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Background and Hypothesis Gut microbiota alterations have been reported in severe mental illness (SMI) but fewer studies have probed for signs of gut barrier disruption and inflammation. We hypothesized that gut leakage of microbial products due to intestinal inflammation could contribute to systemic inflammasome activation in SMI. Study Design We measured plasma levels of the chemokine CCL25 and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) as markers of T cell homing, adhesion and inflammation in the gut, lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP) as markers of bacterial translocation and gut barrier dysfunction, in a large SMI cohort (n = 567) including schizophrenia (SCZ, n = 389) and affective disorder (AFF, n = 178), relative to healthy controls (HC, n = 418). We assessed associations with plasma IL-18 and IL-18BPa and leukocyte mRNA expression of NLRP3 and NLRC4 as markers of inflammasome activation. Study Results Our main findings were: (1) higher levels of sMAdCAM-1 (P =.002), I-FABP (P = 7.6E−11), CCL25 (P = 9.6E−05) and LBP (P = 2.6E−04) in SMI compared to HC in age, sex, BMI, CRP and freezer storage time adjusted analysis; (2) the highest levels of sMAdCAM-1 and CCL25 (both P = 2.6E−04) were observed in SCZ and I-FABP (P = 2.5E−10) and LBP (3) in AFF; and (3), I-FABP correlated with IL-18BPa levels and LBP correlated with NLRC4. Conclusions Our findings support that intestinal barrier inflammation and dysfunction in SMI could contribute to systemic inflammation through inflammasome activation. [ABSTRACT FROM AUTHOR]

Recent findings link cognitive impairment and inflammatory-immune dysregulation in schizophrenia (SZ) and bipolar (BD) spectrum disorders. However, heterogeneity and translation between the periphery and central (blood-to-brain) mechanisms remains a challenge. Starting with a large SZ, BD and healthy control cohort (n = 1235), we aimed to i) identify candidate peripheral markers (n = 25) associated with cognitive domains (n = 9) and elucidate heterogenous immune-cognitive patterns, ii) evaluate the regulation of candidate markers using human induced pluripotent stem cell (iPSC)-derived astrocytes and neural progenitor cells (n = 10), and iii) evaluate candidate marker messenger RNA expression in leukocytes using microarray in available data from a subsample of the main cohort (n = 776), and in available RNA-sequencing deconvolution analysis of postmortem brain samples (n = 474) from the CommonMind Consortium (CMC). We identified transdiagnostic subgroups based on covariance between cognitive domains (measures of speed and verbal learning) and peripheral markers reflecting inflammatory response (CRP, sTNFR1, YKL-40), innate immune activation (MIF) and extracellular matrix remodelling (YKL-40, CatS). Of the candidate markers there was considerable variance in secretion of YKL-40 in iPSC-derived astrocytes and neural progenitor cells in SZ compared to HC. Further, we provide evidence of dysregulated RNA expression of genes encoding YKL-40 and related signalling pathways in a high neuroinflammatory subgroup in the postmortem brain samples. Our findings suggest a relationship between peripheral inflammatory-immune activity and cognitive impairment, and highlight YKL-40 as a potential marker of cognitive functioning in a subgroup of individuals with severe mental illness., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Recent studies indicate accelerated ageing processes, shorter telomere length and poorer cognitive functioning in patients with bipolar disorder. The neurobiology underlying cognitive function in bipolar disorder is yet to be established. We anticipated that accelerated ageing as indicated by shortened telomere length, would be associated with reduced cognitive performance in bipolar disorder, particularly for ageing sensitive functions such as memory and learning., Methods: The study consisted of 647 participants (bipolar disorder [n = 246] and healthy controls [n = 401]). All participants underwent a standardized neuropsychological test battery, including working memory, executive functioning, processing speed, verbal learning, and verbal memory. Leucocyte telomere length was measured via blood and determined by quantitative real-time Polymerase Chain Reaction (qPCR) providing a telomere to single copy ratio (T/S ratio). The T/S ratio was used as an estimate of the mean telomere length of each participant. All analyses were adjusted for medication, Daily Defined Dose (DDD), chronological age, sex, and ethnicity., Results: Patients had shorter telomere lengths than healthy controls (Cohen's d = 0.11, p = 0.01). Within patients', a positive association was observed for verbal learning and telomere length (β = 0.14, p = 0.025), along with a trend for verbal memory and telomere length (β = 0.11, p = 0.07). No other associations were observed for telomere length and cognitive functioning in the patient or the control group (p > 0.1)., Conclusion: Our study may suggest poorer brain health in bipolar disorder as indexed by shorter telomere length and reduced learning correlates. However, the role of telomere length on cognitive functioning in bipolar disorder seems limited., Competing Interests: Declaration of competing interest No conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Metabolic dysregulation has been associated with severe mental disorders (SMD) and with antipsychotic (AP) treatment, but the role of sex is unknown. To identify possible sex-related processes linked to SMD and AP treatment, we investigated sex differences in associations between hormones involved in metabolic regulation in patients with SMD compared to healthy controls (HC) and AP treatment., Methods: We included patients with SMD (N = 1753) and HC (N = 1194) and measured hormones involved in metabolic regulation (insulin, cortisol, thyroid-stimulating hormone (TSH), thyroxine, leptin, adiponectin, testosterone, sex hormone-binding globulin (SHBG), prolactin). Patients were grouped according to use of first-generation AP (N = 163), second-generation AP (N = 1087) or no use of AP (N = 503). Hormones were used one by one as dependent variables in multiple regression analyses with interactions between sex and SMD patients versus HC, and between sex and AP treatment, followed by analyses in males and females separately., Results: We found significant interactions between sex and SMD patients versus HC for testosterone, SHBG and adiponectin, with significantly higher testosterone and lower adiponectin levels in females. Furthermore, we found significant interaction between sex and AP groups for TSH, testosterone and insulin, with significantly lower TSH levels in AP-treated females, and lower testosterone and higher insulin levels in AP-treated males., Conclusions: Our findings suggest sex differences in metabolic hormones related to both SMD and AP treatment, indicating sex-dependent mechanisms. Clinicians should be aware of potential sex-specific metabolic changes during AP treatment and experimental studies are warranted to clarify the underlying mechanisms., Competing Interests: Conflict of interest OAA is a consultant to HealthLytix and received speaker’s honorarium from Sunovion and Lundbeck. IA received speaker’s honorarium from Lundbeck. The remaining authors declare that they have no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)