Postruminal intestinal inflammation and hindgut acidosis caused by increased dietary starch supply and thereby increased quantities of ruminal degradable starch(RDS)in ruminants have been widely studied.Although the r...Postruminal intestinal inflammation and hindgut acidosis caused by increased dietary starch supply and thereby increased quantities of ruminal degradable starch(RDS)in ruminants have been widely studied.Although the roles of the microbiota in mediating hindgut health that are focused on the hindgut have been widely studied,the absence of whole gastrointestinal insight may influence the depth of research.We integrated the microbiome,metabolome,and host transcriptome changes in the rumen,jejunum,ileum,and colon to investigate the contributions of foregut changes to hindgut gene expression driven by gastrointestinal microbiota and metabolite flow.Forty goats were randomly assigned to receive either a low rumen-degradation-rate starch diet(LRDS,n=20)or a high rumen-degradation-rate starch diet(HRDS,n=20).Compared with the HRDS group,the LRDS group significantly decreased the diarrheal rate.Based on the mean values of the fecal scores,6 represented goats of LRDS group(fecal scores=(4.58±0.120))and 6 represented goats of HRDS group(fecal scores=(3.53±0.343))were selected for sampling and subsequent analysis.LRDS had significantly decreased the colonic pathologic scores.Transcriptomic analysis revealed that LRDS reduced jejunal,ileal,and colonic inflammatory responses.An increase in beneficial commensals and a decreased abundance of pathogenic genera in the small intestine and hindgut were found in goats fed the LRDS diet using 16S rRNA gene sequencing.To identify microbial transmission as well as the transmission of microbial metabolites,8 genera were identified as core genera according to their calculated niche width.Metabolomics analysis revealed that a total of 554 metabolites were identified among different gastrointestinal sites.Then,metabolites were incorporated into 3 modules:metabolites increased in the current site(ICS),unchanged inflow metabolites in the current site(UICS),and metabolites decreased in the current site(DCS).The results indicated that the UICS metabolites contributed more than 10%to host gene expression in the jejunum,ileum,and colon.When we further focused on the effects of colonic UICS metabolites on the colonic immune-related differentially expressed genes(DEGs),the results indicated that 1-palmitoylglycerol and deoxycholic acid contributed 60.74 and 11.5%to the colonic immune-related DEGs,respectively.Our findings provide a preliminary framework of microbial effects that includes the microbiota and their metabolite changes,especially reduced 1-palmitoylglycerol and deoxycholic acid,in the former gastrointestinal tract that could be involved in the alleviation of colonic inflammation in goats fed LRDS diets.展开更多
AIM:To investigate the relationship between the methylation status in the SLIT2 and TGFB2 promoters and colonic inflammation in inflammatory bowel disease patients.METHODS:We evaluated the methylation status of 2genes...AIM:To investigate the relationship between the methylation status in the SLIT2 and TGFB2 promoters and colonic inflammation in inflammatory bowel disease patients.METHODS:We evaluated the methylation status of 2genes(SLIT2 and TGFB2)in 226 biopsies taken from62 colonoscopies of 38 patients(29 ulcerative colitis and 9 Crohn’s colitis)using methylation-specific melting curve analysis.The relationships between methylation status and clinical,biological,endoscopic and histological activities were evaluated.Twenty-three of the 38patients had a second colonoscopy and were included in a longitudinal analysis.Numerical results were given as the means±SD of the sample and range,except when specified.Student t analysis,U Mann Whitney and ANOVA factor were used to compare the means.Qualitative results were based on theχ2 test.RESULTS:SLIT2 methylation was more frequent in samples with endoscopic activity than with endoscopic remission(55%vs 18%,P<0.001).SLIT2 methylation was also higher in samples with acute inflammation(56.5%)than in samples with chronic(24%)or absent inflammation(15%)(P<0.001).For TGFB2methylation,the correlation was only significant with endoscopic activity.Methylation was higher in the distal colon for both genes(P<0.001 for SLIT2 and P=0.022for TGFB2).In the multivariate analysis,only inflammation status(and not disease duration or extension)was independently associated with SLIT2 methylation[OR=6.6(95%CI:1.65-27.36),P=0.009].In the longitudinal analysis,the maintenance of endoscopic remission was protective for methylation.CONCLUSION:Endoscopic and histological inflammation are predictive for SLIT2 methylation.展开更多
