Vedolizumab serum trough concentrations with and without thiopurines in ulcerative colitis: The prospective VIEWS pharmacokinetics study

BACKGROUND Ulcerative colitis(UC)is a chronic inflammatory condition requiring continuous treatment and monitoring.There is limited pharmacokinetic data on vedolizumab during maintenance therapy and the effect of thiopurines on vedolizumab trough concentrations is unknown.AIM To investigate the exposure-response relationship of vedolizumab and the impact of thiopurine withdrawal in UC patients who have achieved sustained clinical and endoscopic remission during maintenance therapy.METHODS This is a post-hoc analysis of prospective randomized clinical trial(VIEWS)involving UC patients across 8 centers in Australia from 2018 to 2022.Patients in clinical and endoscopic remission were randomized to continue or withdraw thiopurine while receiving vedolizumab.We evaluated vedolizumab serum trough concentrations,presence of anti-vedolizumab antibodies,and clinical outcomes over 48 weeks to assess exposure-response asso-ciation and impact of thiopurine withdrawal.RESULTS There were 62 UC participants with mean age of 43.4 years and 42%were females.All participants received vedolizumab as maintenance therapy with 67.7%withdrew thiopurine.Vedolizumab serum trough concentrations remained stable over 48 weeks regardless of thiopurine use,with no anti-vedolizumab antibodies detected.Pa-tients with clinical remission had higher trough concentrations at week 48.In quartile analysis,a threshold of>11.3μg/mL was associated with sustained clinical remission,showing a sensitivity of 82.4%,specificity of 60.0%,and an area of receiver operating characteristic of 0.71(95%CI:0.49-0.93).Patients discontinuing thiopurine required higher vedolizumab concentrations for achieving remission.CONCLUSION A positive exposure-response relationship between vedolizumab trough concentrations and UC outcomes suggests that monitoring drug levels may be beneficial.While thiopurine did not influence vedolizumab levels,its with-drawal may necessitate higher vedolizumab trough concentrations to maintain remission.

Ulcerative colitis and bullous pemphigoid:Direct association or a medication side effect:A case report

BACKGROUND Bullous pemphigoid(BP)is an autoimmune blistering skin disorder.It is associated with other autoimmune disorders and the use of certain drugs.We describe a case of BP in a patient with ulcerative colitis(UC)treated with mesalamine.CASE SUMMARY A 38-year-old male patient with UC and a history of multiple flares was maintained on mesalamine with good clinical response.One year after starting mesalamine,he sought medical care following the onset of a severe itchy rash of several weeks’duration with a recent appearance of skin bullae.A biopsy of the skin revealed subepidermal blistering dermatitis with focal eosinophilic spongiosis.Direct immunofluorescence studies revealed linear IgG and C3 immune reactant deposits at the dermoepidermal junction,consistent with the diagnosis of BP.Prednisone therapy alleviated his symptoms.However,tapering prednisone led to re-eruption of the bullae.CONCLUSION BP should be considered when patients with UC develop skin manifestations.Although BP is not one of the extraintestinal manifestations of UC,there may be an association between these two conditions.Whether treatment with mesalamine or other therapeutic agents plays a role in the development of BP remains unclear.

Wdr63 Deletion Aggravates Ulcerative Colitis Likely by Affecting Th17/Treg Balance and Gut Microbiota

Objective Ulcerative colitis is a prevalent immunoinflammatory disease.Th17/Treg cell imbalance and gut microbiota dysregulation are key factors in ulcerative colitis pathogenesis.The actin cytoskeleton contributes to regulating the proliferation,differentiation,and migration of Th17 and Treg cells.Wdr63,a gene containing the WD repeat domain,participates in the structure and functional modulation of actin cytoskeleton.Recent research indicates that WDR63 may serve as a regulator of cell migration and metastasis via actin polymerization inhibition.This article aims to explore the effect of Wdr63 deletion on Th17/Treg cells and ulcerative colitis.Methods We constructed Wdr63-/-mice,induced colitis in mice using dextran sulfate sodium salt,collected colon tissue for histopathological staining,collected mesenteric lymph nodes for flow cytometry analysis,and collected healthy mouse feces for microbial diversity detection.Results Compared with wild-type colitis mice,Wdr63-/-colitis mice had a more pronounced shortening of colonic tissue,higher scores on disease activity index and histological damage index,Treg cells decreased and Th17 cells increased in colonic tissue and mesenteric lymph nodes,a lower level of anti-inflammatory cytokine IL-10,and a higher level of pro-inflammatory cytokine IL-17A.In addition,WDR63 has shown positive effects on maintaining intestinal microbiota homeostasis.It maintains the balance of Bacteroidota and Firmicutes,promoting the formation of beneficial intestinal bacteria linked to immune inflammation.Conclusion Wdr63 deletion aggravates ulcerative colitis in mice,WDR63 inhibits colonic inflammation likely by regulating Th17/Treg balance and maintains intestinal microbiota homeostasis.

