Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases, but no effective anti-fibrotic therapy is currently available. Glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP1R) are both peptide hormone receptors involved in energy metabolism of epithelial cells. However, their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored. Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn's disease as well as in the fibrotic colon of mice with chronic colitis. The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate, resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition (EMT). Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis in vivo. We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis via histone lactylation. Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.

Objective:To assess the long-term risk of relapse in patients with Crohn's disease (CD) who discontinued infliximab (IFX) monoclonal antibody and to identify risk factors associated with relapse.Methods:A single-center retrospective observational study was conducted from February 2006 to October 2016. The study included CD patients who were treated with scheduled IFX infusions at the First Affiliated Hospital of Sun Yat-sen University and assessed in corticosteroid-free clinical remission at the time of withdrawal were included. The primary outcome was clinical relapse. We evaluated the risk of relapse using Kaplan-Meier method. Factors associated with time to relapse was identified using the multiple Cox proportional hazards regression analysis.Results:We included 97 eligible patients, and 75 (77.3%) experienced a relapse after a median follow-up time of 124 months. Among them, 45 patients (46.4%) relapsed within 3 years after IFX withdrawal. The 1-, 2-, 3-, 5-, and 10-year relapse-free survival were 79.4%, 59.8%, 52.6%, 42.0% and 22.6%, respectively. Risk factors for relapse included age ≤ 16 ( HR = 2.62, 95% CI: 1.30-5.31; P = 0.007) and failure to achieve biological remission (CRP > 3 mg/L, HR = 2.37, 95% CI: 1.29-4.36; P = 0.006) at drug withdrawal. Induction with biologics or systemic steroids were both effective (89%-100% relieved) in relapsers. Conclusions:Nearly half of CD patients relapsed within 3 years after discontinuation of IFX treatment. Early age of discontinuation and failure to achieve serum biological remission at the time of discontinuation are independent predictors of clinical relapse.

Objective:To analyze the expression of zinc homeostasis-related genes and related cells in the intestinal mucosa of inflammatory bowel disease (IBD) patients at the single-cell level and to evaluate their value in predicting the response to anti-tumor necrosis factor (TNF) therapy in IBD patients.Methods:Single-cell RNA sequencing data from 75 ileal or colorectal biopsy samples, including those from patients with Crohn's disease (CD), ulcerative colitis (UC), and normal controls (NC), were collected from four gene expression omnibus (GEO) databases. Unsupervised clustering analysis in R language was employed to classify IBD cells, zinc homeostasis-related gene scores were used to assess the zinc homeostasis status of different cell clusters, and the cell clusters closely related to zinc homeostasis-related genes, namely metallothionein-associated macrophages (MT Mph), were identified. Then the colon tissues from IBD patients and healthy individuals treated at the First Affiliated Hospital of Sun Yat-sen University were collected for immunofluorescence (IF) staining to compare the differences in MT Mph numbers between IBD and NC tissues. To further explore the function and origins of MT Mph, the characteristic genes of MT Mph and non- metallothionein-associated macrophages (non-MT Mph) from database were compared, the Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis was further used to enrich the characteristic genes, cell communication analysis was used to investigate the communication mechanisms between MT Mph and different cells, Quasi-time sequence was used to explore the origin of MT Mph and related signaling pathways, and the differences in transcription factors among monocytes, MT Mph and non-MT Mph were analyzed in R language. Single sample gene set enrichment analysis (ssGSEA) was used to evaluate the expression of MT Mph characteristic genes, and ssGSEA combined with the response to anti-TNF were used to construct the model in order to explore the predictive value of MT Mph characteristic genes for the response to anti-TNF therapy in IBD patients.Results:IBD cells were clustered and annotated into seven major cell clusters, namely T cells, B cells, plasma cells, myeloid cells, fibroblasts, endothelial cells, and epithelial cells. The results of zinc homeostasis-related gene scores showed that the scores of IBD myeloid cells were higher than those of the NC group. Myeloid cells could be divided into monocytes, macrophages, neutrophils, and dendritic cells. Based on the expression of zinc homeostasis genes, especially the high expression of metallothionein genes, the macrophages were divided into MT Mph and non-MT Mph, and the number of MT Mph in the IBD intestine was significantly increased compared to the NC group. IF validation showed that the number of CD68 +MT1G + cells (MT Mph) in both UC and CD were significantly higher than that in the NC group under per high-power field of view (UC vs. NC: 30.80 ± 7.29 vs. 9.80 ± 1.80, P < 0.001; CD vs. NC: 36.00 ± 9.30 vs. 9.80 ± 1.80, P < 0.001). KEGG pathway enrichment analysis revealed that the differential genes of MT Mph were enriched in key genes of inflammation-related pathways, especially the TNF signaling pathway. Cell communication analysis showed that the TNF signaling pathway between MT Mph and other cells in IBD was significantly enhanced compared to NC. Quasi-time sequence analysis results showed that monocytes could differentiate into MT Mph, and the expression of metallothionein genes ( MT2A, MT1X, MT1H and MT1G) was significantly upregulated during the differentiation process. Transcription factor analysis showed that the transcription factors SMARCB1 and ZMYND8 of MT Mph were significantly higher than those of monocytes, and the classical inflammatory transcription factors HIF1A, STAT3, and NFKB1 were significantly higher than those of non-MT Mph. Prediction models for CD and UC were constructed respectively based on ssGSEA and TNF treatment response [CD: area under the curve (AUC) = 0.966, P < 0.01; AUC = 0.793, P < 0.01]. Validation results showed that the model could not predict the response of CD and UC patients to vedolizumab therapy (both P > 0.05). Conclusions:There is a zinc homeostasis imbalance in IBD intestine, and MT Mph are a group of cells with high expression of zinc homeostasis-related genes, which are closely related to the TNF inflammatory pathway. The prediction model constructed based on the characteristic genes of MT Mph may be able to predict the response to anti-TNF therapy in IBD.

