Post-stroke cognitive impairment (PSCI) is characterized by progressive cognitive decline following ischemic stroke, and recent studies have suggested that natural compounds may offer therapeutic benefits; however, the effects and mechanisms of Betulin in PSCI remain unclear. Male C57BL/6 mice were subjected to ischemic stroke surgery to induce PSCI and treated with Betulin (50 mg/kg/day) for 3 weeks, followed by assessments of cognitive impairment, pathological changes, and the production of pro-inflammatory cytokines. Network pharmacology and RNA sequencing were performed to explore potential mechanisms. In vitro, BV2 microglia were stimulated with lipopolysaccharide to examine the anti-inflammatory effects of Betulin. Betulin improved cognitive performance, reduced microglial activation, and attenuated neuroinflammation, as evidenced by decreased levels of TNF-α, IL-1β, and IL-6. Mechanistically, the epidermal growth factor receptor (EGFR)/JAK2/STAT3 pathway was identified as a key pathway potentially involved in these effects. Further experiments with EGFR point-mutation constructs indicated that disrupting the Betulin-EGFR interaction attenuated the inhibitory effect of Betulin on the EGFR/JAK2/STAT3 pathway. Collectively, these findings suggest that Betulin mitigates microglia-driven neuroinflammation by targeting EGFR and may represent a potential therapeutic candidate for PSCI.

Benzene is an occupational and environmental toxicant, and its exposure is associated with increased risk of Alzheimer’s disease (AD), yet its underlying mechanisms, particularly the roles of benzene metabolites, have not been elucidated. Here, benzene and its major metabolites were systematically evaluated through physicochemical characterization, blood–brain barrier permeability prediction, target identification, and pathway enrichment analysis. Single-nucleus RNA sequencing data were further analyzed using pathway activity scoring approaches to assess cell-type-specific signaling patterns. Molecular docking and molecular dynamics simulations were performed to explore interactions between selected metabolites and key regulatory proteins, and in vitro experiments were conducted for validation. Among the analyzed compounds, catechol was prioritized based on its predicted central nervous system accessibility and strong association with AD-related pathways. Pathway enrichment and transcriptomic scoring consistently highlighted NF-κB signaling as a key pathway, with preferential activation in microglia. Mechanistically, RELA (p65), a central regulator of NF-κB signaling, was identified as a potential target, and structural as well as experimental analyses supported the interaction between catechol and p65. Functional validation demonstrated that catechol enhanced Aβ-induced microglial activation and inflammatory responses. Collectively, these findings suggest that catechol may act as a critical mediator linking benzene exposure to microglia-driven neuroinflammation in AD, providing mechanistic insight into the contribution of environmental pollutants to neurodegenerative disease progression.

Hexafluoropropylene oxide-dimer acid (GenX or HFPO-DA) is a novel per- and polyfluoroalkyl substance developed as a replacement for legacy compounds, yet its potential neurotoxic effects remain poorly understood. In this study, we combined bibliometric profiling, in silico target prediction, in vivo behavioral assessments, single-nucleus RNA sequencing (snRNA-seq), network biology, machine learning, molecular docking, and in vitro validation to explore the potential relevance of GenX in Alzheimer's disease (AD). Bibliometric analysis revealed increasing research attention to GenX-associated health hazards, including emerging concerns regarding brain-related effects. Target prediction identified 301 putative GenX-related genes, which were significantly enriched in AD-related pathways. Behavioral analyses demonstrated that chronic GenX exposure impaired recognition memory and spatial learning in mice. Analysis of human prefrontal cortex snRNA-seq data revealed pronounced transcriptional alterations in AD neurons and identified 200 AD-related neuronal DEGs. Integration with GenX targets yielded 10 overlapping genes, which were further prioritized through protein-protein interaction (PPI) network analysis. Machine learning further identified an 8-gene signature with robust diagnostic performance across training and external validation cohorts. Molecular docking showed favorable binding affinities between GenX and core target proteins. Finally, GenX exposure reduced SH-SY5Y cell viability, activated the RAS-RAF-MEK-ERK cascade, and promoted apoptosis-related alterations, supporting a MAPK-centered neurotoxic mechanism potentially relevant to AD-associated neuronal vulnerability. Collectively, this integrative multi-level analysis provides mechanistic insights into the potential neurotoxic effects of GenX and underscores its possible relevance to neurodegeneration-associated molecular processes in AD.