Application of Saccharomyces boulardii in combination with sulfasalazine in ulcerative colitis patients demonstrates significant effectiveness

BACKGROUND Ulcerative colitis(UC)is a complex inflammatory bowel disease,and its etiology and pathogenesis remain incompletely elucidated.AIM To analyze the effects of Saccharomyces boulardii in combination with sulfasalazine on intestinal microbiota and intestinal barrier function in patients with UC.METHODS A retrospective analysis of clinical data from 127 UC patients admitted to our hospital between January 2021 and January 2023 was conducted.All patients met complete inclusion and exclusion criteria.Based on the treatment interventions received,they were divided into a control group(n=63)and an observation group(n=64).Both groups of patients received routine treatment upon admission.The control group received sulfasalazine in addition to routine interventions,while the observation group received a combination of Saccharomyces boulardii on the basis of the control group’s treatment.The clinical efficacy,improvement in symptoms,modified Baron endoscopic scores,quality of life“inflammatory bowel disease questionnaire(IBDQ)”,levels of intestinal microbial indicators(such as Lactobacillus,Bifidobacterium,Enterococcus,and Escherichia coli),intestinal mucosal barrier function indicators[diamine oxidase(DAO),lipopolysaccharide(LPS),D-lactic acid(D-LA)],and adverse reaction occurrences were compared between the two groups.RESULTS(1)Clinical efficacy:The total effective rate in the control group was 79.37%,while in the observation group,it was 93.75%,significantly higher than that of the control group(P<0.05);(2)Improvement in symptoms:The observation group showed significantly lower relief time for abdominal pain,diarrhea,rectal bleeding,fever symptoms,and mucosal healing time compared to the control group(P<0.05);(3)Baron endoscopic scores and IBDQ scores:Before treatment,there was no significant difference in Baron endoscopic scores and IBDQ scores between the two groups(P>0.05).However,after treatment,the observation group showed significantly lower Baron endoscopic scores and higher IBDQ scores compared to the control group(P<0.05);(4)Levels of intestinal microbial indicators:Before treatment,there was no significant difference in the levels of Lactobacillus,Bifidobacterium,Enterococcus,and Escherichia coli between the two groups(P>0.05).After treatment,the levels of Lactobacillus and Bifidobacterium in the observation group were significantly higher than those in the control group,while the levels of Enterococcus and Escherichia coli were significantly lower than those in the control group(P<0.05);(5)Levels of intestinal mucosal barrier function indicators:Before treatment,there was no significant difference in the levels of DAO,LPS,and D-LA between the two groups(P>0.05).However,after treatment,the levels of DAO,LPS,and D-LA in the observation group were significantly lower than those in the control group(P<0.05);and(6)Occurrence of adverse reactions:The incidence of adverse reactions in the control group was 9.52%,while in the observation group,it was 10.94%.There was no significant difference in the occurrence of adverse reactions between the two groups(P>0.05).CONCLUSION The application of Saccharomyces boulardii in combination with sulfasalazine in UC patients demonstrates significant effectiveness.Compared to sole sulfasalazine intervention,the combined application of Saccharomyces boulardii further promotes the relief of relevant symptoms in patients,alleviates intestinal mucosal inflammation,and improves the quality of life.Its action may be related to rectifying the imbalance in intestinal microbiota and improving intestinal mucosal barrier function.Moreover,the combined use of Saccharomyces boulardii does not increase the risk of adverse reactions in patients,indicating a higher level of medication safety and advocating for its clinical promotion and application.

Keratin 1 modulates intestinal barrier and immune response via kallikrein kinin system in ulcerative colitis