The risk and incidence of malnutrition among patients with inflammatory bowel disease(IBD)are significantly higher than those in the general population,which affect the therapeutic efficacy and prognosis of patients.Clinical nutrition plays an important role in the treatment of IBD,and with the fact that there have been many studies on the clinical practice of nutrition therapy in IBD both domestically and abroad in recent years,it is necessary to update the expert consensus on nutrition therapy for IBD and provide the latest guidance for clinical practice.This consensus is drafted and revised by experts from Inflammatory Bowel Disease Group of Chinese Society of Gastroenterology,Gastroenterology and Nutrition Cooperative Group of Chinese Society of Parenteral and Enteral Nutrition,and Nutrition Support and Treatment Collaboration Group of Chinese Society of Gastroenterology,Chinese Medical Association.It combines both expert consensus abroad and Chinese expert consensus on nutrition support therapy in inflammatory bowel disease(the second edition),aiming to reflect the latest concepts and research progress,and provide standardized guidance for nutrition therapy of IBD.In order to be consistent with the professional terminology adopted by international authoritative nutrition academic organizations,especially considering the unique role of clinical nutrition in the treatment of IBD,this consensus is hereby renamed as Expert consensus on nutrition therapy for inflammatory bowel disease.

Objective:To assess the long-term risk of relapse in patients with Crohn's disease (CD) who discontinued infliximab (IFX) monoclonal antibody and to identify risk factors associated with relapse.Methods:A single-center retrospective observational study was conducted from February 2006 to October 2016. The study included CD patients who were treated with scheduled IFX infusions at the First Affiliated Hospital of Sun Yat-sen University and assessed in corticosteroid-free clinical remission at the time of withdrawal were included. The primary outcome was clinical relapse. We evaluated the risk of relapse using Kaplan-Meier method. Factors associated with time to relapse was identified using the multiple Cox proportional hazards regression analysis.Results:We included 97 eligible patients, and 75 (77.3%) experienced a relapse after a median follow-up time of 124 months. Among them, 45 patients (46.4%) relapsed within 3 years after IFX withdrawal. The 1-, 2-, 3-, 5-, and 10-year relapse-free survival were 79.4%, 59.8%, 52.6%, 42.0% and 22.6%, respectively. Risk factors for relapse included age ≤ 16 ( HR = 2.62, 95% CI: 1.30-5.31; P = 0.007) and failure to achieve biological remission (CRP > 3 mg/L, HR = 2.37, 95% CI: 1.29-4.36; P = 0.006) at drug withdrawal. Induction with biologics or systemic steroids were both effective (89%-100% relieved) in relapsers. Conclusions:Nearly half of CD patients relapsed within 3 years after discontinuation of IFX treatment. Early age of discontinuation and failure to achieve serum biological remission at the time of discontinuation are independent predictors of clinical relapse.