This study demonstrated the design of whey protein isolate(WPI)-mannose(Man)conjugates with triphenylphosphonium bromide(TPP)through self-assembly to prepare macrophage and mitochondrion dual-targeting astaxanthin(AXT...This study demonstrated the design of whey protein isolate(WPI)-mannose(Man)conjugates with triphenylphosphonium bromide(TPP)through self-assembly to prepare macrophage and mitochondrion dual-targeting astaxanthin(AXT)nanoparticles(AXT@TPP-WPI-Man).The nanoparticles displayed spherical structures with a well-dispersed size of approximately 206.1±39.2 nm,with good biocompatibility,stability,and targeting capabilities.In vitro experiments demonstrated the specific accumulation of AXT@TPP-WPI-Man in mitochondria and exhibited good targeting ability toward macrophages.The AXT@TPP-WPI-Man effectively reduced reactive oxygen species and preserved the normal mitochondrial membrane potential.The AXT@TPP-WPI-Man treated ulcerative colitis mice exhibited a 52.32%increase in colon length with significant improvement in weight loss,disease activity index scores,and reduced release of inflammatory cytokines.Immunofluorescence staining indicated AXT@TPP-WPI-Man alleviated ulcerative colitis by reducing M1 polarization in colonic macrophages while promoting M2 polarization.The dual-targeting AXT@TPP-WPI-Man has the potential to improve astaxanthin bioavailability,presenting a promising delivery method for the treatment of ulcerative colitis.展开更多
In-situ oral delivery of therapeutic antibodies,like monoclonal antibody,for chronic inflammation treatment is the most convenient approach compared with other administration routes.Moreover,the abundant links between...In-situ oral delivery of therapeutic antibodies,like monoclonal antibody,for chronic inflammation treatment is the most convenient approach compared with other administration routes.Moreover,the abundant links between the gut microbiota and colonic inflammation indicate that the synergistic or antagonistic effect of gut microbiota to colonic inflammation.However,the antibody activity would be significantly affected while transferring through the gastrointestinal tract due to hostile conditions.Moreover,these antibodies have short serum half-lives,thus,require to be frequently administered with high doses to be effective,leading to low patient tolerance.Here,we develop a strategy utilizing thin shell hydrogel microcapsule fabricated by microfluidic technique as the oral delivering carrier.By encapsulating antibodies in these microcapsules,antibodies survive in the hostile gastrointestinal environment and rapidly release into the small intestine through oral administration route,achieving the same therapeutic effect as the intravenous injection evaluated by a colonic inflammation disease model.Moreover,the abundance of some intestinal microorganisms as the indication of the improvement of inflammation has remarkably altered after in-situ antibody-laden microcapsules delivery,implying the restoration of micro-ecology of the intestine.These findings prove our microcapsules are exploited as an efficient oral delivery agent for antibodies with programmable function in clinical application.展开更多
BACKGROUND Intermittent fasting(IF),particularly time-restricted feeding(TRF),is increasingly popular has gained popularity for weight loss,yet management,but its effects impact on gut health remain unclear.Remains in...BACKGROUND Intermittent fasting(IF),particularly time-restricted feeding(TRF),is increasingly popular has gained popularity for weight loss,yet management,but its effects impact on gut health remain unclear.Remains inadequately understood.This study explores how investigated the effects of TRF effects on intestinal health and explored the underlying mechanisms.AIM To assess the effects of IF on intestinal health,elucidate the mechanisms involved.METHODS Mice were divided into two groups:Normal control(NC)and IF.The IF group underwent TRF,while the NC group had unrestricted access to food.Body weight,fecal characteristics,and intestinal morphology were analyzed.Colon tissue,serum,and fecal samples were collected for histological analysis,enzymelinked immunosorbent assay,flow cytometry,16S rRNA sequencing,and metabolomic profiling.RESULTS IF significantly affected body weight and intestinal morphology,compromised the intestinal barrier,increased pro-inflammatory cytokines,and heightened gut immune activation(P<0.05).It also disrupted the gut microbiota,promoting proinflammatory bacteria,reducing anti-inflammatory metabolites,and elevating pro-inflammatory metabolites(P<0.05).Indoleacrylic acid(IAA)supplementation notably alleviated intestinal inflammation and reversed immune dysfunction induced by IF(P<0.05).CONCLUSION Prolonged IF exacerbates intestinal inflammation by impairing gut barrier integrity and disrupting microbial homeostasis.However,IAA supplementation effectively mitigates fasting-induced intestinal inflammation and immune imbalance,suggesting its potential as a therapeutic agent.展开更多
