Development of antifibrotic therapy for stricturing Crohn's disease: lessons from randomized trials in other fibrotic diseases.

Intestinal fibrosis is considered an inevitable complication of Crohn's disease (CD) that results in symptoms of obstruction and stricture formation. Endoscopic or surgical treatment is required to treat the majority of patients. Progress in the management of stricturing CD is hampered by the lack of effective antifibrotic therapy; however, this situation is likely to change because of recent advances in other fibrotic diseases of the lung, liver, and skin. In this review, we summarize data from randomized controlled trials (RCTs) of antifibrotic therapies in these conditions. Multiple compounds have been tested for antifibrotic effects in other organs. According to their mechanisms, they were categorized into growth factor modulators, inflammation modulators, 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, intracellular enzymes and kinases, renin-angiotensin system (RAS) modulators, and others. From our review of the results from the clinical trials and discussion of their implications in the gastrointestinal tract, we have identified several molecular candidates that could serve as potential therapies for intestinal fibrosis in CD.

Novel mechanisms and clinical trial endpoints in intestinal fibrosis.

The incidence of inflammatory bowel diseases (IBD) worldwide has resulted in a global public health challenge. Intestinal fibrosis leading to stricture formation and bowel obstruction is a frequent complication in Crohn's disease (CD), and the lack of anti-fibrotic therapies makes elucidation of fibrosis mechanisms a priority. Progress has shown that mesenchymal cells, cytokines, microbial products, and mesenteric adipocytes are jointly implicated in the pathogenesis of intestinal fibrosis. This recent information puts prevention or reversal of intestinal strictures within reach through innovative therapies validated by reliable clinical trial endpoints. Here, we review the role of immune and non-immune components of the pathogenesis of intestinal fibrosis, including new cell clusters, cytokine networks, host-microbiome interactions, creeping fat, and their translation for endpoint development in anti-fibrotic clinical trials.

Milk fat globule-epidermal growth factor 8 (MFGE8) prevents intestinal fibrosis.

OBJECTIVE: Intestinal fibrosis is considered an inevitable consequence of chronic IBD, leading to stricture formation and need for surgery. During the process of fibrogenesis, extracellular matrix (ECM) components critically regulate the function of mesenchymal cells. We characterised the composition and function of ECM in fibrostenosing Crohn's disease (CD) and control tissues. DESIGN: Decellularised full-thickness intestinal tissue platforms were tested using three different protocols, and ECM composition in different tissue phenotypes was explored by proteomics and validated by quantitative PCR (qPCR) and immunohistochemistry. Primary human intestinal myofibroblasts (HIMFs) treated with milk fat globule-epidermal growth factor 8 (MFGE8) were evaluated regarding the mechanism of their antifibrotic response, and the action of MFGE8 was tested in two experimental intestinal fibrosis models. RESULTS: We established and validated an optimal decellularisation protocol for intestinal IBD tissues. Matrisome analysis revealed elevated MFGE8 expression in CD strictured (CDs) tissue, which was confirmed at the mRNA and protein levels. Treatment with MFGE8 inhibited ECM production in normal control HIMF but not CDs HIMF. Next-generation sequencing uncovered functionally relevant integrin-mediated signalling pathways, and blockade of integrin αvß5 and focal adhesion kinase rendered HIMF non-responsive to MFGE8. MFGE8 prevented and reversed experimental intestinal fibrosis in vitro and in vivo. CONCLUSION: MFGE8 displays antifibrotic effects, and its administration may represent a future approach for prevention of IBD-induced intestinal strictures.

Stricturing Crohn's Disease Single-Cell RNA Sequencing Reveals Fibroblast Heterogeneity and Intercellular Interactions.

