为了解决海量数据的高速传输问题,本文以AXIe(Advanced TCA Extensions for Instrumentation)总线为传输架构,重点设计数据的高速缓存和传输接口,并设计时间交织数据采集模块完成AXIe数据采集传输接口验证.通过两片ADC实现时间交织数据...为了解决海量数据的高速传输问题,本文以AXIe(Advanced TCA Extensions for Instrumentation)总线为传输架构,重点设计数据的高速缓存和传输接口,并设计时间交织数据采集模块完成AXIe数据采集传输接口验证.通过两片ADC实现时间交织数据采样功能,将DDR3作为数据的深存储单元,采用PCI Express实现数据高速传输.在FPGA上完成设计,使用ILA嵌入式逻辑分析仪进行功能验证.结果表明,该设计能很好地实现交织采样功能,完成基于AXIe总线的数据传输.展开更多
The comorbidity of skin and gastrointestinal tract(GIT)diseases,primarily driven by the gut-skin axis(GSA),is well established.However,the genetic contribution to the GSA remains unclear.Here,using genome-wide associa...The comorbidity of skin and gastrointestinal tract(GIT)diseases,primarily driven by the gut-skin axis(GSA),is well established.However,the genetic contribution to the GSA remains unclear.Here,using genome-wide association study(GWAS)summary statistics from European populations,we performed a genome-wide pleiotropic analysis to investigate the shared genetic basis and causal associations between skin and GIT diseases.We observed extensive genetic correlations and overlaps between skin and GIT diseases.A total of 298 pleiotropic loci were identified,75 of which were colocalized,and 61 exhibited pleiotropic effects across multiple trait pairs,including 2p16.1(PUS10),6p21.32(HLA-DRB1),10q21.2(ZNF365),and 19q13.11(SLC7A10).Additionally,five novel loci were identified based on the pleiotropic analysis;among them,the 15q22.2 locus harboring RORA was validated by the latest inflammatory bowel disease GWAS.Gene-based analysis identified 394 unique pleiotropic genes,which were enriched in GSA-associated tissues and the immune system,and protein-protein interaction analysis further revealed that the GPCR-cAMP,chromatin remodeling,JAK-STAT,and HLA-mediated immunity pathways were involved in GSA comorbidity.Notably,the JAK-STAT pathway showed strong potential for drug repurposing,with adalimumab targeting tumor necrosis factor and ustekinumab targeting interleukin-12 subunit beta already being used to treat both skin and GIT diseases.Finally,Mendelian randomization analysis identified five significant causal associations,and subsequent mediation analysis identified three potential microbiota-GIT-skin pathways.Taken together,our study demonstrated that the shared genetic factors between skin and GIT diseases were widely distributed across the genome.These findings will enhance our understanding of the genetic mechanisms underlying GSA comorbidity.展开更多
Intracerebral hemorrhage is the most dangerous subtype of stroke,characterized by high mortality and morbidity rates,and frequently leads to significant secondary white matter injury.In recent decades,studies have rev...Intracerebral hemorrhage is the most dangerous subtype of stroke,characterized by high mortality and morbidity rates,and frequently leads to significant secondary white matter injury.In recent decades,studies have revealed that gut microbiota can communicate bidirectionally with the brain through the gut microbiota–brain axis.This axis indicates that gut microbiota is closely related to the development and prognosis of intracerebral hemorrhage and its associated secondary white matter injury.The NACHT,LRR,and pyrin domain-containing protein 3(NLRP3)inflammasome plays a crucial role in this context.This review summarizes the dysbiosis of gut microbiota following intracerebral hemorrhage and explores the mechanisms by which this imbalance may promote the activation of the NLRP3 inflammasome.These mechanisms include metabolic pathways(involving short-chain fatty acids,lipopolysaccharides,lactic acid,bile acids,trimethylamine-N-oxide,and tryptophan),neural pathways(such as the vagus nerve and sympathetic nerve),and immune pathways(involving microglia and T cells).We then discuss the relationship between the activated NLRP3 inflammasome and secondary white matter injury after intracerebral hemorrhage.The activation of the NLRP3 inflammasome can exacerbate secondary white matter injury by disrupting the blood–brain barrier,inducing neuroinflammation,and interfering with nerve regeneration.Finally,we outline potential treatment strategies for intracerebral hemorrhage and its secondary white matter injury.Our review highlights the critical role of the gut microbiota–brain axis and the NLRP3 inflammasome in white matter injury following intracerebral hemorrhage,paving the way for exploring potential therapeutic approaches.展开更多
Short-chain fatty acids,metabolites produced by the fermentation of dietary fiber by gut microbiota,have garnered significant attention due to their correlation with neurodegenerative diseases,particularly Parkinson’...Short-chain fatty acids,metabolites produced by the fermentation of dietary fiber by gut microbiota,have garnered significant attention due to their correlation with neurodegenerative diseases,particularly Parkinson’s disease.In this review,we summarize the changes in short-chain fatty acid levels and the abundance of short-chain fatty acid-producing bacteria in various samples from patients with Parkinson’s disease,highlighting the critical role of gut homeostasis imbalance in the pathogenesis and progression of the disease.Focusing on the nervous system,we discuss the molecular mechanisms by which short-chain fatty acids influence the homeostasis of both the enteric nervous system and the central nervous system.We identify key processes,including the activation of G protein-coupled receptors and the inhibition of histone