Gut microbiota composition links to variation in functional domains across psychiatric disorders.

OBJECTIVE: Changes in microbial composition are observed in various psychiatric disorders, but their specificity to certain symptoms or processes remains unclear. This study explores the associations between the gut microbiota composition and the Research Domain Criteria (RDoC) domains of functioning, representing symptom domains, specifically focusing on stress-related and neurodevelopmental disorders in patients with and without psychiatric comorbidity. METHODS: The gut microbiota was analyzed in 369 participants, comprising 272 individuals diagnosed with a mood disorder, anxiety disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, and/or substance use disorder, as well as 97 psychiatrically unaffected individuals. The RDoC domains were estimated using principal component analysis (PCA) with oblique rotation on a range of psychiatric, psychological, and personality measures. Associations between the gut microbiota and the functional domains were assessed using multiple linear regression and permanova, adjusted for age, sex, diet, smoking, medication use and comorbidity status. RESULTS: Four functional domains, aligning with RDoC's negative valence, social processes, cognitive systems, and arousal/regulatory systems domains, were identified. Significant associations were found between these domains and eight microbial genera, including associations of negative valence with the abundance of the genera Sellimonas, CHKCI001, Clostridium sensu stricto 1, Oscillibacter, and Flavonifractor; social processes with Sellimonas; cognitive systems with Sporobacter and Hungatella; and arousal/regulatory systems with Ruminococcus torques (all pFDR < 0.05). CONCLUSION: Our findings demonstrate associations between the gut microbiota and the domains of functioning across patients and unaffected individuals, potentially mediated by immune-related processes. These results open avenues for microbiota-focused personalized interventions, considering psychiatric comorbidity. However, further research is warranted to establish causality and elucidate mechanistic pathways.

Co-occurrence of gut microbiota dysbiosis and bile acid metabolism alteration is associated with psychological disorders in Crohn's disease.

This study aims to elucidate the relationships between gut microbiota, bile acid metabolism, and psychological comorbidity in Crohn's disease (CD). We profiled the fecal microbiota composition and quantified the bile acid pool of 39 CD patients and 14 healthy controls using 16S rRNA gene sequencing and liquid chromatography-tandem mass spectrometry, respectively. Significant reductions in the secondary bile acids, LCA and DCA, were found in both the feces and serum samples of CD patients, while the concentration of 7-DHCA was particularly higher in the serum of CD patients with psychological disorders. The fecal levels of HDCA and 12-DHCA of the CD patients were inversely correlated with their Self-Rated Depression Scale (SDS) scores, whereas the serum level of 7-DHCA was positively correlated with the SDS scores. In addition, the fecal levels of TDCA, TLCA, and TßMCA showed a positive correlation with the Self-Rated Anxiety Scale (SAS) scores. The fecal microbiota biodiversity was particularly declined in CD patients with psychological disorders. An enrichment of Ruminococcus gnavus in CD patients may cause psychological disorders by affecting the microbiota-gut-brain axis via its ability to degrade the gut barrier, regulate the tryptophan-kynurenine metabolism, and modulate bile acid metabolism. In addition, the overabundant Enterobacteriaceae and Lachnospiraceae in CD patients may contribute to psychological comorbidity via dysregulating their bile acids metabolism. Taken together, changes in the gut microbiota composition may cooperate with alterations in the bile acid metabolism that are involved in the development of psychological disorders in CD.

Mitochondria and Antibiotics: For Good or for Evil?

The discovery and application of antibiotics in the common clinical practice has undeniably been one of the major medical advances in our times. Their use meant a drastic drop in infectious diseases-related mortality and contributed to prolonging human life expectancy worldwide. Nevertheless, antibiotics are considered by many a double-edged sword. Their extensive use in the past few years has given rise to a global problem: antibiotic resistance. This factor and the increasing evidence that a wide range of antibiotics can damage mammalian mitochondria, have driven a significant sector of the medical and scientific communities to advise against the use of antibiotics for purposes other to treating severe infections. Notwithstanding, a notorious number of recent studies support the use of these drugs to treat very diverse conditions, ranging from cancer to neurodegenerative or mitochondrial diseases. In this context, there is great controversy on whether the risks associated to antibiotics outweigh their promising beneficial features. The aim of this review is to provide insight in the topic, purpose for which the most relevant findings regarding antibiotic therapies have been discussed.

