A little ER stress isn't bad: the IRE1α/XBP1 pathway shapes ILC3 functions during intestinal inflammation.

Type 3 innate lymphoid cells (ILC3s) are key regulators of intestinal homeostasis and epithelial barrier integrity. In this issue of the JCI, Cao and colleagues found that a sensor of endoplasmic reticulum (ER) stress, the inositol-requiring kinase 1α/X-box-binding protein 1 (IRE1α/XBP1) pathway, fine-tuned the functions of ILC3s. Activation of IRE1α and XBP1 in ILC3s limited intestinal inflammation in mice and correlated with the efficacy of ustekinumab, an IL-12/IL-23 blocker, in patients with Crohn's disease. These results advance our understanding in the use of ILCs as biomarkers not only to predict disease outcomes but also to indicate the response to biologicals in patients with inflammatory bowel disease.

The Diagnosis of Intestinal Fibrosis in Crohn's Disease-Present and Future.

Crohn's disease (CD) progresses with periods of remission and exacerbations. During exacerbations, chronic inflammation leads to tissue destruction. As a result, intestinal fibrosis may develop in response to the ongoing inflammatory process. Fibrosis in CD should be considered the result of the response of the intestinal wall (over) to the presence of inflammation in the deep structures of the intestinal wall. In the absence of ideal noninvasive methods, endoscopic evaluation in combination with biopsy, histopathological analysis, stool analysis, and blood analysis remains the gold standard for assessing both inflammation and fibrosis in CD. On the contrary, the ability to identify markers of intestinal fibrosis would help to develop new diagnostic and therapeutic methods to detect early stages of fibrosis. It is speculated that miRNAs may, in the future, become biomarkers for early noninvasive diagnosis in the treatment of intestinal fibrosis. The purpose of this review is to summarise existing diagnostic methods for Crohn's disease and present recent scientific reports on molecular testing.

Fibrogenesis in Human Mucosa and Muscularis Precision-Cut Intestinal Slices.

In Crohn's Disease (CD), intestinal fibrosis is a prevalent yet unresolved complication arising from chronic and transmural inflammation. The histological assessment of CD intestines shows changes in tissue morphology in all the layers, including the mucosa and muscularis. This study aimed to determine the differences in fibrogenesis between mucosa and muscularis. Human precision-cut intestinal slices (hPCIS) were prepared from human intestine mucosa and muscularis and treated with TGF-ß1 and/or PDGF-BB for 72 h. Gene and protein expression and matrix metalloproteinase (MMP) activity were determined. The basal gene expression of various fibrosis markers was higher in muscularis compared to mucosa hPCIS. During incubation, Pro-Collagen-1A1 secretion increased in muscularis but not in mucosa hPCIS. MMP gene expression increased during incubation in mucosa and muscularis hPCIS, except for MMP9, MMP12, and MMP13 in muscularis hPCIS. Incubation with TGF-ß1 caused increased COL1A1 expression in the mucosa but not in muscularis hPCIS. In muscularis hPCIS, TGF-ß1 treatment caused a decrease in MMP1 and CTSK expression, while MMP13 was increased. In the presence of TGF-ß1, protease inhibitor expression was stable, except for SERPINE1, which was increased in muscularis hPCIS. We conclude that fibrogenesis is more pronounced in muscularis hPCIS compared to mucosa hPCIS, especially when stimulated with TGF-ß1.

Differences of clinical phenotype between familial and sporadic Crohn's disease in East China.

PURPOSE: Family history is one of the strongest risk factors for inflammatory bowel diseases (IBD) while studies about the clinical phenotype of familial IBD are limited. This study aimed to compare the phenotypic features of familial Crohn's disease (CD) with sporadic CD. METHODS: Familial CD was defined as CD patients having one or more first, second, third, fourth degree, or above relatives with CD. Sporadic CD patients hospitalized during the same period were matched 1:3 by age and gender. Differences in clinical characteristics, phenotype distribution, extraintestinal manifestations, and complications at diagnosis, as well as treatment regimen and surgery, were compared between familial and sporadic CD. RESULTS: The familial CD was associated with a higher rate of past appendectomy history (P = 0.009), more intestinal perforation at onset (P = 0.012), more MRI results of anal lesion (P = 0.023), and gastrointestinal perforation (P = 0.040) at diagnosis, higher rate of past intestinal surgery history (P = 0.007), more number of intestinal surgeries (P = 0.037), longer duration of follow-up (P = 0.017), lower rate of taking biologicals for current maintenance (P = 0.043), lower tendency to upgrade to biologicals during follow-up (P = 0.013), higher possibility to experience gastrointestinal obstruction (P = 0.047), and abdominal abscess during follow-up (P = 0.045). CONCLUSION: Familial CD is associated with a more aggressive clinical phenotype.

