compassion, the two personality traits that are inversely correlated in previous studies. We have offered recommendations for future research studies of neurobiology of loneliness.

Association of Loneliness and Wisdom With Gut Microbial Diversity and Composition: An Exploratory Study.

Loneliness and wisdom have opposite effects on health and well-being. Loneliness is a serious public health problem associated with increased morbidity and mortality. Wisdom is associated with better health and well-being. We have consistently found a strong negative correlation between loneliness and wisdom. The present study aimed to investigate the association of loneliness and wisdom with the gut microbiome. One hundred eighty-four community-dwelling adults (28-97 years) completed validated self-report-based measures of loneliness, wisdom, compassion, social support, and social engagement. Fecal samples were collected and profiled using 16S rRNA sequencing. Linear regression analyses, controlling for age and body mass index, revealed that lower levels of loneliness and higher levels of wisdom, compassion, social support, and social engagement were associated with greater phylogenetic richness and diversity of the gut microbiome. Partial least squares (PLS) analysis to investigate multivariate relationships extracted two composite variables. Linear regression model predicting alpha-diversity with PLS components revealed that a linear combination of all psychosocial predictors (with negative loading for loneliness and positive loadings for all others, including wisdom, compassion, social support, and social engagement) was significantly associated with alpha-diversity. For beta-diversity, compassion and wisdom accounted for a significant proportion of variance in overall microbial community composition. Findings may have implications for interventions to reduce loneliness and possibly its health-related adverse consequences. Future research should explore whether increasing compassion and wisdom may improve loneliness and overall well-being as well as microbial diversity.

Chemokine MCP1 is associated with cognitive flexibility in schizophrenia: A preliminary analysis.

BACKGROUND: Peripheral levels of pro-inflammatory biomarkers have been shown to be altered in schizophrenia (SZ) and associated with cognitive impairments, but their relevance to specific cognitive domains remains unclear. METHODS: Plasma levels of cytokines, chemokines, and vascular biomarkers were quantified and compared between SZ and healthy comparison (HC) groups. Cognition was assessed using the Delis-Kaplan Executive Function System Trail Making (TM) and Color Word Interference (CWI) tests. Linear regression analyses examined differential relationships of inflammatory biomarkers with executive function between groups. RESULTS: Plasma levels of TNFα, ICAM1, and MCP1 were higher in individuals with SZ compared to HCs. Higher level of MCP1 was associated with increased CWI Inhibition Switching Errors in SZ but not HCs. CONCLUSION: Like other studies, we found evidence for increased peripheral inflammation in SZ. We also showed that SZ with particularly high MCP1 levels had poor cognitive flexibility. Interventions to reduce chemokine elevations might prove beneficial for cognitive performance.

Exposure to Epstein Barr virus and cognitive functioning in individuals with schizophrenia.

Cognitive deficits are a central feature of schizophrenia whose etiology is not fully understood. Epstein Barr Virus (EBV) is a potentially neurotropic infectious agent that can generate persistent infections with immunomodulatory effects. Previous studies have found an association between EBV antibodies and cognitive functioning in different populations, but there has been limited investigation in schizophrenia. In this study, 84 individuals with schizophrenia were administered a comprehensive neuropsychological battery, the MATRICS Consensus Cognitive Battery (MCCB). Participants also provided a blood sample, from which antibodies to the EBV whole virion and specific proteins were measured. Multivariate models were constructed to determine the association between these antibodies and cognitive performance on the MCCB overall and domain scores. Using these models, we found a significant association between the MCCB overall percent composite score and level of antibodies to the EBV Nuclear Antigen-1 (EBNA-1) protein, the Viral Capsid Antigen (VCA) protein, and the EBV whole virion. A significant association was also found for the MCCB social cognition domain with the level of antibodies to the EBV Nuclear Antigen-1 (EBNA-1) protein, the Viral Capsid Antigen (VCA) protein, and the EBV whole virion. In all cases, a higher level of antibodies was associated with a lower level cognitive performance. These findings suggest that exposure to EBV may contribute to cognitive deficits in schizophrenia, a finding which may have implications for new methods of prevention and treatment.

Gut microbiome in serious mental illnesses: A systematic review and critical evaluation.

Schizophrenia and bipolar disorder (BD) are associated with debilitating psychiatric and cognitive dysfunction, worse health outcomes, and shorter life expectancies. The pathophysiological understanding of and therapeutic resources for these neuropsychiatric disorders are still limited. Humans harbor over 1000 unique bacterial species in our gut, which have been linked to both physical and mental/cognitive health. The gut microbiome is a novel and promising avenue to understand the attributes of psychiatric diseases and, potentially, to modify them. Building upon our previous work, this systematic review evaluates the most recent evidence of the gut microbiome in clinical populations with serious mental illness (SMI). Sixteen articles that met our selection criteria were reviewed, including cross-sectional cohort studies and longitudinal treatment trials. All studies reported alterations in the gut microbiome of patients with SMI compared to non-psychiatric comparison subjects (NCs), and beta-diversity was consistently reported to be different between schizophrenia and NCs. Ruminococcaceae and Faecalibacterium were relatively decreased in BD, and abundance of Ruminococcaceae was reported across several investigations of SMI to be associated with better clinical characteristics. Lactic acid bacteria were relatively more abundant in SMI and associated with worse clinical outcomes. There was very limited evidence for the efficacy of probiotic or prebiotic interventions in SMI. As microbiome research in psychiatry is still nascent, the extant literature has several limitations. We critically evaluate the current data, including experimental approaches. There is a need for more unified methodological standards in order to arrive at robust biological understanding of microbial contributions to SMI.

Study of loneliness and wisdom in 482 middle-aged and oldest-old adults: a comparison between people in Cilento, Italy and San Diego, USA.

OBJECTIVES: There has been growing research interest in loneliness and wisdom in recent decades, but no cross-cultural comparisons of these constructs using standardized rating measures in older adults, especially the oldest-old. This was a cross-sectional study of loneliness and wisdom comparing middle-aged and oldest-old adults in Cilento, Italy and San Diego, United States. METHOD: We examined loneliness and wisdom, using the UCLA Loneliness Scale Version 3 (UCLA-3) and San Diego Wisdom Scale (SD-WISE), respectively, in four subject groups: adults aged 50-65 and those ≥90 years from Cilento, Italy (N = 212 and 47, respectively) and San Diego, California, USA (N = 138 and 85, respectively). RESULTS: After controlling for education, there were no significant group differences in levels of loneliness, while on SD-WISE the Cilento ≥90 group had lower scores compared to the other three groups. There was a strong inverse correlation between loneliness and wisdom in each of the four subject groups. Loneliness was negatively associated while wisdom was positively associated with general health, sleep quality, and happiness in most groups, with varying levels of significance. CONCLUSION: These results largely support cross-cultural validity of the constructs of loneliness and wisdom, and extend previous findings of strong inverse correlations between these two entities. Loneliness has become a growing public health problem, and the results of our study suggest that wisdom could be a protective factor against loneliness, although alternative explanations are also possible. Research on interventions to reduce loneliness by enhancing wisdom in older adults is needed.