The pathophysiological mechanisms of aggression are manifold and they may closely interconnect. Current study aimed to determine the gut microbiota and its metabolites, and clarify their correlations with inflammation, oxidation, leaky gut and clinical profiles underlying aggression in schizophrenia (ScZ).Serum and stool specimens from ScZ inpatients with (ScZ-Ag, 25 cases) and without aggression (NScZ-Ag, 25 cases) were collected. Systemic inflammation, oxidation and leaky gut biomarkers were determined by ELISA, gut microbiota by 16S rRNA sequencing, short-chain fatty acids (SCFAs) by gas chromatography-mass spectrometry analysis and neurotransmitters by liquid chromatograph mass spectrometry analysis.Significantly higher systemic pro-inflammation, pro-oxidation and leaky gut biomarkers were observed in ScZ-Ag than NScZ-Ag group (all P<0.001). Compared to NScZ-Ag group, the alpha-diversity and evenness of fecal bacterial community were much lower, the abundance of fecal genera Prevotella was significantly increased, while that Bacteroides, Faecalibacterium, Blautia, Bifidobacterium,Collinsella and Eubacterium_coprostanoligenes were remarkably reduced in ScZ-Ag group (all corrected P<0.001). Meanwhile, 6 SCFAs and 6 neurotransmitters were much lower in ScZ-Ag group (all P<0.05). Finally, a few strongly positive or negative correlations among altered gut microbiota, SCFAs, systemic pro-inflammation, leaky gut, pro-oxidation and aggression severity were detected.These results demonstrate that pro-inflammation, pro-oxidation and leaky gut phenotypes relating to enteric dysbacteriosis and microbial SCFAs feature the aggression onset or severity in ScZ individuals. 

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Altered gut microbiota and its metabolites correlate with plasma cytokines in schizophrenia inpatients with aggression

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.

Elevated Systemic Levels of Markers Reflecting Intestinal Barrier Dysfunction and Inflammasome Activation Are Correlated in Severe Mental Illness.

Innate immune components involved in host defense have been implicated in schizophrenia (SCZ). However, studies exploring their clinical utility in SCZ diagnosis are limited. The main purpose of this study was to evaluate whether circulating endotoxin, high mobility group box 1 protein (HMGB1) and complement component 4 (C4) could act as peripheral biomarkers to distinguish first-episode schizophrenia (FES, n = 42) patients from healthy controls (HCs, n = 35) in associations with psychopathological symptoms and cognitive dysfunctions. Also, their changes after 8-week antipsychotic treatment were investigated. The Positive and Negative Syndrome Scale (PANSS), Psychotic Symptom Rating Scale (PSYRATS), and MATRICS Consensus Cognitive Battery (MCCB) were administered. Receiver operating characteristic (ROC) curves were conducted to evaluate the diagnostic effectiveness of the three biological indicators. Compared to HCs, levels of endotoxin, HMGB1, and C4 were remarkably increased in FES patients after controlling for age, gender, body mass index (BMI) and education years, and the combination of the three biomarkers demonstrated desirable diagnostic performance (AUC = 0.933). Moreover, the endotoxin level was positively correlated with the severity of auditory hallucinations. After 8 weeks of treatment, HMGB1 was decreased significantly in patients but still higher than that in HCs, whereas endotoxin and C4 did not change statistically. The baseline levels of endotoxin, HMGB1, and C4, as well as their changes were not associated with changes in any PANSS subscale score and total score. Our preliminary results suggest that a composite peripheral biomarker of endotoxin, HMGB1, and C4 may have accessory diagnostic value to distinguish SCZ patients from HCs. Additionally, endotoxin might be implicated in the pathogenesis of auditory hallucinations.

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Alterations in innate immune defense distinguish first-episode schizophrenia patients from healthy controls

A paradigm shift is currently taking place in the etiopathogenesis of neuropsychiatric disorders as immunometabolism is replacing the earlier neurotransmitter model. According to the new concept, cellular bioenergetics drives information processing in the central nervous system; therefore, neuropathology is conceptualized as a direct consequence of impaired metabolism. Along the same lines, endoplasmic reticulum stress and gut barrier dysfunction are emerging as novel targets in schizophrenia and affective disorders, linking immune responses to cellular distress. Furthermore, microglia, the brain’s innate immune cells, acquire energy through oxidative phosphorylation, while in the resting state, and glycolysis upon activation, contributing to lactate accumulation and reduced brain pH. The same metabolic signature characterizes neuropsychiatric disorders as the central nervous system derives adenosine triphosphate from aerobic glycolysis, upregulating lactate and generating an acidic environment. Although known for over three decades, the link between dysmetabolism and neuropathology was poorly defined until the discovery of brain-resident innate lymphoid cells, including natural killer cells, and lactylation of histone and nonhistone proteins. In this perspective article, we examine three anti-inflammatory microglial systems relevant for neuropsychiatry: lactate, oxytocin, and the aryl hydrocarbon receptor. We also discuss potential interventions for restoring microglial homeostasis.