Fibrostenosing Crohn's Disease: Pathogenetic Mechanisms and New Therapeutic Horizons.

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-ß, 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.

Thrombospondin 2, matrix Gla protein and digital analysis identified distinct fibroblast populations in fibrostenosing Crohn's disease.

Fibrosis is an important complication in inflammatory bowel diseases. Previous studies suggest an important role of matrix Gla protein (MGP) and thrombospondin 2 (THBS2) in fibrosis in various organs. Our aim was to analyse their expression together with regulatory miRNAs in submucosal and subserosal fibroblasts in ulcerative colitis (UC) and Crohn's disease (CD) using immunohistochemistry and qPCR. Digital pathology was used to compare collagen fibre characteristics of submucosal and subserosal fibrosis. Immunohistochemistry showed expression of MGP, but not THBS2 in submucosa in UC and CD. In the subserosa, there was strong staining for both proteins in CD but not in UC. qPCR showed significant upregulation of THBS2 and MGP genes in CD subserosa compared to the submucosa. Digital pathology analysis revealed higher proportion of larger and thicker fibres that were more tortuous and reticulated in subserosal fibrosis compared to submucosal fibrosis. These results suggest distinct fibroblast populations in fibrostenosing CD, and are further supported by image analysis showing significant differences in the morphology and architecture of collagen fibres in submucosal fibrosis in comparison to subserosal fibrosis. Our study is the first to describe differences in submucosal and subserosal fibroblast populations, contributing to understanding of the pathogenesis of fibrostenosis in CD.

Colonic Epithelial Permeability to Ions Is Restored after Vedolizumab Treatment and May Predict Clinical Response in Inflammatory Bowel Disease Patients.

Vedolizumab (VDZ) is used for treating inflammatory bowel disease (IBD) patients. A study investigating colonic epithelial barrier function ex vivo following VDZ is lacking. This work aims to evaluate ex vivo the colonic epithelial barrier function in IBD patients at baseline and during VDZ treatment, and to investigate the relationships between barrier function and clinical parameters. Colonic specimens were obtained from 23 IBD patients before, and at 24 and 52 weeks after VDZ treatment, and from 26 healthy volunteers (HV). Transepithelial electrical resistance (TEER, permeability to ions) and paracellular permeability were measured in Ussing chambers. IBD patients showed increased epithelial permeability to ions (TEER, 13.80 ± 1.04 Ω × cm2 vs. HV 20.70 ± 1.52 Ω × cm2, p < 0.001) without changes in paracellular permeability of a 4 kDa probe. VDZ increased TEER (18.09 ± 1.44 Ω × cm2, p < 0.001) after 52 weeks. A clinical response was observed in 58% and 25% of patients at week 24, and in 62% and 50% at week 52, in ulcerative colitis and Crohn's disease, respectively. Clinical and endoscopic scores were strongly associated with TEER. TEER < 14.65 Ω × cm2 predicted response to VDZ (OR 11; CI 2-59). VDZ reduces the increased permeability to ions observed in the colonic epithelium of IBD patients before treatment, in parallel to a clinical, histological (inflammatory infiltrate), and endoscopic improvement. A low TEER predicts clinical response to VDZ therapy.

Persistent dysbiosis of duodenal microbiota in patients with controlled pediatric Crohn's disease after resolution of inflammation.

