Objective: We used the postoperative recurrence model to better understand the role of adherent and invasive Escherichia coli (AIEC) bacteria in Crohn’s disease (CD), taking advantage of a well-characterised postoperative cohort. Design: From a prospective, multicentre cohort of operated patients with CD, AIEC identification was performed within the surgical specimen (M0) (N=181 patients) and the neoterminal ileum (n=119 patients/181) during colonoscopy performed 6 months after surgery (M6). Endoscopic postoperative recurrence was graded using Rutgeerts’ index. The mucosa-associated microbiota was analysed by 16S sequencing at M0 and M6. Relative risks or ORs were adjusted on potential confounders. Results: AIEC prevalence was twofold higher within the neoterminal ileum at M6 (30.3%) than within the surgical specimen (14.9%) (p<0.001). AIEC within the neoterminal ileum at M6 was associated with higher rate of early ileal lesions (i1) (41.6% vs 17.1%; aRR 3.49 (95% CI 1.01 to 12.04), p=0.048) or ileal lesions (i2b+i3) (38.2% vs 17.1%; aRR 3.45 (95% CI 1.06 to 11.30), p=0.040) compared with no lesion (i0). AIEC within the surgical specimen was predictive of higher risk of i2b-endoscopic postoperative recurrence (POR) (aOR 2.54 (95% CI 1.01 to 6.44), p=0.049) and severe endoscopic POR (aOR 3.36 (95% CI 1.25 to 9.06), p=0.017). While only 5.0% (6/119) of the patients were AIEC-positive at both M0 and M6, 43.7% (52/119), patients with history of positive test for AIEC (M0 or M6) had higher risk of ileal endoscopic POR (aOR 2.32 (95% CI 1.01 to 5.39), p=0.048)), i2b-endoscopic postoperative recurrence (aOR 2.41 (95% CI 1.01 to 5.74); p=0.048) and severe endoscopic postoperative (aOR=3.84 (95% CI 1.32 to 11.18), p=0.013). AIEC colonisation was associated with a specific microbiota signature including increased abundance of Ruminococcus gnavus . Conclusion: Based on the postoperative recurrence model, our data support the idea that AIEC are involved in the early steps of ileal CD. Trial registration number: NCT03458195 .

Lympho-epithelial interactions between intestinal T resident memory cells (Trm) and the epithelium have been associated with inflammatory bowel disease (IBD) activity. We developed ex vivo autologous organoid-mucosal T cell cocultures to functionally assess lymphoepithelial interactions in Crohn’s Disease (CD) patients compared to controls. We demonstrate the direct epithelial cell death induced by autologous mucosal T cells in CD patients but not in controls. These findings were positively correlated with T cell infiltration of the organoids. This potential was inhibited by limiting lympho-epithelial interactions through CD103 and NKG2D blocking antibodies. These data directly demonstrate for the first time the direct deleterious effect of mucosal T cells on the epithelium of CD patients. Such ex-vivo models are promising techniques to unravel the pathophysiology of these diseases and the potential mode of action of current and future therapies.

Objective T cells are major effectors of the antitumoural immune response. Their activation by tumour-associated antigens can unleash their proliferation and cytotoxic functions, leading to tumour cell elimination. However, tumour-related immunosuppressive mechanisms including the overexpression of immune checkpoints like programmed cell death protein-1 (PD-1), are also engaged, promoting immune escape. Current immunotherapies targeting these pathways have demonstrated weak efficacy in colorectal cancer (CRC). It is thus crucial to find new targets for immunotherapy in this cancer type. Design In a prospective cohort of patients with CRC, we investigated the phenotype of tumour-related and non-tumour related intestinal T cells (n=44), particularly the adenosinergic pathway, correlating with clinical phenotype. An autologous coculture model was developed between patient-derived primary tumour spheroids and their autologous tumour-associated lymphocytes. We used this relevant model to assess the effects of CD39 blockade on the antitumour T cell response. Results We show the increased expression of CD39, and its co-expression with PD-1, on tumour infiltrating T cells compared with mucosal lymphocytes. CD39 expression was higher in the right colon and early-stage tumours, thus defining a subset of patients potentially responsive to CD39 blockade. Finally, we demonstrate in autologous conditions that CD39 blockade triggers T cell infiltration and tumour spheroid destruction in cocultures. Conclusion In CRC, CD39 is strongly expressed on tumour infiltrating lymphocytes and its inhibition represents a promising therapeutic strategy for treating patients.

