Haitao Sun

Intracerebral hemorrhage (ICH) causes severe neurological deficits largely attributable to corticospinal tract (CST) injury. The underlying mechanism remains elusive, which hinders the development of effective treatment methods. Our findings indicate that, in addition to peri‐hematomal NLRP3 inflammasome activation and blood‐brain barrier impairment, CST injury after ICH is closely linked to alterations in the gut microbiota, enhanced intestinal inflammasome signaling, and compromised gut barrier function. We therefore systematically investigated how the gut NLRP3 inflammasome and gut dysbiosis exacerbate CST injury after ICH. Knockdown of colon NLRP3 significantly attenuated CST injury and downregulated inflammasome signaling in both the peripheral circulation and the peri‐hematomal brain. Consistently, antibiotic‐mediated gut microbiota depletion suppressed NLRP3 activation in the gut and brain, improved neurological function, and reduced CST damage. Crucially, fecal microbiota transplantation (FMT) from ICH or Sham donors established that the exacerbation of CST injury is dependent on gut dysbiosis. While FMT induced severe pathology in control mice, this pathology was ameliorated in gut NLRP3 knockdown recipients, demonstrating that gut NLRP3 is essential for mediating the harmful effects of microbiota dysbiosis. Our findings described a causal gut‐brain axis in ICH, wherein microbiota dysbiosis activates the gut NLRP3 inflammasome to exacerbate CST injury, thereby identifying the gut NLRP3 inflammasome as a promising therapeutic target.

Objective: To evaluate the relationship between biological ages and the prevalence and incidence of osteoarthritis (OA). Methods: 332 261 participants from UK Biobank were analyzed. Biological aging was measured using phenotypic age (PhenoAge) and Klemera–Doubal (KDMAge). KDMAge was derived from nine clinical biomarkers to gauge system integrity decline, while PhenoAge was computed from chronological age and nine clinical biomarkers to gauge mortality risk. Biological aging accelerations were computed as residuals from regressing KDMAge and PhenoAge against chronological age. The associations between biological aging and prevalence and incidence of OA were analyzed using logistic and Cox regression models. Results: At baseline, 55.4% of included individuals had younger PhenoAge aging acceleration. In cross‐sectional analyses, individuals with accelerated aging had higher odds of OA compared to those with non‐accelerated aging (odds ratios [OR]: 1.12 [95% CI: 1.09–1.14] for PhenoAge acceleration and 1.05 [1.03–1.08] for KDMAge acceleration). In the longitudinal analyses, increased PhenoAge acceleration was associated with a higher risk of incident OA (hazard ratios [HR]: 1.12 [1.10–1.15]). However, the association between KDMAge acceleration and the incidence of OA was not statistically significant (HR: 0.99 [0.97–1.01]). Accelerated biological aging showed a more pronounced association with OA among individuals > 60 years. No additive or multiplicative interactions were found between OA polygenic risk score (PRS) and biological aging. Conclusion: Advanced biological aging may increase the risk of OA, independent of OA genetic risk, particularly in individuals aged over 60 years. The two biological aging indicators hold potential as novel composite clinical biomarkers, directing prevention and intervention strategies for high‐risk populations for OA.

Both myelination and remyelination in the central nervous system (CNS) rely on the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs). However, the microenvironment and underlying mechanisms of these two processes are significantly different. Myelination is driven by intrinsic developmental programs, whereas remyelination is triggered as a response to demyelinating injury. These distinct origins shape unique microenvironmental conditions that critically influence the respective processes. The microenvironment comprises, the extracellular matrix (ECM) and cellular components. Neurons, microglia, and astrocytes play stage-specific roles, ensuring proper myelin turnover under physiological conditions and regeneration after demyelination. Dysregulation of the microenvironment represents a critical driver of aberrant myelination and remyelination failure, as well as a key limitation of current pro-regenerative strategies. In this review, we discuss the cellular and molecular basis of microenvironmental regulation, recent advances in pathological microenvironmental alterations across demyelinating diseases (multiple sclerosis and neuromyelitis optica spectrum disorder) and myelin-associated disorders (Alzheimer’s disease and ischemic stroke), and emerging pro-remyelination strategies targeting the microenvironment, such as Bruton’s tyrosine kinase (BTK) inhibitors and microglia replacement strategies. We provide a non-cell autonomous perspective to advance the understanding of OLs differentiation and CNS remyelination.