Crohn's disease is an inflammatory condition of the intestine characterized by largely unknown etiology and a relapse remission cycle of disease control. While possible triggers have been identified, research is inconsistent on the precise cause of these relapses, especially in the under-researched pediatric population. We hypothesized that patients in remission would have persistent microbial and inflammatory changes in small intestinal tissue that might trigger relapse. To this end, we analyzed intestinal biopsy samples from six patients with pediatric Crohn's disease in remission and a control group of 16 pediatric patients with no evident pathogenic abnormality. We identified compositional microbiota differences, including decreases in the genera Streptococcus and Actinobacillus as well as increases in Oribacterium and Prevotella in patients with controlled Crohn's disease compared to controls. Further, a histologic analysis found that patients with controlled Crohn's disease had increased epithelial integrity, and decreased intraepithelial lymphocytes compared with controls. Additionally, we observed increased peripheral CD4+ T cells in patients with pediatric Crohn's disease. These results indicate that markers of intestinal inflammation are responsive to Crohn's disease treatment, however the interventions may not resolve the underlying dysbiosis. These findings suggest that persistent dysbiosis may increase vulnerability to relapse of pediatric Crohn's disease. This study used a nested cohort of patients from the Bangladesh Environmental Enteric Dysfunction (BEED) study (ClinicalTrials.gov ID: NCT02812615 Date of first registration: 24/06/2016).

Azathioprine promotes intestinal epithelial cell differentiation into Paneth cells and alleviates ileal Crohn's disease severity.

Paneth cells (PCs), a subset of intestinal epithelial cells (IECs) found at the base of small intestinal crypts, play an essential role in maintaining intestinal homeostasis. Altered PCs function is associated with diverse intestinal pathologies, including ileal Crohn's disease (CD). CD patients with ileal involvement have been previously demonstrated to display impairment in PCs and decreased levels of anti-microbial peptides. Although the immunosuppressive drug Azathioprine (AZA) is widely used in CD therapy, the impact of AZA on IEC differentiation remains largely elusive. In the present study, we hypothesized that the orally administered drug AZA also exerts its effect through modulation of the intestinal epithelium and specifically via modulation of PC function. AZA-treated CD patients exhibited an ileal upregulation of AMPs on both mRNA and protein levels compared to non-AZA treated patients. Upon in vitro AZA stimulation, intestinal epithelial cell line MODE-K exhibited heightened expression levels of PC marker in concert with diminished cell proliferation but boosted mitochondrial OXPHOS activity. Moreover, differentiation of IECs, including PCs differentiation, was boosted in AZA-treated murine small intestinal organoids and was associated with decreased D-glucose consumption and decreased growth rates. Of note, AZA treatment strongly decreased Lgr5 mRNA expression as well as Ki67 positive cells. Further, AZA restored dysregulated PCs associated with mitochondrial dysfunction. AZA-dependent inhibition of IEC proliferation is accompanied by boosted mitochondria function and IEC differentiation into PC.

Transmural cross-sectional findings and bowel damage assessment in preclinical Crohn's disease: a case-control study.

PURPOSE: Crohn's disease (CD) is a progressive disorder leading to cumulative bowel damage. The Lémann index is a validated tool that can help in monitoring the progression of the disease and evaluating the effectiveness of different therapies. Our aim was to describe the main radiological findings in incidentally diagnosed CD and to evaluate bowel damage in this subgroup compared to patients diagnosed at later stages. METHODS: Patients with an incidental diagnosis of CD during the colorectal cancer screening program were compared to controls with a CD cohort diagnosed after symptomatic onset and matched 1:1 by disease extent. All cross-sectional examinations were centrally read, performing a descriptive analysis of the main findings and calculation of Lémann index. RESULTS: Thirty-eight patients were included: 19 with preclinical CD (median age 55 years (IQR, 54-62), 53% male, 74% non-smokers; 74% B1 and 26% B2) and 19 matched-controls with symptomatic CD. In those with preclinical CD, the most frequent transmural findings on MRE were contrast enhancement (79%), wall thickening (79%), followed by lymphadenopathy (68%), edema (42%), and increased vascularity (42%). Among those with strictures, controls showed a higher rate of preestenotic dilation (100% vs. 0%, p = 0.01). Bowel damage assessment revealed no statistically significant differences in the Lémann index between preclinical CD and controls (p = 0.95). A statistically significant higher score in the colonic/rectum score was observed (p = 0.014). CONCLUSION: Patients with preclinical CD demonstrate similar radiological findings and degree of bowel damage as new-onset symptomatic CD.