BACKGROUND External factors in ulcerative colitis(UC)exacerbate colonic epithelial permea-bility and inflammatory responses.Keratin 1(KRT1)is crucial in regulating these alterations,but its specific role in the progression of UC remains to be fully eluci-dated.AIM To explore the role and mechanisms of KRT1 in the regulation of colonic epithelial permeability and inflammation in UC.METHODS A KRT1 antibody concentration gradient test,along with a dextran sulfate sodium(DSS)-induced animal model,was implemented to investigate the role of KRT1 in modulating the activation of the kallikrein kinin system(KKS)and the cleavage of bradykinin(BK)/high molecular weight kininogen(HK)in UC.RESULTS Treatment with KRT1 antibody in Caco-2 cells suppressed cell proliferation,induced apoptosis,reduced HK expression,and increased BK expression.It further downregulated intestinal barrier proteins,including occludin,zonula occludens-1,and claudin,and negatively impacted the coagulation factor XII.These changes led to enhanced activation of BK and HK cleavage,thereby intensifying KKS-mediated inflammation in UC.In the DSS-induced mouse model,administration of KRT1 antibody mitigated colonic injury,increased colon length,alleviated weight loss,and suppressed inflammatory cytokines such as interleukin(IL)-1,IL-6,tumor necrosis factor-α.It also facilitated repair of the intestinal barrier,reducing DSS-induced injury.CONCLUSION KRT1 inhibits BK expression,suppresses inflammatory cytokines,and enhances markers of intestinal barrier function,thus ameliorating colonic damage and maintaining barrier integrity.KRT1 is a viable therapeutic target for UC.

Targeted screening of an anti-inflammatory polypeptide from Rhopilema esculentum Kishinouye cnidoblasts and elucidation of its mechanism in alleviating ulcerative colitis based on an analysis of the gut microbiota and metabolites

Ulcerative colitis(UC)is a recurrent inflammatory bowel disease that imposes a severe burden on families and society.In recent years,exploiting the potential of marine bioactive peptides for the treatment of diseases has become a topic of intense research interest.This study revealed the mechanism underlying the protective effect of the dominant polypeptide PKKVV(Pro-Lys-Lys-Val-Val)of Rhopilema esculentum cnidoblasts against DSS-induced UC through a combined analysis of the metagenome and serum metabolome.Specifically,the polypeptide composition of R.esculentum cnidoblasts was determined by matrix-assisted laser desorption ionization time-of-flight mass spectrometry(MALDI-TOF/TOF-MS).Molecular docking showed that the dominant peptide PKKVV could bind better with tumor necrosis factor-α(TNF-α)than the original ligand.Subsequent animal experiments suggested that PKKVV could modulate disorganized gut microorganisms in mice with UC;affect serum metabolites through the arachidonic acid,glycerophospholipid and linoleic acid metabolism pathways;and further alleviate UC symptoms.This study provides a reference for the comprehensive development of marine bioactive substances and nonpharmaceutical treatments for UC.

Structural characteristics of phenylboronic acid-modified astaxanthin ester and its effect on DSS-induced ulcerative colitis by blocking reactive oxygen species and maintaining intestinal homeostasis

A novel and reactive oxygen species(ROS)responsive astaxanthin phenylboronic acid derivative(AstaDPBA)was constructed by grafting phenylboronic acid(PBA)onto astaxanthin succinate diester(AstaD),and its chemical structure and physicochemical property were identified.AstaD-PBA could effectively improve the ROS quenching ability in the lipopolysaccharide(LPS)-induced RAW264.7 cell inflammation model.Then,the bioactivity of AstaD-PBA was studied by 4 zebrafish ROS-responsive infl ammatory models induced by LPS,copper(Cu^(2+)),high-fat diet,and dextran sodium sulfate(DSS).The results suggest that AstaD-PBA might have high biosafety and the best effect on ulcerative colitis(UC)induced by DSS.Furtherly,AstaDPBA significantly alleviated and treated weight loss and colonic shrinkage,inhibited infl ammatory cytokines,and maintained microbiota homeostasis to improve UC in C57BL/6J mice.Alistipes and Oscillibacter were expected to be considered UC marker fl ora according to the Metastats analysis and Pearson correlation Mantel test(P<0.01)of 16S rRNA gene sequencing data.In conclusion,AstaD-PBA has been promised to be a functional compound to improve UC and maintain intestinal microbiota homeostasis.

The role of a novel antibacterial substance,cyclic opine-producing Lacticaseibacillus rhamnosus LS8 in ameliorating ulcerative colitis:a fecal microbiota transplantation study

Intestinal microbiota imbalance may worsen the progression of ulcerative colitis(UC).Lacticaseibacillus rhamnosus LS8(LR)has the potential ability to regulate microbiota through producing a novel antibacterial substance,cyclic opine:cycloalanopine.This study aimed to investigate whether LR could ameliorate dextran sulfate sodium-induced UC in mice via modulating intestinal microbiota using fecal microbiota transplantation(FMT)experiment.The results showed that both LR and FMT attenuated UC as evidenced by 1)alleviating disease activity index and colonic pathology;2)up-regulating MUCs and tight junction proteins;3)increasing oxidative mediators and decreasing antioxidant mediators;4)down-regulating proinflammatory cytokines and chemokines.These results were mainly attributable to the microbiota-regulating effect of LR,including increasing beneficial bacteria(like Akkermansia)and its related SCFAs,while decreasing harmful bacteria(like Proteobacteria)and its related LPS,thereby suppressing the hyperactivation of TLR4/NF-κB pathway.Consequently,LR can alleviate UC and is a potential dietary supplement to attenuate UC.