The Genus Alistipes: Gut Bacteria With Emerging Implications to Inflammation, Cancer, and Mental Health.

Alistipes is a relatively new genus of bacteria isolated primarily from medical clinical samples, although at a low rate compared to other genus members of the Bacteroidetes phylum, which are highly relevant in dysbiosis and disease. According to the taxonomy database at The National Center for Biotechnology Information, the genus consists of 13 species: Alistipes finegoldii, Alistipes putredinis, Alistipes onderdonkii, Alistipes shahii, Alistipes indistinctus, Alistipes senegalensis, Alistipes timonensis, Alistipes obesi, Alistipes ihumii, Alistipes inops, Alistipes megaguti, Alistipes provencensis, and Alistipes massiliensis. Alistipes communis and A. dispar, and the subspecies A. Onderdonkii subspecies vulgaris (vs. onderdonkii subsp.) are the newest strains featured outside that list. Although typically isolated from the human gut microbiome various species of this genus have been isolated from patients suffering from appendicitis, and abdominal and rectal abscess. It is possible that as Alistipes spp. emerge, their identification in clinical samples may be underrepresented as novel MS-TOF methods may not be fully capable to discriminate distinct species as separate since it will require the upgrading of MS-TOF identification databases. In terms of pathogenicity, there is contrasting evidence indicating that Alistipes may have protective effects against some diseases, including liver fibrosis, colitis, cancer immunotherapy, and cardiovascular disease. In contrast, other studies indicate Alistipes is pathogenic in colorectal cancer and is associated with mental signs of depression. Gut dysbiosis seems to play a role in determining the compositional abundance of Alistipes in the feces (e.g., in non-alcoholic steatohepatitis, hepatic encephalopathy, and liver fibrosis). Since Alistipes is a relatively recent sub-branch genus of the Bacteroidetes phylum, and since Bacteroidetes are commonly associated with chronic intestinal inflammation, this narrative review illustrates emerging immunological and mechanistic implications by which Alistipes spp. correlate with human health.

A Case of Pulmonary Histoplasmosis Presenting with Hypercalcemia and Altered Mental Status in a Patient Following Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND Histoplasmosis results from the inhalation of spores from the fungus, Histoplasma capsulatum. A case is presented of pulmonary histoplasmosis associated with altered mental state and hypercalcemia following allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML). CASE REPORT A 75-year-old man with a five-day history of AML treated with allogeneic hematopoietic stem cell transplantation, presented with weakness, fatigue, and slow mentation. Computed tomography (CT) of the brain was unremarkable. Laboratory investigations showed serum albumin of 2.9 g/dL, calcium of 11.6 mg/dL, ionized calcium of 1.55 mmol/L, parathyroid hormone (PTH) <6.3 pg/mL, and 25-hydroxy vitamin D of 14.4 ng/mL. Treatment began with intravenous cefepime 1 gm bid, normal saline, and the bisphosphonate, pamidronate, administered as a single dose. Three days later, his clinical status declined. He developed a dry productive cough, his oxygen saturation (O2 Sat) was 90%, and his mental status worsened. Chest CT showed diffuse bilateral lung infiltrates with ground glass opacities. Bronchioalveolar lavage and transbronchial biopsy were negative for Pneumocystis jiroveci pneumonia (PJP). The CMV rival load was 195 IU/mL. Urinalysis for Histoplasma antigen and the Fungitell® assay were positive. Treatment commenced with intravenous voriconazole (250 mg, bid) and ganciclovir (5 mg/kg, bid). A left lower lobe transbronchial lung biopsy was positive for Histoplasma capsulatum and negative for CMV. CONCLUSIONS This case report has highlighted the need for awareness of the diagnosis of histoplasmosis in patients with allogeneic hematopoietic stem cell transplantation who present with an altered mental state in the setting of hypercalcemia.

The Role of the Microbiome in Drug Response.