BACKGROUND & AIMS: Fibroblasts play a key role in stricture formation in Crohn's disease (CD) but understanding its pathogenesis requires a systems-level investigation to uncover new treatment targets. We studied full-thickness CD tissues to characterize fibroblast heterogeneity and function by generating the first single-cell RNA sequencing (scRNAseq) atlas of strictured bowel and providing proof of principle for therapeutic target validation. METHODS: We performed scRNAseq of 13 fresh full-thickness CD resections containing noninvolved, inflamed nonstrictured, and strictured segments as well as 7 normal non-CD bowel segments. Each segment was separated into mucosa/submucosa or muscularis propria and analyzed separately for a total of 99 tissue samples and 409,001 cells. We validated cadherin-11 (CDH11) as a potential therapeutic target by using whole tissues, isolated intestinal cells, NanoString nCounter, next-generation sequencing, proteomics, and animal models. RESULTS: Our integrated dataset revealed fibroblast heterogeneity in strictured CD with the majority of stricture-selective changes detected in the mucosa/submucosa, but not the muscle layer. Cell-cell interaction modeling revealed CXCL14+ as well as MMP/WNT5A+ fibroblasts displaying a central signaling role in CD strictures. CDH11, a fibroblast cell-cell adhesion molecule, was broadly expressed and up-regulated, and its profibrotic function was validated using NanoString nCounter, RNA sequencing, tissue target expression, in vitro gain- and loss-of-function experiments, proteomics, and knock-out and antibody-mediated CDH11 blockade in experimental colitis. CONCLUSIONS: A full-thickness bowel scRNAseq atlas revealed previously unrecognized fibroblast heterogeneity and interactions in CD strictures and CDH11 was validated as a potential therapeutic target. These results provide a new resource for a better understanding of CD stricture formation and open potential therapeutic developments. This work has been posted as a preprint on Biorxiv under doi: 10.1101/2023.04.03.534781.

Activated intestinal muscle cells promote preadipocyte migration: a novel mechanism for creeping fat formation in Crohn's disease.

OBJECTIVE: Creeping fat, the wrapping of mesenteric fat around the bowel wall, is a typical feature of Crohn's disease, and is associated with stricture formation and bowel obstruction. How creeping fat forms is unknown, and we interrogated potential mechanisms using novel intestinal tissue and cell interaction systems. DESIGN: Tissues from normal, UC, non-strictured and strictured Crohn's disease intestinal specimens were obtained. The muscularis propria matrisome was determined via proteomics. Mesenteric fat explants, primary human preadipocytes and adipocytes were used in multiple ex vivo and in vitro cell migration systems on muscularis propria muscle cell derived or native extracellular matrix. Functional experiments included integrin characterisation via flow cytometry and their inhibition with specific blocking antibodies and chemicals. RESULTS: Crohn's disease muscularis propria cells produced an extracellular matrix scaffold which is in direct spatial and functional contact with the immediately overlaid creeping fat. The scaffold contained multiple proteins, but only fibronectin production was singularly upregulated by transforming growth factor-ß1. The muscle cell-derived matrix triggered migration of preadipocytes out of mesenteric fat, fibronectin being the dominant factor responsible for their migration. Blockade of α5ß1 on the preadipocyte surface inhibited their migration out of mesenteric fat and on 3D decellularised intestinal tissue extracellular matrix. CONCLUSION: Crohn's disease creeping fat appears to result from the migration of preadipocytes out of mesenteric fat and differentiation into adipocytes in response to an increased production of fibronectin by activated muscularis propria cells. These new mechanistic insights may lead to novel approaches for prevention of creeping fat-associated stricture formation.

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.

A New Model Based on 25-Hydroxyvitamin D3 for Predicting Active Crohn's Disease in Chinese Patients.

BACKGROUND: The association between vitamin D3 and activity of Crohn's disease (CD) is unclear in Chinese patients. In this study, we aimed to evaluate the correlations between serum levels of 25-hydroxyvitamin D3 (25(OH)D3) and disease activity and predict active disease based on vitamin D status. METHODS: Between January 2014 and December 2017, 346 CD patients from the First Affiliated Hospital of Sun Yat-sen University were recruited and categorized into a group with 25(OH)D3 ≤ 20 ng/ml and a group with 25(OH)D3 > 20 ng/ml. The clinical characteristics, medication, and health-care needs were compared between the groups. The correlations among 25(OH)D3 and routine serum biomarkers and disease activity were examined. The predictive efficiency of 25(OH)D3 and other biomarkers for active diseases was also explored using receiver-operating characteristic (ROC) curve analysis. A new predictive model, -(5∗25(OH)D3 + 2∗Hb) + ESR, and a nomogram were established using Logistic Regression. RESULTS: Patients with 25(OH)D3 ≤ 20 ng/ml had higher serum levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and platelets (PLT) and lower levels of hemoglobin (Hb) and albumin (ALB). Serum levels of 25(OH)D3 were inversely correlated with the score of Crohn's Disease Activity Index (CDAI) (r s = -0.608). ROC analysis showed a better predictive value of -25(OH)D3 and the new model with areas under curve (AUC) of 0.804 and 0.879, respectively, than those of CRP (0.693) and ESR (0.713) in disease activity. A nomogram for prediction was established with a c-index of 0.882. CONCLUSIONS: Serum levels of 25(OH)D3 negatively correlated with CD activity in Chinese patients. The new model and a nomogram based on 25(OH)D3 showed a better efficiency in predicting disease activity in CD patients but warrants further study.