BACKGROUND:The probiotic Lactobacillus mucosae has been widely shown to have many positive effects. However, its neuroprotective effects and underlying mechanism in Alzheimer's disease (AD) remain elusive. METHODS:Male APP/PS1 mice were treated for 4 weeks with L. mucosae WMU007, followed by the evaluation of cognitive function, neuronal damage, amyloid-β (Aβ) deposition, and Tau phosphorylation. RNA-seq coupled with Gene Ontology (GO) enrichment analysis implicated L. mucosae WMU007 in modulating oxidative stress in this AD model. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and qPCR were performed to identify the specific mechanism by which this probiotic suppresses oxidative stress in the pathogenesis of AD. In addition, we quantified the levels of classical oxidative stress markers, such as superoxide dismutase 2 (SOD2) and glutathione peroxidase 4 (GPX4). We also examined the expression of cannabinoid receptor type 2 (CB2) and its key downstream regulators in the redox pathway, namely nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1), in both animal and cellular models. RESULTS:Our results showed that treatment with L. mucosae WMU007 significantly decreased cognitive impairment, neuronal damage, Aβ deposits, and Tau phosphorylation in APP/PS1 mice. Activation of CB2 was identified as the key mechanism by which L. mucosae WMU007 reduces oxidative stress in AD. In addition, L. mucosae WMU007 reduced oxidative stress and increased the levels of CB2 pathway-related proteins in vivo and in vitro. CONCLUSIONS:These results indicate that L. mucosae WMU007 confers neuroprotection in AD by targeting CB2-mediated oxidative pathways, highlighting its therapeutic potential as a novel probiotic intervention.

BACKGROUND:Trimethylamine-N-oxide (TMAO), a metabolite produced by gut microbiota, has been linked to brain disease; however, its role in intracerebral hemorrhage (ICH) remains unclear. METHODS:Animal experiments were conducted to demonstrate the effects of TMAO on collagenase-induced rat models of ICH. Neurological function was evaluated using the modified neurological severity score (mNSS), and neuronal damage was assessed by NeuN staining. Microglial activation and pro-inflammatory cytokine expression were examined. To further investigate the mechanism of TMAO, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis on its predicted molecular targets. BV2 microglia were treated with TMAO to assess the levels of reactive oxygen species (ROS), cyclooxygenase-2 (COX-2), NOD-like receptor protein 3 (NLRP3), and caspase-1. Moreover, ICH rats were intragastrically treated with TMAO precursor L-carnitine (LC), and antibiotic cocktail treatment was used to deplete the gut microbiota, then assessed the effect. RESULTS:Our results showed that TMAO administration exacerbated neurological deficits and microglial-mediated neuroinflammation in ICH rats. NOD-like receptor signaling pathway was a key mechanism promoting ICH pathogenesis and confirmed that TMAO supplementation exacerbated microglial activation by regulating NLRP3 inflammasome activity in vitro. Moreover, gut microbiota depletion attenuated TMAO-induced activation of NLRP3 and the subsequent neuroinflammatory response in ICH. CONCLUSION:Collectively, these findings showed that Microbial Metabolite TMAO contributes to ICH-induced neuroinflammation by activating the NLRP3 signaling pathway.

Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra. However, the metabolic mechanisms linking neuronal vulnerability to ferroptosis remain poorly understood. To address this question, we integrated single-nucleus and bulk RNA sequencing datasets from human substantia nigra to characterize cell-type-specific transcriptional alterations in PD. Integrative transcriptomic analyses including Weighted gene co-expression network analysis, pathway enrichment analysis, and correlation analysis, were further validated using MPTP-induced mouse models and MPP⁺-treated SH-SY5Y cells combined with gene silencing and ferroptosis-related assays. In addition, structure-based virtual screening of 12,316 DrugBank compounds was conducted to identify potential modulators of key metabolic targets. We found that dopaminergic neurons exhibited preferential activation of ferroptosis signatures accompanied by marked dysregulation of amino acid metabolic pathways. Among metabolism-related genes, argininosuccinate synthase 1 (ASS1) emerged as a key candidate with favorable diagnostic performance and significant positive correlations with ferroptosis-suppressive genes, including GPX4 and GSS. In MPTP-induced mice, ASS1 expression was significantly reduced in the substantia nigra and dopaminergic neurons. Consistently, ASS1 silencing in MPP⁺-treated SH-SY5Y cells further decreased cell viability and reduced TH and GPX4 expression, while markedly increasing lipid peroxidation, indicating enhanced ferroptosis susceptibility. Virtual screening further identified several therapeutically relevant compounds with favorable predicted binding to an ASS1 docking pocket. Collectively, these findings identify ASS1-associated amino acid metabolic impairment as a prominent feature of dopaminergic ferroptosis in PD and highlight ASS1 as a potential therapeutic target for neuroprotective intervention.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by prominent neuroinflammation. Microglia, the resident immune cells of the central nervous system, play a key role in AD-associated neuroinflammation, yet the molecular mechanisms regulating their inflammatory activation remain incompletely understood. In this study, we integrated human single-nucleus RNA sequencing with computational analyses and experimental validation to identify potential regulators of inflammatory microglial states in AD. Microglial subpopulations were characterized, and pseudotime analysis was performed to infer transcriptional state transitions across neuropathological stages. High-dimensional weighted gene co-expression network analysis (hdWGCNA) and machine learning were used to prioritize candidate genes for functional validation. KLHL2 was identified as a candidate regulator, and its expression progressively decreased along the inferred pseudotime trajectory, with concordant decreases in Klhl2 mRNA and KLHL2 protein levels observed in APP/PS1 mice and Aβ42-stimulated BV2 cells. In contrast, WNK3 expression level increased without corresponding changes in Wnk3 mRNA. In BV2 cells, Klhl2 overexpression reduced WNK3 expression level, JNK and c-Jun phosphorylation, and pro-inflammatory mediator expression, whereas Klhl2 knockdown produced the opposite effects. Collectively, these findings support KLHL2 as a negative regulator of microglial inflammatory activation and suggest the involvement of WNK3/JNK/c-Jun signaling in this process.

Gut microbial metabolites abnormity links to Alzheimer’s disease (AD) progression, yet the mechanism remains unknown. Here, we observed a markedly decreased level of indole-3-acetic acid (IAA) in AD patients, and the IAA level was negatively correlated with cognitive impairment. IAA supplementation improved cognitive dysfunction and synaptic damage, and suppressed microglial activation and synaptic phagocytosis in AD mouse and cell models. RNA sequencing revealed an increase in phagocytosis-associated pathway activity and gene expression, and C-C chemokine receptor 4 (CCR4) was identified as a key regulator of this process. IAA could inhibit the expression level of CCR4, and siRNAs CCR4 markedly inhibited microglia-mediated phagocytosis of synapse. We further demonstrated that microglial CCR4 interacts with aryl hydrocarbon receptor (AHR), a key receptor of IAA, and proposed the hypothesis that AHR binds to the CCR4 promoter, thereby inhibiting its transcriptional activity. Moreover, we further revealed that bacteria producing IAA supplementation inhibited microglia-mediated synaptic loss by down-regulating CCR4, thus delaying Alzheimer’s progression. These findings elucidate the mechanisms underlying microbial metabolite IAA’s impact on AD, highlighting that targeting CCR4 inhibition in microglia-mediated synaptic phagocytosis represents a promising therapeutic strategy for AD.