The microbiome is known to regulate many aspects of host health and disease and is increasingly being recognized as a key mediator of drug action. However, investigating the complex multidirectional relationships between drugs, the microbiota, and the host is a challenging endeavor, and the biological mechanisms that underpin these interactions are often not well understood. In this review, we outline the current evidence that supports a role for the microbiota as a contributor to both the therapeutic benefits and side effects of drugs, with a particular focus on those used to treat mental disorders, type 2 diabetes, and cancer. We also provide a snapshot of the experimental and computational tools that are currently available for the dissection of drug-microbiota-host interactions. The advancement of knowledge in this area may ultimately pave the way for the development of novel microbiota-based strategies that can be used to improve treatment outcomes.

Probiotics of Diverse Origin and Their Therapeutic Applications: A Review.

The increased awareness about the harmful effects of excessive use of antibiotics has created an interest in probiotics due to its beneficial effects on gut microbiota. These advantages of probiotics have attracted researchers to find out effects on human metabolism and their role in the treatment of diverse types of diseases or disorders. Additionally, they are clinically used as biocontrol agents in the treatment of mental disorders, anticancer agents and in decreasing the threat of necrotizing enterocolitis in premature infants. In this review, we have focused on various kinds of probiotics and various nondairy substrates for their production. We have also included the importance of probiotics in the treatment of metabolic disorders, type II diabetes and infectious diseases. Furthermore, this review emphasizes applications of probiotics originated from different organisms. Their future health perspectives are discussed to gain insight into their applications.KEY TEACHING POINTSThe global market of probiotics is enormously rising day by day due to its highly beneficial effect on human microbiota.Additionally, these are used as biocontrol agents; mental disorders prevent cancer and decrease the threat of necrotizing enterocolitis (NEC) in premature infants.This review focuses on various kinds of sources of probiotics and various non-dairy substrates for the production of probiotics.The importance of probiotics in the treatment of metabolic disorders, type II diabetes control, cancer and treatment of infectious diseases are also described.It emphasizes diversified probiotics and their applications in various human health aspects and future perspectives.

Cryptococcal meningitis initially presenting with ST elevations and elevated cardiac biomarkers.

Acute neurological events are a common cause of ECG abnormalities and transient elevations in cardiac biomarkers. This case describes an uncommon presentation of cryptococcal meningitis in a non-immunosuppressed patient, presenting with altered sensorium and derangements in cardiac profile. Delay in diagnosing meningitis was avoided by paying close attention to the patient's presenting symptoms and by pursuing non-cardiac causes of ECG changes and elevations in cardiac troponin. Expeditious treatment and involvement of the infectious disease consultant resulted in excellent clinical response without permanent neurological sequelae.

Gut microbiota-immune-brain interactions in chemotherapy-associated behavioral comorbidities.

Increasing scientific attention is focused on the gut-brain axis, including the ability of the gastrointestinal (GI) tract to modulate central nervous system function. Changes in the intestinal microbiome can influence affective-like behavior, cognitive performance, fatigue, and sleep in rodents and humans. Patients with cancer who are receiving chemotherapy experience similar negative behavioral changes and concurrent GI symptoms. These chemotherapy comorbidities can be long-lasting and may reduce patients' quality of life and motivation to comply with treatment. This review summarizes the clinical and preclinical evidence supporting a role for the intestinal microbiome in mediating behavioral comorbidities through peripheral immune activation in patients with cancer who are receiving chemotherapy. In addition, evidence suggesting that targeted modification of the intestinal microbiome during cancer treatment could ameliorate associated behavioral comorbidities is reviewed.

A Coding Variant of ANO10, Affecting Volume Regulation of Macrophages, Is Associated with Borrelia Seropositivity.

In a first genome-wide association study (GWAS) approach to anti-Borrelia seropositivity, we identified two significant single nucleotide polymorphisms (SNPs) (rs17850869, P = 4.17E-09; rs41289586, P = 7.18E-08). Both markers, located on chromosomes 16 and 3, respectively, are within or close to genes previously connected to spinocerebellar ataxia. The risk SNP rs41289586 represents a missense variant (R263H) of anoctamin 10 (ANO10), a member of a protein family encoding Cl(-) channels and phospholipid scramblases. ANO10 augments volume-regulated Cl(-) currents (IHypo) in Xenopus oocytes, HEK293 cells, lymphocytes and macrophages and controls volume regulation by enhancing regulatory volume decrease (RVD). ANO10 supports migration of macrophages and phagocytosis of spirochetes. The R263H variant is inhibitory on IHypo, RVD and intracellular Ca(2+) signals, which may delay spirochete clearance, thereby sensitizing adaptive immunity. Our data demonstrate for the first time that ANO10 has a central role in innate immune defense against Borrelia infection.