deacetylases by short-chain fatty acids.Importantly,structural or functional disruptions in the enteric nervous system mediated by these fatty acids may lead to abnormalα-synuclein expression and gastrointestinal dysmotility,which could serve as an initiating event in Parkinson’s disease.Furthermore,we propose that short-chain fatty acids help establish communication between the enteric nervous system and the central nervous system via the vagal nerve,immune circulation,and endocrine signaling.This communication may shed light on their potential role in the transmission ofα-synuclein from the gut to the brain.Finally,we elucidate novel treatment strategies for Parkinson’s disease that target short-chain fatty acids and examine the challenges associated with translating short-chain fatty acid-based therapies into clinical practice.In conclusion,this review emphasizes the pivotal role of short-chain fatty acids in regulating gut-brain axis integrity and their significance in the pathogenesis of Parkinson’s disease from the perspective of the nervous system.Moreover,it highlights the potential value of short-chain fatty acids in early intervention for Parkinson’s disease.Future research into the molecular mechanisms of short-chain fatty acids and their synergistic interactions with other gut metabolites is likely to advance the clinical translation of innovative short-chain fatty acid-based therapies for Parkinson’s disease.展开更多
Accumulating evidence indicates that the neuro-immune axis is central to gastric cancer pathogenesis.Dynamic,bidirectional signaling between neural circuits and immune cells promotes tumor progression,shapes an immuno...Accumulating evidence indicates that the neuro-immune axis is central to gastric cancer pathogenesis.Dynamic,bidirectional signaling between neural circuits and immune cells promotes tumor progression,shapes an immunosuppressive microenvironment,and contributes to therapeutic resistance.We synthesize current knowledge on how autonomic(sympathetic and parasympathetic)and sensory innervation regulate gastric cancer biology.These circuits act through neurotransmitters(catecholamines,acetylcholine)and neuropeptides(substance P[SP],calcitonin gene-related peptide[CGRP])to foster tumor growth and angiogenesis,facilitate perineural invasion,and enable immune evasion by recruiting suppressive myeloid and lymphoid populations and by inducing checkpoint molecule expression.We also examine how chronic stress and the microbiota-gut-brain axis intensify immunosuppression via glucocorticoid signaling and microbially derived metabolites.In parallel,we discuss why current immunotherapies achieve only modest response rates(approximately 10%-20%)in many settings,emphasizing neurally mediated mechanisms of resistance.We evaluate therapeutic strategies that target the neuro-immune axis-including pharmacological neuromodulation,selective neural ablation,and rational combination regimens-and outline how single-cell approaches and neural-tumor-microenvironment organoid models can accelerate mechanism-driven translation.This review aims to integrate current evidence from neuroscience and immuno-oncology to construct a conceptual framework for neuro-immune regulation in gastric cancer and to identify potential therapeutic strategies to overcome treatment resistance by targeting neural-tumor-immune crosstalk.展开更多
The gut microbiota has emerged as a pivotal regulator of host lipid metabolism and energy homeostasis.A growing body of evidence reveals that variations in the composition and metabolic activity of intestinal microbes...The gut microbiota has emerged as a pivotal regulator of host lipid metabolism and energy homeostasis.A growing body of evidence reveals that variations in the composition and metabolic activity of intestinal microbes are closely associated with differences in adipose tissue deposition across species.Notably,increased abundance of Firmicutes and a reduced proportion of Bacteroidetes and butyrate-producing bacteria have been linked to enhanced fat accumulation.Key microbial metabolites such as short-chain fatty acids(SCFAs)influence lipid metabolism through multiple pathways,including the activation of GPR41/43 receptors,modulation of the bile acid–FXR/TGR5 axis,and regulation of hepatic lipogenesis.Additionally,the gut–brain axis plays a critical role in controlling feeding behavior via neuroendocrine signaling.This review summarizes current advances in understanding the roles of dominant bacterial phyla and beneficial genera—including Clostridium butyricum and Faecalibacterium prausnitzii—in fat metabolism.We further explore the mechanisms by which gut microbiota modulate lipid synthesis and catabolism through SCFA production,bile acid signaling,and AMPK/PPAR-related pathways.These insights highlight the potential of microbiota-targeted strategies to restore lipid metabolic balance,offering novel opportunities for applications in health management,nutritional interventions,and microbial therapeutics.展开更多
