INTRODUCTION: Keverprazan is a novel potassium-competitive acid blocker for the treatment of acid-related disorders requiring potent acid inhibition. This study aimed to establish the noninferiority of keverprazan to lansoprazole in the treatment of patients with duodenal ulcer (DU). METHODS: In this phase III, double-blind, multicenter study, 360 Chinese patients with endoscopically confirmed active DU were randomized 1:1 to take either keverprazan (20 mg) or lansoprazole (30 mg) treatment for up to 6 weeks. The primary end point was DU healing rate at week 6. The secondary end point was DU healing rate at week 4. Symptom improvement and safety were also assessed. RESULTS: Based on the full analysis set, the cumulative healing rates at week 6 were 94.4% (170/180) and 93.3% (166/178) for keverprazan and lansoprazole, respectively (difference: 1.2%; 95% confidence intervel: −4.0%–6.5%). At week 4, the respective healing rates were 83.9% (151/180) and 80.3% (143/178). In the per protocol set, the 6-week healing rates in keverprazan and lansoprazole groups were 98.2% (163/166) and 97.6% (163/167), respectively (difference: 0.6%; 95% confidence intervel: −3.1%–4.4%); the 4-week healing rates were respectively 86.8% (144/166) and 85.6% (143/167). Keverprazan was noninferior to lansoprazole in DU healing after the treatment for 4 and 6 weeks. The incidence of treatment-emergent adverse events was comparable among groups. DISCUSSION: Keverprazan 20 mg had a good safety profile and was noninferior to lansoprazole 30 mg once daily for DU healing.

Background: Incomplete mucosal healing contributes to progression and relapse in ulcerative colitis (UC). Currently, therapeutic strategies that promote mucosal healing and regeneration are limited and may potentiate oncogenic transformation. Objective: We aimed to identify whether modulating macrophage metabolism may facilitate mucosal healing without driving tumourigenesis. Design: Potential therapeutic targets associated with UC disease activity and relapse were assessed in multiple omics datasets and three clinical UC studies. The function and mechanism of macrophage pyruvate kinase M2 (PKM2) in UC progression were demonstrated by macrophage-specific PKM2 knockout mice, single-cell and spatial transcriptomic profiling, and human macrophage-colonic organoid coculture models. Results: Glycolysis was markedly upregulated in intestinal macrophages within damaged regions in UC patients, whereas PKM2 expression was associated with increased disease severity and a greater incidence of relapse. PKM2 depletion in macrophages enhanced intestinal barrier function and ameliorated colitis progression in mice. Mechanistically, PKM2 deficiency promoted monocyte differentiation into reparative Cadm1 ⁺ macrophages and enhanced Lgr5 ⁺ stem cell self-renewal via the PGE2/EP4 axis. Cross-species analysis revealed that human STAB1 ⁺ macrophages, which exhibit transcriptomic and metabolic similarities to mouse Cadm1 ⁺ macrophages, were positively associated with UC remission and spatial distribution of CD8 ⁺ T cells in colorectal cancer. Interestingly, macrophage PKM2 deletion greatly suppressed tumourigenesis in mice, accompanied by an increased abundance of Cadm1 ⁺ macrophages and enhanced CD8 ⁺ T-cell infiltration. Furthermore, targeting PKM2 in intestinal macrophages attenuated colitis progression in mice. Conclusions: Therapeutic targeting of PKM2-dependent glycolysis in macrophages enhanced Cadm1 ⁺ macrophage-mediated mucosal healing without driving tumourigenesis.

INTRODUCTION: Several studies have investigated the role of linaclotide in bowel preparation; however, dosage and timing still warrant further exploration. METHODS: This noninferiority randomized controlled study was performed in 16 medical centers. The eligible subjects were randomly assigned to 3 groups: the Lct + 3 L polyethylene glycol (PEG) group (group A), the 3 L PEG group (group B), or the Lct + 2 L PEG group (group C). The primary outcome was the adequate bowel preparation rate based on the Boston Bowel Preparation Scale. Safety was assessed based on the incidence of adverse reactions. RESULTS: A total of 1,607 eligible subjects were enrolled, and 1,545 colonoscopy videos were uploaded. In the intention-to-treat analysis, the results of the noninferiority test indicated that the adequate bowel preparation rate in group C (87.58%, 95% confidence interval [CI] 85.08%–90.62%) was neither inferior to that of group A (88.79%, 95% CI 86.11%–91.46%) nor group B (83.99%, 95% CI 80.88%–87.09%). The overall incidence of adverse reactions in group A was higher than that in group C (13.64% vs 8.19%, P = 0.012). There were no significant differences in polyp detection rate ( P = 0.089), adenoma detection rate ( P = 0.776), and bowel preparation completion rate ( P = 0.052). DISCUSSION: The adequate bowel preparation rate of the combination of 3-day linaclotide and 2 L PEG was neither inferior to the combination of 3-day linaclotide and 3 L PEG nor 3 L PEG alone in the average-risk population.