Intestinal strictures in Crohn's disease: An update from 2023.

Crohn's disease (CD) is a chronic inflammatory disease that leads to intestinal stricture in nearly 35% of cases within 10 years of initial diagnosis. The unknown pathogenesis, lack of universally accepted criteria, and absence of an effective management approach remain unconquered challenges in structuring CD. The pathogenesis of stricturing CD involves intricate interactions between factors such as immune cell dysbiosis, fibroblast activation, and microecology imbalance. New techniques such as single-cell sequencing provide a fresh perspective. Non-invasive diagnostic tools such as serum biomarkers and novel cross-sectional imaging techniques offer a precise understanding of intestinal fibrostenosis. Here, we provide a timely and comprehensive review of the worthy advancements in intestinal strictures in 2023, aiming to dispense cutting-edge information regarding fibrosis and to build a cornerstone for researchers and clinicians to make greater progress in the field of intestinal strictures.

Validation of disease severity index for predicting complicated disease in Crohn's disease: A comparison study with Lémann index.

BACKGROUND: Disease Severity Index (DSI) provides comprehensive assessment of bowel damage (BD). AIMS: To evaluate DSI in patients with Crohn's disease (CD) at high risk of disease progression, compared to Lémann Index (LI). METHODS: Patients with CD in our center were reviewed consecutively between 2017 and 2019. DSI, LI, and complicated CD course were analyzed. RESULTS: The median LI and DSI of included 300 patients were 1.63 (IQR 1.25-3.13) and 42 (IQR 32-51), respectively. 152 patients (50.7%) experienced a complicated disease course (median 5.1 months; IQR 1.1-20.2). DSI (AUC 0.66; 95% CI 0.60-0.72) better predicted a complicated course of CD over LI (AUC 0.56; 95% CI 0.50-0.63; P = 0.007). The cumulative probability of complicated CD course in severe patients was higher than those with 'mild CD' (P < 0.001). The Cox analysis identified DSI>43 (HR 2.18; 95% CI 1.54-3.09; P < 0.001), B2/3 vs. B1 (HR 2.80; 95% CI 1.99-3.94; P < 0.001), and a higher level of CRP (HR 1.01; 95% CI 1.00-1.02; P = 0.005) as independent prognostic factors for complicated CD. However, LI was not associated with complicated CD (P = 0.164). CONCLUSIONS: Higher DSI was associated with complicated disease outcomes. DSI might play a better role than LI in identifying patients at high risks of disease progression.

Decreased TMIGD1 aggravates colitis and intestinal barrier dysfunction via the BANF1-NF-κB pathway in Crohn's disease.

BACKGROUND: Disrupted intestinal epithelial barrier is one of the major causes of Crohn's disease (CD). Novel molecular targets for intestinal epithelial barrier are essential to treatment of CD. Transmembrane and immunoglobulin domain-containing protein 1 (TMIGD1) is an adhesion molecule that regulates cell adhesion, migration, and enterocyte differentiation. However, the function and mechanism of TMIGD1 in CD and intestinal epithelial barrier has rarely been studied. Furthermore, the association between TMIGD1 and the clinical features of CD remains unclear. METHODS: Transcriptome analysis on colonic mucosa from CD patients and healthy individuals were performed to identify dysregulated genes. Multi-omics integration of the 1000IBD cohort including genomics, transcriptomics of intestinal biopsies, and serum proteomics identified the association between genes and characteristics of CD. Inflammation was assessed by cytokine production in cell lines, organoids and intestinal-specific Tmigd1 knockout (Tmigd1INT-KO) mice. Epithelial barrier integrity was evaluated by trans-epithelium electrical resistance (TEER), paracellular permeability, and apical junction complex (AJC) expression. Co-immunoprecipitation, GST pull-down assays, mass spectrometry, proteomics, and transcriptome analysis were used to explore downstream mechanisms. RESULTS: Multi-omics integration suggested that TMIGD1 was negatively associated with inflammatory characteristics of CD. TMIGD1 was downregulated in inflamed intestinal mucosa of patients with CD and mice colitis models. Tmigd1INT-KO mice were more susceptible to chemically induced colitis. In epithelial cell lines and colonic organoids, TMIGD1 knockdown caused impaired intestinal barrier integrity evidenced by increased paracellular permeability and reduced TEER and AJC expression. TMIGD1 knockdown in intestinal epithelial cells also induced pro-inflammatory cytokine production. Mechanistically, TMIGD1 directly interacted with cytoplasmic BAF nuclear assembly factor 1 (BANF1) to inhibit NF-κB activation. Exogenous expression of TMIGD1 and BANF1 restored intestinal barrier function and inhibited inflammation in vitro and in vivo. TMIGD1 expression predicted response to anti-TNF treatment in patients with CD. CONCLUSIONS: Our study demonstrated that TMIGD1 maintained intestinal barrier integrity and inactivated inflammation, and was therefore a potential therapeutic target for CD.

