Qin Huang

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a severe complication of systemic lupus erythematosus (SLE). Despite its high morbidity, the exact pathogenesis of NPSLE remains poorly understood, and effective therapeutic options remain unavailable. Here we show gut bacterium Lactobacillus reuteri (L. reuteri) and its metabolite indole-3-acetic acid (IAA) play key roles in the progression of NPSLE. L. reuteri and IAA induce behavioral deficits, microglial activation, pro-inflammatory cytokine secretion, neuronal loss, and blood brain barrier (BBB) disruption in female lupus-prone mice. Mechanistic studies show that IAA activates the aryl hydrocarbon receptor (AHR) and signal transducer and activator of transcription 3 (STAT3) signaling pathways in microglia, thereby upregulating inflammatory responses and exacerbating neuroinflammation. These findings suggest a critical role for gut-microbiota-metabolite-brain axis in NPSLE pathogenesis and provide insights into potential therapeutic targets.

Introduction Methods We used Mendelian randomization (MR) methods, including inverse-variance weighted (IVW), MR-Egger, and weighted median (WM) models, along with metabolic pathway analysis, meta-analysis, colocalization analysis, and genetic correlation studies to explore the relationship between plasma metabolites and SS. Results Our analysis uncovered 53 metabolites with potential causal links to SS, among which nine demonstrated statistically significant associations. In the validation stage, two metabolites were found to play a role in SS pathogenesis: gluconate, which exhibited a protective effect, and 1,3,7-trimethylurate, which was associated with increased risk. The reliability of these results was further reinforced by sensitivity analyses and validation procedures. Additionally, metabolic pathway analysis identified four key pathways associated with SS risk: cysteine and methionine metabolism, glycine, serine, and threonine metabolism, alanine, aspartate, and glutamate metabolism, and oxaloacetate and dicarboxylate metabolism. Although no genetic correlations were identified, colocalization analysis suggested that the top single nucleotide polymorphism (SNP) in the LINC01572 gene may contribute to increased SS risk. Conclusion These findings provide novel insights into the metabolic etiology of SS, highlighting both protective and harmful metabolites. Key points: • Identified 53 metabolites linked to Sjögren’s syndrome (SS), with 9 showing significant associations. • Validated gluconate (protective) and 1,3,7-trimethylurate (risk-increasing) in SS pathogenesis. • Found four key metabolic pathways associated with SS risk. • First two-sample MR study to assess plasma metabolites and SS risk using the largest GWAS dataset.

Anti-HMGCR-positive immune-mediated necrotizing myopathy (IMNM), also anti-HMGCR myopathy, was initially considered as an exclusively skeletal muscular disease, observed in elderly patients with an acute onset. However, there is an increasing number of patients presenting greater clinical diversity than previously recognized. The aim of this study is to establish a comprehensive clinical-pathological classification for these patients, capturing the spectrum of disease presentations including both typical and atypical cases. We conducted a retrospective analysis and follow-up study of the clinical features, pathological manifestations, and treatment outcomes of 18 anti-HMGCR myopathy patients from Nanfang Hospital, along with data from 61 patients reported before. We defined 31 patients who presented with extra-muscular symptoms as overlap patients, while those who had merely muscular symptoms as non-overlap patients. Overlap patients had higher MMT-score, less muscular symptoms, specifically muscle weakness, and more extra-muscular symptoms, including ILD, arthralgia, weight loss and mostly skin involvement. Based on clinical, pathological, and genetic criteria, 12 peculiar patients were classified as MD-like patients. These cases, with earlier onset and longer duration, hardly had myalgia and extra-muscular symptoms, particularly skin involvement. Our study highlights the clinical and pathological heterogeneity of anti-HMGCR-positive IMNM. We identified a distinct subgroup of overlap patients, as well as MD-like patients. The classification system we proposed offers a practical framework for distinguishing these subtypes.