Peiminine ameliorates Crohn's disease-like colitis by enhancing the function of the intestinal epithelial barrier through Nrf2/HO1 signal.

BACKGROUND AND AIMS: Impaired intestinal barrier function is key in maintaining intestinal inflammation in Crohn's disease (CD). However, no targeted treatment in clinical practice has been developed. Peiminine (Pm) strongly protects the epithelial barrier, the purpose of this study is to investigate whether Pm affects CD-like colitis and potential mechanisms for its action. METHODS: Trinitro-benzene-sulfonic acid (TNBS)-induced mice and Il-10-/- mice were used as CD animal models. Colitis symptoms, histological analysis, and intestinal barrier permeability were used to assess the Pm's therapeutic effect on CD-like colitis. The colon organoids were induced by TNF-α to evaluate the direct role of Pm in inhibiting apoptosis of the intestinal epithelial cells. Western blotting and small molecule inhibitors were used to investigate further the potential mechanism of Pm in inhibiting apoptosis of intestinal epithelial cells. RESULTS: Pm treatment reduced body weight loss, disease activity index (DAI) score, and inflammatory score, demonstrating that colonic inflammation in mice were alleviated. Pm decreased the intestinal epithelial apoptosis, improved the intestinal barrier function, and prevented the loss of tight junction proteins (ZO1 and claudin-1) in the colon of CD mice and TNF-α-induced colonic organoids. Pm activated Nrf2/HO1 signaling, which may protect intestinal barrier function. CONCLUSIONS: Pm inhibits intestinal epithelial apoptosis in CD mice by activating Nrf2/HO1 pathway. This partially explains the potential mechanism of Pm in ameliorating intestinal barrier function in mice and provides a new approach to treating CD.

Ileal Crohn's Disease Exhibits Reduced Activity of Phospholipase C-ß3-Dependent Wnt/ß-Catenin Signaling Pathway.

Crohn's disease is a chronic, debilitating, inflammatory bowel disease. Here, we report a critical role of phospholipase C-ß3 (PLC-ß3) in intestinal homeostasis. In PLC-ß3-deficient mice, exposure to oral dextran sodium sulfate induced lethality and severe inflammation in the small intestine. The lethality was due to PLC-ß3 deficiency in multiple non-hematopoietic cell types. PLC-ß3 deficiency resulted in reduced Wnt/ß-catenin signaling, which is essential for homeostasis and the regeneration of the intestinal epithelium. PLC-ß3 regulated the Wnt/ß-catenin pathway in small intestinal epithelial cells (IECs) at transcriptional, epigenetic, and, potentially, protein-protein interaction levels. PLC-ß3-deficient IECs were unable to respond to stimulation by R-spondin 1, an enhancer of Wnt/ß-catenin signaling. Reduced expression of PLC-ß3 and its signature genes was found in biopsies of patients with ileal Crohn's disease. PLC-ß regulation of Wnt signaling was evolutionally conserved in Drosophila. Our data indicate that a reduction in PLC-ß3-mediated Wnt/ß-catenin signaling contributes to the pathogenesis of ileal Crohn's disease.

Systematic review: Patient-related, microbial, surgical, and histopathological risk factors for endoscopic post-operative recurrence in patients with Crohn's disease.

BACKGROUND: Risk 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. AIMS: To assess the current evidence on patient-related, microbial, surgical and histopathological risk factors for ePOR in patients with CD after ileocolic (re-)resection. METHODS: Multiple 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. RESULTS: In 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. CONCLUSION: Risk 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.