BACKGROUND:Major Depressive Disorder (MDD) is increasingly viewed through the lens of the neuroinflammatory hypothesis and gut-brain axis dysfunction. Short-Chain Fatty Acids (SCFAs), the primary metabolites produced by the gut microbiota, are vital signaling molecules that maintain intestinal barrier integrity, modulate peripheral immunity, and influence microglial function. While individual studies suggest altered SCFAs levels in MDD, a definitive, quantitative synthesis establishing a robust biomarker signature is currently lacking. This meta-analysis aimed to precisely characterize the signature of SCFAs (acetic, propionic, butyric, and isobutyric acid) in MDD patients compared to healthy controls. METHODS:We systematically searched major databases across PubMed, Embase, and Web of Science databases for studies quantifying SCFAs levels up to September 15, 2025. Studies examining SCFAs levels in depressed patients and depressive-like murine models, as well as studies investigating SCFAs interventions for depressive-like behavior, were selected for synthesis. Risk of bias was evaluated using the Newcastle-Ottawa Scale. The effect sizes were synthesized using a random-effects model and presented as standardized mean differences. RESULTS:Eight human and 52 murine studies were included in the meta-analyses. Depressed patients showed significantly lower concentrations in blood (plasma and serum) of propionic (SMD = -0.60, p-value = 0.007), butyric (SMD = -0.50, p-value = 0.006), isobutyric (SMD = -0.72, p-value = 0.020), valeric (SMD = -0.43, p-value = 0.040) and isovaleric acids (SMD = -0.75, p-value = 0.002). Secondary analysis of MDD patients confirmed consistent reductions. High heterogeneity was observed. In murine models, SCFAs depletion was frequently observed, while supplementation improved depressive-like behaviors. CONCLUSION:MDD is characterized by a significant, quantifiable deficit in the circulating SCFAs metabolome, which provides strong empirical validation for the gut-brain axis hypothesis in depression. We advocate for the investigation of SCFAs as novel, measurable peripheral biomarkers and targeted therapeutic agents (e.g., butyrate supplementation) for precision nutritional psychiatry.

Microglia-mediated neuroinflammation is a key driver of Alzheimer's disease (AD) progression, exacerbating neuronal damage and pathological changes. Pterostilbene (PTE), a natural anti-inflammatory stilbenoid, shows neuroprotective potential in AD, but its specific mechanism in regulating AD-related neuroinflammation remains unclear. Here, we explored the anti-neuroinflammatory effect and mechanisms of PTE against AD. APPswe/PS1dE9 (APP/PS1) transgenic mice were treated intragastrically with PTE for 4 weeks, followed by evaluation of cognitive function and pathological changes. Amyloid-β burden, Tau protein phosphorylation, microglial activation, and proinflammatory cytokines production were analyzed. To further investigate the potential mechanism of PTE, an integrated approach combining network pharmacology, RNA sequencing, molecular docking, molecular dynamics simulations, and cell transfection techniques were conducted. Our results showed that PTE treatment improved cognitive impairment, amyloid-β deposits, Tau protein phosphorylation, microglia activation, and production of tumor necrosis factor-α, interleukin-1β, and interleukin-6 in vivo and in vitro. Notably, molecular docking predicted that PTE has binding affinity for Janus kinase 2 (JAK2) at LYS-857, LYS-882, and LEU-932. Consistently, site-directed mutagenesis reduced the inhibitory effect of PTE on JAK2/signal transducer and activator of transcription 3 (STAT3) phosphorylation, supporting JAK2 as a functional target. Meanwhile, we revealed that PTE effectively inhibited activation of microglia in the APP/PS1 mice by regulating JAK2-STAT3 pathway. These findings indicate that PTE treatment could attenuate microglia-mediated neuroinflammation via regulating JAK2-STAT3 signaling pathway, which might provide a novel option to elucidate the effects of PTE on AD.

