Colonic stenosis in Crohn's disease (CD) is uncommon, and data on surgery-free survival are limited. This study aimed to determine surgery-free survival rates and identify associated factors.

A retrospective study was conducted from 2003 to 2022, including patients with CD complicated by colonic stenosis. Patients with uncertain diagnoses or follow-up periods of less than six months were excluded.

Fifty-six patients were included (median age 44 years [range 14-65], male-to-female ratio = 0.93). Surgery-free survival rates were 58.9% at 6 months, 43.7% at 2 years, and 31.7% at 5 years, with an average surgery-free survival of 46.7 months. Univariate analysis showed that joint manifestations (p = 0.01), corticosteroids (p = 0.02), anti-TNF alpha (p = 0.02), salicylates (p = 0.02), and azathioprine (p = 0.01) increased surgery-free survival. Complications such as collections or internal fistulas (p = 0.03), parietal ulceration on imaging (p = 0.01), and acute intestinal obstruction (p = 0.01) were associated with reduced surgery-free survival. In multivariate analysis, biologic therapy was the only independent protective factor against surgery (p = 0.001, OR = 0.19).

The early introduction of biologic therapy is crucial for increasing surgery-free survival in patients with colonic stenosis in CD, given the limited effectiveness of conventional treatments.

Inflammatory bowel diseases (IBDs) are relapsing, remitting inflammatory diseases of the intestinal tract. Familial aggregation and genome-wide association studies revealed susceptibility variants that point toward a combination of innate immune and adaptive immune dysregulation that in concert with environmental factors, such as our microbiome, can initiate and perpetuate inflammation. Innate immune perturbations include functional abnormalities in the intestinal barrier, endoplasmic reticulum stress, and abnormal recognition of microbes. Adaptive immune changes include dysregulation of cytokines, regulatory T cells, and leukocyte migration. IBD is linked with an abnormal wound-healing response leading to fibrosis. This article summarizes key pathogenic mechanisms in the pathogenesis of IBDs.

Crohn's Disease (CD) is a chronic inflammatory condition characterized by intestinal fibrosis, severely impacting patient quality of life. The molecular mechanisms driving this fibrosis remain inadequately understood. Recent evidence implicates mesenteric adipose tissue (MAT) in CD pathogenesis, particularly through its exosome secretion, which may influence fibrogenic pathways. Understanding the role of MAT-derived exosomes is crucial for unraveling these molecular processes.

This study aims to elucidate the role of MAT-derived exosomes in CD-related intestinal fibrosis. We focus on investigating their molecular composition and the potential impact on fibrosis progression, with an emphasis on identifying novel therapeutic targets.

We induced chronic intestinal inflammation in mice using dinitrobenzene sulfonic acid (DNBS), simulating CD-like fibrosis. Exosomes were isolated from DNBS-treated mice (MG) and normal controls (NG) for characterization using electron microscopy and proteomic analysis. Additionally, human colonic fibroblasts were exposed to exosomes from CD patients and healthy individuals, with subsequent assessment of fibrogenesis through proteomic and RNA sequencing analyses.

Proteomic analyses revealed a significant activation of the TGF-β signaling pathway in MG-treated mice compared to controls, correlating with enhanced intestinal fibrosis. In vitro experiments demonstrated that colonic fibroblasts exposed to CD patient-derived exosomes exhibited increased fibrogenic activity. Protein docking and co-immunoprecipitation studies suggested a critical interaction between TINAGL1 and SMAD4, enhancing fibrosis. Importantly, in vivo experiments corroborated that recombinant TINAGL1 protein exacerbated DNBS-induced intestinal fibrosis.

Our findings highlight the pivotal role of MAT-derived exosomes, particularly those carrying TINAGL1, in the progression of intestinal fibrosis in CD. The involvement of the TGF-β signaling pathway, especially the SMAD4 protein, offers new insights into the molecular mechanisms of CD-related fibrosis and presents potential targets for therapeutic intervention.

Dual-energy computed tomography enterography (DECTE) has significantly improved gastrointestinal imaging quality. Double-balloon endoscopy (DBE) has enabled comprehensive visualization of the small intestinal mucosa. This study aimed to assess the diagnostic efficacy of small-intestine DECTE and DBE for small bowel Crohn's disease (CD).

This retrospective study was conducted between 1 July 2016 and 1 November 2023 at the First Affiliated Hospital of Soochow University. The study included 72 CD patients who underwent both DECTE and DBE, with 4 patients repeating both procedures within 3 months.

The diagnostic rate of small bowel CD using DBE was 80.3%, which was higher than that using DECTE (65.8%, P = 0.044). The combined small bowel CD diagnostic rate was 89.5%, which was higher than that of DECTE alone (P < 0.001). The detection rate of stenosis using DBE was 46.1%, which was higher than that using DECTE (13.2%; P < 0.001). The combined detection rate of stenosis was 52.6%, which was higher than that of DECTE alone (P < 0.001). For ulcers, DBE had a higher detection rate (73.7%) than DECTE (7.9%; P < 0.001). The combined ulcer detection rate was 76.3%, which was higher than that of DECTE alone (P < 0.001). The detection rate of long ulcers (≥ 2 cm) and non-ileocecal ulcers by DBE were both 17.9%. For patients with abdominal pain, DBE had a diagnostic rate of 79.4%, higher than 63.5% of DECTE (χ2 = 3.889, P = 0.049). The combined diagnostic rate was 87.3%, which was higher than that of DECTE alone (χ2 = 9.626, P = 0.002). For patients with diarrhoea, the DBE's diagnostic rates were 86.8% and 68.4% for DECTE (P = 0.097). The combined diagnostic rate was 94.7%, higher than DECTE alone (χ2 = 7.092, P = 0.008). For patients with other symptoms, such as abdominal distension or vomiting, the DBE diagnostic rate was 79.4% compared with 61.8% for DECTE (P = 0.183). The combined diagnostic rate was higher than DECTE alone (χ2 = 6.620, P = 0.010). Furthermore, notable differences in C-reactive protein, erythrocyte sedimentation rate, faecal calprotectin, haemoglobin, platelet count, albumin, haematocrit, Crohn's Disease Activity Index scores, and Simple Endoscopic Score for Crohn's Disease scores were observed between ulcer-positive and ulcer-negative patients detected by DBE (P < 0.05), whereas DECTE did not show significant differences (P > 0.05).

