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.

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.

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.

Intestinal fibrosis associated stricture is a common complication of inflammatory bowel disease usually requiring endoscopic or surgical intervention. Effective anti-fibrotic agents aiming to control or reverse intestinal fibrosis are still unavailable. Thus, clarifying the mechanism underpinning intestinal fibrosis is imperative. Fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM) proteins at the injured sites. Multiple cellular types are implicated in fibrosis development. Among these cells, mesenchymal cells are major compartments that are activated and then enhance the production of ECM. Additionally, immune cells contribute to the persistent activation of mesenchymal cells and perpetuation of inflammation. Molecules are messengers of crosstalk between these cellular compartments. Although inflammation is necessary for fibrosis development, purely controlling intestinal inflammation cannot halt the development of fibrosis, suggesting that chronic inflammation is not the unique contributor to fibrogenesis. Several inflammation-independent mechanisms including gut microbiota, creeping fat, ECM interaction, and metabolic reprogramming are involved in the pathogenesis of fibrosis. In the past decades, substantial progress has been made in elucidating the cellular and molecular mechanisms of intestinal fibrosis. Here, we summarized new discoveries and advances of cellular components and major molecular mediators that are associated with intestinal fibrosis, aiming to provide a basis for exploring effective anti-fibrotic therapies in this field.

Humans ; Inflammatory Bowel Diseases/drug therapy* ; Interleukin-6/therapeutic use*

Inflammatory bowel disease (IBD) is a chronic relapsing autoimmune disorder of the gastrointestinal tract. In recent years, biologic agents have been widely used in the treatment of IBD, significantly ameliorating symptoms in affected individuals. However, immunogenicity of these medications remains a limiting factor in IBD biologic therapy. The appropriate drug concentration is of great significance in improving the efficacy of biological agents, reducing the production of anti-drug antibodies, and reducing adverse reactions. Therefore, monitoring drug trough concentrations and anti-drug antibody levels during treatment can optimize medication usage and facilitate more informed adjustments to treatment strategies. This article elaborates on the mechanism and reasons for the generation of anti-drug antibodies, as well as the significance, timing, effectiveness, and detection methods of drug concentration and anti-drug antibody monitoring. Thus, it underscores the value of drug concentration and anti-drug antibody monitoring in the context of biologic therapy for IBD.

The extremely low bioavailability of oral paclitaxel (PTX) mainly due to the complicated gastrointestinal environment, the obstruction of intestinal mucus layer and epithelium barrier. Thus, it is of great significance to construct a coordinative delivery system which can overcome multiple intestinal physicochemical obstacles simultaneously. In this work, a high-density PEGylation-based glycocholic acid-decorated micelles (PTX@GNPs) was constructed by a novel polymer, 9-Fluorenylmethoxycarbonyl-polyethylene glycocholic acid (Fmoc-PEG-GCA). The Fmoc motif in this polymer could encapsulate PTX via π‒π stacking to form the core of micelles, and the low molecular weight and non-long hydrophobic chain of Fmoc ensures the high-density of PEG. Based on this versatile and flexible carriers, PTX@GNPs possess mucus trapping escape ability due to the flexible PEG, and excellent intestine epithelium targeting attributed to the high affinity of GCA with apical sodium-dependent bile acid transporter. The in vitro and in vivo results showed that this oral micelle could enhance oral bioavailability of PTX, and exhibited similar antitumor efficacy to Taxol injection via intravenous route. In addition, oral PTX@GNPs administered with lower dosage within shorter interval could increase in vivo retention time of PTX, which supposed to remodel immune microenvironment and enhance oral chemotherapy efficacy by synergistic effect.

Beh?et′s syndrome is a kind of chronic systemic vasculitis with involvement of multiple organs. Intestinal involvement of Beh?et′s syndrome is presently named as intestinal Beh?et′s syndrome. Recently, there is considering another kind of disease type with only typical intestinal ulcers. Since it is difficult to differentiate intestinal Beh?et′s syndrome from Crohn′s disease, intestinal tuberculosis, intestinal lymphoma, and intestinal manifestations of many other autoimmune diseases, and there is limited evidence for the therapy of intestinal Beh?et′s syndrome, proposing diagnosis and treatment recommendations for intestinal Beh?et′s syndrome through evidence-based judgment will be of great significance for clinical practice.

Objective:To investigate the psychology status and quality of life in patients with inflammatory bowel disease(IBD) in China, and to analyze the influencing factors.Methods:From September 2021 to May 2022, 42 hospitals in 22 provinces(autonomous regions and municipalities directly under the central government) in China, the clinical data of 2 478 IBD patients were collected, which included age, gender, weight, first visit or not, disease activity, disease course, main clinical manifestations(diarrhea, abdominal pain, hematochezia, extraintestinal manifestations), complications, treatment medication(5-aminosalicylic acid, glucocorticoids, immunosuppressive agents, and biological agents), and whether to have surgery. Anxiety, depression, sleep quality and quality of life of IBD patients were evaluated by generalized anxiety disorder-7 items, patient health questionnaire-9 items, Pittsburgh sleep quality index and inflammatory bowel disease questionnaire, and the related influencing factors were analyzed. Univariate analysis and multiple linear regression analysis were used for statistical analysis.Results:The average age of 2 478 IBD patients was 37.96 years old, and male counted for 62.43%(1 547/2 478). There were 61.82%(1 532/2 478) of the IBD patients in the active stage of disease, mostly mild or moderate(588 and 734 cases). There were 60.61%(1 502/2 478) of the IBD patients with different degrees of anxiety, 58.35%(1 446/2 478) of the IBD patients with different degrees of depression, and 48.87%(1 211/2 478) of the IBD patients had different degrees of sleep problems. The results of multiple linear regression analysis indicated that female, higher level of disease activity and longer disease course were independent risk factors of anxiety, depression and sleep quality in the IBD patients(unstandardized regression coefficient(95% confidence interval) 1.08(0.65 to 1.50), 0.45(0.23 to 0.68), 0.19(0.02 to 0.36), 0.83(0.33 to 1.32), 0.62(0.36 to 0.88), 0.28(0.08 to 0.47), 0.47(0.16 to 0.77), 0.39(0.23 to 0.55), 0.14(0.02 to 0.26); P<0.001, <0.001, =0.025 , =0.001, <0.001, =0.005, =0.003, <0.001, =0.027). The usage of biological agents was an independent protective factor of anxiety(unstandardized regression coefficient(95% confidence interval) -0.67(-1.17 to -0.17), P=0.008), and older age was an independent risk factor of sleep quality(unstandardized regression coefficient(95% confidence interval) 0.35(0.09 to 0.61), P=0.008). Higher level of disease activity, symptoms of diarrhea, abdominal pain, presence of extraintestinal manifestations, usage of 5-aminosalicylic acid and glucocorticoid, and with surgical treatment were independent risk factors of quality of life(unstandardized regression coefficient(95% confidence interval) -11.00(-12.24 to -9.76), -2.90(-5.26 to -0.55), -3.93(-6.25 to -1.61), -5.79(-9.87 to -1.71), -4.78(-7.79 to -1.76), -7.71(-11.07 to -4.35), -4.37(-8.00 to -0.73); P<0.001, =0.016, =0.001, =0.005 , =0.002, <0.001, =0.019), while the usage of biological agents was an independent protective factor of quality of life (unstandardized regression coefficient(95% confidence interval) 4.72(1.97 to 7.48), P=0.001). Conclusion:IBD patients generally have different degrees of anxiety, depression and sleep problems, which affect the quality of life of patients. Gender, disease activity and disease course are the influencing factors of mental disorders in IBD patients.