Oxidized cholesterol(OXC)is a harmful dietary substance.Although the consumption of OXC has been associated with colonic inflammation,related underlying mechanisms are still limited.We evaluated the influence of dieta...Oxidized cholesterol(OXC)is a harmful dietary substance.Although the consumption of OXC has been associated with colonic inflammation,related underlying mechanisms are still limited.We evaluated the influence of dietary OXC on gut health and ecology by applying the murine model.Results showed that the thickness of the mucus layer was significantly reduced in healthy mice treated with OXC.Short-term intake of OXC did not influence the expression of pro-inflammatory factors in healthy mice but it induced the decrease of Muc2 expression in the proximal colon,accompanied by an increase in the abundance of 2 mucusdegrading bacteria,namely Akkermansia muciniphila and Bacteroides acidifaciens.Consistently,oral exposure of OXC promoted mucus barrier erosion in dextran sulfate sodium(DSS)-induced colitis mice and facilitated bacteria infiltration in the colon.The adverse effect of OXC on mucus layer disappeared in antibiotics-treated healthy mice,suggesting that the damaging effect of OXC on the gut mucus layer was not direct and instead was mediated by causing microbiota dysbiosis.Finally,the impact of OXC on the mucus layer and colitis was partly alleviated by green tea catechins.These studies demonstrated that the OXC-induced mucus barrier damage was mainly induced by the dysregulation of gut microbiota at least in this mouse model.展开更多
AIM: To investigate the effects of ZK1916784, a low calcemic analog of calcitriol on intestinal inflammation. METHODS: Acute and chronic colitis was induced by dextran sodium sulfate (DSS) according to standard proced...AIM: To investigate the effects of ZK1916784, a low calcemic analog of calcitriol on intestinal inflammation. METHODS: Acute and chronic colitis was induced by dextran sodium sulfate (DSS) according to standard procedures. Mice were treated intraperitoneally with ZK1916784 or placebo and colonic inflammation was evaluated. Cytokine production by mesenterial lymph node (MLN) cells was measured by ELISA. Immunohistochemistry was performed to detect intestinal dendritic cells (DCs) within the colonic tissue, and the effect of the calcitriol analog on DCs was investigated. RESULTS: Treatment with ZK191784 resulted in significant amelioration of disease with a reduced histological score in acute and chronic intestinal inflammation. In animals with acute DSS colitis, down- regulation of colonic inflammation was associated with a dramatic reduction in the secretion of the proinflammatory cytokine interferon (IFN)-γ and a significant increase in intereleukin (IL)-10 by MLN cells. Similarly, in chronic colitis, IL-10 expression in colonic tissue increased 1.4-fold when mice were treated with ZK191784, whereas expression of the Th1-specific transcription factor T-beta decreased by 81.6%. Lower numbers of infiltrating activated CD11c+ DCs were found in the colon in ZK191784-treated mice with acute DSScolitis, and secretion of proinflammatory cytokines by primary mucosal DCs was inhibited in the presence of the calcitriol analog. CONCLUSION: The calcitriol analog ZK191784 demonstrated significant anti-inflammatory properties in experimental colitis that were at least partially mediated by the immunosuppressive effects of the derivate on mucosal DCs.展开更多
Human consumption of linoleic acid(LA,18:2ω-6,abundant in vegetable oils)is very high.Animal experiments showed that excessive LA intake increased azoxymethane-induced colon tumorigenesis,however,the impact of excess...Human consumption of linoleic acid(LA,18:2ω-6,abundant in vegetable oils)is very high.Animal experiments showed that excessive LA intake increased azoxymethane-induced colon tumorigenesis,however,the impact of excessive LA on colon cancer in human is not conclusive,making it difficult to make dietary recommendations for optimal intake of LA.Understanding the molecular mechanisms of LA on colon tumorigenesis could help to clarify its health effect,and facilitate development of mechanismbased strategies for preventing colon cancer.Recent studies show that the previously unappreciated cytochrome P450 monooxygenase-mediated eicosanoid pathway is upregulated in colon cancer and plays critical roles in its pathogenesis,and could contribute to the effects of dietary LA,as well asω-3 fatty acids,on colon tumorigenesis.In this review,we will discuss recent studies about the roles of cytochrome P450 monooxygenases in fatty acid metabolism and its roles in colonic inflammation and colon cancer,and how this information could help us to clarify the health impacts of dietary fatty acids.展开更多