DBE or the combined use of DECTE and DBE provides superior diagnostic performance for small bowel CD, particularly in detecting stenosis and ulcers, compared with DECTE alone. DBE can be used to identify long ulcers and non-ileocecal ulcers. Moreover, DBE helps diagnose small bowel CD across different clinical manifestations and assess disease activity in various inflammatory states.

Intestinal fibrous stenosis due to Crohn's disease (CD) is highly prevalent. Although several clinical risk factors for fibrous stenosis have been identified, such as perianal fistulizing disease, small bowel disease location, and deep mucosal ulceration, predicting fibrous stenosis remains challenging. The intestinal microbiota plays a crucial role in the development and progression of CD. However, its role in intestinal fibrous stenosis is poorly understood. Leveraging a single-center cross-sectional study, we aimed to investigate the role of fecal microbiota in CD-associated fibrous stenosis.

Using metagenomic analysis, we examined the differences in fecal microbiota between CD patients with intestinal fibrous stenosis and those without stenosis. We identified specific microbiota and assessed their predictive accuracy for intestinal fibrous stenosis. Additionally, we explored functional differences in intestinal microbiota between the two groups.

: Our investigation of fecal samples revealed no significant differences in the gut microbiota structure between patients with fibrous stenosis and those without stenosis in CD. However, taxonomically, we found 70 taxa with significantly different abundance (p < 0.05) between the two groups. Furthermore, LEfSe analysis indicated that g_Bacteroides and g_Enterocloster could predict intestinal fibrous stenosis while p_Actinobacteria, c_Actinomycetia, c_Bacilli, o_Lactobacillales, f_Streptococcaceae and g_Streptococcus could predict CD without stenosis. Functional analysis revealed differential enrichment in five metabolic pathways at the KEGG pathway level in CD patients with fibrous stenosis, including sphingolipid metabolism, lipoic acid metabolism, and biosynthesis of neomycin, kanamycin and gentamicin. In the eggNOG database, we observed differences in four functional categories between the two groups, encompassing cellular process, signaling, and metabolism.

Fecal microbiota significantly impacted intestinal fibrous stenosis in CD. Although there were no significant differences in alpha and beta diversities, fibrous stenosis was associated with changes in microbiota composition and function, suggesting the potential of fecal microbiota in predicting CD-associated fibrous stenosis.

The development of an intestinal stricture in patients with Crohn's disease represents an important and frequent complication, reflecting the progressive nature of the disease. Depending on the inflammatory and fibrotic composition of the stricture, intensified medical therapy, interventional endoscopy, or surgical intervention is required. However, currently available diagnostic approaches can only assess the level of inflammation, but not the degree of fibrosis, limiting rational therapeutic management of Crohn's disease patients. Recently, prolyl endopeptidase fibroblast activating protein (FAP) has been functionally implicated in fibrotic tissue remodelling, indicating it as a promising target for detection of sites of fibrotic tissue remodelling. Thus, intestinal fibrosis might be visualized using Gallium-68 labelled inhibitors of FAP (FAPI). While F-18-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT is a standard diagnostic tool for visualizing inflammatory processes, we combined Ga-68-FAPI-46-PET/CT and F-18-FDG-PET/CT to differentiate predominantly fibrotic or inflammatory areas in Crohn's disease patients with ileo-colonic strictures.

In our study, we analysed three Crohn's disease patients with anastomotic ileo-colonic strictures who underwent both dynamic Ga-68-FAPI-46-PET/CT and static F-18-FDG-PET/CT imaging to assess the level of visualized fibrotic areas within the stricture and differentiate it from inflammatory ones. PET images were analysed both visually and quantitatively. Furthermore, conventional MR enterography and endoscopy were performed in parallel to correlate observed findings. Two of the included patients underwent surgery and the histological specimen were analysed for the level of inflammation and fibrosis, which results were similarly compared to the findings of the PET imaging procedures.

Different uptake patterns of Ga-68-FAPI-46 could be observed in the anastomotic ileo-colonic strictures of the examined Crohn's disease patients, respectively. Immunohistochemical analyses demonstrated that there was a correlation between the level of Ga-68-FAPI-46 uptake and severity of fibrosis, while FDG uptake correlated with the inflammatory activity in the analysed strictures.

The combination with F-18-FDG-PET/CT represents a promising imaging modality to distinguish inflammation from fibrosis and guide subsequent therapy in stricturing Crohn's disease patients, warranting further studies.

Crohn's disease (CD) is a chronic inflammatory condition of the intestines with a rising global incidence. Traditional diagnostic and therapeutic methods have limitations, necessitating the exploration of more effective strategies.

In this study, we employed the Gene Expression Omnibus database to identify genes that are differentially expressed in CD. RT-PCR and immunohistochemical analysis were used to SLC6A14 RNA and protein expression in the colons of CD mice and CD tissues from patients. The mouse model of CD was induced by dextran sodium sulfate (DSS). Infiltrating immune cells in mouse model were screened by flow cytometry.

We discovered that SLC6A14 is significantly overexpressed in CD samples, and its expression is positively correlated with the degree of infiltration by CD4+ and CD8+ T cells. The elevated levels of SLC6A14 RNA and protein were confirmed in clinical CD tissues. The SLC6A14 inhibitor α-methyl-tryptophan (α-MT) significantly decreased the expression of SLC6A14 RNA and protein in the colons of CD mice. The α-MT treatment group also exhibited reduced levels of cytokines involved in T cell differentiation (IFN-γ and TNF-α) and the expression of immune cell surface markers CXCR-3 and LAG-3. Flow cytometry analysis revealed a significant increase in the infiltration of CD4+ and CD8+ T cells in the DSS-treated group compared to the control group. Conversely, the α-MT treatment group showed a significant reduction in CD4+ and CD8+ T cell infiltration and the restoration of intestinal parameters in CD mice. These findings underscore the role of SLC6A14 in regulating intestinal immune cell infiltration during CD progression.