Early transmural healing and its predictors assessed by magnetic resonance enterography in patients with Crohn's disease receiving ustekinumab.

Background: Transmural healing (TH) is a potential therapeutic goal of Crohn's disease (CD) and is associated with better clinical outcomes. However, few studies have described early TH and its predictors. Objectives: We aimed to evaluate early TH and its predictors using magnetic resonance enterography (MRE) in patients with CD receiving ustekinumab (UST). Design: This was a retrospective observational study. Methods: Patients with active CD treated with UST and their intestinal segments with bowel wall thickness (BWT) ⩽ 3 mm at baseline were included. Clinical characteristics, laboratory indicators, endoscopic manifestations, and MRE indices were evaluated at baseline and week 26 (W26) of the therapy. The following MRE parameters were assessed: BWT, edema, apparent diffusion coefficient (ADC), Clermont score, Magnetic Resonance Index of Activity score, fat stranding, comb sign, and stricture. TH was defined as BWT ⩽ 3 mm without any signs of inflammation (i.e., ulceration, edema, diffusion-weighted hyperintensity, and increased contrast enhancement) at W26. Results: The study included 37 patients with 106 intestinal segments (including 15 proximal small intestines, 33 terminal ilea, and 58 colons). Clinical features, laboratory indicators, endoscopic results, and MRE parameters at W26 were significantly improved after UST treatment in both patient-based and intestinal segment-based analysis. Seven (18.9%) patients and 26 (24.5%) intestinal segments achieved TH at W26. Baseline BWT [odds ratio (OR) = 0.287, 95% confidence interval (CI), 0.090-0.918, p = 0.035] and ADC (OR = 2.997, 95% CI, 1.009-8.908, p = 0.048) predict TH of patients at W26. Baseline ADC (OR = 2.857, 95% CI, 1.285-6.349, p = 0.010) and presence of stenosis (OR = 0.196, 95% CI, 0.052-0.735, p = 0.016) were associated with TH of segments at W26. Conclusion: Early TH assessed by MRE was observed in nearly one-fifth of patients with CD and intestinal segments after UST treatment for 26 weeks. Baseline MRE indices such as BWT and presence of stenosis might negatively predict TH, while ADC might positively predict early TH.

Ulcerative colitis increases risk of hypertension in a UK biobank cohort study.

OBJECTIVE: Inflammatory bowel disease (IBD) is not only a chronic inflammatory disorder of the gastrointestinal tract but also accompanied by systemic inflammation. The onset of hypertension is closely related to systemic inflammation. However, the relationship between IBD and hypertension has not been investigated. We aimed to investigate the potential association between IBD and the incidence of hypertension. METHOD: We retrieved IBD onset and the incidence of hypertension from a public database UK Biobank. The association between the onset of IBD and subsequent incidence of hypertension was analyzed using a multivariate Cox regression analysis, and propensity score matching was performed for sensitivity analysis. RESULT: Of a total of 281,064 participants included in the study, 2376 (0.8%) were diagnosed with IBD at baseline, and 20,129 (7.2%) in the whole cohort developed hypertension with a median follow-up duration of 8.1 years (interquartile range [IQR] 7.3-8.8 years). Patients with IBD had a higher cumulative risk of hypertension compared with general population (10.9% in ulcerative colitis [UC], 7.7% in Crohn's disease [CD], and 9.3% in IBD unclassified [IBD-U] vs. 7.1% in non-IBD, p < 0.001). Multivariate Cox regression analysis identified that UC, rather than CD or IBD-U, was independently associated with subsequent occurrence of hypertension (HR 1.30, 95% CI: 1.11-1.52, p = 0.001). In propensity matching analysis, UC also showed its robustness as a risk factor for the prediction of hypertension (HR 1.56, 95% CI: 1.21-2.03, p = 0.001). CONCLUSION: In IBD patients, UC rather than CD is associated with a higher risk for the incidence of hypertension compared with general population. Close monitoring of hypertension might be required in clinical practice.