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OBJECTIVES: To explore the value of different endoscopic scoring methods in assessing disease activity in pediatric Crohn's disease (CD). METHODS: A total of 70 children diagnosed with CD at the Children's Hospital of Chongqing Medical University from January 2018 to January 2023 were included. Clinical disease activity was assessed using the Pediatric Crohn's Disease Activity Index (PCDAI), while different endoscopic scores were assigned based on endoscopic findings. Spearman rank correlation analysis was used to evaluate the correlation between each endoscopic scoring method and PCDAI as well as laboratory indicators. Kappa test was used to assess the consistency between colonoscopy/capsule endoscopy scoring methods and PCDAI in determining CD activity. Receiver operating characteristic curve analysis was performed to assess the diagnostic efficacy of laboratory indicators in predicting endoscopic activity. RESULTS: The PCDAI score showed a moderate positive correlation with the scores of Crohn's Disease Endoscopic Index of Severity (CDEIS) (rs=0.696, P<0.01), Simple Endoscopic Score for Crohn's Disease (SES-CD) (rs=0.680, P<0.01), Lewis Score (rs=0.540, P<0.01), and Capsule Endoscopy-Crohn's Disease Index (CE-CD) (rs=0.502, P<0.01). The consistency between all endoscopic scoring methods and PCDAI in determining CD activity was poor (Kappa=0.069-0.226). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hematocrit (HCT), and serum albumin (ALB) levels showed a moderate correlation with the PCDAI score and the scores of colonoscopy scoring methods (CDEIS and SES-CD) (|rs|=0.581-0.725, P<0.01), but a weak correlation with the scores of capsule scoring methods (P<0.05). ESR and CRP had higher area under the curve (AUC) values in predicting disease activity based on PCDAI, CDEIS, SES-CD, and Lewis Score compared to HCT and ALB (P<0.05). CONCLUSIONS: CDEIS, SES-CD, Lewis Score, and CE-CD can be used to evaluate disease activity in pediatric CD, but they do not fully correspond with disease activity assessed by PCDAI. Elevated levels of ESR and CRP can predict clinical and endoscopic disease activity in children with CD.

Positive resection margins in Crohn's disease are a relevant risk factor for postoperative disease recurrence.

Postoperative disease recurrence in Crohn's disease represents a relevant issue despite recent advancements in surgical and medical therapies. Additional criteria are necessary to improve the identification of patients at risk and to enable selective therapeutic approaches. The role of resection margins on disease recurrence remains unclear and general recommendations are lacking. A single-center retrospective analysis was performed including all patients who received ileocecal resection due to Crohn's disease. Resection margins were analyzed by two independent pathologists and defined by histopathological criteria based on previous consensus reports. 158 patients were included for analysis with a median follow up of 35 months. While postoperative morbidity was not affected, positive resection margins resulted in significantly increased rates of severe endoscopic recurrence at 6 months (2.0% versus 15.6%, p = 0.02) and overall (4.2% versus 19.6%, p = 0.001), which resulted in significantly increased numbers of surgical recurrence (0% versus 4.5%, p = 0.04). Additionally, positive margins were identified as independent risk factor for severe endoscopic disease recurrence in a multivariate analysis. Based on that, positive margins represent an independent risk factor for postoperative endoscopic and surgical disease recurrence. Prospective studies are required to determine whether extended resection or postoperative medical prophylaxis is beneficial for patients with positive resection margins.

Intraintestinal Heterogeneity of Drug Target Expression in Inflammatory Bowel Disease.

OBJECTIVE: There has been no significant improvement in remission rate in inflammatory bowel disease (IBD) despite several new drugs being introduced in the past two decades. Post-treatment biopsies sometimes show histologic healing in some areas of the intestine while other areas within the same intestine continue to show active inflammation. The aim of this short descriptive study was to determine whether heterogeneous treatment response in IBD may be caused by heterogeneous expression of treatment targets within the same intestine. METHODS: Six cases of Crohn's disease and five cases of ulcerative colitis in which moderate to severe active inflammation was present in at least two biopsies from the same intestine obtained during the same endoscopy procedure were entered in the study. Sections were stained for TNFα and phospho-JAK1 (p-JAK1) using immunohistochemistry. Expression of TNFα and p-JAK1 was recorded as high when the staining intensity was moderate or high, or low when there was no or week staining. The number of eosinophils per high power field was counted in the area of peak density. RESULTS: Different sites within the same intestine from IBD patients with moderate to severe active inflammation may express different levels of TNFα and p-JAK1. For example, in one patient with Crohn's disease with histologically moderate to severe activity in biopsies from the ileum (site 1) and cecum (site 2), there was high expression of p-JAK1 and low TNFα in the ileum biopsy with the exact opposite in the cecum biopsy (low p-JAK1 and high TNFα expression). In this example neither small molecule drug targeting JAK1 nor anti-TNFα biologic given as single agent therapy would be expected to induce histologic remission in both actively inflamed sites in this patient. CONCLUSIONS: The heterogeneous expression of treatment targets within the same intestine may explain why some patients with IBD may not have complete remission on single drug. Studies are needed to determine whether assay for target expression in mucosal biopsies from IBD patients can help to optimize treatment selection.