Our findings suggest that SLC6A14 could serve as a potential diagnostic biomarker and therapeutic target for CD. Furthermore, α-MT offers a novel approach for the clinical diagnosis and treatment of CD by targeting SLC6A14 for therapeutic intervention.

Inflammatory bowel disease (IBD)-associated fibrosis causes significant morbidity. Mechanisms are poorly understood but implicate the microbiota, especially adherent-invasive Escherichia coli (AIEC). We previously demonstrated that AIEC producing the metallophore yersiniabactin (Ybt) promotes intestinal fibrosis in an IBD mouse model. Since macrophages interpret microbial signals and influence inflammation/tissue remodeling, we hypothesized that Ybt metal sequestration disrupts this process. Here, we show that macrophages are abundant in human IBD-fibrosis tissue and mouse fibrotic lesions, where they co-localize with AIEC. Ybt induces profibrotic gene expression in macrophages via stabilization and nuclear translocation of hypoxia-inducible factor 1-alpha (HIF-1α), a metal-dependent immune regulator. Importantly, Ybt-producing AIEC deplete macrophage intracellular zinc and stabilize HIF-1α through inhibition of zinc-dependent HIF-1α hydroxylation. HIF-1α+ macrophages localize to sites of disease activity in human IBD-fibrosis strictures and mouse fibrotic lesions, highlighting their physiological relevance. Our findings reveal microbiota-mediated metal sequestration as a profibrotic trigger targeting macrophages in the inflamed intestine.

Crohn's disease is a chronic inflammatory bowel condition that frequently leads to complications such as strictures and bowel obstruction, often necessitating surgical intervention. Surgical approaches like ileocecectomy and right colectomy are commonly performed, with an ongoing debate about whether to close the mesenteric defect during these procedures to prevent internal hernias and small bowel obstruction. In this case, a 39-year-old male individual with longstanding Crohn's disease underwent robotic-assisted colon mobilization, ileocecectomy with Kono-S anastomosis, and gastrojejunostomy to address strictures. On postoperative day two, he developed nausea, vomiting, and abdominal distension. Imaging revealed a small bowel closed-loop obstruction, which prompted reoperation. Laparoscopy and exploratory laparotomy identified an internal hernia through the ileocolic mesocolon defect, which was repaired by closing the defect. The closure of the mesenteric defect has been shown to significantly reduce the risk of internal hernias and small bowel obstruction. Numerous studies indicate that leaving the defect open can increase the likelihood of these complications, which often necessitate additional surgery. Concerns about tension and ischemia following defect closure have not been substantiated when appropriate techniques are used. Although literature specific to procedures like Kono-S anastomosis is limited, general surgical evidence supports mesenteric defect closure to mitigate the risk of postoperative complications. Mesenteric defect closure during surgeries for Crohn's disease reduces the risk of internal hernias and other postoperative complications without significantly increasing other surgical risks. Routine closure is therefore recommended to enhance patient outcomes and reduce the need for further interventions.

While hematochezia is common in Crohn's disease (CD), severe gastrointestinal hemorrhage causing hemodynamic instability is rare. Strictures, another frequent complication, usually cause obstructive symptoms. We report the first case of hemorrhagic shock from ulcerated ileal strictures as the initial presentation of CD. Standard endoscopy and abdominal imaging did not identify the bleeding source, but capsule endoscopy detected ulcerated strictures confirmed by double-balloon enteroscopy. The patient underwent small bowel resection to reduce rebleeding risk and was started on anti-tumor necrosis factor therapy. This atypical presentation of stricturing CD with hemorrhagic shock underscores the importance of small bowel enteroscopy in guiding clinical decisions.

To evaluate correlation between terminal ileal (TI) stricture diagnosis at MR enterography (MRE) and ileocolonoscopy (IC) in patients with Crohn's disease (CD).

One hundred and four patients with CD (51% females; 41 ± 15 years) underwent IC and MRE within 3 months in this retrospective case-control study. Positive cases had TI strictures diagnosed by endoscopy (n = 35); or MRE (threshold small bowel dilation ≥ 3cm; n = 34). Negative controls did not have stricture by either modality (n = 35). Three radiologists examined MRE exams, with per-patient stricture diagnosis based on majority agreement. Sensitivity for stricture diagnosis using threshold dilation of 2.5 cm at MRE was also evaluated.

There were 69 CD TI strictures (57 by endoscopy; 43 by MRE). Sensitivity by endoscopy and MRE criteria were 82.6% (57/69) and 62.3% (43/69), respectively, with additional 20.3% (14/69) of MRE exams classified as "probable stricture" by SAR/AGA/SPR criteria. Lowering MRE small bowel dilation threshold to 2.5 cm increased MRE sensitivity for endoscopically-diagnosed strictures to 71.9% (41/57; up from 56.1% [32/57]), without sacrificing interobserver agreement (κ = 0.684 vs. κ = 0.587). Of 25 new patients diagnosed with a TI stricture using a 2.5 cm threshold by 2 or more readers, 96% (24/25) had hospitalization, small bowel obstruction, endoscopic dilation, and/or surgical resection during clinical follow-up. Nine false negative MRE exams had short strictures with bowel dilation ≥ 2.5 cm.

Either IC or MRE alone is insufficient to diagnose Crohn's small bowel strictures. Diagnostic criteria should incorporate endoscopic and MRE findings. Lowering threshold dilation to 2.5 cm increases sensitivity in stricture diagnosis and identifies clinically significant strictures.

More than half of patients with Crohn's disease develop intestinal fibrosis induced intestinal obstruction with debilitating symptoms throughout their disease course. The incidence of stricture formation in CD has remained unchanged over the last several decades. Factors promoting intestinal fibrosis are currently unclear, but diet may represent an underestimated risk factor for intestinal fibrosis by modification of both the host immune response and intestinal microbial composition. Evaluating the impact of diet on the course of IBD is very complex. Sarcopenia is a common problem in IBD patients and correlates with an increased rate of disease. Skeletal muscle index (SMI) is an important parameter to measure sarcopenia and is an easily accessible tool for evaluating the likelihood of complications in individuals with CD.