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.

MFGE8 links absorption of dietary fatty acids with catabolism of enterocyte lipid stores through HNF4γ-dependent transcription of CES enzymes.

Enterocytes modulate the extent of postprandial lipemia by storing dietary fats in cytoplasmic lipid droplets (cLDs). We have previously shown that the integrin ligand MFGE8 links absorption of dietary fats with activation of triglyceride (TG) hydrolases that catabolize cLDs for chylomicron production. Here, we identify CES1D as the key hydrolase downstream of the MFGE8-αvß5 integrin pathway that regulates catabolism of diet-derived cLDs. Mfge8 knockout (KO) enterocytes have reduced CES1D transcript and protein levels and reduced protein levels of the transcription factor HNF4γ. Both Ces1d and Hnf4γ KO mice have decreased enterocyte TG hydrolase activity coupled with retention of TG in cLDs. Mechanistically, MFGE8-dependent fatty acid uptake through CD36 stabilizes HNF4γ protein level; HNF4γ then increases Ces1d transcription. Our work identifies a regulatory network that regulates the severity of postprandial lipemia by linking dietary fat absorption with protein stabilization of a transcription factor that increases expression of hydrolases responsible for catabolizing diet-derived cLDs.

Stricturing Crohn's disease single-cell RNA sequencing reveals fibroblast heterogeneity and intercellular interactions.

Background: Fibroblasts play a key role in stricture formation in Crohn's disease (CD) but understanding it's pathogenesis requires a systems-level investigation to uncover new treatment targets. We studied full thickness CD tissues to characterize fibroblast heterogeneity and function by generating the first single cell RNA sequencing (scRNAseq) atlas of strictured bowel and providing proof of principle for therapeutic target validation. Methods: We performed scRNAseq of 13 fresh full thickness CD resections containing non-involved, inflamed non-strictured, and strictured segments as well as 7 normal non-CD bowel segments. Each segment was separated into mucosa/submucosa or muscularis propria and analyzed separately for a total of 99 tissue samples and 409,001 cells. We validated cadherin-11 (CDH11) as a potential therapeutic target by using whole tissues, isolated intestinal cells, NanoString nCounter, next generation sequencing, proteomics and animal models. Results: Our integrated dataset revealed fibroblast heterogeneity in strictured CD with the majority of stricture-selective changes detected in the mucosa/submucosa, but not the muscle layer. Cell-cell interaction modeling revealed CXCL14+ as well as MMP/WNT5A+ fibroblasts displaying a central signaling role in CD strictures. CDH11, a fibroblast cell-cell adhesion molecule, was broadly expressed and upregulated, and its pro-fibrotic function was validated by NanoString nCounter, RNA sequencing, tissue target expression, in vitro gain- and loss-of-function experiments, proteomics, and two animal models of experimental colitis. Conclusion: A full-thickness bowel scRNAseq atlas revealed previously unrecognized fibroblast heterogeneity and interactions in CD strictures and CDH11 was validated as a potential therapeutic target. These results provide a new resource for a better understanding of CD stricture formation and opens potential therapeutic developments.

Review article: the sphingosine 1 phosphate/sphingosine 1 phosphate receptor axis - a unique therapeutic target in inflammatory bowel disease.