Background:Endoplasmic reticulum(ER)stress and autophagy are implicated in the pathophysiology of intestinal inflammation;however,their roles in intrauterine growth retardation(IUGR)-induced colon inflammation are unc...Background:Endoplasmic reticulum(ER)stress and autophagy are implicated in the pathophysiology of intestinal inflammation;however,their roles in intrauterine growth retardation(IUGR)-induced colon inflammation are unclear.This study explored the protective effects of natural stilbene pterostilbene on colon inflammation using the IUGR piglets and the tumor necrosis factor alpha(TNF-α)-treated human colonic epithelial cells(Caco-2)by targeting ER stress and autophagy.Results:Both the IUGR colon and the TNF-α-treated Caco-2 cells exhibited inflammatory responses,ER stress,and impaired autophagic flux(P<0.05).The ER stress inducer tunicamycin and the autophagy inhibitor 3-methyladenine further augmented inflammatory responses and apoptosis in the TNF-α-treated Caco-2 cells(P<0.05).Conversely,pterostilbene inhibited ER stress and restored autophagic flux in the IUGR colon and the TNF-α-treated cells(P<0.05).Pterostilbene also prevented the release of inflammatory cytokines and nuclear translocation of nuclear factor kappa B p65,reduced intestinal permeability and cell apoptosis,and facilitated the expression of intestinal tight junction proteins in the IUGR colon and the TNF-α-treated cells(P<0.05).Importantly,treatment with tunicamycin or autophagosome-lysosome binding inhibitor chloroquine blocked the positive effects of pterostilbene on inflammatory response,cell apoptosis,and intestinal barrier function in the TNF-α-exposed Caco-2 cells(P<0.05).Conclusion:Pterostilbene mitigates ER stress and promotes autophagic flux,thereby improving colon inflammation and barrier dysfunction in the IUGR piglets and the TNF-α-treated Caco-2 cells.展开更多
Loss of the colonic inner mucus layer leads to spontaneously severe colitis and colorectal cancer.However,key host factors that may control the generation of the inner mucus layer are rarely reported.Here,we identify ...Loss of the colonic inner mucus layer leads to spontaneously severe colitis and colorectal cancer.However,key host factors that may control the generation of the inner mucus layer are rarely reported.Here,we identify a novel function of TRIM34 in goblet cells(GCs)in controlling inner mucus layer generation.Upon DSS treatment,TRIM34 deficiency led to a reduction in Muc2 secretion by GCs and subsequent defects in the inner mucus layer.This outcome rendered TRIM34-deficient mice more susceptible to DSS-induced colitis and colitis-associated colorectal cancer.Mechanistic experiments demonstrated that TRIM34 controlled TLR signaling-induced Nox/Duox-dependent ROS synthesis,thereby promoting the compound exocytosis of Muc2 by colonic GCs that were exposed to bacterial TLR ligands.Clinical analysis revealed that TRIM34 levels in patient samples were correlated with the outcome of ulcerative colitis(UC)and the prognosis of rectal adenocarcinoma.This study indicates that TRIM34 expression in GCs plays an essential role in generating the inner mucus layer and preventing excessive colon inflammation and tumorigenesis.展开更多
Methamphetamine(Meth)abuse can cause serious mental disorders,including anxiety and depression.The gut microbiota is a crucial contributor to maintaining host mental health.Here,we aim to investigate if microbiota par...Methamphetamine(Meth)abuse can cause serious mental disorders,including anxiety and depression.The gut microbiota is a crucial contributor to maintaining host mental health.Here,we aim to investigate if microbiota participate in Meth-induced mental disorders,and the potential mechanisms involved.Here,15 mg/kg Meth resulted in anxiety-and depression-like behaviors of mice successfully and suppressed the Sigma-1 receptor(SIGMAR1)/BDNF/TRKB pathway in the hippocampus.Mean-while,Meth impaired gut homeostasis by arousing the Toll-like receptor 4(TLR4)-related colonic inflammation,disturbing the gut microbiome and reducing the microbiota-derived short-chain fatty acids(SCFAs).Moreover,fecal microbiota from Meth-administrated mice mediated the colonic inflam-mation and reproduced anxiety-and depression-like behaviors in recipients.Further,SCFAs supple-mentation optimized Meth-induced microbial dysbiosis,ameliorated colonic inflammation,and repressed anxiety-and depression-like behaviors.Finally,Sigmarl knockout(Sigmar1^(-/-))repressed the BDNF/TRKB pathway and produced similar behavioral phenotypes with Meth exposure,and elim-inated the anti-anxiety and-depression effects of SCFAs.The activation of SIGMAR1 with fluvoxamine attenuated Meth-induced anxiety-and depression-like behaviors.Our findings indicated that gut microbiota-derived SCFAs could optimize gut homeostasis,and ameliorate Meth-induced mental disorders in a SIGMAR1-dependent manner.This study confirms the crucial role of microbiota in Methrelated mental disorders and provides a potential preemptive therapy.展开更多
基金supported by the National Natural Science Foundation of China(32072761,31902184 and 32102570)the Shaanxi Provincial Science and Technology Association Young Talents Lifting Program Project,China(20220203)。