Using a randomized and controlled pilot design, we aimed to investigate the efficacy of 12 months of short-term dietary intervention based on essential amino acid (EAA) and sodium butyrate (NaB) supplementation in the management of stricturing Crohn's disease patients.

After the treatment in the diet EAA/NaB group, we revealed a statistically significant improvement of muscle mass (61.49 ± 5.47 vs. control 86 ± 10.70, p = 0.01) and SMI index (9.97 ± 1.79 vs. control 7.60 ± 2.29, p = 0.02). In addition, the measurement of skeletal muscle mass in CD patients has been suggested to be crucial for predicting the disease course. Indeed, after one year, surgery was required in 4/10 control group patients (40%) and 1/10 study group (10%) patients, underlining the importance of body composition alterations and adequate dietary intake in the management of these patients.

Further prospective studies are needed to confirm these results; nonetheless this nutritional approach could become an integral part in the treatment of stricturing CD patients to improve disease outcomes and increase the quality of life in these patients.

Background/Objectives: The management of inflammatory bowel disease (IBD) includes, besides the control of symptoms, the prevention of organ damage and the improvement of the overall disability. Methods: A single-centered, cross-sectional, non-interventional and population-based study was conducted between October 2023 and August 2024 in the Department of Internal Medicine 2 and Gastroenterology of Bucharest Emergency University Hospital to assess the disease disability and quality of life impact using IBD-disk and correlation with different parameters. Results: We included 112 patients; their mean age was 52.35 ± 16.67 years, with a disease duration of 114.9 ± 97.93 months. The majority of patients were represented by men (51.79%). We observed a strong correlation between the CDAI score and overall disability compared to the Mayo score for UC (p = 0.0068). Also, patients with CD and stenotic patterns, as well as the presence of extraintestinal complications, have associated high disability scores. Low hemoglobin levels are associated with high disability (p = 0.0164), while biological treatment is associated with low disability (p = 0.0481). Conclusions: IBD-disk can be used as a valuable tool to assess disability in patients with IBD, also in terms of the activity of the disease, but mostly in terms of the psychological burden of the disease.

Contemporary techniques to assess disease activity or bowel damage in patients with inflammatory bowel disease [IBD], such as endoscopy and imaging, are either invasive or lack accuracy. Non-invasive biomarkers for this purpose remain an unmet medical need. Herein, we provide a comprehensive systematic review of studies evaluating blood extracellular matrix [ECM] biomarkers and their relevance in IBD.

We conducted a systematic review of PubMed, EMBASE, Web of Science, and Scopus to identify citations pertaining to ECM biomarkers of IBD up to March 1, 2024. Studies were categorized based on marker subtype and clinical use.

Thirty-one ECM markers were identified, 28 of which demonstrated the ability to differentiate IBD disease activity. Collagen III emerged as the most extensively investigated [1212 IBD patients], with the degradation marker C3M and deposition marker PRO-C3 being associated with IBD and subtypes. Collagen V markers C5M and PRO-C5 emerged as the most accurate single markers for diagnosis of IBD, with an area under the curve of 0.91 and 0.93, respectively. Overall, studies were characterized by variable endpoints. None of the studies included histological grading of intestinal damage, repair, or fibrosis formation as the primary outcome in relation to the ECM blood markers.

Multiple ECM markers are linked with IBD and its phenotypes. However, more rigorous study designs and clearly defined endpoints are needed to ensure reproducibility and develop reliable and accurate biomarkers. ECM markers hold promise as they provide a 'window' into transmural tissue remodelling and fibrosis burden, warranting further investigation.

Fibrosis characterized by intestinal strictures is a common complication of Crohn's disease (CD), without specific antifibrotic drugs, which usually relies on surgical intervention. The transcription factor XBP1, a key component of endoplasmic reticulum (ER) stress, is required for degranulation of mast cells and linked to PAR2 activation and fibrosis. Many studies have confirmed that naringin (NAR) can inhibit ER stress and reduce organ fibrosis. We hypothesized that ER stress activated the PAR2-induced epithelial-mesenchymal transition process by stimulating mast cell degranulation to release tryptase and led to intestinal fibrosis in CD patients; NAR might play an antifibrotic role by inhibiting ER stress-induced PAR2 activation. We report that the expression levels of XBP1, mast cell tryptase, and PAR2 are upregulated in fibrotic strictures of CD patients. Molecular docking simulates the interaction of NAR and spliced XBP1. ER stress stimulates degranulation of mast cells to secrete tryptase, activates PAR2-induced epithelial-mesenchymal transition process, and promotes intestinal fibrosis in vitro and vivo experiments, which is inhibited by NAR. Moreover, F2rl1 (the coding gene of PAR2) deletion in intestinal epithelial cells decreases the antifibrotic effect of NAR. Hence, the ER stress-mast cell tryptase-PAR2 axis can promote intestinal fibrosis, and NAR administration can alleviate intestinal fibrosis by inhibiting ER stress-induced PAR2 activation.

Treatment options for the medical management of inflammatory bowel disease (IBD) have expanded substantially over the past decade. Multiple classes of advanced therapies, including both monoclonal antibodies and novel oral small molecules, are now available for the treatment of moderately-to-severely active Crohn's disease and ulcerative colitis, highlighted by the approvals of the first IL23p19 antagonists, selective Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators. These advances have been accompanied by the identification of novel targets and the rapid growth in both the number and size of IBD clinical trials. Over a dozen landmark randomized controlled trials (RCTs) have been completed in the past 5 years, including the first head-to-head biologic trials, the first combination biologic studies, and multiple phase III registrational trials of novel compounds with new co-primary and composite end points that will change the treatment landscape for years to come. Importantly, the methodology of RCTs in IBD has evolved substantially, with new trial designs, evaluation of unique patient populations, and different types of efficacy and safety end points being key innovations. In this Review, we provide a comprehensive evaluation of how modern RCTs of IBD medical therapies have evolved and the implications for their appraisal that will help guide the application of these data to clinical practice.

