Ustekinumab and vedolizumab are both effective for treating Crohn’s disease (CD). However, no head-to-head trials have been conducted thus far. We aimed to compare the effectiveness of ustekinumab and vedolizumab in CD patients either naïve or exposed to tumor necrosis factor-alpha inhibitors (TNFi). Patients treated with vedolizumab or ustekinumab for luminal CD were included from six centers in China from May 2020 to July 2023. Steroid-free remission, clinical remission, objective response, and remission at Weeks 26 and 52 were evaluated in a retrospective multicenter propensity score–weighted cohort. A total of 536 patients were included (386 ustekinumab, and 150 vedolizumab). After adjustment, ustekinumab showed higher rates of clinical remission (56.4% vs. 47.8%, P = 0.005), steroid-free remission (55.4% vs. 46.1%, P = 0.003), and objective response (67.8% vs. 42.7%, P < 0.001) than vedolizumab at Week 26. At Week 52, ustekinumab exhibited significantly higher rates of clinical remission (65.8% vs. 37.5%, P < 0.001), steroid-free remission (65.8% vs. 37.5%, P < 0.001), objective response (66.7% vs. 23.8%, P < 0.001), and objective remission (31.4% vs. 12.7%, P < 0.001). Subgroup analyses revealed that ustekinumab had higher rates of clinical remission, steroid-free remission, and objective response at Weeks 26 and 52, and objective remission at Week 52 in TNFi-exposed patients, while ustekinumab showed higher rates of objective response at Weeks 26 and 52 and clinical remission, steroid-free remission and objective remission at Week 52 in TNFi-naïve patients. Adverse event rates were similar between the groups (4.9% ustekinumab vs. 6.7% vedolizumab, P = 0.423). Ustekinumab showed superior clinical and objective outcomes compared to vedolizumab, with comparable safety outcomes. The therapeutic superiority was observed in both short-term and long-term phases in TNFi-exposed patients, and the long-term phase in TNFi-naïve patients. 10.13039/501100001809 National Natural Science Foundation of China , 10.13039/501100021171 Guangdong Basic and Applied Basic Research Foundation , Key Research Projects of the Sixth Affiliated Hospital, 10.13039/501100002402 Sun Yat-sen University , the program of Guangdong Provincial Clinical Research Center for Digestive Diseases, and National Key Clinical Discipline.

Background: Intestinal ultrasound (IUS) is becoming a standard assessment tool in Crohn’s disease (CD), but limited data exist on its ability to predict long-term objective outcomes. Therefore, we aimed to investigate the predictive value of IUS findings for long-term transmural healing (TH) and mucosal healing (MH) in CD. Methods: We prospectively included consecutive CD patients with active endoscopic disease and bowel wall thickness (BWT) >3.0 mm, initiating infliximab. Intestinal ultrasound parameters (ie, BWT, inflammatory mesenteric fat [i-fat], bowel blood flow and stratification) and International Bowel Ultrasound Segmental Activity Score (IBUS-SAS) were collected at baseline, after 14 to 26 weeks (visit 1, postinduction) and 44 to 56 weeks (visit 2). Transmural healing (normalization of all IUS parameters) and MH (SES-CD ≤2) were assessed at visit 2. Results: One hundred twenty-nine patients were evaluated. At visit 2, 38.0% and 48.1% of patients achieved TH and MH, respectively. All the IUS parameters and IBUS-SAS showed improvement at visit 1 and visit 2 compared with the baseline (all P < .001). Multivariable analysis found that presence of i-fat at baseline (odds ratio [OR], 0.57; P = .008) and greater postinduction BWT (OR, 0.24; P < .001) were negative predictors for TH, while higher baseline (OR, 0.98; P = .013) and postinduction (OR, 0.94; P < .001) IBUS-SAS predicted negatively for MH. Postinduction BWT <4.5mm best predicted TH (AUC 0.85; P < .001), while postinduction IBUS-SAS <25.0 best predicted MH (AUC 0.82; P < .001). Moreover, colonic disease was associated with higher risk of TH (OR, 2.55; P = .027), and disease duration >24 months with lower risk of MH (OR, 0.27; P = .006). Conclusions: Baseline and postinduction IUS findings reliably predict long-term TH and MH in patients with CD receiving infliximab.

Background: Achieving long-term clinical remission in Crohn’s disease (CD) with antitumor necrosis factor α (anti-TNF-α) agents remains challenging. Aims: This study aims to establish a prediction model based on patients’ clinical characteristics using a machine-learning approach to predict the long-term efficacy of infliximab (IFX). Methods: Three cohorts comprising 746 patients with CD were included from 3 inflammatory bowel disease (IBD) centers between June 2013 and January 2022. Clinical records were collected from baseline, 14-, 30-, and 52-week post-IFX treatment. Three machine-learning approaches were employed to develop predictive models based on 23 baseline predictors. The SHapley Additive exPlanations (SHAP) algorithm was used to dissect underlying predictors, and latent class mixed model (LCMM) was applied for trajectory analysis of the longitudinal change of blood routine tests along with long-term IFX therapy. Results: The XGBoost model exhibited the best discrimination between long-term responders and nonresponders. In the internal training and testing set, the model achieved an AUC of 0.91 (95% CI, 0.86-0.95) and 0.71 (95% CI, 0.66-0.87), respectively. Moreover, it achieved a moderate predictive performance in the independent external cohort, with an AUC of 0.68 (95% CI, 0.59-0.77). The SHAP algorithm revealed disease-relevant laboratory measurements, notably hemoglobin (HB), white blood cells (WBC), erythrocyte sedimentation rate (ESR), albumin (ALB), and platelets (PLT), alongside age at diagnosis and the Montreal classification, as the most influential predictors. Furthermore, 2 distinct patient clusters based on dynamic laboratory tests were identified for monitoring the long-term remission. Conclusions: The established prediction model demonstrated remarkable discriminatory power in distinguishing long-term responders from nonresponders to IFX therapy. The identification of distinct patient clusters further emphasizes the need for tailored therapeutic approaches in CD management.

Background: The gut microbiome and diet are important factors in the pathogenesis and management of Crohn’s disease (CD). However, the role of the gut phageome under dietary influences is unknown. Objective: We aim to explore the effect of diet on the gut phageome-bacteriome interaction linking to CD protection. Design: We recruited CD patients and healthy subjects (n=140) and conducted a multiomics investigation, including paired ileal mucosa phageome and bacteriome profiling, dietary survey and phenome interrogation. We screened for the effect of diet on the gut phageome and bacteriome, as well as its epidemiological association with CD risks. The underlying mechanisms were explored in target phage-bacteria monocultures and cocultures in vitro and in two mouse models in vivo. Results: On dietary screening in humans, whey protein (WP) consumption was found to profoundly impact the gut phageome and bacteriome (more pronounced on the phageome) and was associated with a lower CD risk. Indeed, the WP reshaped gut phageome can causally attenuate intestinal inflammation, as shown by faecal phageome versus bacteriome transplantation from WP-consuming versus WP-non-consuming mice to recipient mice. Mechanistically, WP induced phage (a newly isolated phage AkkZT003P herein) lysis of the mucin-foraging bacterium Akkermansia muciniphila , which unleashed the symbiotic bacterium Streptococcus thermophilus to counteract intestinal inflammation. Conclusion: Our study charted the importance of cross-kingdom interaction between gut phage and bacteria in mediating the dietary effect on CD protection. Importantly, we uncovered a beneficial dietary WP, a keystone phage AkkZT003P, and a probiotic S. thermophilus that can be used in CD management in the future.