Abstract Background Major depression (MDD) is linked to neuro-immune, metabolic, and oxidative stress (NIMETOX) pathways. The gut microbiome may contribute to these pathways via leaky gut and immune-metabolic processes. Aims To identify gut microbial alterations in MDD and to quantify functional pathways and enzyme gene families and integrate these with the clinical phenome and immune–metabolic biomarkers of MDD. Methods Shotgun metagenomics with t axonomic profiling was performed in MDD versus controls using MetaPhlAn v4.0.6, and functional profiling was conducted using HUMAnN v3.9, aligning microbial reads to species-specific pangenomes (Bowtie2 v2.5.4) followed by alignment to the UniRef90 v201901 protein database (DIAMOND v2.1.9). Results Gut microbiome diversity, both species richness and evenness, is quite similar between MDD and controls. The top enriched taxa in the multivariate discriminant profile of MDD reflect gut dysbiosis associated with leaky gut and NIMETOX mechanisms, i.e., Ruminococcus gnavus, Veillonella rogosaem and Anaerobutyricum hallii . The top four protective taxa enriched in controls indicate an anti-inflammatory ecosystem and microbiome resilience, i.e., Vescimonas coprocola , C oprococcus , Faecalibacterium prausnitzii , and Faecalibacterium parasitized . Pathway analysis indicates loss of barrier protection, antioxidants and short-chain fatty acids, and activation of NIMETOX pathways. The differential abundance of gene families suggests that there are metabolic distinctions between both groups, indicating aberrations in purine, sugar, and protein metabolism. The gene and pathway scores explain a larger part of the variance in suicidal ideation, recurrence of illness, neurocognitive impairments, immune functions, and atherogenicity. Conclusion The gut microbiome changes might contribute to activated peripheral NIMETOX pathways in MDD.
Autoimmune responses contribute to the pathophysiology of Long COVID, affective symptoms and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). To examine whether Long COVID, and its accompanying affective symptoms and CFS are associated with immunoglobulin (Ig)A/IgM/IgG directed at neuronal proteins including myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), synapsin, α + β-tubulin, neurofilament protein (NFP), cerebellar protein-2 (CP2), and the blood-brain-barrier-brain-damage (BBD) proteins claudin-5 and S100B. IgA/IgM/IgG to the above neuronal proteins, human herpes virus-6 (HHV-6) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were measured in 90 Long COVID patients and 90 healthy controls, while C-reactive protein (CRP), and advanced oxidation protein products (AOPP) in association with affective and CFS ratings were additionally assessed in a subgroup thereof. Long COVID is associated with significant increases in IgG directed at tubulin (IgG-tubulin), MBP, MOG and synapsin; IgM-MBP, MOG, CP2, synapsin and BBD; and IgA-CP2 and synapsin. IgM-SARS-CoV-2 and IgM-HHV-6 antibody titers were significantly correlated with IgA/IgG/IgM-tubulin and -CP2, IgG/IgM-BBD, IgM-MOG, IgA/IgM-NFP, and IgG/IgM-synapsin. Binary logistic regression analysis shows that IgM-MBP and IgG-MBP are the best predictors of Long COVID. Multiple regression analysis shows that IgG-MOG, CRP and AOPP explain together 41.7 % of the variance in the severity of CFS. Neural network analysis shows that IgM-synapsin, IgA-MBP, IgG-MOG, IgA-synapsin, IgA-CP2, IgG-MBP and CRP are the most important predictors of affective symptoms due to Long COVID with a predictive accuracy of r = 0.801. Brain-targeted autoimmunity contributes significantly to the pathogenesis of Long COVID and the severity of its physio-affective phenome.
Several studies have reported a suppressed immune function (e.g. blast transformation) during depression. In an attempt to define the cellular basis of the reported immune disorders, the present study investigates the leukocyte cell subset profile of minor, simple major, and melancholic depressives, versus normal controls. We have counted the number of white blood cells (WBC) lymphocytes, monocytes, and granulocytes, while the number of lymphocyte (sub)populations has been identified by phenotype, using monoclonal antibody staining in conjunction with flow cytometry. The following cell surface antigens were determined: CD3+ (pan T), CD19+ (pan B), CD4+ (T helper/inducer), CD8+ (T suppressor/cytotoxic), CD4+CD45RA (T-memory cells), CD4+CD45RA+ (T-virgin cells), surface Ig, class II MHC HLA-DR, and CD25+ (IL-2 receptor). By means of pattern recognition methods, we established distinct immunological changes in minor and simple major depressed and in melancholic patients, setting them apart from the reference population. Depression, per se, is characterized by a higher number of WBC, monocytes, class II MHC HLA-DR, and memory T cells. Minor and simple major depressives exhibited an increased T helper/suppressor ratio. Increased numbers of IL-2 receptor bearing cells are a hallmark for major depression. Melancholics showed an increased number of pan T, pan B and T suppressor/cytotoxic cells. It was concluded that the established immune cell profile of depressed patients may point towards the existence of a systemic immune activation during that illness.