Background:The topic of this review is the study of the gut microbiota(GM),and the use of probiotics,especially in humans,as a new frontier in the field of prevention and health in general.The beneficial effects and f...Background:The topic of this review is the study of the gut microbiota(GM),and the use of probiotics,especially in humans,as a new frontier in the field of prevention and health in general.The beneficial effects and functions performed by probiotics in the GM are increasingly at the centre of both scientific,medical,and pharmaceutical interest.It is now known that diet and probiotics can modify the GM,although in these situations there is a need for greater and more in-depth research regarding the methods and timing of treatment.However,the relationship between physical activity,GM,and probiotics is still largely unclear,as regards certain mechanisms between physical exercise and probiotics in humans.Discussion:In this study,we tried to demonstrate whether and how physical exercise was able to alter the composition of the microbiota and how probiotics can facilitate it.Therefore,alteration of the microbiota was considered in terms of both diversity and composition.Conclusions:The ones examined propose vastly different physical exercises,both in terms of timing and type of intervention itself,and the use of probiotics.展开更多
Early life stress correlates with a higher prevalence of neurological disorders,including autism,attention-deficit/hyperactivity disorder,schizophrenia,depression,and Parkinson's disease.These conditions,primarily...Early life stress correlates with a higher prevalence of neurological disorders,including autism,attention-deficit/hyperactivity disorder,schizophrenia,depression,and Parkinson's disease.These conditions,primarily involving abnormal development and damage of the dopaminergic system,pose significant public health challenges.Microglia,as the primary immune cells in the brain,are crucial in regulating neuronal circuit development and survival.From the embryonic stage to adulthood,microglia exhibit stage-specific gene expression profiles,transcriptome characteristics,and functional phenotypes,enhancing the susceptibility to early life stress.However,the role of microglia in mediating dopaminergic system disorders under early life stress conditions remains poorly understood.This review presents an up-to-date overview of preclinical studies elucidating the impact of early life stress on microglia,leading to dopaminergic system disorders,along with the underlying mechanisms and therapeutic potential for neurodegenerative and neurodevelopmental conditions.Impaired microglial activity damages dopaminergic neurons by diminishing neurotrophic support(e.g.,insulin-like growth factor-1)and hinders dopaminergic axon growth through defective phagocytosis and synaptic pruning.Furthermore,blunted microglial immunoreactivity suppresses striatal dopaminergic circuit development and reduces neuronal transmission.Furthermore,inflammation and oxidative stress induced by activated microglia can directly damage dopaminergic neurons,inhibiting dopamine synthesis,reuptake,and receptor activity.Enhanced microglial phagocytosis inhibits dopamine axon extension.These long-lasting effects of microglial perturbations may be driven by early life stress–induced epigenetic reprogramming of microglia.Indirectly,early life stress may influence microglial function through various pathways,such as astrocytic activation,the hypothalamic–pituitary–adrenal axis,the gut–brain axis,and maternal immune signaling.Finally,various therapeutic strategies and molecular mechanisms for targeting microglia to restore the dopaminergic system were summarized and discussed.These strategies include classical antidepressants and antipsychotics,antibiotics and anti-inflammatory agents,and herbal-derived medicine.Further investigations combining pharmacological interventions and genetic strategies are essential to elucidate the causal role of microglial phenotypic and functional perturbations in the dopaminergic system disrupted by early life stress.展开更多
Acute pancreatitis(AP)is sudden inflammation of the pancreas,which can lead to multiple organ dysfunction in severe cases.Hypertriglyceridemia(HTG)is the third most common cause.In recent years,HTG-induced AP(HTG-AP)h...Acute pancreatitis(AP)is sudden inflammation of the pancreas,which can lead to multiple organ dysfunction in severe cases.Hypertriglyceridemia(HTG)is the third most common cause.In recent years,HTG-induced AP(HTG-AP)has garnered increasing attention.Compared to AP caused by other causes,HTG-AP often has a more subtle onset but is more likely to progress to a severe,critical illness that poses a serious threat to a patient’s life and health.Research suggests a potential connection between the gut microbiota and AP,which could be mediated by bacterial metabolites,immune cells,and inflammatory factors.This is supported by observations of microbial imbalance and higher intestinal permeability in patients with AP.In addition,studies have shown that HTG-induced changes in gut microbiota can worsen AP by negatively impacting the host metabolism,immune response,and function of the intestinal barrier.In this review,we summarize recent clinical and animal studies on the role and mechanism of gut microbiota in the severity of AP aggravated by HTG.The application prospects of the newly proposed microbial-host-isozyme concept are summarized,focusing on its potential for the precision diagnosis and treatment of HTG-AP through gut microbiota regulation.展开更多