Objective:To analyze the expression of zinc homeostasis-related genes and related cells in the intestinal mucosa of inflammatory bowel disease (IBD) patients at the single-cell level and to evaluate their value in predicting the response to anti-tumor necrosis factor (TNF) therapy in IBD patients.Methods:Single-cell RNA sequencing data from 75 ileal or colorectal biopsy samples, including those from patients with Crohn's disease (CD), ulcerative colitis (UC), and normal controls (NC), were collected from four gene expression omnibus (GEO) databases. Unsupervised clustering analysis in R language was employed to classify IBD cells, zinc homeostasis-related gene scores were used to assess the zinc homeostasis status of different cell clusters, and the cell clusters closely related to zinc homeostasis-related genes, namely metallothionein-associated macrophages (MT Mph), were identified. Then the colon tissues from IBD patients and healthy individuals treated at the First Affiliated Hospital of Sun Yat-sen University were collected for immunofluorescence (IF) staining to compare the differences in MT Mph numbers between IBD and NC tissues. To further explore the function and origins of MT Mph, the characteristic genes of MT Mph and non- metallothionein-associated macrophages (non-MT Mph) from database were compared, the Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis was further used to enrich the characteristic genes, cell communication analysis was used to investigate the communication mechanisms between MT Mph and different cells, Quasi-time sequence was used to explore the origin of MT Mph and related signaling pathways, and the differences in transcription factors among monocytes, MT Mph and non-MT Mph were analyzed in R language. Single sample gene set enrichment analysis (ssGSEA) was used to evaluate the expression of MT Mph characteristic genes, and ssGSEA combined with the response to anti-TNF were used to construct the model in order to explore the predictive value of MT Mph characteristic genes for the response to anti-TNF therapy in IBD patients.Results:IBD cells were clustered and annotated into seven major cell clusters, namely T cells, B cells, plasma cells, myeloid cells, fibroblasts, endothelial cells, and epithelial cells. The results of zinc homeostasis-related gene scores showed that the scores of IBD myeloid cells were higher than those of the NC group. Myeloid cells could be divided into monocytes, macrophages, neutrophils, and dendritic cells. Based on the expression of zinc homeostasis genes, especially the high expression of metallothionein genes, the macrophages were divided into MT Mph and non-MT Mph, and the number of MT Mph in the IBD intestine was significantly increased compared to the NC group. IF validation showed that the number of CD68 +MT1G + cells (MT Mph) in both UC and CD were significantly higher than that in the NC group under per high-power field of view (UC vs. NC: 30.80 ± 7.29 vs. 9.80 ± 1.80, P < 0.001; CD vs. NC: 36.00 ± 9.30 vs. 9.80 ± 1.80, P < 0.001). KEGG pathway enrichment analysis revealed that the differential genes of MT Mph were enriched in key genes of inflammation-related pathways, especially the TNF signaling pathway. Cell communication analysis showed that the TNF signaling pathway between MT Mph and other cells in IBD was significantly enhanced compared to NC. Quasi-time sequence analysis results showed that monocytes could differentiate into MT Mph, and the expression of metallothionein genes ( MT2A, MT1X, MT1H and MT1G) was significantly upregulated during the differentiation process. Transcription factor analysis showed that the transcription factors SMARCB1 and ZMYND8 of MT Mph were significantly higher than those of monocytes, and the classical inflammatory transcription factors HIF1A, STAT3, and NFKB1 were significantly higher than those of non-MT Mph. Prediction models for CD and UC were constructed respectively based on ssGSEA and TNF treatment response [CD: area under the curve (AUC) = 0.966, P < 0.01; AUC = 0.793, P < 0.01]. Validation results showed that the model could not predict the response of CD and UC patients to vedolizumab therapy (both P > 0.05). Conclusions:There is a zinc homeostasis imbalance in IBD intestine, and MT Mph are a group of cells with high expression of zinc homeostasis-related genes, which are closely related to the TNF inflammatory pathway. The prediction model constructed based on the characteristic genes of MT Mph may be able to predict the response to anti-TNF therapy in IBD.

The risk and incidence of malnutrition among patients with inflammatory bowel disease(IBD)are significantly higher than those in the general population,which affect the therapeutic efficacy and prognosis of patients.Clinical nutrition plays an important role in the treatment of IBD,and with the fact that there have been many studies on the clinical practice of nutrition therapy in IBD both domestically and abroad in recent years,it is necessary to update the expert consensus on nutrition therapy for IBD and provide the latest guidance for clinical practice.This consensus is drafted and revised by experts from Inflammatory Bowel Disease Group of Chinese Society of Gastroenterology,Gastroenterology and Nutrition Cooperative Group of Chinese Society of Parenteral and Enteral Nutrition,and Nutrition Support and Treatment Collaboration Group of Chinese Society of Gastroenterology,Chinese Medical Association.It combines both expert consensus abroad and Chinese expert consensus on nutrition support therapy in inflammatory bowel disease(the second edition),aiming to reflect the latest concepts and research progress,and provide standardized guidance for nutrition therapy of IBD.In order to be consistent with the professional terminology adopted by international authoritative nutrition academic organizations,especially considering the unique role of clinical nutrition in the treatment of IBD,this consensus is hereby renamed as Expert consensus on nutrition therapy for inflammatory bowel disease.