Construction of the underlying circRNA-miRNA-mRNA regulatory network and a new diagnostic model in ulcerative colitis by bioinformatics analysis

BACKGROUND Circular RNAs(circRNAs)are involved in the pathogenesis of many diseases through competing endogenous RNA(ceRNA)regulatory mechanisms.AIM To investigate a circRNA-related ceRNA regulatory network and a new predictive model by circRNA to understand the diagnostic mechanism of circRNAs in ulcerative colitis(UC).METHODS We obtained gene expression profiles of circRNAs,miRNAs,and mRNAs in UC from the Gene Expression Omnibus dataset.The circRNA-miRNA-mRNA network was constructed based on circRNA-miRNA and miRNA-mRNA interactions.Functional enrichment analysis was performed to identify the biological mechanisms involved in circRNAs.We identified the most relevant differential circRNAs for diagnosing UC and constructed a new predictive nomogram,whose efficacy was tested with the C-index,receiver operating characteristic curve(ROC),and decision curve analysis(DCA).RESULTS A circRNA-miRNA-mRNA regulatory network was obtained,containing 12 circRNAs,three miRNAs,and 38 mRNAs.Two optimal prognostic-related differentially expressed circRNAs,hsa_circ_0085323 and hsa_circ_0036906,were included to construct a predictive nomogram.The model showed good discrimination,with a C-index of 1(>0.9,high accuracy).ROC and DCA suggested that the nomogram had a beneficial diagnostic ability.CONCLUSION This novel predictive nomogram incorporating hsa_circ_0085323 and hsa_circ_0036906 can be conveniently used to predict the risk of UC.The circRNa-miRNA-mRNA network in UC could be more clinically significant.

Real-world efficacy and safety of tofacitinib treatment in Asian patients with ulcerative colitis

BACKGROUND Real-world data on tofacitinib(TOF)covering a period of more than 1 year for a sufficient number of Asian patients with ulcerative colitis(UC)are scarce.AIM To investigate the long-term efficacy and safety of TOF treatment for UC,including clinical issues.METHODS We performed a retrospective single-center observational analysis of 111 UC patients administered TOF at Hyogo Medical University as a tertiary inflammatory bowel disease center.All consecutive UC patients who received TOF between May 2018 and February 2020 were enrolled.Patients were followed up until August 2020.The primary outcome was the clinical response rate at week 8.Secondary outcomes included clinical remission at week 8,cumulative persistence rate of TOF administration,colectomy-free survival,relapse after tapering of TOF and predictors of clinical response at week 8 and week 48.RESULTS The clinical response and remission rates were 66.3%and 50.5%at week 8,and 47.1%and 43.5%at week 48,respectively.The overall cumulative clinical remission rate was 61.7%at week 48 and history of anti-tumor necrosis factor-alpha(TNF-α)agents use had no influence(P=0.25).The cumulative TOF persistence rate at week 48 was significantly lower in patients without clinical remission than in those with remission at week 8(30.9%vs 88.1%;P<0.001).Baseline partial Mayo Score was significantly lower in responders vs non-responders at week 8(odds ratio:0.61,95%confidence interval:0.45-0.82,P=0.001).Relapse occurred in 45.7%of patients after TOF tapering,and 85.7%of patients responded within 4 wk after re-increase.All 6 patients with herpes zoster(HZ)developed the infection after achieving remission by TOF.CONCLUSION TOF was more effective in UC patients with mild activity at baseline and its efficacy was not affected by previous treatment with anti-TNF-αagents.Most relapsed patients responded again after re-increase of TOF and nearly half relapsed after tapering off TOF.Special attention is needed for tapering and HZ.

Emerging role of exosomes in ulcerative colitis: Targeting NOD-like receptor family pyrin domain containing 3 inflammasome

Ulcerative colitis(UC)is a chronic recurrent inflammatory bowel disease.Despite ongoing advances in our understanding of UC,its pathogenesis is yet unelu-cidated,underscoring the urgent need for novel treatment strategies for patients with UC.Exosomes are nanoscale membrane particles that mediate intercellular communication by carrying various bioactive molecules,such as proteins,RNAs,DNA,and metabolites.The NOD-like receptor family pyrin domain containing 3(NLRP3)inflammasome is a cytosolic tripartite protein complex whose activation induces the maturation and secretion of proinflammatory cytokines interleukin-1β(IL-1β)and IL-18,triggering the inflammatory response to a pathogenic agent or injury.Growing evidence suggests that exosomes are new modulators of the NLRP3 inflammasome,with vital roles in the pathological process of UC.Here,recent evidence is reviewed on the role of exosomes and NLRP3 inflammasome in UC.First,the dual role of exosomes on NLRP3 inflammasome and the effect of NLRP3 inflammasome on exosome secretion are summarized.Finally,an outlook on the directions of exosome-NLRP3 inflammasome crosstalk research in the context of UC is proposed and areas of further research on this topic are high-lighted.