Large bowel obstructions (LBOs) often require urgent surgical intervention. Diagnosis relies on astute history and physical examination, as well as imaging with computed tomography (CT) scan for stable patients. Because of the high mortality associated with colonic perforation in patients with LBOs, decisive surgical decision-making is needed for optimal outcomes. This review seeks to provide an overview of the etiologies of LBO, diagnosis, and general management principles, as well as specific management for the most common etiologies, including colorectal cancer and strictures.

Patients with Crohn's disease (CD) experience disease progression over time, including strictures/stenoses, penetrating fistulae, and abscesses.

This retrospective US population-based study aimed to characterize CD progression in newly diagnosed patients.

Patient-level data from the Optum® Market Clarity database from January 1, 2016, to June 30, 2020, were used. The study comprised a 12-month baseline period (pre-diagnosis), an index date (diagnosis date), and a follow-up period. The risk of, and time to, CD progression since CD diagnosis, dispensed treatment changes following CD progression, and healthcare resource utilization before and after CD progression were assessed.

Overall, 6804 newly diagnosed patients were included. Of these, 1714 (25.2%) experienced CD progression as follows: 19.3% (1183/6117) in the first 6 months, 21.6% (1188/5503) by 1 year, 24.6% (953/3875) by 2 years, and 26.6% (444/1668) by 3 years. Intestinal obstruction/stenosis was more common than fistula or abscess. Among patients with CD progression, the median (interquartile range) estimated time to progression was 2 (0-140) days; the shortest time to progression was seen with a first intestinal obstruction/stenosis (0 [0-137] days). The frequency of several dispensed treatments increased following CD progression. Among patients who experienced progression, CD-related inpatient hospital admissions/visits increased from 436 of 1714 patients (25.4%) in the month before progression to 965 (56.3%) in the month after progression.

Over one quarter of patients with newly diagnosed CD experienced CD progression and complications within 3 years of diagnosis, highlighting the importance of monitoring for progression and early intervention to limit progression.

CT and MR enterography are cross-sectional imaging examinations used in the assessment of inflammatory bowel disease. Consistent reporting and standardized nomenclature are important for clear communication with referring clinicians. Enterography has not only been used to depict inflammation in the small bowel, but it has also been used to quantify disease activity, assess distribution of disease, and detect complications including penetrating disease. This article reviews cross-sectional imaging findings in inflammatory bowel disease, including the current literature focusing on small bowel Crohn's disease and ulcerative colitis, with evidence-based guidelines on appropriate protocols and imaging procedures.

The efficacy of ustekinumab (UST) and infliximab (IFX) in Crohn's disease (CD) patients with intestinal stenosis remains uncertain.

This study aims to compare the efficacy of UST and IFX in the treatment of CD patients with intestinal stenosis.

This was a retrospective and multicenter cohort study.

In this retrospective study, we included CD patients treated with IFX or UST at five centers. We assessed the clinical response rate at weeks 12 and 24, steroid-free clinical remission rate at weeks 24 and 52 for overall patients and those with stenosis, and objective examination (intestinal ultrasound and/or endoscopy) response rate at week 52 for stenosis patients.

A total of 211 CD patients (106 IFX and 105 UST) were included, with 119 (56 IFX and 63 UST) having intestinal stenosis. In the overall patient population, there were no significant differences in clinical response rate and steroid-free clinical remission rate at weeks 12, 24, and 52 between the IFX and UST groups. In patients with stenosis, the steroid-free clinical remission rate at week 52 was significantly lower in the IFX group compared to the UST group (51.79% IFX vs 69.84% UST, p = 0.044). The objective examination response rate did not significantly differ between the IFX and UST groups at week 52 (66.67% IFX vs 76.19% UST, p = 0.690). In the UST group, steroid-free clinical remission rate was higher in bio-naïve patients than bio-experienced patients at week 24 (75.00% bio-naïve vs 55.38% bio-experienced, p = 0.043).

UST may be considered a more advantageous treatment option for those CD patients with intestinal stenosis, as it has better steroid-free clinical remission rates compared to IFX.

Intestinal fibrosis, a prominent consequence of inflammatory bowel disease (IBD), presents considerable difficulty owing to the absence of licensed antifibrotic therapies. This review assesses the therapeutic potential of phytochemicals as alternate methods for controlling intestinal fibrosis. Phytochemicals, bioactive molecules originating from plants, exhibit potential antifibrotic, anti-inflammatory, and antioxidant activities, targeting pathways associated with inflammation and fibrosis. Compounds such as Asperuloside, Berberine, and olive phenols have demonstrated potential in preclinical models by regulating critical signaling pathways, including TGF-β/Smad and NFκB, which are integral to advancing fibrosis.

The main findings suggest that these phytochemicals significantly reduce fibrotic markers, collagen deposition, and inflammation in various experimental models of IBD. These phytochemicals may function as supplementary medicines to standard treatments, perhaps enhancing patient outcomes while mitigating the adverse effects of prolonged immunosuppressive usage. Nonetheless, additional clinical trials are necessary to validate their safety, effectiveness, and bioavailability in human subjects.

Therefore, investigating phytochemicals may lead to crucial advances in the formulation of innovative treatment approaches for fibrosis associated with IBD, offering a promising avenue for future therapeutic development.

The therapeutic potential of adipose-derived mesenchymal stromal cells (AMSCs) in the treatment of intestinal fibrosis occured in patients with Crohn's disease (CD) remains unclear. Tumor necrosis factor-stimulated gene 6 (TSG6) protein plays a critical role in inflammation regulation and tissue repair. This study aimed to determine if AMSCs attenuate intestinal fibrosis by secreting paracrine TSG6 protein and explore the underlying mechanisms.

Two murine models for intestinal fibrosis were established using 2,4,6-trinitrobenzene sulfonic acid in BALB/c mice and dextran sulfate sodium in C57BL/6 mice. Primary human fibroblasts and CCD-18co cells were incubated with transforming growth factor (TGF)-β1 to build two fibrosis cell models in vitro.