Increased serum interleukin-6 levels in early stages of psychosis: associations with at-risk mental states and the severity of psychotic symptoms.

Schizophrenia patients experience activated inflammatory responses, but little is known about the presence of such inflammatory processes at or prior to disease onset. We measured interleukin-6 (IL-6) and C-reactive protein (CRP) serum levels and plasma fibrinogen in 17 at-risk mental state (ARMS) subjects, 77 patients with psychotic disorder (PD) and 25 healthy control subjects (HC). ARMS subjects were followed-up, and transition to psychosis was registered. IL6 rs1800795 SNP was genotyped, as IL-6 levels may be influenced by this genetic variant. We did not observe significant differences in the IL6 rs1800795 SNP genotype frequencies between the groups. ARMS subjects exhibited significantly higher IL-6 levels than did controls (p=0.019). In subjects not taking cannabis, we found that patients diagnosed with ARMS or PD exhibited increased IL-6 levels when compared with HC (p=0.004). In both ARMS and PD subjects, IL-6 levels were positively associated with negative symptoms. However, with respect to positive psychotic symptoms, a different relationship was observed in the ARMS and PD groups (positive relationship in ARMS; negative relationship in PD). These findings could not be attributed to confounding variables, including gender, body mass index (BMI), tobacco consumption or the rs1800795 genotype. Six of 17 ARMS subjects (35%) exhibited a transition to psychosis during the follow-up period of 26 months. ARMS subjects who developed psychosis exhibited increased median IL-6 levels compared with those who did not transition (0.61 vs. 0.35pg/mL). However, this difference was not statistically significant, which could be explained by a lack of statistical power due to the small sample size. Our results suggest that IL-6 may be a biomarker for early psychotic symptoms; however, further studies in larger samples are needed to confirm this result.

Microbial origins of chronic diseases.

Chronic diseases such as cardiovascular disease and cancer are among the leading causes of death worldwide and have been on the rise over the past decade. Associations between microbial agents and development of chronic diseases have been made in the past, and new connections are currently being assessed. Investigators are examining the relationship between infectious agents and chronic disease using new technologies with more rigor and specificity. This review examines microbial agents' links to and associations with cardiovascular diseases, cancer, neurodegenerative diseases, renal diseases, psychiatric disorders, and obesity and addresses the important role of the human microbiome in maintenance of health and its potential role in chronic diseases. These associations and relationships will impact future research priorities, surveillance approaches, treatment strategies, and prevention programs for chronic diseases.

Behavioral, pharmacological, and immunological abnormalities after streptococcal exposure: a novel rat model of Sydenham chorea and related neuropsychiatric disorders.

Group A streptococcal (GAS) infections and autoimmunity are associated with the onset of a spectrum of neuropsychiatric disorders in children, with the prototypical disorder being Sydenham chorea (SC). Our aim was to develop an animal model that resembled the behavioral, pharmacological, and immunological abnormalities of SC and other streptococcal-related neuropsychiatric disorders. Male Lewis rats exposed to GAS antigen exhibited motor symptoms (impaired food manipulation and beam walking) and compulsive behavior (increased induced-grooming). These symptoms were alleviated by the D2 blocker haloperidol and the selective serotonin reuptake inhibitor paroxetine, respectively, drugs that are used to treat motor symptoms and compulsions in streptococcal-related neuropsychiatric disorders. Streptococcal exposure resulted in antibody deposition in the striatum, thalamus, and frontal cortex, and concomitant alterations in dopamine and glutamate levels in cortex and basal ganglia, consistent with the known pathophysiology of SC and related neuropsychiatric disorders. Autoantibodies (IgG) of GAS rats reacted with tubulin and caused elevated calcium/calmodulin-dependent protein kinase II signaling in SK-N-SH neuronal cells, as previously found with sera from SC and related neuropsychiatric disorders. Our new animal model translates directly to human disease and led us to discover autoantibodies targeted against dopamine D1 and D2 receptors in the rat model as well as in SC and other streptococcal-related neuropsychiatric disorders.