Upadacitinib for refractory ulcerative colitis with primary nonresponse to infliximab and vedolizumab:A case report

BACKGROUND Many patients with ulcerative colitis(UC)do not respond well to,or tolerate conventional and biological therapies.There is currently no consensus on the treatment of refractory UC.Studies have demonstrated that the selective Janus kinase 1 inhibitor upadacitinib,a small-molecule drug,is effective and safe for treating UC.However,no studies have revealed that upadacitinib is effective in treating refractory UC with primary nonresponse to infliximab and vedolizumab.CASE SUMMARY We report the case of a 44-year-old male patient with a chief complaint of bloody diarrhoea with mucus and pus,in addition to dizziness.The patient had recurrent disease after receiving mesalazine,prednisone,azathioprine,infliximab and vedolizumab over four years.Based on the endoscopic findings and pathological biopsy,the patient was diagnosed with refractory UC.In particular,the patient showed primary nonresponse to infliximab and vedolizumab.Based on the patient’s history and recurrent disease,we decided to administer upadacitinib.During hospitalisation,the patient was received upadacitinib under our guidance.Eight weeks after the initiation of upadacitinib treatment,the patient’s symptoms and endoscopic findings improved significantly.No notable adverse reactions have been reported to date.CONCLUSION Our case report suggests that upadacitinib may represent a valuable strategy for treating refractory UC with primary nonresponse.

Five commonly used traditional Chinese medicine formulas in the treatment of ulcerative colitis:A network meta-analysis

BACKGROUND Currently,traditional Chinese medicine(TCM)formulas are commonly being used as adjunctive therapy for ulcerative colitis in China.Network meta-analysis,a quantitative and comprehensive analytical method,can systematically compare the effects of different adjunctive treatment options for ulcerative colitis,providing scientific evidence for clinical decision-making.AIM To evaluate the clinical efficacy and safety of commonly used TCM for the treatment of ulcerative colitis(UC)in clinical practice through a network metaanalysis.METHODS Clinical randomized controlled trials of these TCM formulas used for the adjuvant treatment of UC were searched from the establishment of the databases to July 1,2022.Studies that met the inclusion criteria were screened and evaluated for literature quality and risk of bias according to the Cochrane 5.1 standard.The methodological quality of the studies was assessed using ReviewManager(RevMan)5.4,and a funnel plot was constructed to test for publication bias.ADDIS 1.16 statistical software was used to perform statistical analysis of the treatment measures and derive the network relationship and ranking diagrams of the various intervention measures.RESULTS A total of 64 randomized controlled trials involving 5456 patients with UC were included in this study.The adjuvant treatment of UC using five TCM formulations was able to improve the clinical outcome of the patients.Adjuvant treatment with Baitouweng decoction(BTWT)showed a significant effect[mean difference=36.22,95%confidence interval(CI):7.63 to 65.76].For the reduction of tumor necrosis factor in patients with UC,adjunctive therapy with BTWT(mean difference=−9.55,95%CI:−17.89 to−1.41),Shenlingbaizhu powder[SLBZS;odds ratio(OR)=0.19,95%CI:0.08 to 0.39],and Shaoyao decoction(OR=−23.02,95%CI:−33.64 to−13.14)was effective.Shaoyao decoction was more effective than BTWT(OR=0.12,95%CI:0.03 to 0.39),SLBZS(OR=0.19,95%CI:0.08 to 0.39),and Xi Lei powder(OR=0.34,95%CI:0.13 to 0.81)in reducing tumor necrosis factor and the recurrence rate of UC.CONCLUSION TCM combined with mesalazine is more effective than mesalazine alone in the treatment of UC.

Are we ready to use new endoscopic scores for ulcerative colitis?

For ulcerative colitis(UC),the variability in inflammatory activity along the colon poses a challenge in management.The focus on achieving endoscopic healing in UC is evident,where the UC Endoscopic Index of Severity and Mayo Endoscopic Subscore are commonly used for evaluation.However,these indices primarily consider the most severely affected region.Liu et al recent study validates the Toronto Inflammatory Bowel Disease Global Endoscopic Reporting(TIGER)score offering a comprehensive assessment of inflammatory activity across diverse segments of the colon and rectum and a reliable index correlating strongly with UC Endoscopic Index of Severity and moderately with Mayo Endoscopic Subscore(MES).Despite recommendation,certain aspects warrant further invest-igation.Fecal calprotectin,an intermediate target,correlates with TIGER and should be explored.Determining TIGER scores defining endoscopic remission and response,evaluating agreement with histological activity,and assessing inter-endoscopist agreement for TIGER require scrutiny.Exploring the correlation between TIGER and intestinal ultrasound,akin to MES,adds value.