Intraperitoneally administered AMSCs attenuated intestinal fibrosis in the two murine models, as evidenced by significant alleviation of colon shortening, collagen protein deposits, and submucosal thickening, and also decrease in the endoscopic and fibrosis scores (P < 0.001). Although intraperitoneally injected AMSCs did not migrate to the colon lesions, high levels of TSG6 expression and secretion were noticed both in vivo and in vitro. Similar to the role of AMSCs, injection of recombinant human TSG6 attenuated intestinal fibrosis in the mouse models, which was not observed with the administration of AMSCs with TSG6 knockdown or TSG6 neutralizing antibody. Mechanistically, TSG6 alleviates TGF-β1-stimulated upregulation of α-smooth muscle actin (αSMA) and collagen I by inhibiting Smad2 phosphorylation. Furthermore, the expression of TSG6 is lower in intestinal fibrosis tissue of patients with Crohn's disease and can reduce pro-fibrotic protein (αSMA) secretion from primary ileal fibrotic tissue.

AMSCs attenuate intestinal fibrosis by secreting paracrine TSG6 protein, which inhibits Smad2 phosphorylation. TSG6, a novel anti-fibrotic factor, could potentially improve intestinal fibrosis treatments.

Crohn's disease (CD) is a chronic inflammatory disease associated with a significant burden in terms of quality of life and health care costs. It is frequently associated with several complications, including the development of intestinal strictures. Stricturing CD requires a careful multidisciplinary approach involving medical therapy and surgery, still posing a continuous management challenge; in this context, endoscopic treatment represents a valuable, in-between opportunity as a minimally invasive strategy endorsed by extensive yet heterogeneous evidence and evolving research and techniques. This review summarizes current knowledge on the role of therapeutic endoscopy in stricturing CD, focusing on evidence gaps, recent updates, and novel techniques intended for optimizing efficacy, safety, and tailoring of this approach in the view of precision endoscopy.

Stricture is a common complication in Crohn's disease (CD). Accurate identification of strictures that poorly respond to biologic therapy is essential for making optimal therapeutic decisions. The aim of this study was to determine the association between ultrasound characteristics of strictures and their therapeutic outcomes.

Consecutive CD patients with symptomatic strictures scheduled for biologic therapy were retrospectively recruited at a tertiary hospital. Baseline intestinal ultrasound was conducted to assess stricture characteristics, including bowel wall thickness, length, stratification, vascularity, and creeping fat wrapping angle. Patients were followed up for a minimum of 1 year, during which long-term outcomes including surgery, steroid-free clinical remission, and mucosal healing were recorded. Statistical analyses were performed.

A total of 43 patients were enrolled. Strictures were located in the ileocecal region (39.5%), colon (37.2%), anastomosis (20.9%), and small intestine (2.3%). The median follow-up time was 17 months (interquartile range 7-25), with 27 patients (62.8%) undergoing surgery. On multivariant analysis, creeping fat wrapping angle > 180° (odds ratio: 6.2, 95% confidence interval [CI]: 1.1-41.1) and a high Limberg score (odds ratio: 2.3, 95% CI: 1.4-6.0) were independent predictors of surgery, with an area under the curve of 0.771 (95% CI: 0.602-0.940), accuracy of 83.7%, sensitivity of 96.3%, and specificity of 62.5%. On Cox survival analysis, creeping fat >180° was significantly associated with surgery (hazard ratio, 5.2; 95% CI: 1.2-21.8; P = 0.03). In addition, creeping fat was significantly associated with steroid-free clinical remission ( P = 0.015) and mucosal healing ( P = 0.06).

Intestinal ultrasound characteristics can predict outcomes in patients with stricturing CD who undertook biologic therapy.

We review the etiologies of bowel obstruction in infants and children that can be identified on ultrasound (US) including perforated appendicitis, intussusception, foreign body ingestion, colonic volvulus, intra-abdominal mass lesions, internal hernia, and stricturing inflammatory bowel disease. US can potentially identify the cause of bowel obstruction in these age groups, without the need for additional cross-sectional imaging, and can aid in patient management including interventional and surgical planning. Hence, it is important to be familiar with the sonographic imaging findings of bowel obstruction in infants and children.

Background Clinical decision making and drug development for fibrostenosing Crohn disease is constrained by a lack of imaging definitions, scoring conventions, and validated end points. Purpose To assess the reliability of MR enterography features to describe Crohn disease strictures and determine correlation with stricture severity. Materials and Methods A retrospective study of patients with symptomatic terminal ileal Crohn disease strictures who underwent MR enterography at tertiary care centers (Cleveland Clinic: September 2013 to November 2020; Mayo Clinic: February 2008 to March 2019) was conducted by using convenience sampling. In the development phase, blinded and trained radiologists independently evaluated 26 MR enterography features from baseline and follow-up examinations performed more than 6 months apart, with no bowel resection performed between examinations. Follow-up examinations closest to 12 months after baseline were selected. Reliability was assessed using the intraclass correlation coefficient (ICC). In the validation phase, after five features were redefined, reliability was re-estimated in an independent convenience sample using baseline examinations. Multivariable linear regression analysis identified features with at least moderate interrater reliability (ICC ≥0.41) that were independently associated with stricture severity. Results Ninety-nine (mean age, 40 years ± 14 [SD]; 50 male) patients were included in the development group and 51 (mean age, 45 years ± 16 [SD]; 35 female) patients were included in the validation group. In the development group, nine features had at least moderate interrater reliability. One additional feature demonstrated moderate reliability in the validation group. Stricture length (ICC = 0.85 [95% CI: 0.75, 0.91] and 0.91 [95% CI: 0.75, 0.96] in development and validation phase, respectively) and maximal associated small bowel dilation (ICC = 0.74 [95% CI: 0.63, 0.80] and 0.73 [95% CI: 0.58, 0.87] in development and validation group, respectively) had the highest interrater reliability. Stricture length, maximal stricture wall thickness, and maximal associated small bowel dilation were independently (regression coefficients, 0.09-3.97; P < .001) associated with stricture severity. Conclusion MR enterography definitions and scoring conventions for reliably assessing features of Crohn disease strictures were developed and validated, and feature correlation with stricture severity was determined. © RSNA, 2024 Supplemental material is available for this article. See also the article by Rieder and Ma et al in this issue. See also the editorial by Galgano and Summerlin in this issue.