Recent evidence suggests that microglial activation, driven by a metabolic shift towards glycolysis, was involved in the pathogenesis of Alzheimer’s disease (AD). Although sphingolipid (SL) dysregulation has been linked to AD, the role of 1-deoxysphinganine (deoxySO), an atypical and neurotoxic SL, on microglial glycolytic reprogramming remains unclear. We measured serum deoxySO levels in AD patients and evaluated their association with cognitive performance. In APP/PS1 mice, we examined cerebral deoxySO level and the effects of deoxySO supplementation on cognitive function, neuropathology, and microglial activation. In vitro, BV2 microglia were used to assess inflammatory and metabolic changes via qPCR, western blot, ELISA, and RNA-seq analyses. The serum deoxySO levels were significantly elevated in AD patients, which was positively correlated with cognitive impairment. APP/PS1 mice exhibited increased cerebral deoxySO level, and supplementation with deoxySO could exacerbate cognitive deficits and Aβ plaque accumulation. Moreover, deoxySO supplementation increased microglial activation and enhanced inflammation in vivo and in vitro AD models. qPCR analysis identified disease-associated microglia (DAM) as a key deoxySO-responsive subpopulation, while RNA-seq revealed significant enrichment of genes related to glycolytic metabolism and inflammatory responses. Subsequently, qPCR confirmed that deoxySO promoted glycolytic metabolic reprogramming, which promoted DAM activation, thereby aggravating AD pathology. These findings identify deoxySO as a critical metabolic driver that links to microglial glycolytic activation and neuroinflammation, suggesting that targeting deoxySO-mediated metabolic pathways may offer a novel therapeutic strategy for AD.

Recent studies have highlighted the vital role of gut microbiota in the pathogenesis of Ischemic stroke (IS). However, the effects and underlying mechanisms of atorvastatin on IS via regulating gut-brain axis remain unclear. Thus, this study aimed to explore the relationship between atorvastatin, gut microbiota and IS through animal experiments, clinical trials and Mendelian randomization (MR) analysis. Male mice were induced with bilateral common carotid artery occlusion (BCCAO) to establish an IS animal model, and then intragastrically treated with atorvastatin. Neurological deficits, microglia activation, and the levels of NLRP3 inflammasome and NF-κB pathway-related proteins were detected. Meanwhile, gut microbiota composition and intestinal barrier integrity were evaluated. In this prospective study, we recruited IS patients undergoing atorvastatin treatment, evaluated their functional outcomes, collected fecal samples, and assessed gut microbiota functions. Moreover, the causal relationships between specific bacteria, inflammation and IS were assessed via MR analysis. Our results showed that atorvastatin treatment significantly improved neurobehavioral deficits, suppressed activation of microglia, and inhibited NF-κB pathway as well as the formation of the NLRP3 inflammasome, reduced the release of inflammatory cytokines, including IL-1β and IL-18, which were reversed by antibiotics treatment. We further identified an increase in the genus Lachnospiraceae NK4A136 in atorvastatin-treated mice. Subsequent clinical experiments were conducted to explore the effects by analyzing the characteristic bacteria, such as Ruminococcus torques and Lachnospiraceae NK4A136. The higher abundances of Ruminococcus torques and Lachnospiraceae NK4A136 were associated with a good outcome in atorvastatin-treated IS patients. MR analysis further revealed that these microbes were negatively correlated with inflammatory factor levels, and showed inhibitory effects on the Akt/NF-κB/NLRP3 pathway and PLA2G7 gene expression. These findings demonstrated the roles of atorvastatin in regulating Akt/NF-κB/NLRP3 pathway to inhibit neuroinflammation through specific bacteria, which implied a novel way for IS treatment.