SLC6A14 promotes ulcerative colitis progression by facilitating NLRP3 inflammasome-mediated pyroptosis

BACKGROUND Ulcerative colitis(UC)is an inflammatory condition with frequent relapse and recurrence.Evidence suggests the involvement of SLC6A14 in UC pathogenesis,but the central regulator remains unknown.AIM To explore the role of SLC6A14 in UC-associated pyroptosis.METHODS Quantitative real-time polymerase chain reaction(qRT-PCR),immunoblotting,and immunohistochemical were used to assess SLC6A14 in human UC tissues.Lipopolysaccharide(LPS)was used to induce inflammation in FHC and NCM460 cells and model enteritis,and SLC6A14 levels were assessed.Pyroptosis markers were quantified using enzyme-linked immunosorbent assay,Western blotting,and qRT-PCR,and EdU incubation,CCK-8 assays and flow cytometry were used to examine proliferation and apoptosis.Mouse models of UC were used for verification.RESULTS SLC6A14 was increased and correlated with NLRP3 in UC tissues.LPS-induced FHC and NCM460 cells showed increased SLC6A14 levels.Reducing SLC6A14 increased cell proliferation and suppressed apoptosis.Reducing SLC6A14 decreased pyroptosis-associated proteins(ASC,IL-1β,IL-18,NLRP3).NLRP3 overexpression counteracted the effects of sh-SLC6A14 on LPS-induced FHC and NCM460 cell pyroptosis.SLC6A14 improved the mucosa in mice with dextran sulfate sodium-induced colitis.CONCLUSION SLC6A14 promotes UC pyroptosis by regulating NLRP3,suggesting the therapeutic potential of modulating the SLC6A14/NLRP3 axis.

Exploring the autophagy-related pathogenesis of active ulcerative colitis

BACKGROUND The pathogenesis of ulcerative colitis(UC)is complex,and recent therapeutic advances remain unable to fully alleviate the condition.AIM To inform the development of novel UC treatments,bioinformatics was used to explore the autophagy-related pathogenesis associated with the active phase of UC.METHODS The GEO database was searched for UC-related datasets that included healthy controls who met the screening criteria.Differential analysis was conducted to obtain differentially expressed genes(DEGs).Au-tophagy-related targets were collected and intersected with the DEGs to identiy differentially expressed autophagy-related genes(DEARGs)associated with active UC.DEARGs were then subjected to KEGG,GO,and DisGeNET disease enrichment analyses using R software.Differential analysis of immune infiltrating cells was performed using the CiberSort algorithm.The least absolute shrinkage and selection operator algorithm and protein-protein interaction network were used to narrow down the DEARGs,and the top five targets in the Dgree ranking were designated as core targets.RESULTS A total of 4822 DEGs were obtained,of which 58 were classified as DEARGs.SERPINA1,BAG3,HSPA5,CASP1,and CX3CL1 were identified as core targets.GO enrichment analysis revealed that DEARGs were primarily enriched in processes related to autophagy regulation and macroautophagy.KEGG enrichment analysis showed that DEARGs were predominantly associated with NOD-like receptor signaling and other signaling pathways.Disease enrichment analysis indicated that DEARGs were significantly linked to diseases such as malignant glioma and middle cerebral artery occlusion.Immune infiltration analysis demonstrated a higher presence of immune cells like activated memory CD4 T cells and follicular helper T cells in active UC patients than in healthy controls.CONCLUSION Autophagy is closely related to the active phase of UC and the potential targets obtained from the analysis in this study may provide new insight into the treatment of active UC patients.