Ulcerative colitis(UC)is a chronic and prolonged condition spanning multiple disciplines.Standardized diagnostics and treatment are paramount for enhancing the therapeutic efficacy and improving the prognosis of UC.In the last a couple of years,substantial progress has been achieved in both basic and clinical research on UC in our country.The integration of novel diagnostic and therapeutic paradigms,new treatment modalities,have necessitated the update of consensus on UC management,offering imperative,evidence-based guidelines for health providers.This guideline,collaboratively developed by the Inflammatory Bowel Disease Group of Chinese Society of Gastroenterology,Chinese Medical Association,and the Inflammatory Bowel Disease Quality Control Center of China,incorporates the latest international consensus,domestic research findings,and practical considerations,as an update based on the 2018 Chinese consensus on diagnosis and treatment in inflammatory bowel disease.The formulation of this guideline aims to reflect the latest concepts and research findings in the clinical diagnosis and treatment of UC,providing standardized guidance for the clinical management of UC.

Crohn's disease(CD)is a complex condition spanning multiple disciplines.Standardized diagnostics and treatment are paramount for enhancing the therapeutic efficacy and improving the prognosis of CD.In recent years,substantial progress has been achieved in both basic and clinical research on CD in China.The integration of novel diagnostic and therapeutic paradigms,new treatment modalities,have necessitated the update of consensus on CD management,offering imperative,evidence-based guidelines for health providers.This guideline,collaboratively developed by the Inflammatory Bowel Disease Group of Chinese Society of Gastroenterology,Chinese Medical Association,and the Inflammatory Bowel Disease Quality Control Center of China,incorporates the latest international consensus,domestic research findings,and practical considerations,as an update based on the 2018 Chinese consensus on diagnosis and treatment in inflammatory bowel disease.The formulation of this guideline aims to reflect the latest concepts and research findings in the clinical diagnosis and treatment of CD,providing standardized guidance for the clinical management of CD.

Background::Erosive esophagitis (EE) is a gastroesophageal reflux disease characterized by mucosal breaks in the esophagus. Proton pump inhibitors are widely used as maintenance therapy for EE, but many patients still relapse. In this trial, we evaluated the noninferiority of vonoprazan vs. lansoprazole as maintenance therapy in patients with healed EE. Methods::We performed a double-blind, double-dummy, multicenter, phase 3 clinical trial among non-Japanese Asian adults with endoscopically confirmed healed EE from April 2015 to February 2019. Patients from China, South Korea, and Malaysia were randomized to vonoprazan 10 mg or 20 mg once daily or lansoprazole 15 mg once daily for 24 weeks. The primary endpoint was endoscopically confirmed EE recurrence rate over 24 weeks with a noninferiority margin of 10% using a two-sided 95% confidence interval (CI). Treatment-emergent adverse events (TEAEs) were recorded.Results::Among 703 patients, EE recurrence was observed in 24/181 (13.3%) and 21/171 (12.3%) patients receiving vonoprazan 10 mg or 20 mg, respectively, and 47/184 (25.5%) patients receiving lansoprazole (differences: -12.3% [95% CI, -20.3% to-4.3%] and -13.3% [95% CI, -21.3% to -5.3%], respectively), meeting the primary endpoint of noninferiority to lansoprazole in preventing EE recurrence at 24 weeks. Evidence of superiority (upper bound of 95% CI <0%) was also observed. At 12 weeks, endoscopically confirmed EE recurrence was observed in 5/18, 2/20, and 7/20 of patients receiving vonoprazan 10 mg, vonoprazan 20 mg, and lansoprazole, respectively. TEAEs were experienced by 66.8% (157/235), 69.0% (156/226), and 65.3% (158/242) of patients receiving vonoprazan 10 mg, vonoprazan 20 mg, and lansoprazole, respectively. The most common TEAE was upper respiratory tract infection in 12.8% (30/235) and 12.8% (29/226) patients in vonoprazan 10 mg and 20 mg groups, respectively and 8.7% (21/242) patients in lansoprazole group.Conclusion::Vonoprazan maintenance therapy was well-tolerated and noninferior to lansoprazole for preventing EE recurrence in Asian patients with healed EE.Trial Registration::https://clinicaltrials.gov; NCT02388737.