Emerging evidence suggests that probiotics may have a significant impact on the regulation of mitochondrial oxidative stress in Alzheimer’s disease (AD). However, the research focusing on the specific bacteria responsible for mitochondrial oxidative stress of AD remains limited. This study explores the impact and underlying mechanisms of probiotic W. confusa WMU005 on mitochondrial oxidative stress in AD. The probiotic W. confusa WMU005 was isolated from the healthy people. APP/PS1 mice were administered live W. confusa WMU005 for 4 weeks and then subjected to cognitive test. Aβ deposition, Tau phosphorylation, neuronal apoptosis, oxidative stress, and mitochondrial damage of brain were measured. Additionally, APP/SWE cells treated with W. confusa WMU005 fermentation broth showed altered levels of silent information regulator 1 (SIRT1) and proliferator-activated receptor γ coactivator 1α (PGC-1α). Meanwhile, we confirmed that W. confusa WMU005 could regulate SIRT1 pathway in APP/PS1 mice. Our results revealed that W. confusa WMU005 improved cognitive function, reduced Aβ and Tau pathology. Furthermore, W. confusa WMU005 treatment exerted antioxidative effects by activating the SIRT1 pathway. We further demonstrated that W. confusa WMU005 mitigated the mitochondrial oxidative stress via activating SIRT1 pathway in vitro. Meanwhile, we revealed that W. confusa WMU005 effectively inhibited the mitochondrial oxidative stress in the APP/PS1 mice by regulating SIRT1 pathway. These findings suggest that W. confusa WMU005 exerts protective effects on AD through the involvement of the SIRT1 signaling pathway, which opened avenues for novel therapeutic strategies towards treating AD.

Organoids are three-dimensional (3D) cell cultures derived from human pluripotent stem cells or adult stem cells that recapitulate the cellular heterogeneity, structure, and function of human organs. These microstructures are invaluable for biomedical research due to their ability to closely mimic the complexity of native tissues while retaining human genetic material. This fidelity to native organ systems positions organoids as a powerful tool for advancing our understanding of human biology and for enhancing preclinical drug testing. Recent advancements have led to the successful development of a variety of organoid types, reflecting a broad range of human organs and tissues. This progress has expanded their application across several domains, including regenerative medicine, where organoids offer potential for tissue replacement and repair; disease modeling, which allows for the study of disease mechanisms and progression in a controlled environment; drug discovery and evaluation, where organoids provide a more accurate platform for testing drug efficacy and safety; and microecological research, where they contribute to understanding the interactions between microbes and host tissues. This review provides a comprehensive overview of the historical development of organoid technology, highlights the key achievements and ongoing challenges in the field, and discusses the current and emerging applications of organoids in both laboratory research and clinical practice.

Depression, a highly prevalent and relapsing mental disorder, exacts profound personal and socioeconomic tolls globally, warranting urgent scientific and clinical attention. Emerging evidence from both preclinical models and human clinical investigations has established the microbiota-gut-brain axis (MGBA) as a critical determinant in depression pathogenesis. This intricate bidirectional network integrates gut microbiota with central nervous system function, influencing mental health through mechanisms previously underrecognized. This review systematically synthesizes gut microbiota alterations associated with depression and their impacts on neuroendocrine, neuroimmune, and metabolic pathways. Advanced therapeutic strategies targeting the MGBA are discussed, including probiotics, fecal microbiota transplantation, and artificial intelligence-enabled microbiome interventions for depression management. While challenges in standardization, mechanistic understanding, efficacy and safety remain, MGBA-centered approaches offer a promising shift toward microbiota-based diagnostics and personalized treatments for depression.

Many diseases are influenced by environmental temperature, and recent studies have confirmed that cold exposure increases the risk of conditions such as ischemic stroke (IS). However, direct evidence supporting this hypothesis is lacking, and the molecular mechanisms through which cold exposure affects IS remain unclear. In this study, we found that chronic cold exposure increased platelet aggregation and the levels of certain inflammatory factors in high-risk stroke patients (HR), thereby increasing the risk of IS. Furthermore, before and after a cold wave, we observed gut microbiota dysbiosis in the HR group, including reduced relative abundance differences in Lachnospiraceae and Ruminococcaceae. The relative abundances of the Prevotella_9 and Catenibacterium genera increased, whereas that of Anaerostipes decreased. Notably, the results of fecal microbiota transplantation (FMT) indicated that cold-adapted microbiota transplantation partially replicated the microbiota characteristics of each donor subject and replicated the effects of cold exposure in C57BL/6J mice. Cold exposure impaired intestinal barrier function and interfered with microbial functions, such as increased lipid metabolism and LPS production, particularly by increasing the levels of TMAO derived from the gut microbiota. Our findings identify the significant role of abnormal gut microbiota-derived metabolites in cold exposure-related IS and highlight the potential opportunity to prevent or treat cold-related IS through the modulation of the gut microbiota.