Intracerebral hemorrhage (ICH) causes severe neurological deficits, largely attributable to corticospinal tract (CST) injury. However, the underlying mechanism remains unclear, which hinders the development of effective treatment methods. Here, we found that CST injury is not only associated with the activation of NLRP3 inflammasome in the surrounding area of the hematoma as expected, and dysfunction of the blood-brain barrier, but also related to the severe imbalance of the gut microbiota, the activation of NLRP3 inflammasome in the gut and the impairment of gut barrier function after ICH. We therefore systematically investigated how the gut NLRP3 inflammasome and gut dysbiosis exacerbate CST injury after ICH. Knockdown of colon NLRP3 significantly attenuated CST injury and downregulated inflammasome signaling in both the peripheral circulation and the peri-hematomal brain. Consistently, antibiotic-mediated gut microbiota depletion suppressed NLRP3 activation in the gut and brain, improved neurological function, and reduced CST damage. Crucially, fecal microbiota transplantation (FMT) from ICH donors established that the exacerbation of CST injury is dependent on gut dysbiosis. While FMT induced severe pathology in control mice, this effect was improved in gut NLRP3 knockdown recipients, demonstrating that gut NLRP3 is essential for mediating the harmful effects of microbiota dysbiosis. Our findings described a causal gut-brain axis in ICH, wherein microbiota dysbiosis activates the gut NLRP3 inflammasome to exacerbate CST injury, thereby identifying the gut NLRP3 inflammasome as a promising therapeutic target.

SUMMARY: Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy, yet its mechanism remains partially understood. Here, through an integrated clinical–translational approach, we demonstrate that VNS modulates the gut microbiome and alter the level of butyrate to reduce seizure susceptibility via vagus nerve–dependent signaling. In a longitudinal cohort of epilepsy patients, VNS enriched short-chain fatty acid–producing bacteria, including Akkermansia muciniphila , Prevotella , Alistipes , and Odoribacter . Among clinical responders, fecal butyrate levels decreased concomitantly with an increase in plasma butyrate concentrations. Fecal microbiota transplantation from post-VNS patients into mice reduced seizure severity and improved gut barrier integrity. In a murine model of epilepsy, VNS similarly increased the abundance of Akkermansia and plasma butyrate concentrations, decreased fecal butyrate levels, and abolished its antiseizure effects upon vagotomy. Either colonization with Akkermansia muciniphila or exogenous butyrate supplementation was sufficient to reduce seizures and anxiety-like behavior, effects that also required intact vagal signaling. Our findings define a microbiota–butyrate–vagal pathway essential for the therapeutic effects of VNS, highlighting the gut–brain axis as a target for epilepsy treatment. GRAPHICAL HIGHLIGHTS: Vagus nerve stimulation (VNS) remodels the gut microbiota and alter the level of butyrate. VNS enriches short-chain fatty acids-producing bacteria, specifically Akkermansia muciniphila , in both humans and mice. Transplantation of VNS-conditioned microbiota confers seizure protection and restores gut barrier integrity. Akkermansia muciniphila or exogenous butyrate is sufficient to reduce seizures via a vagus nerve-dependent pathway.