Role of Telemedicine in Inflammatory Bowel Disease: Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Telemedicine plays an important role in the management of inflammatory bowel disease (IBD), particularly during a pandemic such as COVID-19. However, the effectiveness and efficiency of telemedicine in managing IBD are unclear. OBJECTIVE: This systematic review and meta-analysis aimed to compare the impact of telemedicine with that of standard care on the management of IBD. METHODS: We systematically searched the PubMed, Cochrane Library, EMBASE, Web of Science, and Scopus databases on April 22, 2020. Randomized controlled trials comparing telemedicine with standard care in patients with IBD were included, while conference abstracts, letters, reviews, laboratory studies, and case reports were excluded. The IBD-specific quality of life (QoL), disease activity, and remission rate in patients with IBD were assessed as primary outcomes, and the number of in-person clinic visits per patient, patient satisfaction, psychological outcome, and medication adherence were assessed as secondary outcomes. Review Manage 5.3 and Stata 15.1 were used for data analysis. RESULTS: A total of 17 randomized controlled trials (2571 participants) were included in this meta-analysis. The telemedicine group had higher IBD-specific QoL than the standard care group (standard mean difference 0.18, 95% CI 0.01 to 0.34; P.03). The number of clinic visits per patient in the telemedicine group was significantly lower than that in the standard care group (standard mean difference -0.71, 95% CI -1.07 to -0.36; P<.001). Subgroup analysis showed that adolescents in the telemedicine group had significantly higher IBD-specific QoL than those in the standard care group (standard mean difference 0.42, 95% CI 0.15 to 0.69; I2=0; P.002), but there was no significant difference between adults in the 2 groups. There were no significant differences in disease activity, remission rate, patient satisfaction, depression, self-efficacy, generic QoL, and medication adherence outcomes between the telemedicine and standard care groups. CONCLUSIONS: Telemedicine intervention showed a promising role in improving IBD-specific QoL among adolescents and decreased the number of clinic visits among patients with IBD. Further research is warranted to identify the group of patients with IBD who would most benefit from telemedicine.

The effects of target-controlled infusion of lidocaine undergoing vocal cord polypectomy: A randomized controlled trial (CONSORT compliant).

BACKGROUND: The present study aimed to assess the efficacy and safety of general anesthesia-assisted target-controlled plasma infusion of lidocaine in patients with vocal cord polypectomy using a supporting laryngoscope. METHODS: In total, 80 patients undergoing vocal cord polypectomy using a supporting laryngoscope were randomly divided into an intervention group and a control group; each group contained 40 subjects: both groups received general anesthesia; subjects in the intervention also received an additional 3 mg/L of lidocaine by target-controlled plasma infusion during induction and maintenance of anesthesia; heart rate (HR) mean arterial pressure (MAP), propofol and urapidil consumption (Uradil, which is a blood pressure drug that blocks alpha-1, is called Urapidi Hydrochloride Injection. It is produced by Germany, the enterprise name is Nycomed Deutschland GmbH, the import drug registration number is H20090715, and it is widely used in China), recovery time, and cough score (measured by Minogue et al's 5-grade scoring method) during extubation, and throat pain score (measured by visual analogue scale,[VAS]) after extubation and adverse events were recorded. RESULTS: Significant differences were observed in HR (P < .05) and MAP (P < .05) immediately after intubation (T2), immediately after the operation starting to support laryngoscope exposure (T3), immediately after operation field adrenergic tampon hemostasis (T4), and 5 minutes after hemostasis (T5) between the 2 groups, and significant differences were also observed in HR (P < .05) before intubation (T1). Moreover, significant differences were observed in propofol consumption (P < .05), urapidil consumption (P < .05), cough score during extubation (P < .05), and throat pain score after extubation (P < .05). However, no significant difference was observed in the recovery time (P > .05). Furthermore, no adverse events were detected in either group. CONCLUSION: The results of this study showed that target-controlled plasma infusion of lidocaine can reduce propofol consumption in patients undergoing vocal cord polypectomy by supporting laryngoscopy, and the hemodynamics are more stable and reduce the coughing reaction in the wake period and throat pain after extubation without adverse events.