Cholangiocarcinoma(CCA)is a highly malignant tumor of the biliary tract with a poor prognosis.Currently,specific methods for the early diagnosis and risk stratification if CCA are lacking.With the emergence of the“gu...Cholangiocarcinoma(CCA)is a highly malignant tumor of the biliary tract with a poor prognosis.Currently,specific methods for the early diagnosis and risk stratification if CCA are lacking.With the emergence of the“gut-biliary-liver axis”concept,the intestinal and biliary microbiota are being increasingly recognized to play key roles in the initiation and progression of CCA.This review systematically synthesizes recent clinical and basic research and outlines characteristic patterns of dysbiosis in the feces,bile,and tumor tissues of patients with CCA.It further discusses key mechanisms,including microbiota-bile acid-biliary epithelial signaling,pathogen-associated molecular patterns-mediated chronic inflammation,and immune-metabolic remodeling.It also examines the associations of these mechanisms with tumor progression and treatment responses.On this basis,the review evaluates the potential of intestinal and biliary microbiota and their metabolites as biomarkers for the diagnosis,prognosis,and prediction of the treatment response of CCA.We believe this review demonstrates a theoretical basis for microbiota-targeted precision prevention and therapeutic strategies for the disease.展开更多
Background:Immunosuppression compromises the host’s ability to combat pathogens,thereby increasing susceptibility to multisystem disorders.However,safe and effective curative treatments for this condition are current...Background:Immunosuppression compromises the host’s ability to combat pathogens,thereby increasing susceptibility to multisystem disorders.However,safe and effective curative treatments for this condition are currently lacking.Modulating the gut microbiota and their metabolites represents a promising therapeutic strategy.Notably,the Chinese herbal compound Yunzhi Guben Gao(YZG)has demonstrated multi-target immunomodulatory potential.Methods:A mouse model of dexamethasone-induced immunosuppression was employed to evaluate the effects of YZG.Immune organ indices(thymus,spleen),serum cytokine levels(IL-2,TNF-α),mucosal immunity markers(pulmonary/colonic SIgA),gut microbiota structure,and short-chain fatty acids(SCFAs)abundance were evaluated.Key microbial genera and metabolites were identified via Spearman correlation analysis.Pseudo-germ-free model mice established via quadruple antibiotic treatment combined with isovaleric acid intervention were employed to evaluate whether YZG efficacy depends on the intestinal microbiota and its metabolites,and whether its intrinsic mechanisms involve the promotion of isovaleric acid production.Results:YZG intervention ameliorated systemic and mucosal immune function in immunosuppressed mice.Mechanistically,YZG remodeled gut microbiota structure and significantly increased SCFAs levels.Notably,the abundance of the genus Ligilactobacillus exhibited the strongest positive correlation with isovaleric acid levels.Ligilactobacillus abundance was also positively correlated with immune-enhancing parameters and negatively correlated with the proinflammatory cytokine TNF-α,suggesting that Ligilactobacillus plays a pivotal role in the YZG regulatory network.Experiments using pseudo-germ-free mice and isovaleric acid intervention further demonstrated that the immunoprotective effects of YZG are closely related to intestinal microbiota remodeling and increased isovaleric acid production.Conclusion:YZG alleviates immunosuppression through multiple mechanisms,primarily involving the enrichment of the probiotic genus Ligilactobacillus and the consequent increase in isovaleric acid production.This process coordinately modulates mucosal immunity,cytokine networks,and immune organ function.The elucidation of this“microbiota-metabolite-immunity”axis provides both a pharmacological basis for the clinical application of YZG and novel immune-restorative strategies targeting gut microecological regulation.展开更多
Background:The gut microbiome has emerged as a critical modulator of cancer immunotherapy response.However,the mechanisms by which gut-associated metabolites influence checkpoint blockade efficacy in prostate cancer(P...Background:The gut microbiome has emerged as a critical modulator of cancer immunotherapy response.However,the mechanisms by which gut-associated metabolites influence checkpoint blockade efficacy in prostate cancer(PC)remain not fully explored.The study aimed to explore how gut metabolites regulate death-ligand 1(PD-L1)blockade via exosomes and boost immune checkpoint inhibitors(ICIs)in PC.Methods:We recruited 70 PC patients to set up into five subgroups.The integrated multi-omics analysis was performed.In parallel,we validated the function of gut microbiome-associated metabolites on PD-L1 production and immunotherapy treatment efficacy in PC cell lines and transgenic adenocarcinoma of the mouse prostate(TRAMP)models.Results:We identified two metabolites,16(R)-Hydroxyeicosatetraenoic acid(16(R)-HETE)and 6-Keto-Prostaglandin E1(6-Keto-PGE1),that positively correlated with the plasma exosomal PD-L1 levels.The in vitro experiments found that both 16(R)-HETE and 6-Keto-PGE1 can enhance PD-L1 expression at the mRNA,protein,and exosome levels in both human and mouse PC cell lines,which were also validated in vivo based on subcutaneous mouse models.Both metabolites significantly promoted the anti-PD-L1 efficacy against PC in situ on a TRAMP mouse model.Conclusions:Targeting the“gut-tumor metabolic axis”is a promising strategy to improve the efficacy of immune checkpoint inhibitors in tumors.展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant No.32470658)the National Key Research and Development Program of China(Grant Nos.2022YFC2502400 and 2022YFC2502402).