/pdf/the-role-of-lactylation-in-mental-illness-emphasis-on-17ub73ra.pdf

The Role of Lactylation in Mental Illness: Emphasis on Microglia

Inflammation centered on non-IgE-mediated mast cell activation characterizes chronic spontaneous urticaria (CSU) resistant to non-sedating H1-antihistamines (nsAH). We recently uncovered a strong positive association between inflammation and the fecal Escherichia. To further explore the actions of bacterial DNA (btDNA) derived from Escherichia on mast cells, intestinal permeability of CSU patients with or without nsAH resistance and healthy controls were determined, and LAD2 cells with knockdown of spleen tyrosine kinase (Syk), neuronally expressed developmentally downregulated 4L (Nedd4L), or serum and glucocorticoid-induced protein kinase 1 (Sgk1) or with incubation of inhibitors GS9973, GSK650394, and MG132 were post-treated with btDNA. We found that 1) serum intestinal permeability indices and btDNA markedly increased in CSU patients with nsAH resistance compared with those without (all P<0.001), and btDNA positively correlated with the degree of inflammation; 2) IL-6 and TNF-α levels were time- and dose-dependently up-regulated in btDNA-stimulated LAD2 cells, which relied on unmethylated CpG in btDNA and Toll-like receptor 9 protein in cells; 3) Syk knockdown or inhibition of Syk Tyr525/526 phosphorylation blocked btDNA-initiated cytokine production; 4) Nedd4L interacted with Tyr525/526-phosphorylated-Syk, and inhibition of Nedd4L Ser448 phosphorylation induced by btDNA-activated Sgk1 was mandatory for btDNA's pro-inflammatory property; and 5) Sgk1 suppression showed an inhibitory effect on btDNA-induced inflammation by ensuring Nedd4L-mediated ubiquitination of Tyr525/526-phosphorylated-Syk. Collectively, we identiﬁed previously unknown contributory roles of bacterial translocation and serum btDNA on the inflammation phenotype in CSU patients with nsAH resistance and further uncovered a vital negative regulatory role for the Sgk1/Nedd4L/Syk pathway in btDNA-induced inflammation in LAD2 cells.

Bacterial DNA promoting inflammation via the Sgk1/Nedd4L/Syk pathway in mast cells contributes to antihistamine non-responsive CSU.

Objective: Accumulating evidence indicates that inflammation abnormalities may contribute to aggression behaviors in psychotic patients, however, the possible sources of inflammation remain elusive. We aimed to evaluate the associations among aggression, inflammation, and bacterial translocation (BT) in aggression-affected schizophrenia (ScZ) inpatients with 2 weeks of antipsychotics discontinuation.

Methods: Serum specimens collected from 112 aggression and 112 non-aggression individuals with ScZ and 56 healthy adults were used for quantifications of inflammation- or BT-related biomarkers. Aggression severity was assessed by Modified Overt Aggression Scale (MOAS).

Results: Proinflammation phenotype dominated and leaky gut-induced BT occurred only in cases with ScZ with a history of aggression, and the MOAS score positively related to levels of C-reactive protein, interleukin (IL)-6, IL-1β, and tumor necrosis factor-α. Furthermore, serum levels of BT-derived lipopolysaccharide (LPS), as well as LPS-responded soluble CD14, were not only positively correlated with levels of above proinflammation mediators but also the total MOAS score and subscore for aggression against objects or others.

Conclusion: Our results collectively demonstrate the presence of leaky gut and further correlate BT-derived LPS and soluble CD14 to onset or severity of aggression possibly by driving proinflammation response in inpatients with ScZ, which indicates that BT may be a novel anti-inflammation therapeutic target for aggression prophylaxis.

/pdf/bacterial-translocation-associates-with-aggression-in-1nne47h6q8.pdf

Lei He

Papers

Bacterial Translocation Associates With Aggression in Schizophrenia Inpatients.