BackgroundRisk stratification for endoscopic post-operative recurrence (ePOR) in Crohn's disease (CD) is required to identify patients who would benefit most from initiation of prophylactic medication and intensive monitoring of recurrence.AimsTo assess the current evidence on patient-related, microbial, surgical and histopathological risk factors for ePOR in patients with CD after ileocolic (re-)resection.MethodsMultiple online databases (Embase, MEDLINE, Web of Science and Cochrane Library) were searched up to March 2024. Studies with reported associations of patient-related, microbial, surgical and/or histopathological factors for ePOR (i.e., Rutgeerts' score >= i2 or modified Rutgeerts' score >= i2a) were included. The risk of bias was assessed with the Newcastle-Ottawa Scale for observational cohort studies and case-control studies.ResultsIn total, 47 studies were included (four RCTs, 29 cohort studies, 12 case-control studies, one cross-sectional study and one individual participant data meta-analysis) including 6006 patients (median sample size 87 patients [interquartile range 46-170]). Risk of bias assessment revealed a poor quality in 41% of the studies. An association was reported in multiple studies of ePOR with active smoking at and post-surgery, male sex and prior bowel resection. A heterogeneous association with ePOR was reported for other risk factors included in the current guidelines (penetrating disease, perianal disease, younger age, extensive small bowel disease and presence of granulomas in the resection specimen or myenteric plexitis in the resection margin), and other patient-related, microbial, surgical and histopathological factors.ConclusionRisk factors for ePOR in international guidelines are not consistently reported as risk factors in current literature except for active smoking and prior bowel resection. To develop evidence-based, personalised strategies, large prospective studies are warranted to identify risk factors for ePOR. Validation studies of promising (bio)markers are also required. Risk factors for ePOR in international guidelines are not consistently reported as risk factors in the current literature except for active smoking and a prior bowel resection. To develop evidence-based and personalised strategies, future large prospective studies are warranted for the identification of risk factors for ePOR in patients with CD. In addition, validation studies of promising (bio)markers are required.image

Background and Aims: Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), remain heterogeneous disorders with variable response to biologics. Post-operative recurrence in CD is common despite surgery and prophylactic biotherapies. Understanding the inflammatory mediators associated with recurrence and treatment response could pave the way for personalized strategies. Methods: We analyzed serum inflammatory protein signatures using proteomics in two prospective cohorts. The REMIND cohort included post-operative CD patients undergoing ileocecal resection with endoscopic assessment at 6 months (M6). Serum samples were collected at surgery and 6 months later. The ELYP cohort consisted of active IBD patients starting new biotherapies (anti-tumor necrosis factor [anti-TNF], ustekinumab, or vedolizumab). Serum samples were collected pre- and post-treatment (Weeks 14 and 52). Results: In the REMIND cohort, proteomic analysis revealed elevated levels of IFN-γ, CXCL9, and MMP-10 in patients with recurrence, with concentrations associated with recurrence severity. Preoperative MMP-10 levels predicted severe recurrence (AUC = 0.70). Under biotherapies, treatment-specific proteins were associated with recurrence: CXCL9 for anti-TNF and OSM/TGFα modules for ustekinumab. In the ELYP cohort, IFN-γ and CXCL9 were significantly elevated in CD compared to UC and associated with disease activity. Early response to anti-TNF treatment (Week 14) was associated with reductions in CXCL9, MMP-10, and OSM, while deep remission (Week 52) correlated with decreases in CXCL9 and OSM. Conclusion: Our findings reveal inflammatory blood proteomic signatures associated with post-operative recurrence and biologic treatment failure in IBD. Several key biomarkers were identified. These results support the rationale for personalized approaches, including combination therapies targeting multiple pathways. ClincialTrials.gov number, NCT02693340 and NCT02693340

Early ileocolonoscopy within the first year after surgery is the gold standard to evaluate post-operative recurrence after ileocolonic resection for Crohn’s disease (CD). The aim of the study was to evaluate the association between lesions at ileocolonoscopy 6 months after surgery and long-term outcomes. The REMIND group conducted a prospective multicentre study. Patients operated for ileal or ileocolonic CD were included. An ileocolonoscopy was performed 6 months after surgery. An endoscopic classification separating anastomotic and ileal lesions was built (Ax for anastomotic lesions; Ix for neo-terminal ileum lesions evaluated according to the Rutggerts score). Clinical relapse was defined by CD-related symptoms confirmed by imaging, endoscopy or therapeutic intensification, CD-related complication or subsequent surgery. A total of 225 patients were included. Long-term data were available for 193 patients (86%). Median follow-up was 3.82 years (IQR:2.56–5.41) from surgery. Median clinical recurrence-free survival was 47.6 months. Clinical recurrence-free survival was significantly shorter in patients with ileal lesions at early post-operative endoscopy whatever their severity (I1 or I2I3I4) compared with patients without (I0) (median survivals: 68.5, 33.0 and 39.1 months, respectively, for I0, I1 and I2I3I4; I0 vs. I2I3I4: p = 0.0003; I0 vs. I1: p = 0.0008 and I1 vs. I2I3I4: p = 0.43). Patients with at least semi-circumferential anastomotic ulcerations (A2 or A3) had more anastomotic occlusive manifestations than patients without (A0 or A1) (A0 vs. A2A3: p = 0.01; A0 vs. A1: p = 0.83; A1 vs. A2A3: p = 0.05). A classification separating anastomotic and ileal lesions might be more appropriate to define post-operative endoscopic recurrence. Patients with ileal lesions, including mild ones (I1), could beneficiate from treatment step up to improve long-term outcome.