文摘The comorbidity of skin and gastrointestinal tract(GIT)diseases,primarily driven by the gut-skin axis(GSA),is well established.However,the genetic contribution to the GSA remains unclear.Here,using genome-wide association study(GWAS)summary statistics from European populations,we performed a genome-wide pleiotropic analysis to investigate the shared genetic basis and causal associations between skin and GIT diseases.We observed extensive genetic correlations and overlaps between skin and GIT diseases.A total of 298 pleiotropic loci were identified,75 of which were colocalized,and 61 exhibited pleiotropic effects across multiple trait pairs,including 2p16.1(PUS10),6p21.32(HLA-DRB1),10q21.2(ZNF365),and 19q13.11(SLC7A10).Additionally,five novel loci were identified based on the pleiotropic analysis;among them,the 15q22.2 locus harboring RORA was validated by the latest inflammatory bowel disease GWAS.Gene-based analysis identified 394 unique pleiotropic genes,which were enriched in GSA-associated tissues and the immune system,and protein-protein interaction analysis further revealed that the GPCR-cAMP,chromatin remodeling,JAK-STAT,and HLA-mediated immunity pathways were involved in GSA comorbidity.Notably,the JAK-STAT pathway showed strong potential for drug repurposing,with adalimumab targeting tumor necrosis factor and ustekinumab targeting interleukin-12 subunit beta already being used to treat both skin and GIT diseases.Finally,Mendelian randomization analysis identified five significant causal associations,and subsequent mediation analysis identified three potential microbiota-GIT-skin pathways.Taken together,our study demonstrated that the shared genetic factors between skin and GIT diseases were widely distributed across the genome.These findings will enhance our understanding of the genetic mechanisms underlying GSA comorbidity.
基金supported by the Guangdong Basic and Applied Basic Research Foundation,No.2023A1515030045(to HS)Presidential Foundation of Zhujiang Hospital of Southern Medical University,No.yzjj2022ms4(to HS)。
文摘Intracerebral hemorrhage is the most dangerous subtype of stroke,characterized by high mortality and morbidity rates,and frequently leads to significant secondary white matter injury.In recent decades,studies have revealed that gut microbiota can communicate bidirectionally with the brain through the gut microbiota–brain axis.This axis indicates that gut microbiota is closely related to the development and prognosis of intracerebral hemorrhage and its associated secondary white matter injury.The NACHT,LRR,and pyrin domain-containing protein 3(NLRP3)inflammasome plays a crucial role in this context.This review summarizes the dysbiosis of gut microbiota following intracerebral hemorrhage and explores the mechanisms by which this imbalance may promote the activation of the NLRP3 inflammasome.These mechanisms include metabolic pathways(involving short-chain fatty acids,lipopolysaccharides,lactic acid,bile acids,trimethylamine-N-oxide,and tryptophan),neural pathways(such as the vagus nerve and sympathetic nerve),and immune pathways(involving microglia and T cells).We then discuss the relationship between the activated NLRP3 inflammasome and secondary white matter injury after intracerebral hemorrhage.The activation of the NLRP3 inflammasome can exacerbate secondary white matter injury by disrupting the blood–brain barrier,inducing neuroinflammation,and interfering with nerve regeneration.Finally,we outline potential treatment strategies for intracerebral hemorrhage and its secondary white matter injury.Our review highlights the critical role of the gut microbiota–brain axis and the NLRP3 inflammasome in white matter injury following intracerebral hemorrhage,paving the way for exploring potential therapeutic approaches.
基金supported by the National Key R&D Program of China,No.2021YFC2501200(to PC).