This study aimed to evaluate the activity of the glymphatic system in SLE using a diffusion-based method termed ‘Diffusion Tensor Image Analysis aLong the Perivascular Space (DTI-ALPS)’, and to examine its correlations with morphological changes in the brain. In this cross-sectional study, 45 female patients with SLE and 30 healthy controls (HCs) were included. Voxel-based and surface-based morphometric analyses were performed to examine T1-weighted images, and diffusion tensor images were acquired to determine diffusivity along the x-, y- and z-axes in the plane of the lateral ventricle body. The DTI-ALPS index (ALPS index) was calculated for each patient. The differences in values between patients with SLE and the HC group were compared using the independent samples t test or the Mann–Whitney U test. To determine correlations between the ALPS index and brain morphological parameters, partial correlation analysis and Pearson’s correlation analysis were conducted. Patients with SLE showed lower values for the ALPS index in the left (1.543 ± 0.141 vs 1.713 ± 0.175, P < 0.001), right (1.428 ± 0.142 vs 1.556 ± 0.139, P < 0.001) and whole (1.486 ± 0.121 vs 1.635 ± 0.139, P < 0.001) brain compared with the HC group. Reduced ALPS index showed significant positive correlations with grey matter loss. The non-invasive ALPS index could serve as a sensitive and effective neuroimaging biomarker for individually quantifying glymphatic activity in patients with SLE. Glymphatic system abnormality may be involved in the pathophysiologic mechanism underlying CNS damage in SLE patients.

Introduction: Previous fMRI studies revealed that the abnormal functional connectivity (FC) was related to cognitive impairment in patients with SLE. However, it remains unclear how the disease severity affects the functional topological organization of the whole-brain network in SLE patients without neuropsychiatric symptoms (non-NPSLE). Objective: We aim to examine the impairment of the whole-brain functional network in SLE patients without neuropsychiatric symptoms (non-NPSLE), which may improve the understanding of neural mechanism in SLE. Methods: We acquired resting-state fMRI data from 32 non-NPSLE patients and 32 healthy controls (HC), constructed their whole-brain functional network, and then estimated the topological properties including global and nodal parameters by using graph theory. Meanwhile, we also investigated the differences in intra- and inter-network FC between the non-NPSLE patients and the HC. Results: The non-NPSLE patients showed significantly lower clustering coefficient, global and local efficiency, but higher characteristic path length than the HC. The non-NPSLE patients had significantly lower nodal strength in two regions, ventromedial prefrontal cortex (vmPFC) and anterior PFC (aPFC) than the HC. We found the non-NPSLE patients had significantly lower intra-network FC within frontal-parietal network (FPN) and within default mode network (DMN), and significantly lower inter-network FC between DMN and FPN than the HC. The intra-network FC within DMN was negatively correlated with systemic lupus erythematosus disease activity index (SLEDAI). Conclusion: Abnormal whole-brain functional network properties and abnormal intra- and inter-network FC may be related to cognitive impairment and disease degree in the non-NPSLE patients. Our findings provide a network perspective to understand the neural mechanisms of SLE.

Objective: The study aimed to explore the effect of serum uric acid (SUA) level on the progression of kidney function in systemic lupus erythematosus (SLE) patients Methods: A total of 123 biopsy-proven lupus nephritis (LN) patients were included in this retrospective observational study. Cox proportional hazard regression analyses as well as restricted cubic spline analyses were performed to identify predictors of renal outcome in LN patients. We also performed a systematic review and meta-analysis for SUA and overall kidney outcomes in SLE patients. Results: Based on the laboratory tests at renal biopsy, 72 (58.5%) of the 123 patients had hyperuricemia. The median (IQR) follow-up duration was 3.67 years (1.79–6.63 years), and a total of 110 (89.4%) patients experienced progression of LN. Increased serum uric acid level, whether analyzed as continuous or categorical variable, was associated with higher risk of LN progression in Cox proportional hazard regression model (hazard ratio [HR]: 1.003, 95% confidence interval [CI]: 1.001–1.005; HR: 1.780, 95% CI: 1.201–2.639, respectively). This relationship maintained in women (HR: 1.947, 95% CI: 1.234–3.074) but not men (HR: 2.189, 95% CI: 0.802–5.977). The meta-analysis showed a similar result that both continuous and categorical SUA were positively associated with the risk of kidney function progression in LN (weighted mean difference [WMD]: 1.73, 95% CI: 0.97–2.49; odds ratio [OR]: 1.55, 95% CI: 1.20–2.01, respectively). Conclusions: Our study found overall and especially in women that higher SUA in LN patients were associated with increased risk of renal progression. Meta-analysis yielded consistent results. Future studies are required to establish if uric acid can be used as a biomarker for risk assessment and/or as a novel therapeutic target in SLE.