Background: Intracerebral hemorrhage (ICH) causes neurological dysfunction and white matter injury (WMI) characterized by myelin loss, axonal injury and myelin debris accumulation. Microglia-mediated debris clearance is critical for WMI repair. The microbiota-gut-brain axis plays an essential role in the central nervous system diseases, one of the ways in which gut microbiota affects brain is via producing metabolites. Indole-3-proprionic acid (IPA), a tryptophan-derived metabolite that mainly produced by Clostridium sporogenes , exhibits anti-inflammatory and neuroprotective properties. However, its effect on ICH remains unclear. This study aims to investigate the IPA level after ICH and the therapeutic effects of IPA on neurological deficits and WMI, as well as the potential mechanisms underlying IPA-mediated neuroprotection. Methods: An ICH model was established using C57BL/6 mice, which then received intragastric IPA (20 mg/kg/day). Fecal abundance of IPA-related genes and IPA levels in feces and plasma were measured by qPCR and UPLC-MS/MS. Behavioral tests, qPCR, and immunofluorescence staining were used to assess neurological function, myelin integrity, and axonal injury. In vitro , BV2 microglia, with or without Stap1 knockdown, were co-cultured with myelin debris to assess IPA’s effects on phagocytosis. Additionally, targeted plasma IPA profiling was performed in 30 ICH patients and 30 matched healthy controls. Results: The relative abundance of IPA production-related genes and IPA levels in feces and plasma were significantly decreased after ICH and remained low into the chronical phase. After IPA administration, the neurological deficits, myelin loss and axonal injury of mice with ICH were significantly improved. In vitro , IPA increased BV2 microglia myelin debris phagocytosis by inhibiting Stap1 expression. IPA levels were significantly reduced in ICH patients, consistent with ICH mouse model. Conclusions: Our findings demonstrated that the gut microbiota-derived metabolite IPA could facilitate neurological deficits recovery and alleviate WMI, which could be a promising therapeutic strategy to improve ICH prognosis.

Gliomas, with their intricate and aggressive nature, call for a detailed visualisation of their vasculature. Traditional 2D imaging often overlooks the spatial heterogeneity of tumours. Our study overcomes this by combining tissue clearing, 3D‐confocal microscopy imaging and deep learning‐aided vessel extraction, achieving comprehensive 3D visualisation of glioma vasculature in intact human tissue. Specifically, we treated formalin‐fixed thick human glioma tissue sections (500 μm) with OPTIClear for transparency and performed immunofluorescent labelling. Using confocal microscopy, we obtained 3D images of glioma vasculature. For vessel extraction, we employed a specialised 3D U‐Net, enriched with image preprocessing and post‐processing methods. In addition, we obtained 3D images of astrocytes or glioma cells, cell nuclei and vasculature with vascular basement membrane staining. Our findings indicated that OPTIClear‐enabled tissue clearing yielded a holistic 3D representation of immunolabelled vessels and surrounding cells in human glioma samples. Our deep learning technique outperformed the traditional Imaris approach in terms of accuracy and efficiency in vessel extraction. Furthermore, discernible variations in vascular morphological metrics were observed between low‐ and high‐grade gliomas, revealing the spatial heterogeneity of human glioma vessels. Analysis of other markers demonstrated differences in glioma cell morphology and vessel wall disruption across grades. In essence, our innovative blend of tissue clearing and deep learning not only enhances 3D visualisation of human glioma vasculature but also underscores morphological disparities across glioma grades, potentially influencing pathological grading, therapeutic strategies and prognostic evaluations.

Despite extensive research, currently, no biomarkers are available for clinical use in intracranial aneurysm (IA). However, recent advancements in high‐throughput technologies have opened new possibilities for understanding IA's complex pathophysiology. These technologies generate extensive datasets across multiple molecular domains, including genomics, transcriptomics, proteomics, metabolomics, and microbiomics. By integrating multi‐omics data, it is now possible to analyze thousands of genes, RNAs, proteins, metabolites, and microbiota simultaneously, revealing complex interaction networks across these molecular layers. This integrative approach offers significant insights into IA pathogenesis, helps identify potential therapeutic targets, and paves the way for discovering novel biomarkers. In this review, we provide an overview of the current understanding of IA pathology and highlight recent advances in biomarker research through multi‐omics approaches. We also propose strategies for integrating multi‐modal data to accelerate the development of molecular tools for the diagnosis, rupture prediction, prognosis, and personalized treatment of IA.