文摘Short-chain fatty acids,metabolites produced by the fermentation of dietary fiber by gut microbiota,have garnered significant attention due to their correlation with neurodegenerative diseases,particularly Parkinson’s disease.In this review,we summarize the changes in short-chain fatty acid levels and the abundance of short-chain fatty acid-producing bacteria in various samples from patients with Parkinson’s disease,highlighting the critical role of gut homeostasis imbalance in the pathogenesis and progression of the disease.Focusing on the nervous system,we discuss the molecular mechanisms by which short-chain fatty acids influence the homeostasis of both the enteric nervous system and the central nervous system.We identify key processes,including the activation of G protein-coupled receptors and the inhibition of histone deacetylases by short-chain fatty acids.Importantly,structural or functional disruptions in the enteric nervous system mediated by these fatty acids may lead to abnormalα-synuclein expression and gastrointestinal dysmotility,which could serve as an initiating event in Parkinson’s disease.Furthermore,we propose that short-chain fatty acids help establish communication between the enteric nervous system and the central nervous system via the vagal nerve,immune circulation,and endocrine signaling.This communication may shed light on their potential role in the transmission ofα-synuclein from the gut to the brain.Finally,we elucidate novel treatment strategies for Parkinson’s disease that target short-chain fatty acids and examine the challenges associated with translating short-chain fatty acid-based therapies into clinical practice.In conclusion,this review emphasizes the pivotal role of short-chain fatty acids in regulating gut-brain axis integrity and their significance in the pathogenesis of Parkinson’s disease from the perspective of the nervous system.Moreover,it highlights the potential value of short-chain fatty acids in early intervention for Parkinson’s disease.Future research into the molecular mechanisms of short-chain fatty acids and their synergistic interactions with other gut metabolites is likely to advance the clinical translation of innovative short-chain fatty acid-based therapies for Parkinson’s disease.
文摘Accumulating evidence indicates that the neuro-immune axis is central to gastric cancer pathogenesis.Dynamic,bidirectional signaling between neural circuits and immune cells promotes tumor progression,shapes an immunosuppressive microenvironment,and contributes to therapeutic resistance.We synthesize current knowledge on how autonomic(sympathetic and parasympathetic)and sensory innervation regulate gastric cancer biology.These circuits act through neurotransmitters(catecholamines,acetylcholine)and neuropeptides(substance P[SP],calcitonin gene-related peptide[CGRP])to foster tumor growth and angiogenesis,facilitate perineural invasion,and enable immune evasion by recruiting suppressive myeloid and lymphoid populations and by inducing checkpoint molecule expression.We also examine how chronic stress and the microbiota-gut-brain axis intensify immunosuppression via glucocorticoid signaling and microbially derived metabolites.In parallel,we discuss why current immunotherapies achieve only modest response rates(approximately 10%-20%)in many settings,emphasizing neurally mediated mechanisms of resistance.We evaluate therapeutic strategies that target the neuro-immune axis-including pharmacological neuromodulation,selective neural ablation,and rational combination regimens-and outline how single-cell approaches and neural-tumor-microenvironment organoid models can accelerate mechanism-driven translation.This review aims to integrate current evidence from neuroscience and immuno-oncology to construct a conceptual framework for neuro-immune regulation in gastric cancer and to identify potential therapeutic strategies to overcome treatment resistance by targeting neural-tumor-immune crosstalk.
基金supported by National Key R&D Program of China(2024YFF1001500)Sichuan Science and Technology Program(2021YFYZ0007,2024NSFSC0298,SCCXTD-2025-8)+1 种基金China Agriculture Research System(CARS-35)National Natural Science Foundation of China(32421005)。
文摘The gut microbiota has emerged as a pivotal regulator of host lipid metabolism and energy homeostasis.A growing body of evidence reveals that variations in the composition and metabolic activity of intestinal microbes are closely associated with differences in adipose tissue deposition across species.Notably,increased abundance of Firmicutes and a reduced proportion of Bacteroidetes and butyrate-producing bacteria have been linked to enhanced fat accumulation.Key microbial metabolites such as short-chain fatty acids(SCFAs)influence lipid metabolism through multiple pathways,including the activation of GPR41/43 receptors,modulation of the bile acid–FXR/TGR5 axis,and regulation of hepatic lipogenesis.Additionally,the gut–brain axis plays a critical role in controlling feeding behavior via neuroendocrine signaling.This review summarizes current advances in understanding the roles of dominant bacterial phyla and beneficial genera—including Clostridium butyricum and Faecalibacterium prausnitzii—in fat metabolism.We further explore the mechanisms by which gut microbiota modulate lipid synthesis and catabolism through SCFA production,bile acid signaling,and AMPK/PPAR-related pathways.These insights highlight the potential of microbiota-targeted strategies to restore lipid metabolic balance,offering novel opportunities for applications in health management,nutritional interventions,and microbial therapeutics.