Aim:No studies have examined whether interactions between the apolipoprotein E4 (ApoE4) allele and peripheral biomarkers, hypertension, and type 2 diabetes mellitus (T2DM) may impact the neurocognitive, behavioral, and social dysfunctions in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD).We aimed to clinically define and biologically validate a subgroup of aMCI subjects who take up an intermediate position between controls and AD patients. Methods:In 61 healthy controls, 60 subjects with aMCI, and 60 AD patients, we measured the features of aMCI/AD using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD).A composite BIORISK score was computed using the ApoE4 allele, serum folate, albumin, white blood cells, fasting blood glucose, atherogenic index of plasma, T2DM, and hypertension.Results: Clustering and nearest neighbor analyses were unable to validate the aMCI subgroup.We constructed two z unit-based composite scores, the first indicating overall burden of cognitive, social, and behavioral deterioration (OBD) and the second reflecting the interactions among ApoE4, all other biomarkers, hypertension, and T2DM (BIORISK).We found that 40.2% of the variance in the OBD score was explained by BIORISK, ApoE4, age, and education.The OBD index was used to construct three subgroups (normal, medium, and high OBD) with the medium group (n = 45) showing mild cognitive dysfunctions (MCD) in memory, language, orientation, and ADL.People with MCD show OBD and BIORISK scores that are significantly different from controls and AD. Conclusion:Petersen's aMCI criteria cannot be validated and should be replaced by the more restrictive, biologically validated MCD class.
Relatively few studies have assessed the prevalence, correlates, and independent impact on quality of life (QoL) of trichotillomania (TTM) in large samples.Consecutive participants (N = 7639) were recruited from a cross-sectional web-based study. Sociodemographic data were collected and several validated self-reported mental health measures were completed (Minnesota Impulsive Disorders Interview, Hypomania checklist, Fagerström Test for Nicotine Dependence, Alcohol Use Disorders Identification Test, Early Trauma Inventory Self Report-Short Form, and the Symptom Checklist-90-Revised Inventory). Health-related QoL was assessed with the World Health Organization QoL abbreviated scale (WHOQOL-Bref). Multivariable models adjusted associations to potential confounders.The sample was predominantly composed of young females (71.3%; mean age: 27.2 ± 7.9 years). The prevalence of probable TTM was 1.4% (95% confidence intervals [CI]: 1.2-1.7), and was more common among females. Participants with probable TTM had a greater likelihood of having co-occurring probable depression (adjusted odds ratio [ORadj] = 1.744; 95% CI: 1.187-2.560), tobacco (ORadj = 2.250; 95% CI: 1.191-4.250), and alcohol (ORadj = 1.751; 95% CI: 1.169-2.621) use disorders. Probable TTM was also independently associated with suicidal ideation (ORadj = 1.917; 95% CI: 1.224-3.003) and exposure to childhood sexual abuse (ORadj = 1.221; 95% CI: 1.098-1.358). In addition, a positive screen for TTM had more impaired physical and mental QoL.TTM was associated with a positive screen for several psychiatric comorbidities as well as impaired physical and psychological QoL. Efforts towards the recognition and treatment of TTM across psycho-dermatology services are warranted.
The hypothalamic-pituitary-adrenal axis (HPA axis) plays a critical role in stress management. Involvement of this physiological axis in the underlying mechanisms of panic disorder (PD) has been suggested. Studies using 35% CO(2) inhalation to provoke panic found no evidence for robust increases in cortisol levels in PD. However, cortisol levels alone may not be conclusive, as this hormone is merely the end product of a complex physiological axis. Sixteen PD patients and 16 healthy control subjects underwent a 35% CO(2) inhalation and a placebo inhalation on separate days according to a fixed order, double-blind design. Both serum and salivary cortisol, as well as adrenocorticotropic hormone (ACTH) were measured at regular time intervals. Cortisol and ACTH levels increased in the patient and control groups following 35% CO(2) inhalation. The magnitude of the increase was similar in patients and controls despite marked differences in anxiety. This study is the first to document a clear HPA response following 35% CO(2) inhalation in both PD patients and controls. This effect occurs independently of the specific panicogenic properties of the CO(2) challenge. It remains to be clarified whether panic is initially accompanied by major HPA axis activation or whether other stress-responsive systems underlie panic.
The measurement of the total radical trapping antioxidant potential (TRAP) is a general marker of peripheral blood antioxidant defenses. Paraoxonase 1 (PON1) is a potent antioxidant, which protects against lipid peroxidation. The study aimed to examine the relation between TRAP levels and PON1 activity, PON1 Q192R functional genotypes, smoking, interactions between PON1 genotypes and smoking, and mood disorders, while adjusting for effects of ethnicity, marital status, body mass index (BMI) and gender. The analyses were performed in 197 controls and 136 subjects with mood disorders. TRAP levels were significantly associated with higher plasma PON1 activity, the RR functional genotype, non smoking by RR carriers, male gender and a higher BMI. TRAP levels were significantly lower in patients with mood disorders than in controls, but this association was no longer significant after considering the effects of the above predictors. The risk in the subgroup with low TRAP levels is increased by a smoking X RR genotype interaction and decreased by male gender, the RR genotype, and higher BMI and PON1 activity. Plasma PON1 activity, the PON1 Q192R functional genotypes and specific interactions between this genotype and smoking contribute significantly to TRAP levels. Gender and BMI also appear to influence TRAP levels.