High risk of schizophrenia and other mental disorders associated with chlamydial infections: hypothesis to combine drug treatment and adoptive immunotherapy.

Many microbial factors have been implicated as pathogenic factors in mental disorders. Occurrence of such microbial factors also in the mentally unaffected population raised skepticism against such findings, although each microbial factor may cause mental problems only in some individuals, depending on the individual's immunogenetic disposition. Skepticism against the role of infection in schizophrenia was also fostered by the low impact of antiinfections treatment on the course of disease progression in schizophrenia. We discovered previously that neurotrophins like neurotrophin3 (NT-3) and brain-derived neurotrophic factor (BDNF), involved in processes of neuroplasticity, are also secreted by immune cells, but only by subpopulations of immune cells. Therefore, infection of the immune cell subpopulation, specialized in secreting BDNF, or of another subpopulation, specialized in secreting NT-3, could distort communication of immune cells with the central nervous system (CNS). Chlamydiaceae could cause disbalancement of immune cell sub-populations and, in some individuals with a vulnerable disposition, symptoms of mental illness. Based on previous observations of persisting IgA titers in some patients with mental illness we hypothesize that the intracellular parasites Chlamydiaceae are main pathogenic factors in schizophrenia. We hypothesize furthermore that antiinfectious treatment has to be accompanied by adoptive immunotherapy because antibiotics alone will not restore the balance of immune subpopulations. Our hypothesis is supported by examination of patients with schizophrenia and other mental disorders. Using nested PCR we found a significant prevalence of the intracellular parasites Chlamydophila psittaci, C. pneumoniae and Chlamydia trachomatis (9/18, 50%), as compared to controls (8/115, 6.97%) (chi(2)=25.86, Fisher's exact p two-tailed=5x10(-5)). Treatment with in vitro-activated immune cells together with antibiotic modalities showed sustained mental improvements in patients that did not depend on treatment with antipsychotic drugs. Future controlled studies including sham treatment of patients have to be carried out to prove our hypotheses.

"Non-infectious" syndromes associated with infectious agents.

Over the past two decades there has been numerous new associations between chronic diseases traditionally considered non-infectious with infectious agents. This list of diseases include peptic ulcer, coronary heart disease, neuropsychiatric disorders, haematological disorders and malignancies. These associations have been made possible through improvements in diagnostic tests based on molecular biology techniques. The discovery of these associations is important as it opens up exciting opportunities for the prevention and treatment of many diseases hitherto considered incurable.

Isolation frequency of human immunodeficiency virus from cerebrospinal fluid and blood of patients with varying severity of HIV infection.

Isolation of the human immunodeficiency virus (HIV) has been attempted from the cerebrospinal fluid (CSF) of 63 subjects at different stages of HIV infection, including asymptomatic carriers and patients with or without neurologic or psychiatric complications. In addition blood was collected from 40 of these subjects for virus isolation. HIV could be isolated from the CSF at all clinical stages with an overall frequency of 40%. In contrast, the frequency of HIV isolation from the blood was lower (32%) at the early stages of infection than in patients with severe disease (77%). HIV isolation from the CSF was more frequently positive in patients with neurologic or psychiatric complications than in patients showing no such disturbances (48 and 32%, respectively).

Latent herpesvirus hominis 1 in the central nervous system of psychotic patients.

Cerebrospinal fluids (CSF) from 35 patients with senile or presenile dementia and from 13 patients with schizophrenia and related syndromes were examined in cell cultures with the aim to isolate Herpesvirus hominis 1 (HVH 1) or other viruses. Serum and CSF antibodies to HVH 1 and/or interferon in the patients indicated a recent HVH 1 antigenic or viral activity. In the CSF of two senile demented patients and of one patient with schizoaffective psychosis, agents of low virulence, causing a cytopathic effect in 3 or 4, but not more, subsequent passages were detected and identified as HVH 1 by immunofluorescence. A focus of cells containing HVH 1 antigen at the cell membrane and in cytoplasm was visualized by immunofluorescence in an explant from nucleus amygdalae from 1 of 6 patients with schizophrenia and related syndromes examined. In the original biopsy materials, various virus-like structures were found in nuclei and cytoplasm of astrocytes and neurocytes and in axons in the neuropil.