Multi-Omics Characterization of Colon Mucosa and Submucosa/Wall from Crohn's Disease Patients.

Crohn's disease (CD) is a subtype of inflammatory bowel disease (IBD) characterized by transmural disease. The concept of transmural healing (TH) has been proposed as an indicator of deep clinical remission of CD and as a predictor of favorable treatment endpoints. Understanding the pathophysiology involved in transmural disease is critical to achieving these endpoints. However, most studies have focused on the intestinal mucosa, overlooking the contribution of the intestinal wall in Crohn's disease. Multi-omics approaches have provided new avenues for exploring the pathogenesis of Crohn's disease and identifying potential biomarkers. We aimed to use transcriptomic and proteomic technologies to compare immune and mesenchymal cell profiles and pathways in the mucosal and submucosa/wall compartments to better understand chronic refractory disease elements to achieve transmural healing. The results revealed similarities and differences in gene and protein expression profiles, metabolic mechanisms, and immune and non-immune pathways between these two compartments. Additionally, the identification of protein isoforms highlights the complex molecular mechanisms underlying this disease, such as decreased RTN4 isoforms (RTN4B2 and RTN4C) in the submucosa/wall, which may be related to the dysregulation of enteric neural processes. These findings have the potential to inform the development of novel therapeutic strategies to achieve TH.

Spatial features of skip lesions in Crohn's disease.

Skip lesions are an enigmatic spatial feature characterizing Crohn's disease (CD). They comprise inflamed and adjacent non-inflamed tissue sections with a clear demarcation. Currently, spatial features of the human gastrointestinal (GI) system lack clarity regarding the organization of microbes, mucus, tissue, and host cells during inflammation. New technologies with multiplexing abilities and innovative approaches provide ways of examining the spatial organization of inflamed and non-inflamed tissues in CD, which may open new avenues for diagnosis, prognosis, and treatment. In this review, we present evidence of the relevance of spatial context in patients with CD and the methods and ideas recently published in studies of spatiality during inflammation. With this review, we aim to provide inspiration for further research to address existing gaps.

Magnolin inhibits intestinal epithelial cell apoptosis alleviating Crohn's disease-like colitis by suppressing the PI3K/AKT signalling pathway.

BACKGROUND AND AIMS: Previous reports have shown that preventing excessive intestinal epithelial cell (IEC) apoptosis is a crucial approach for protecting the intestinal barrier in patients with Crohn's disease (CD). Magnolin (MGL) has various biological activities, including antiapoptotic activities, but its role in CD has largely not been determined. This study investigated how MGL impacts CD-like colitis and the underlying mechanism involved. METHODS: Mice were treated with TNBS to establish a disease model, and these mice were used to assess the therapeutic effects of MGL on CD-like colitis. TNF-α-treated colon organoids were used to evaluate the impact of MGL on intestinal barrier function and IEC apoptosis. Enrichment analysis was performed to examine the potential pathways through which MGL inhibits IEC apoptosis. Finally, rescue experiments showed the mechanism by which MGL suppresses IEC apoptosis. RESULTS: The animal experiments demonstrated that MGL treatment alleviated the weight loss, colon shortening, elevated disease activity index (DAI) scores, increased colitis histological scores and upregulated inflammatory factor expression that were observed in model mice. MGL ameliorated intestinal barrier dysfunction and the loss of tight junction (TJ) proteins (ZO-1 and Claudin-1) by inhibiting IEC apoptosis in both TNBS-treated mice and TNF-α-treated colon organoids. MGL inhibited the PI3K/AKT signalling pathway, thus safeguarding the intestinal barrier and alleviating CD-like colitis in vivo and in vitro. CONCLUSIONS: MGL improves the intestinal barrier integrity and prevents CD-like colitis by inhibiting IEC apoptosis. The potential mechanism of its anti-apoptotic impact on IECs could be associated with the PI3K/AKT pathway, presenting novel approaches and avenues for the clinical management of CD.