Endostatin inhibits the proliferation and migration of B16 cells by inducing macrophage polarity to M1­type.

Malignant melanoma is a common skin tumor that easily metastasizes and has a poor prognosis. Endostatin is an endogenous vascular endothelial inhibitor that mainly suppresses tumor growth by inhibiting the proliferation of vascular endothelial cells and by reducing the formation of tumor microvessels, however the immunological function of endostatin remains unclear. Previously, we have found that an over­expression endostatin (pEndostatin) plasmid induced RAW264.7 cells' polarity to M1­type macrophage. To elucidate the effect of M1­type macrophages induced by endostatin on melanoma B16 cells, the present study transfected RAW264.7 cells with pEndostatin plasmid and co­cultured them with B16 cells. Compared with the control group, the expression of matrix metalloproteinase (MMP)­2, MMP­9 and proliferating cell nuclear antigen in B16 cells was inhibited by M1­type macrophages, but cleaved Caspase­3 and cleaved Caspase­8 were significantly upregulated and the ratio of Bax/Bcl­2 was increased. These results indicated that M1 macrophages induced by pEndostatin plasmid inhibited the proliferation and migration of B16 cells and promoted their apoptosis. These findings suggest that the inhibitory effect of endostatin on melanoma is not limited to directly inhibiting tumor microvessel formation, but it may also be related to regulating changes in macrophage polarity.

Noncoding RNAs as Promising Diagnostic Biomarkers and Therapeutic Targets in Intestinal Fibrosis of Crohn's Disease: The Path From Bench to Bedside.

Fibrosis is a major pathway to organ injury and failure, accounting for more than one-third of deaths worldwide. Intestinal fibrosis causes irreversible and serious clinical complications, such as strictures and obstruction, secondary to a complex pathogenesis. Under the stimulation of profibrotic soluble factors, excessive activation of mesenchymal cells causes extracellular matrix deposition via canonical transforming growth factor-ß/Smads signaling or other pathways (eg, epithelial-to-mesenchymal transition and endothelial-to-mesenchymal transition) in intestinal fibrogenesis. In recent studies, the importance of noncoding RNAs (ncRNAs) stands out in fibrotic diseases in that ncRNAs exhibit a remarkable variety of biological functions in modulating the aforementioned fibrogenic responses. In this review, we summarize the role of ncRNAs, including the emerging long ncRNAs and circular RNAs, in intestinal fibrogenesis. Notably, the translational potential of ncRNAs as diagnostic biomarkers and therapeutic targets in the management of intestinal fibrosis is discussed based on clinical trials from fibrotic diseases in other organs. The main points of this review include the following: • Characteristics of ncRNAs and mechanisms of intestinal fibrogenesis • Wide participation of ncRNAs (especially the emerging long ncRNAs and circular RNAs) in intestinal fibrosis, including transforming growth factor-ß signaling, epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition, and extracellular matrix remodeling • Translational potential of ncRNAs in the diagnosis and treatment of intestinal fibrosis based on clinical trials from fibrotic diseases in other organs.

Role of RING-Type E3 Ubiquitin Ligases in Inflammatory Signalling and Inflammatory Bowel Disease.

Ubiquitination is a three-step enzymatic cascade for posttranslational protein modification. It includes the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3). RING-type E3 ubiquitin ligases catalyse the posttranslational proteolytic and nonproteolytic functions in various physiological and pathological processes, such as inflammation-associated signal transduction. Resulting from the diversity of substrates and functional mechanisms, RING-type ligases regulate microbe recognition and inflammation by being involved in multiple inflammatory signalling pathways. These processes also occur in autoimmune diseases, especially inflammatory bowel disease (IBD). To understand the importance of RING-type ligases in inflammation, we have discussed their functional mechanisms in multiple inflammation-associated pathways and correlation between RING-type ligases and IBD. Owing to the limited data on the biology of RING-type ligases, there is an urgent need to analyse their potential as biomarkers and therapeutic targets in IBD in the future.