Interventional endoscopy can play a key role in the multidisciplinary management of complex inflammatory bowel disease (IBD) as an adjunct to medical and surgical therapy. The primary role of interventional IBD (IIBD) includes the treatment of Crohn's disease-related stricture, fistula, and abscess. Endoscopic balloon dilation (EBD), endoscopic stricturotomy, and placement of endoscopic stents are different forms of endoscopic stricture therapy. EBD is the most widely used therapy whereas endoscopic stricturotomy has higher long-term efficacy than EBD. Fully covered and partially covered self-expanding metal stents are useful in long and refractory strictures whereas lumen-apposing metal stents can be used in short, and anastomotic strictures. Endoscopic fistula/abscess therapy includes endoscopic fistulotomy, seton placement, endoscopic ultrasound-guided drainage of rectal/pelvic abscess, and endoscopic injection of filling agents (fistula plug/glue/stem cell). Endoscopic seton placement and fistulotomy are mainly feasible in short, superficial, single tract fistula and in those with prior surgical seton placement. Similarly, endoscopic fistulotomy is usually feasible in short, superficial, single-tract fistula. Endoscopic closure therapies like over-the-scope clips, suturing, and self-expanding metal stent should be avoided for de novo/bowel to hollow organ fistulas. Other indications include management of postoperative complications in IBD such as management of surgical leaks and complications of pouchitis in ulcerative colitis. Additional indications include endoscopic resection of ulcerative colitis-associated neoplasia (by endoscopic mucosal resection, endoscopic submucosal dissection, and endoscopic full-thickness resection), retrieval of retained capsule endoscope, and control of bleeding. IIBD therapies can potentially act as a bridge between medical and surgical therapy for properly selected IBD patients.

Observational studies have reported an association between inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), and hemorrhoids (HEM). However, the presence of a causal relationship within this observed association remains to be confirmed. Consequently, we utilized the Mendelian randomization (MR) method to assess the causal effects of IBD on hemorrhoids. We validated the association between IBD and hemorrhoids in humans based on genome-wide association studies (GWAS) data. To investigate the causal relationship between IBD and hemorrhoids, we performed a two-sample Mendelian randomization study using training and validation sets. The genetic variation data for IBD, CD, UC, and hemorrhoids were derived from published genome-wide association studies (GWAS) of individuals of European. Two-sample Mendelian randomization and Multivariable Mendelian randomization (MVMR) were employed to determine the causal relationship between IBD (CD or UC) and hemorrhoids. Genetically predicted overall IBD was positively associated with hemorrhoids risk, with ORs of 1.02 (95% CIs 1.01-1.03, P = 4.39 × 10-4) and 1.02 (95% CIs 1.01-1.03, P = 4.99 × 10-5) in the training and validation sets, respectively. Furthermore, we found that CD was positively associated with hemorrhoids risk, with ORs of 1.02 (95% CIs 1.01-1.03, P = 4.12 × 10-6) and 1.02 (95% CIs 1.01-1.02, P = 3.78 × 10-5) for CD in the training and validation sets, respectively. In addition, we found that UC in the training set was positively associated with hemorrhoids risk (ORs 1.02, 95% CIs 1.01-1.03, P = 4.65 × 10-3), while no significant causal relationship between UC and hemorrhoids was shown in the validation set (P > 0.05). However, after MVMR adjustment, UC in the training set was not associated with an increased risk of hemorrhoids. Our study showed that there is a causal relationship between CD and hemorrhoids, which may suggest that clinicians need to prevent the occurrence of hemorrhoids in CD patients.

Intestinal fibrosis, a severe complication of Crohn's disease (CD), is characterized by excessive extracellular matrix (ECM) deposition and induces intestinal strictures, but there are no effective antifibrosis drugs available for clinical application. We performed single-cell RNA sequencing (scRNA-Seq) of fibrotic and nonfibrotic ileal tissues from patients with CD with intestinal obstruction. Analysis revealed mesenchymal stromal cells (MSCs) as the major producers of ECM and the increased infiltration of its subset FAP+ fibroblasts in fibrotic sites, which was confirmed by immunofluorescence and flow cytometry. Single-cell transcriptomic profiling of chronic dextran sulfate sodium salt murine colitis model revealed that CD81+Pi16- fibroblasts exhibited transcriptomic and functional similarities to human FAP+ fibroblasts. Consistently, FAP+ fibroblasts were identified as the key subtype with the highest level of ECM production in fibrotic intestines. Furthermore, specific knockout or pharmacological inhibition of TWIST1, which was highly expressed by FAP+ fibroblasts, could significantly ameliorate fibrosis in mice. In addition, TWIST1 expression was induced by CXCL9+ macrophages enriched in fibrotic tissues via IL-1β and TGF-β signal. These findings suggest the inhibition of TWIST1 as a promising strategy for CD fibrosis treatment.

Background: Crohn's disease (CD) is a chronic, progressive inflammatory condition, involving primarily the bowel, characterized by a typical remitting-relapsing pattern. Despite endoscopy representing the reference standard for the diagnosis and assessment of disease activity, radiological imaging has a key role, providing information about mural and extra-visceral involvement. Methods: Computed Tomography and Magnetic Resonance Imaging are the most frequently used radiological techniques in clinical practice for both the diagnosis and staging of CD involving the small bowel in non-urgent settings. The contribution of imaging in the management of CD is reported on by answering the following practical questions: (1) What is the best technique for the assessment of small bowel CD? (2) Is imaging a good option to assess colonic disease? (3) Which disease pattern is present: inflammatory, fibrotic or fistulizing? (4) Is it possible to identify the presence of strictures and to discriminate inflammatory from fibrotic ones? (5) How does imaging help in defining disease extension and localization? (6) Can imaging assess disease activity? (7) Is it possible to evaluate post-operative recurrence? Results: Imaging is suitable for assessing disease activity, extension and characterizing disease patterns. CT and MRI can both answer the abovementioned questions, but MRI has a greater sensitivity and specificity for assessing disease activity and does not use ionizing radiation. Conclusions: Radiologists are essential healthcare professionals to be involved in multidisciplinary teams for the management of CD patients to obtain the necessary answers for clinically relevant questions.