文摘Postruminal intestinal inflammation and hindgut acidosis caused by increased dietary starch supply and thereby increased quantities of ruminal degradable starch(RDS)in ruminants have been widely studied.Although the roles of the microbiota in mediating hindgut health that are focused on the hindgut have been widely studied,the absence of whole gastrointestinal insight may influence the depth of research.We integrated the microbiome,metabolome,and host transcriptome changes in the rumen,jejunum,ileum,and colon to investigate the contributions of foregut changes to hindgut gene expression driven by gastrointestinal microbiota and metabolite flow.Forty goats were randomly assigned to receive either a low rumen-degradation-rate starch diet(LRDS,n=20)or a high rumen-degradation-rate starch diet(HRDS,n=20).Compared with the HRDS group,the LRDS group significantly decreased the diarrheal rate.Based on the mean values of the fecal scores,6 represented goats of LRDS group(fecal scores=(4.58±0.120))and 6 represented goats of HRDS group(fecal scores=(3.53±0.343))were selected for sampling and subsequent analysis.LRDS had significantly decreased the colonic pathologic scores.Transcriptomic analysis revealed that LRDS reduced jejunal,ileal,and colonic inflammatory responses.An increase in beneficial commensals and a decreased abundance of pathogenic genera in the small intestine and hindgut were found in goats fed the LRDS diet using 16S rRNA gene sequencing.To identify microbial transmission as well as the transmission of microbial metabolites,8 genera were identified as core genera according to their calculated niche width.Metabolomics analysis revealed that a total of 554 metabolites were identified among different gastrointestinal sites.Then,metabolites were incorporated into 3 modules:metabolites increased in the current site(ICS),unchanged inflow metabolites in the current site(UICS),and metabolites decreased in the current site(DCS).The results indicated that the UICS metabolites contributed more than 10%to host gene expression in the jejunum,ileum,and colon.When we further focused on the effects of colonic UICS metabolites on the colonic immune-related differentially expressed genes(DEGs),the results indicated that 1-palmitoylglycerol and deoxycholic acid contributed 60.74 and 11.5%to the colonic immune-related DEGs,respectively.Our findings provide a preliminary framework of microbial effects that includes the microbiota and their metabolite changes,especially reduced 1-palmitoylglycerol and deoxycholic acid,in the former gastrointestinal tract that could be involved in the alleviation of colonic inflammation in goats fed LRDS diets.
基金Grants from Fondo de Investigacion Sanitaria,FIS 12/01420 Ministerio de Ciencia e Innovacion,SAF 09-07319,12-33636+2 种基金Fundacio Gastroenterologia Dr.Francisco Vilardell,F05-01Ministerio de Educacion y Ciencia Spanish Networks RTICC,RD06/0020/0021,1050 and 1051RD12/0036/0031 and Fundacion Cientifica de la Asociacion Espanola contra el Cancer Triana Lobaton supported by a grant from the Institut d’Investigacio Biomedica de Bellvitge (IDIBELL)
文摘AIM:To investigate the relationship between the methylation status in the SLIT2 and TGFB2 promoters and colonic inflammation in inflammatory bowel disease patients.METHODS:We evaluated the methylation status of 2genes(SLIT2 and TGFB2)in 226 biopsies taken from62 colonoscopies of 38 patients(29 ulcerative colitis and 9 Crohn’s colitis)using methylation-specific melting curve analysis.The relationships between methylation status and clinical,biological,endoscopic and histological activities were evaluated.Twenty-three of the 38patients had a second colonoscopy and were included in a longitudinal analysis.Numerical results were given as the means±SD of the sample and range,except when specified.Student t analysis,U Mann Whitney and ANOVA factor were used to compare the means.Qualitative results were based on theχ2 test.RESULTS:SLIT2 methylation was more frequent in samples with endoscopic activity than with endoscopic remission(55%vs 18%,P<0.001).SLIT2 methylation was also higher in samples with acute inflammation(56.5%)than in samples with chronic(24%)or absent inflammation(15%)(P<0.001).For TGFB2methylation,the correlation was only significant with endoscopic activity.Methylation was higher in the distal colon for both genes(P<0.001 for SLIT2 and P=0.022for TGFB2).In the multivariate analysis,only inflammation status(and not disease duration or extension)was independently associated with SLIT2 methylation[OR=6.6(95%CI:1.65-27.36),P=0.009].In the longitudinal analysis,the maintenance of endoscopic remission was protective for methylation.CONCLUSION:Endoscopic and histological inflammation are predictive for SLIT2 methylation.
基金supported by the National Natural Science Fund for Distinguished Young Scholars of China(31925031).