文摘Background:The topic of this review is the study of the gut microbiota(GM),and the use of probiotics,especially in humans,as a new frontier in the field of prevention and health in general.The beneficial effects and functions performed by probiotics in the GM are increasingly at the centre of both scientific,medical,and pharmaceutical interest.It is now known that diet and probiotics can modify the GM,although in these situations there is a need for greater and more in-depth research regarding the methods and timing of treatment.However,the relationship between physical activity,GM,and probiotics is still largely unclear,as regards certain mechanisms between physical exercise and probiotics in humans.Discussion:In this study,we tried to demonstrate whether and how physical exercise was able to alter the composition of the microbiota and how probiotics can facilitate it.Therefore,alteration of the microbiota was considered in terms of both diversity and composition.Conclusions:The ones examined propose vastly different physical exercises,both in terms of timing and type of intervention itself,and the use of probiotics.
基金supported by the National Natural Science Foundation of China,Nos.82304990(to NY),81973748(to JC),82174278(to JC)the National Key R&D Program of China,No.2023YFE0209500(to JC)+4 种基金China Postdoctoral Science Foundation,No.2023M732380(to NY)Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine,No.202102010014(to JC)Huang Zhendong Research Fund for Traditional Chinese Medicine of Jinan University,No.201911(to JC)National Innovation and Entrepreneurship Training Program for Undergraduates in China,No.202310559128(to NY and QM)Innovation and Entrepreneurship Training Program for Undergraduates at Jinan University,Nos.CX24380,CX24381(both to NY and QM)。
文摘Early life stress correlates with a higher prevalence of neurological disorders,including autism,attention-deficit/hyperactivity disorder,schizophrenia,depression,and Parkinson's disease.These conditions,primarily involving abnormal development and damage of the dopaminergic system,pose significant public health challenges.Microglia,as the primary immune cells in the brain,are crucial in regulating neuronal circuit development and survival.From the embryonic stage to adulthood,microglia exhibit stage-specific gene expression profiles,transcriptome characteristics,and functional phenotypes,enhancing the susceptibility to early life stress.However,the role of microglia in mediating dopaminergic system disorders under early life stress conditions remains poorly understood.This review presents an up-to-date overview of preclinical studies elucidating the impact of early life stress on microglia,leading to dopaminergic system disorders,along with the underlying mechanisms and therapeutic potential for neurodegenerative and neurodevelopmental conditions.Impaired microglial activity damages dopaminergic neurons by diminishing neurotrophic support(e.g.,insulin-like growth factor-1)and hinders dopaminergic axon growth through defective phagocytosis and synaptic pruning.Furthermore,blunted microglial immunoreactivity suppresses striatal dopaminergic circuit development and reduces neuronal transmission.Furthermore,inflammation and oxidative stress induced by activated microglia can directly damage dopaminergic neurons,inhibiting dopamine synthesis,reuptake,and receptor activity.Enhanced microglial phagocytosis inhibits dopamine axon extension.These long-lasting effects of microglial perturbations may be driven by early life stress–induced epigenetic reprogramming of microglia.Indirectly,early life stress may influence microglial function through various pathways,such as astrocytic activation,the hypothalamic–pituitary–adrenal axis,the gut–brain axis,and maternal immune signaling.Finally,various therapeutic strategies and molecular mechanisms for targeting microglia to restore the dopaminergic system were summarized and discussed.These strategies include classical antidepressants and antipsychotics,antibiotics and anti-inflammatory agents,and herbal-derived medicine.Further investigations combining pharmacological interventions and genetic strategies are essential to elucidate the causal role of microglial phenotypic and functional perturbations in the dopaminergic system disrupted by early life stress.
基金Supported by the Innovation Foundation for Doctor Dissertation of Northwestern Polytechnical University,No.CX2023021.
文摘Acute pancreatitis(AP)is sudden inflammation of the pancreas,which can lead to multiple organ dysfunction in severe cases.Hypertriglyceridemia(HTG)is the third most common cause.In recent years,HTG-induced AP(HTG-AP)has garnered increasing attention.Compared to AP caused by other causes,HTG-AP often has a more subtle onset but is more likely to progress to a severe,critical illness that poses a serious threat to a patient’s life and health.Research suggests a potential connection between the gut microbiota and AP,which could be mediated by bacterial metabolites,immune cells,and inflammatory factors.This is supported by observations of microbial imbalance and higher intestinal permeability in patients with AP.In addition,studies have shown that HTG-induced changes in gut microbiota can worsen AP by negatively impacting the host metabolism,immune response,and function of the intestinal barrier.In this review,we summarize recent clinical and animal studies on the role and mechanism of gut microbiota in the severity of AP aggravated by HTG.The application prospects of the newly proposed microbial-host-isozyme concept are summarized,focusing on its potential for the precision diagnosis and treatment of HTG-AP through gut microbiota regulation.
