Relationship between methylation and colonic inflammation in inflammatory bowel disease

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.

Micro-ecology restoration of colonic inflammation by in-Situ oral delivery of antibody-laden hydrogel microcapsules

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.

Pterostilbene attenuates intrauterine growth retardation-induced colon inflamm tion in piglets by modulating endoplasmic reticulum stress and autophagy

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.

Calcitriol analog ZK191784 ameliorates acute and chronic dextran sodium sulfate-induced colitis by modulation of intestinal dendritic cell numbers and phenotype

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.

Cytochrome P450 monooxygenase-mediated eicosanoid pathway:A potential mechanistic linkage between dietary fatty acid consumption and colon cancer risk

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.

TRIM34 attenuates colon inflammation and tumorigenesis by sustaining barrier integrity

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.

Gut microbiota-derived short-chain fatty acids ameliorate methamphetamine-induced depression-and anxiety-like behaviors in a Sigmar-1 receptor-dependent manner

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.