BACKGROUND: Ozanimod, a high selective sphingosine 1 phosphate (S1P) receptor (S1PR) 1/5 modulator was approved by the Food and Drug Administration for the treatment of adult patients with moderately to severely active ulcerative colitis. Additional S1PR modulators are being tested in clinical development programmes for both ulcerative colitis and Crohn's disease. AIM: To provide an overview of advances in understanding S1PRs biology and summarise preclinical and clinical investigations of S1P receptor modulators in chronic inflammatory disease with special emphasis on inflammatory bowel diseases (IBD). METHODS: We performed a narrative review using PubMed and ClinicalTrials.gov. RESULTS: Through S1PRs, S1P regulates multiple cellular processes, including proliferation, migration, survival, and vascular barrier integrity. The S1PRs function of regulating lymphocyte trafficking is well known, but new functions of S1PRs expand our knowledge of S1PRs biology. Several S1PR modulators are in clinical development for both ulcerative colitis and Crohn's disease and have shown promise in phase II and III studies with ozanimod now being approved for ulcerative colitis. CONCLUSIONS: S1P receptor modulators constitute a novel, promising, safe, and convenient strategy for the treatment of IBD.

Fibrosis in fat: From other diseases to Crohn's disease.

Creeping fat is a specific feature of Crohn's disease (CD) and is characterized by mesenteric fat wrapping around the intestine. It highly correlates with intestinal transmural inflammation, muscular hypertrophy, fibrosis, and stricture formation. However, the pathogenesis of creeping fat remains unclear. Molecular crosstalk exists between mesenteric fat and the intestine. Indeed, creeping fat contains different types of cells, including adipocytes and immune cells. These cell types can produce various cytokines, fatty acids, and growth factors, which affect the mesenteric fat function and modulate intestinal inflammation and immunity. Moreover, adipocyte progenitors can produce extracellular matrix to adapt to fat expansion. Previous studies have shown that fat fibrosis is an important feature of adipose tissue malfunction and exists in other diseases, including metabolic disorders, cancer, atrial fibrillation, and osteoarthritis. Furthermore, histological sections of CD showed fibrosis in the creeping fat. However, the role of fibrosis in the mesenteric fat of CD is not well understood. In this review, we summarized the possible mechanisms of fat fibrosis and its impact on other diseases. More specifically, we illustrated the role of various cells (adipocyte progenitors, macrophages, mast cells, and group 1 innate lymphoid cells) and molecules (including hypoxia-inducible factor 1-alpha, transforming growth factor-beta, platelet-derived growth factor, and peroxisome proliferator-activated receptor-gamma) in the pathogenesis of fat fibrosis in other diseases to understand the role of creeping fat fibrosis in CD pathogenesis. Future research will provide key information to decipher the role of fat fibrosis in creeping fat formation and intestinal damage, thereby helping us identify novel targets for the diagnosis and treatment of CD.

Intestinal strictures in Crohn's disease: a 2021 update.

Intestinal strictures remain one of the most intractable and common complications of Crohn's disease (CD). Approximately 70% of CD patients will develop fibrotic strictures after 10 years of CD diagnosis. Since specific antifibrotic therapies are unavailable, endoscopic balloon dilation and surgery remain the mainstay treatments despite a high recurrence rate. Besides, there are no reliable methods for accurately evaluating intestinal fibrosis. This is largely due to the fact that the mechanisms of initiation and propagation of intestinal fibrosis are poorly understood. There is growing evidence implying that the pathogenesis of stricturing CD involves the intricate interplay of factors including aberrant immune and nonimmune responses, host-microbiome dysbiosis, and genetic susceptibility. Currently, the progress on intestinal strictures has been fueled by the advent of novel techniques, such as single-cell sequencing, multi-omics, and artificial intelligence. Here, we perform a timely and comprehensive review of the substantial advances in intestinal strictures in 2021, aiming to provide prompt information regarding fibrosis and set the stage for the improvement of diagnosis, treatment, and prognosis of intestinal strictures.

Human intestinal myofibroblasts deposited collagen VI enhances adhesiveness for T cells - A novel mechanism for maintenance of intestinal inflammation.