Protective effect of naringenin on acetic acid-induced ulcerative colitis in rats

AIM:To evaluate the ameliorative effect of naringenin(NG)during ulcerative colitis(UC)in rats.METHODS:Rats were treated with three different doses(25,50 and 100 mg/kg per day)of NG and a single dose of mesalazine(MES,300 mg/kg per day)for seven days prior to ulcerative colitis induction by4%acetic acid(AA).Twenty four hours after AA rectal administration,animals were scarified and the colonic tissues were dissected.Colonic mucus content was estimated using Alcian blue dye binding technique.In colon tissues,levels of total glutathione sulphadryls(T-GSH),non-protein sulphadryls(NP-SH)and thiobarbituric acid reactive substances(TBARS)were evaluated.The activities of the antioxidant enzymes,catalase(CAT)and superoxide dismutase(SOD)were measured.Concentrations of nucleic acids(DNA and RNA)and total protein were also estimated in colon tissues.Colonic levels of tumor necrosis factor-(TNF-),interleukin-1(IL-1),interleukin-6(IL-6),prostaglandin E2(PGE2)and nitric oxide(NO)were estimated.In cross section of colitis tissue the histopathological changes were observed.RESULTS:Colonic mucus content was decreased in AA compared to controls(587.09±65.59 mg/kg vs941.78±68.41 mg/kg,P<0.001).AA administration markedly reduced T-GSH(5.25±0.37 nmol/L vs 3.04±0.24 nmol/L,P<0.01),NP-SH(3.16±0.04 nmol/L vs 2.16±0.30 nmol/L,P<0.01),CAT(6.77±0.40 U/mg vs 3.04±0.2 U/mg,P<0.01)and SOD(3.10±0.11U/mg vs 1.77±0.18 U/mg,P<0.01)while TBARS,TNF-,IL-1,IL-6,PGE2 and NO levels(15.09±3.84nmol/L vs 59.90±16.34 nmol/L,P<0.01;113.56±1.91 pg/mg vs 134.24±4.77 pg/mg,P<0.01;209.20±36.38 pg/mg vs 422.19±31.47 pg/mg,P<0.01;250.83±25.09 pg/mg vs 638.58±115.9 pg/mg,P<0.01;248.19±36.98 pg/mg vs 541.74±58.34 pg/mg,P<0.01 and 81.26±2.98 mmol/g vs 101.90±10.73 mmol/g,P<0.001)were increased in colon of rats with UC compared controls respectively.Naringenin supplementation,significantly and dose dependently increased the colonic mucus content.The elevated TBARS levels were significantly decreased(39.35±5.86nmol/L,P<0.05;26.74±3.17 nmol/L,P<0.01 nmol/L and 17.74±2.69 nmol/L,P<0.01)compared to AA(59.90±16.34 nmol/L)group while the decreased levels of T-GSH and NP-SH and activities of CAT and SOD found increased by NG treatments in dose dependent manner.The decreased values of nucleic acids and total protein in AA group were also significantly(P<0.01)increased in all three NG supplemented groupsrespectively.NG pretreatment inhibited the TNF-levels(123.76±3.76 pg/mg,122.62±3.41 pg/mg and121.51±2.61 pg/mg vs 134.24±4.78 pg/mg,P<0.05)compared to AA group,respectively.Interleukins,IL-1 and IL-6 levels were also decreased in NG50+AA(314.37±16.31 pg/mg and 292.58±23.68 pg/mg,P<0.05)and NG100+AA(416.72±49.62 pg/mg and 407.96±43.87 pg/mg,P<0.05)when compared to AA(352.46±8.58 pg/mg and 638.58±115.98pg/mg)group.Similar decrease(P<0.05)was seen in PGE2and NO values when compared to AA group.The group pretreated with MES,as a reference drug,showed significant(P<0.01)protection against the changes induced in colon tissue by AA administration respectively.CONCLUSION:In present study,NG produced antioxidant and anti-inflammatory effects demonstrating protective effect in inflammatory bowel disease.

Remission induction and maintenance effect of probiotics on ulcerative colitis: A meta-analysis

AIM:To evaluate the induction of remission and main-tenance effects of probiotics for ulcerative colitis.METHODS: Information was retrieved from MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. The induction of remission and promotion of mainte-nance were compared between probiotics treatment and non-probiotics treatment in ulcerative colitis.RESULTS: Thirteen randomized controlled studies met the selection criteria. Seven studies evaluated the remission rate, and eight studies estimated the recur-rence rate; two studies evaluated both remission and recurrence rates. Compared with the non-probiotics group, the remission rate for ulcerative colitis patients who received probiotics was 1.35 (95% CI: 0.98-1.85). Compared with the placebo group, the remission rate of ulcerative colitis who received probiotics was 2.00 (95% CI: 1.35-2.96). During the course of treatment, in patients who received probiotics for less than 12 mo compared with the group treated by non-probiotics, the remission rate of ulcerative colitis was 1.36 (95% CI: 1.07-1.73). Compared with the non-probioticsgroup, the recurrence rate of ulcerative colitis patients who received probiotics was 0.69 (95% CI: 2.47-1.01). In the mild to moderate group who received probiotics, compared to the group who did not receive probiotics, the recurrence rate was 0.25 (95% CI: 0.12-0.51). The group who received Bifidobacterium bifidum treatment had a recurrence rate of 0.25 (95% CI: 0.12-0.50) compared with the non-probiotics group.CONCLUSION: Probiotic treatment was more effec-tive than placebo in maintaining remission in ulcerative colitis.