文摘This study demonstrated the design of whey protein isolate(WPI)-mannose(Man)conjugates with triphenylphosphonium bromide(TPP)through self-assembly to prepare macrophage and mitochondrion dual-targeting astaxanthin(AXT)nanoparticles(AXT@TPP-WPI-Man).The nanoparticles displayed spherical structures with a well-dispersed size of approximately 206.1±39.2 nm,with good biocompatibility,stability,and targeting capabilities.In vitro experiments demonstrated the specific accumulation of AXT@TPP-WPI-Man in mitochondria and exhibited good targeting ability toward macrophages.The AXT@TPP-WPI-Man effectively reduced reactive oxygen species and preserved the normal mitochondrial membrane potential.The AXT@TPP-WPI-Man treated ulcerative colitis mice exhibited a 52.32%increase in colon length with significant improvement in weight loss,disease activity index scores,and reduced release of inflammatory cytokines.Immunofluorescence staining indicated AXT@TPP-WPI-Man alleviated ulcerative colitis by reducing M1 polarization in colonic macrophages while promoting M2 polarization.The dual-targeting AXT@TPP-WPI-Man has the potential to improve astaxanthin bioavailability,presenting a promising delivery method for the treatment of ulcerative colitis.
基金support from the National Key Science and Technology Project of China(grant number 2018YFC2000500,03)National Natural Science Foundation of China 81703430 and 81803449,CAMS Innovation Fund for Medical Sciences(grant number 2019-I2M-5-045)the Natural Science Foundation of Zhejiang Province(LYY20H300003).
文摘In-situ oral delivery of therapeutic antibodies,like monoclonal antibody,for chronic inflammation treatment is the most convenient approach compared with other administration routes.Moreover,the abundant links between the gut microbiota and colonic inflammation indicate that the synergistic or antagonistic effect of gut microbiota to colonic inflammation.However,the antibody activity would be significantly affected while transferring through the gastrointestinal tract due to hostile conditions.Moreover,these antibodies have short serum half-lives,thus,require to be frequently administered with high doses to be effective,leading to low patient tolerance.Here,we develop a strategy utilizing thin shell hydrogel microcapsule fabricated by microfluidic technique as the oral delivering carrier.By encapsulating antibodies in these microcapsules,antibodies survive in the hostile gastrointestinal environment and rapidly release into the small intestine through oral administration route,achieving the same therapeutic effect as the intravenous injection evaluated by a colonic inflammation disease model.Moreover,the abundance of some intestinal microorganisms as the indication of the improvement of inflammation has remarkably altered after in-situ antibody-laden microcapsules delivery,implying the restoration of micro-ecology of the intestine.These findings prove our microcapsules are exploited as an efficient oral delivery agent for antibodies with programmable function in clinical application.
基金Supported by the Anhui University Research Project,No.2022AH051171Natural Science Foundation Project of Anhui Province,No.2408085QH271+6 种基金Anhui Medical University Scientific Research Level Improvement Plan,No.2022xkjT028Health Research Project of Anhui Province,No.AHWJ2023A30047the Anhui Provincial Natural Science Foundation,No.2208085MH240the Scientific Research Project of Anhui Provincial Department of Education,No.2022AH051167the Anhui Quality Engineering Project,No.2023sx200,No.2023jyjxggyjY087 and No.2023zyxwjxalk046the Anhui Provincial Postgraduate Education Quality Project,No.2024cxcysj062and Anhui Medical University Graduate Research and Practice Innovation Project,No.YJS20240095.
文摘BACKGROUND Intermittent fasting(IF),particularly time-restricted feeding(TRF),is increasingly popular has gained popularity for weight loss,yet management,but its effects impact on gut health remain unclear.Remains inadequately understood.This study explores how investigated the effects of TRF effects on intestinal health and explored the underlying mechanisms.AIM To assess the effects of IF on intestinal health,elucidate the mechanisms involved.METHODS Mice were divided into two groups:Normal control(NC)and IF.The IF group underwent TRF,while the NC group had unrestricted access to food.Body weight,fecal characteristics,and intestinal morphology were analyzed.Colon tissue,serum,and fecal samples were collected for histological analysis,enzymelinked immunosorbent assay,flow cytometry,16S rRNA sequencing,and metabolomic profiling.RESULTS IF significantly affected body weight and intestinal morphology,compromised the intestinal barrier,increased pro-inflammatory cytokines,and heightened gut immune activation(P<0.05).It also disrupted the gut microbiota,promoting proinflammatory bacteria,reducing anti-inflammatory metabolites,and elevating pro-inflammatory metabolites(P<0.05).Indoleacrylic acid(IAA)supplementation notably alleviated intestinal inflammation and reversed immune dysfunction induced by IF(P<0.05).CONCLUSION Prolonged IF exacerbates intestinal inflammation by impairing gut barrier integrity and disrupting microbial homeostasis.However,IAA supplementation effectively mitigates fasting-induced intestinal inflammation and immune imbalance,suggesting its potential as a therapeutic agent.