Inflammatory Bowel Disease (IBD) is a complex and challenging health problem that exerts a significant impact on the quality of life of millions of individuals worldwide [...].

Bowel strictures are well recognized as one of the most severe complications in Crohn's disease, with variable impacts on the prognosis and often needing surgical or endoscopic treatment. Distinguishing inflammatory strictures from fibrotic ones is of primary importance due to the different therapeutic approaches required. Indeed, to better understand the pathogenesis of fibrosis, it is crucial to investigate molecular processes involving genetic factors, cytokines, alteration of the intestinal barrier, and epithelial and endothelial damage, leading to an increase in extracellular matrix synthesis, which ultimately ends in fibrosis. In such a complex mechanism, the gut microbiota also seems to play a role. A better comprehension of molecular processes underlying bowel fibrosis, in addition to radiological and histopathological findings, has led to the identification of high-risk patients for personalized follow-up and testing of new therapies, primarily in preclinical models, targeting specific pathways involving Transforming Growth Factor-β, interleukins, extracellular matrix balance, and gut microbiota. Our review aims to summarize current evidence about molecular factors involved in intestinal fibrosis' pathogenesis, paving the way for potential diagnostic biomarkers or anti-fibrotic treatments for stricturing Crohn's disease.

Accurately and early detection of intestinal fibrosis in Crohn's disease (CD) is crucial for clinical management yet remains an unmet need. Fibroblast activation protein inhibitor (FAPI) PET/CT has emerged as a promising tool to assess fibrosis. We aimed to investigate the diagnostic capability of [18F]F-FAPI PET/CT in detecting intestinal fibrosis and compared it with[18F]F-FDG PET/CT and magnetization transfer MR imaging (MTI).

Twenty-two rats underwent TNBS treatment to simulate fibrosis development, followed by three quantitative imaging sessions within one week. Mean and maximum standardized uptake values (SUVmean and SUVmax) were calculated on[18F]F-FAPI and [18F]F-FDG PET/CT, along with normalized magnetization transfer ratio on MTI. Intestinal fibrosis was assessed pathologically, with MTI serving as imaging standard for fibrosis. The diagnostic efficacy of imaging parameters in fibrosis was compared using pathological and imaging standards. Ten patients with 34 bowel strictures were prospectively recruited to validate their diagnostic performance, using the identical imaging protocol.

In CD patients, the accuracy of FAPI uptake (both AUCs = 0.87, both P ≤ 0.01) in distinguishing non-to-mild from moderate-to-severe fibrosis was higher than FDG uptake (both AUCs = 0.82, P ≤ 0.01) and comparable to MTI (AUCs = 0.90, P ≤ 0.001). In rats, FAPI uptake responded earlier to fibrosis development than FDG and MTI; consistently, during early phase, FAPI uptake showed a stronger correlation (SUVmean: R = 0.69) with pathological fibrosis than FDG (SUVmean: R = 0.17) and MTI (R = 0.52).

The diagnostic efficacy of [18F]F-FAPI PET/CT in detecting CD fibrosis is superior to [18F]F-FDG PET/CT and comparable to MTI, exhibiting great potential for early detection of intestinal fibrosis.

Epithelial adherens junctions (AJs) are cell-cell adhesion complexes that are influenced by tissue mechanics, such as those emanating from the extracellular matrix (ECM). Here, we introduce a mechanism whereby epithelial AJs can also regulate the ECM. We show that the AJ component PLEKHA7 regulates levels and activity of the key ECM remodeling components MMP1 and LOX in well-differentiated colon epithelial cells, through the miR-24 and miR-30c miRNAs. PLEKHA7 depletion in epithelial cells results in LOX-dependent ECM remodeling in culture and in the colonic mucosal lamina propria in mice. Furthermore, PLEKHA7-depleted cells exhibit increased migration and invasion rates that are MMP1- and LOX- dependent, and form colonies in 3D cultures that are larger in size and acquire aberrant morphologies in stiffer matrices. These results reveal an AJ-mediated mechanism, through which epithelial cells drive ECM remodeling to modulate their behavior, including acquisition of phenotypes that are hallmarks of conditions such as fibrosis and tumorigenesis.

IκB kinase (IKK) complex is central regulators of the NF-κB pathway, and dysregulation of IKK phosphorylation leads to hyperactivation of proinflammatory response in various chronic inflammatory diseases, including inflammatory bowel disease (IBD). However, the dynamic modulation of IKK phosphorylation and dephosphorylation in intestinal inflammation remains uncharacterized. Here, we found that autophagy/beclin-1 regulator 1 (AMBRA1) was highly expressed in inflamed colons in a colitis mouse model and in clinical IBD samples. Importantly, AMBRA1 deletion significantly decreased proinflammatory cytokine expression and enhanced the therapeutic effect of infliximab on intestinal inflammation. Mechanistically, the N-term F1 domain of AMBRA1 was required for AMBRA1 to competitively interact with protein phosphatase 4 regulatory subunit 1 (PP4R1) and catalytic protein phosphatase 4 (PP4c) to suppress their interactions with IKK, promote the dissociation of the PP4R1/PP4c complex, and antagonize the dephosphorylation activity of this complex towards the IKK complex. In response to TNF-α stimulation, IKKα phosphorylates AMBRA1 at S1043 to stabilize AMBRA1 expression by impairing its binding to Cullin4A (CUL4A) to decrease its CUL4A-mediated K48-linked ubiquitination. Overall, our study identifies an autophagy-independent function of AMBRA1 as a positive modulator of IKK phosphorylation to promote intestinal inflammation, thus providing a new targeted therapeutic strategy for patients with refractory IBD.