In vitro production of TNFα,IL-6 and sIL-2R in Chinese patients with ulcerative colitis

AIM To determine the tumor necrosis factor alpha (TNFα), interleukin 6 (IL 6) and soluble interleukin 2 receptor (sIL 2r) from peripheral blood mononuclear cells (PBMC) in 25 Chinese patients with ulcerative colitis and 20 healthy controls. METHODS PBMC were isolated by density gradient centrifugation of heparinized blood and cultures for 24 or 48 hours by stimulation with LPS or PHA. TNFα and sIL 2r were measured by ELISA method and IL 6 measured by bioassay. RESULTS TNFα production stimulated by LPS and sIL 2r production by PHA in ulcerative colitis were significantly lower than in healthy controls (TNFα 509(46-7244)ng/L vs 1995(117-18 950)ng/L, P <0 05; sIL 2r 320U/ml±165U/ml vs 451U/ml±247U/ml, P <0 05). Spontaneous TNFα and sIL 2r production were not significantly different between ulcerative colitis and controls (TNFα 304(46-7044)ng/L vs 215(46-4009)ng/L, P >0 05; sIL 2r 264U/ml±115U/ml vs 236U/ml±139U/ml, P >0 05). IL 6 production by spontaneous release from PBMC in ulcerative colitis group was 109U/ml±94U/ml vs 44U/ml±39U/ml for those in healthy controls, P <0 01. IL 6 stimulated by LPS in ulcerative colitis group was (261U/ml±80U/ml) higher than in healthy controls (102U/ml±54U/ml, P <0 01). No correlation of TNFα, IL 6, sIL 2r production was found to disease activity, disease location and medication. CONCLUSION Cytokine production from PBMC was also disturbed in Chinese patients with ulcerative colitis.

Fluctuations in butyrate-producing bacteria in ulcerative colitis patients of North India

AIM: To study the interplay between butyrate concentration and butyrate-producing bacteria in fecal samples of ulcerative colitis (UC) patients vs control individuals. METHODS: Fecal samples were collected from 14 control individuals (hemorrhoid patients only) and 26 UC patients (severe: n = 12, moderate: n = 6, remission: n = 8), recruited by the gastroenterologist at the Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India. Disease activity in UC patients was determined by clinical colitis activity index. We employed fluorescent in situ hybridization in combination with flow cytometry to enumerate the clostridium cluster population targeted by 16S rRNA gene probe. Major butyrate-producing species within this cluster were quantified to see if any change existed in control vs UC patients with different disease activity. This observed change was further validated by quantitative polymerase chain reaction. In addition to this,we carried out gas chromatography to evaluate the changes in concentration of major short chain fatty acids (SCFAs), namely acetate, n -butyrate, iso -butyrate, in the above samples. Student t test and Graph pad prism-6 were used to compare the data statistically. RESULTS: There was a significant decrease of Clostridium coccoides (control, 25.69% ± 1.62% vs severe, 9.8% ± 2.4%, P = 0.0001) and Clostridium leptum clusters (control, 13.74% ± 1.05% vs severe, 6.2% ± 1.8%, P = 0.0001) in fecal samples of UC patients. Furthermore, we demonstrated that some butyrateproducing members of the clostridial cluster, like Fecalibacterium prausnitzii (control, 11.66% ± 1.55% vs severe, 6.01% ± 1.6%, P = 0.0001) and Roseburia intestinalis (control, 14.48% ± 1.52% vs severe, 9% ± 1.83%, P = 0.02) were differentially present in patients with different disease activity. In addition, we also demonstrated decreased concentrations of fecal SCFAs, especially of n -butyrate (control, 24.32 ± 1.86 mmol/μL vs severe, 12.74 ± 2.75 mmol/μL, P = 0.003), iso -butyrate (control, 1.70 ± 0.41 mmol/μL vs severe, 0.68 ± 0.24 mmol/μL, P = 0.0441) and acetate (control, 39.51 ± 1.76 mmol/μL vs severe, 32.12 ± 2.95 mmol/ μL,P = 0.047), in the fecal samples of UC patients. The observed decrease of predominant butyrate producers of clostridial clusters correlated with the reduced SCFA levels in active UC patients. This was further confirmed by the restoration in the population of some butyrate producers with simultaneous increase in the level of SCFA in remission samples. CONCLUSION: Our observations indicate that decreases in members of the clostridial cluster resulting in reduced butyrate levels contribute to the etiology of UC.