文摘Cholangiocarcinoma(CCA)is a highly malignant tumor of the biliary tract with a poor prognosis.Currently,specific methods for the early diagnosis and risk stratification if CCA are lacking.With the emergence of the“gut-biliary-liver axis”concept,the intestinal and biliary microbiota are being increasingly recognized to play key roles in the initiation and progression of CCA.This review systematically synthesizes recent clinical and basic research and outlines characteristic patterns of dysbiosis in the feces,bile,and tumor tissues of patients with CCA.It further discusses key mechanisms,including microbiota-bile acid-biliary epithelial signaling,pathogen-associated molecular patterns-mediated chronic inflammation,and immune-metabolic remodeling.It also examines the associations of these mechanisms with tumor progression and treatment responses.On this basis,the review evaluates the potential of intestinal and biliary microbiota and their metabolites as biomarkers for the diagnosis,prognosis,and prediction of the treatment response of CCA.We believe this review demonstrates a theoretical basis for microbiota-targeted precision prevention and therapeutic strategies for the disease.
基金supported by the Research Fund Project of the Education Department of Yunnan Province(No.2023Y0464)Research Project for Scientific Research Funds of Provincial Research Institutions in Heilongjiang Province(No.CZBZ2025ZR003).
文摘Background:Immunosuppression compromises the host’s ability to combat pathogens,thereby increasing susceptibility to multisystem disorders.However,safe and effective curative treatments for this condition are currently lacking.Modulating the gut microbiota and their metabolites represents a promising therapeutic strategy.Notably,the Chinese herbal compound Yunzhi Guben Gao(YZG)has demonstrated multi-target immunomodulatory potential.Methods:A mouse model of dexamethasone-induced immunosuppression was employed to evaluate the effects of YZG.Immune organ indices(thymus,spleen),serum cytokine levels(IL-2,TNF-α),mucosal immunity markers(pulmonary/colonic SIgA),gut microbiota structure,and short-chain fatty acids(SCFAs)abundance were evaluated.Key microbial genera and metabolites were identified via Spearman correlation analysis.Pseudo-germ-free model mice established via quadruple antibiotic treatment combined with isovaleric acid intervention were employed to evaluate whether YZG efficacy depends on the intestinal microbiota and its metabolites,and whether its intrinsic mechanisms involve the promotion of isovaleric acid production.Results:YZG intervention ameliorated systemic and mucosal immune function in immunosuppressed mice.Mechanistically,YZG remodeled gut microbiota structure and significantly increased SCFAs levels.Notably,the abundance of the genus Ligilactobacillus exhibited the strongest positive correlation with isovaleric acid levels.Ligilactobacillus abundance was also positively correlated with immune-enhancing parameters and negatively correlated with the proinflammatory cytokine TNF-α,suggesting that Ligilactobacillus plays a pivotal role in the YZG regulatory network.Experiments using pseudo-germ-free mice and isovaleric acid intervention further demonstrated that the immunoprotective effects of YZG are closely related to intestinal microbiota remodeling and increased isovaleric acid production.Conclusion:YZG alleviates immunosuppression through multiple mechanisms,primarily involving the enrichment of the probiotic genus Ligilactobacillus and the consequent increase in isovaleric acid production.This process coordinately modulates mucosal immunity,cytokine networks,and immune organ function.The elucidation of this“microbiota-metabolite-immunity”axis provides both a pharmacological basis for the clinical application of YZG and novel immune-restorative strategies targeting gut microecological regulation.
基金supported by Tianjian advanced biomedical laboratory key research and development projectHenan Province Natural Science Foundation(Grant Number 242300421283)Major Science and Technology Project of Henan Province(221100310200)。
文摘Background:The gut microbiome has emerged as a critical modulator of cancer immunotherapy response.However,the mechanisms by which gut-associated metabolites influence checkpoint blockade efficacy in prostate cancer(PC)remain not fully explored.The study aimed to explore how gut metabolites regulate death-ligand 1(PD-L1)blockade via exosomes and boost immune checkpoint inhibitors(ICIs)in PC.Methods:We recruited 70 PC patients to set up into five subgroups.The integrated multi-omics analysis was performed.In parallel,we validated the function of gut microbiome-associated metabolites on PD-L1 production and immunotherapy treatment efficacy in PC cell lines and transgenic adenocarcinoma of the mouse prostate(TRAMP)models.Results:We identified two metabolites,16(R)-Hydroxyeicosatetraenoic acid(16(R)-HETE)and 6-Keto-Prostaglandin E1(6-Keto-PGE1),that positively correlated with the plasma exosomal PD-L1 levels.The in vitro experiments found that both 16(R)-HETE and 6-Keto-PGE1 can enhance PD-L1 expression at the mRNA,protein,and exosome levels in both human and mouse PC cell lines,which were also validated in vivo based on subcutaneous mouse models.Both metabolites significantly promoted the anti-PD-L1 efficacy against PC in situ on a TRAMP mouse model.Conclusions:Targeting the“gut-tumor metabolic axis”is a promising strategy to improve the efficacy of immune checkpoint inhibitors in tumors.