基金supported by Hong Kong Research Grants Council General Research Fund(CUHK 14102321,14103722 and 14104923)。
文摘Oxidized cholesterol(OXC)is a harmful dietary substance.Although the consumption of OXC has been associated with colonic inflammation,related underlying mechanisms are still limited.We evaluated the influence of dietary OXC on gut health and ecology by applying the murine model.Results showed that the thickness of the mucus layer was significantly reduced in healthy mice treated with OXC.Short-term intake of OXC did not influence the expression of pro-inflammatory factors in healthy mice but it induced the decrease of Muc2 expression in the proximal colon,accompanied by an increase in the abundance of 2 mucusdegrading bacteria,namely Akkermansia muciniphila and Bacteroides acidifaciens.Consistently,oral exposure of OXC promoted mucus barrier erosion in dextran sulfate sodium(DSS)-induced colitis mice and facilitated bacteria infiltration in the colon.The adverse effect of OXC on mucus layer disappeared in antibiotics-treated healthy mice,suggesting that the damaging effect of OXC on the gut mucus layer was not direct and instead was mediated by causing microbiota dysbiosis.Finally,the impact of OXC on the mucus layer and colitis was partly alleviated by green tea catechins.These studies demonstrated that the OXC-induced mucus barrier damage was mainly induced by the dysregulation of gut microbiota at least in this mouse model.
基金Supported by Grants from the German Research Foundation DFG (UGS, HCR)as well as research grants from the University of Regensburg, Germany, as part of the ReForM-program (UGS, FO)
文摘AIM: To investigate the effects of ZK1916784, a low calcemic analog of calcitriol on intestinal inflammation. METHODS: Acute and chronic colitis was induced by dextran sodium sulfate (DSS) according to standard procedures. Mice were treated intraperitoneally with ZK1916784 or placebo and colonic inflammation was evaluated. Cytokine production by mesenterial lymph node (MLN) cells was measured by ELISA. Immunohistochemistry was performed to detect intestinal dendritic cells (DCs) within the colonic tissue, and the effect of the calcitriol analog on DCs was investigated. RESULTS: Treatment with ZK191784 resulted in significant amelioration of disease with a reduced histological score in acute and chronic intestinal inflammation. In animals with acute DSS colitis, down- regulation of colonic inflammation was associated with a dramatic reduction in the secretion of the proinflammatory cytokine interferon (IFN)-γ and a significant increase in intereleukin (IL)-10 by MLN cells. Similarly, in chronic colitis, IL-10 expression in colonic tissue increased 1.4-fold when mice were treated with ZK191784, whereas expression of the Th1-specific transcription factor T-beta decreased by 81.6%. Lower numbers of infiltrating activated CD11c+ DCs were found in the colon in ZK191784-treated mice with acute DSScolitis, and secretion of proinflammatory cytokines by primary mucosal DCs was inhibited in the presence of the calcitriol analog. CONCLUSION: The calcitriol analog ZK191784 demonstrated significant anti-inflammatory properties in experimental colitis that were at least partially mediated by the immunosuppressive effects of the derivate on mucosal DCs.
基金This research is supported by a new faculty start-up from the University of Massachusetts Amherst,USDA NIFA2016-67017-24423,USDA NIFA 2019-67017-29248,USDA/HatchMAS00492,and NIH/NCIR03 CA218520(to G.Z.).
文摘Human consumption of linoleic acid(LA,18:2ω-6,abundant in vegetable oils)is very high.Animal experiments showed that excessive LA intake increased azoxymethane-induced colon tumorigenesis,however,the impact of excessive LA on colon cancer in human is not conclusive,making it difficult to make dietary recommendations for optimal intake of LA.Understanding the molecular mechanisms of LA on colon tumorigenesis could help to clarify its health effect,and facilitate development of mechanismbased strategies for preventing colon cancer.Recent studies show that the previously unappreciated cytochrome P450 monooxygenase-mediated eicosanoid pathway is upregulated in colon cancer and plays critical roles in its pathogenesis,and could contribute to the effects of dietary LA,as well asω-3 fatty acids,on colon tumorigenesis.In this review,we will discuss recent studies about the roles of cytochrome P450 monooxygenases in fatty acid metabolism and its roles in colonic inflammation and colon cancer,and how this information could help us to clarify the health impacts of dietary fatty acids.