Background: Since dysregulation of total Interleukin (IL)-18 and IL-18 binding protein (IL-18BP) may participate in systemic lupus erythematosus (SLE) and contribute to the occurrence of non-autoimmune epilepsy, the aim of the current work is to investigate whether the interaction between IL-18 and IL-18BP plays any role in neuropsychiatric systemic lupus erythematosus related seizures. Methods: Data from 137 SLE patients and 30 healthy controls (HC) were consecutively collected from 2020 to 2021. Serum levels of total IL-18 and IL-18BP for all patients and HC were measured by ELISA test. Free IL-18 was calculated based on the law of mass action. Results: Among the 137 SLE patients, 103 had active disease and were classified into NPSLE ( n = 50) and Non-NPSLE ( n = 53) groups. Among the NPSLE patients, 16 had seizure disorders. Serum free IL-18 levels were increased in NPSLE (277.6 [150.9–428.8]pg/mL) and were correlated with disease activity (r = 0.268, p = 0.002). Moreover, serum free IL-18 levels in NPSLE patients with seizure disorders (350.9 [237.9–455.9]pg/mL) were significantly higher than the levels in those with other neuropsychiatric symptoms (237.7 [124.6–428.8] pg/mL). Conclusions: The expression of free IL-18 was increased in neuropsychiatric systemic lupus erythematosus(NPSLE), especially in NPSLE related seizures. Also, serum levels of free IL-18 were significantly increased in active SLE patients. In this regard, free IL-18 may be involved in the pathogenesis of NPSLE related seizures and associated with disease activity.

Researches on the bidirectional communications between the gut microbiota and brain, termed the gut-brain axis, often bring about discoveries and drive the development of medicine and biology for stroke. Following stroke, the gut-brain axis is perturbed significantly on dysbiotic gut microbiome, intestinal dysfunction, enteric nervous system, increased gut permeability, and activated immune cells in the gut, which in turn results in infiltration of pro-inflammatory cells or bacterial toxins into brain tissue through impaired blood–brain barrier (BBB), finally exacerbated brain infarction. Herein, we illuminate the changes in the immune system and highlight the possible mechanisms of the gut microbiota to regulate inflammatory and immune processes in the context of stroke. We conducted a systematic literatures search in PubMed, Web of Science, Embase, and guideline-specific databases until May 2021 using the following key terms: gut microbiota, stroke, immune, and inflammation.

Recent studies implicate microbiota-brain communication as an essential factor for physiology and pathophysiology in brain function and neurodevelopment. One of the pivotal mechanisms about gut to brain communication is through the regulation and interaction of gut microbiota on the host immune system. In this review, we will discuss the role of microbiota-immune systeminteractions in human neurological disorders. The characteristic features in the development of neurological diseases include gut dysbiosis, the disturbed intestinal/Blood-Brain Barrier (BBB) permeability, the activated inflammatory response, and the changed microbial metabolites. Neurological disorders contribute to gut dysbiosis and some relevant metabolites in a top-down way. In turn, the activated immune system induced by the change of gut microbiota may deteriorate the development of neurological diseases through the disturbed gut/BBB barrier in a down-top way. Understanding the characterization and identification of microbiome-immune- brain signaling pathways will help us to yield novel therapeutic strategies by targeting the gut microbiome in neurological disease.