An increasing number of studies have shown that commensal gut microbes may be involved in the pathogenesis of Alzheimer's disease (AD). The influence of gut microbe-derived metabolites, such as trimethylamine N-oxide (TMAO), has attracted a lot of attention. However, the influence and pathways mediated by gut microbe-derived metabolites in the pathogenesis of AD remain uncertain. Here, we observed a significant increase in the abundance of Blautia coccoides in AD patients, which showed positive predictive value for serum p-Tau181 levels. Supplementation with B. coccoides could exacerbate cognitive impairment and Tau phosphorylation in P301s mice. We identified TMAO as a key B. coccoides-derived metabolite promoting Tau phosphorylation by functional gene analysis, metabolomic analysis and VIP analysis, and further demonstrated that it was able to promote oxidative stress of AD in vitro. Mechanistically, TMAO could bind to hypoxia-inducible factor 1 alpha (HIF1α) at 235-238 sites, which promoted oxidative stress through the inhibition of HIF1α signal, thereby aggravating AD pathology. This study elucidated the important role of B. coccoides-derived metabolite TMAO in exacerbating AD and provided new insights for gut microbe/metabolite-based therapeutic strategies.

Phthalates (PEs) are widely used plasticizers in polymer products, and humans are increasingly exposed to them. This study was designed to investigate the alleviative effect of phytochemicals quercetin (Que) against male reproductive toxicity caused by the mixture of three commonly used PEs (MPEs), and further to explore the underlying mechanism. Forty-eight male SD rats were randomly and evenly divided into control group, Que group, MPEs group and MPEs+Que group (n = 12); The oral exposure doses of MPEs and Que were 450 mg/kg/d and 50 mg/kg/d, respectively. After 91 days of continuous intervention, compared with control group, the testes weight, epididymis weight, serum sex hormones, and anogenital distance were significantly decreased in MPEs group (P < 0.05); Testicular histopathological observation showed that all seminiferous tubules were atrophy, leydig cells were hyperplasia, spermatogenic cells growth were arrested in MPEs group. Ultrastructural observation of testicular germ cells showed that the edges of the nuclear membranes were indistinct, and the mitochondria were severely damaged with the cristae disrupted, decreased or even disappeared in MPEs group. Immunohistochemistry and Western blot analysis showed that testicular CYP11A1, CYP17A1 and 17β-HSD were up-regulated, while StAR, PIWIL1 and PIWIL2 were down-regulated in MPEs group (P < 0.05); However, the alterations of these parameters were restored in MPEs+Que group. The results indicated MPEs disturbed steroid hormone metabolism, and caused male reproductive injuries; whereas, Que could inhibit MPEs’ male reproductive toxicity, which might relate to the restored regulation of steroid hormone metabolism.

Gut microbiota plays a crucial role in the pathogenesis of Alzheimer disease (AD). Here, we found that AD patients had significantly lower abundance of Agathobacter, which were negatively correlated with cognitive impairment. Animal experiments showed that Agathobacter rectalis (A. rectalis) supplementation increased beneficial commensal bacteria, significantly improved pathological damage, and suppressed microglial activation in APP/PS1 mice. We further demonstrated that butyric acid, a metabolite of A. rectalis, reduced microglial activation and pro-inflammatory factor production via Akt/ nuclear factor κB (NF-κB) signal pathway in vitro. Meanwhile, we revealed that A. rectalis effectively inhibited activation of microglia in the APP/PS1 mice by regulating Akt/ NF-κB pathway. This finding highlights the role of A. rectalis and its metabolite butyrate in mitigating neuroinflammation in AD by modulating the Akt/NF-κB pathway.