基金supported by grants from the National Natural Science Foundation of China (Nos.31902197 and 31802094)the Natural Science Foundation of Jiangsu Province (No.BK20180531)。
文摘Background:Endoplasmic reticulum(ER)stress and autophagy are implicated in the pathophysiology of intestinal inflammation;however,their roles in intrauterine growth retardation(IUGR)-induced colon inflammation are unclear.This study explored the protective effects of natural stilbene pterostilbene on colon inflammation using the IUGR piglets and the tumor necrosis factor alpha(TNF-α)-treated human colonic epithelial cells(Caco-2)by targeting ER stress and autophagy.Results:Both the IUGR colon and the TNF-α-treated Caco-2 cells exhibited inflammatory responses,ER stress,and impaired autophagic flux(P<0.05).The ER stress inducer tunicamycin and the autophagy inhibitor 3-methyladenine further augmented inflammatory responses and apoptosis in the TNF-α-treated Caco-2 cells(P<0.05).Conversely,pterostilbene inhibited ER stress and restored autophagic flux in the IUGR colon and the TNF-α-treated cells(P<0.05).Pterostilbene also prevented the release of inflammatory cytokines and nuclear translocation of nuclear factor kappa B p65,reduced intestinal permeability and cell apoptosis,and facilitated the expression of intestinal tight junction proteins in the IUGR colon and the TNF-α-treated cells(P<0.05).Importantly,treatment with tunicamycin or autophagosome-lysosome binding inhibitor chloroquine blocked the positive effects of pterostilbene on inflammatory response,cell apoptosis,and intestinal barrier function in the TNF-α-exposed Caco-2 cells(P<0.05).Conclusion:Pterostilbene mitigates ER stress and promotes autophagic flux,thereby improving colon inflammation and barrier dysfunction in the IUGR piglets and the TNF-α-treated Caco-2 cells.
基金We thank Dangsheng Li for critical suggestions.We are grateful to Guomei Lin for breeding the animals and Li Li for animal management.We also acknowledge the individuals involved in technical support at the Core Facility for Cell Biology and the Animal Core Facility.This work was supported by grants from the National Key Research and Development Program of China(2018YFA0507402)the National Natural Science Foundation of China(31230024)+1 种基金the Chinese Academy of Sciences(XDB19000000)the National Natural Science Foundation of China(81761128009 and 81630016).
文摘Loss of the colonic inner mucus layer leads to spontaneously severe colitis and colorectal cancer.However,key host factors that may control the generation of the inner mucus layer are rarely reported.Here,we identify a novel function of TRIM34 in goblet cells(GCs)in controlling inner mucus layer generation.Upon DSS treatment,TRIM34 deficiency led to a reduction in Muc2 secretion by GCs and subsequent defects in the inner mucus layer.This outcome rendered TRIM34-deficient mice more susceptible to DSS-induced colitis and colitis-associated colorectal cancer.Mechanistic experiments demonstrated that TRIM34 controlled TLR signaling-induced Nox/Duox-dependent ROS synthesis,thereby promoting the compound exocytosis of Muc2 by colonic GCs that were exposed to bacterial TLR ligands.Clinical analysis revealed that TRIM34 levels in patient samples were correlated with the outcome of ulcerative colitis(UC)and the prognosis of rectal adenocarcinoma.This study indicates that TRIM34 expression in GCs plays an essential role in generating the inner mucus layer and preventing excessive colon inflammation and tumorigenesis.
基金supported by the National Natural Science Foundation of China under Grant No.82171877the Department of Science and Technology of Guangzhou city under Grant No.202002030043(China)the Guangdong Natural Science Foundation under Grant No.2021A1515012456(China).
文摘Methamphetamine(Meth)abuse can cause serious mental disorders,including anxiety and depression.The gut microbiota is a crucial contributor to maintaining host mental health.Here,we aim to investigate if microbiota participate in Meth-induced mental disorders,and the potential mechanisms involved.Here,15 mg/kg Meth resulted in anxiety-and depression-like behaviors of mice successfully and suppressed the Sigma-1 receptor(SIGMAR1)/BDNF/TRKB pathway in the hippocampus.Mean-while,Meth impaired gut homeostasis by arousing the Toll-like receptor 4(TLR4)-related colonic inflammation,disturbing the gut microbiome and reducing the microbiota-derived short-chain fatty acids(SCFAs).Moreover,fecal microbiota from Meth-administrated mice mediated the colonic inflam-mation and reproduced anxiety-and depression-like behaviors in recipients.Further,SCFAs supple-mentation optimized Meth-induced microbial dysbiosis,ameliorated colonic inflammation,and repressed anxiety-and depression-like behaviors.Finally,Sigmarl knockout(Sigmar1^(-/-))repressed the BDNF/TRKB pathway and produced similar behavioral phenotypes with Meth exposure,and elim-inated the anti-anxiety and-depression effects of SCFAs.The activation of SIGMAR1 with fluvoxamine attenuated Meth-induced anxiety-and depression-like behaviors.Our findings indicated that gut microbiota-derived SCFAs could optimize gut homeostasis,and ameliorate Meth-induced mental disorders in a SIGMAR1-dependent manner.This study confirms the crucial role of microbiota in Methrelated mental disorders and provides a potential preemptive therapy.