OBJECTIVE: Inflammatory bowel diseases (IBD) cause chronic intestinal damage and extracellular matrix (ECM) remodeling. The ECM may play an active role in inflammation by modulating immune cell functions, including cell adhesion, but this hypothesis has not been tested in IBD. DESIGN: Primary human intestinal myofibroblast (HIMF)-derived ECM from IBD and controls, 3D decellularized colon or ECM molecule-coated scaffolds were tested for their adhesiveness for T cells. Matrisome was analysed via proteomics. Functional integrin blockade was used to investigate the underlying mechanism. Analysis of the pediatric Crohn's disease (CD) RISK inception cohort was used to explore an altered ECM gene expression as a potential predictor for a future complicated disease course. RESULTS: HIMF-derived ECM and 3D decellularized colonic ECM from IBD bound more T cells compared to control. Control HIMFs exposed to the pro-inflammatory cytokines Iinterleukin-1ß (IL-1ß) and tumor necrosis factor (TNF) increased, and to transforming growth factor-ß1 (TGF-ß1) decreased ECM adhesiveness to T cells. Matrisome analysis of the HIMF-derived ECM revealed collagen VI as a major culprit for differences in T cell adhesion. Collagen VI knockdown in HIMF reduced adhesion T cell as did the blockage of integrin αvß1. Elevated gene expression of collagen VI in biopsies of pediatric CD patients was linked to risk for future stricturing disease. CONCLUSION: HIMF-derived ECM in IBD binds a remarkably enhanced number of T cells, which is dependent on Collagen VI and integrin αvß1. Collagen VI expression is a risk factor for a future complicated CD course. Blocking immune cells retention may represent a novel approach to treatment in IBD.

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.

Classifying Crohn's disease into colon-involving versus non-colon-involving groups is a better predictor of clinical outcomes than the Montreal classification.

BACKGROUND: A suitable disease classification is essential for individualized therapy in patients with Crohn's disease (CD). Although a potential mechanistic classification of colon-involving and non-colon-involving disease was suggested by recent genetic and microbiota studies, the clinical implication has seldom been investigated. We aimed to explore the association of this colonic-based classification with clinical outcomes in patients with CD compared with the Montreal classification. METHODS: This was a retrospective study of CD patients from a tertiary referral center. Patients were categorized into colon-involving and non-colon-involving disease, and according to the Montreal classification. Clinico-demographic data, medications, and surgeries were compared between the two classifications. The primary outcome was the need for major abdominal surgery. RESULTS: Of 934 patients, those with colonic involvement had an earlier median (interquartile range) age of onset [23.0 (17.0-30.0) versus 26.0 (19.0-35.0) years, p = 0.001], higher frequency of perianal lesions (31.2% versus 14.5%, p < 0.001) and extraintestinal manifestations (21.8% versus 14.5%, p = 0.010), but lower frequency of stricture (B2) (16.3% versus 24.0%, p = 0.005), than those with non-colon-involving disease. Colon-involving disease was a protective factor against major abdominal surgery [hazard ratio, 0.689; 95% confidence interval (CI), 0.481-0.985; p = 0.041]. However, patients with colon-involving CD were more prone to steroids [odds ratio (OR), 1.793; 95% CI, 1.206-2.666; p = 0.004] and azathioprine/6-mercaptopurine (AZA/6-MP) treatment (OR, 1.732; 95% CI, 1.103-2.719; p = 0.017) than were patients with non-colon-involving disease. The Montreal classification was not predictive of surgery or steroids and AZA/6-MP treatment. CONCLUSION: This study supports the rationale for disease classification based on the involvement of colon. This new classification of CD is a better predictor of clinical outcomes than the Montreal classification.

Impact of COVID-19 on the Healthcare of Patients With Inflammatory Bowel Disease: A Comparison Between Epicenter vs. Non-epicenter Areas.

Background and Aims: The COVID-19 pandemic poses a great challenge to healthcare. We aimed to investigate the impact of COVID-19 on the healthcare of patients with inflammatory bowel disease (IBD) in epicenter and non-epicenter areas. Methods: Patients with IBD from Hubei province (the epicenter of COVID-19) and Guangdong province (a non-epicenter area), China were surveyed during the pandemic. The questionnaire included change of medications (steroids, immunomodulators, and biologics), procedures (lab tests, endoscopy, and elective surgery), and healthcare mode (standard healthcare vs. telemedicine) during 1 month before and after the outbreak of COVID-19. Results: In total, 324 IBD patients from Guangdong province (non-epicenter) and 149 from Hubei province (epicenter) completed the questionnaire with comparable demographic characteristics. Compared to patients in Guangdong province (non-epicenter), significantly more patients in Hubei (epicenter) had delayed lab tests/endoscopy procedures [61.1% (91/149) vs. 25.3% (82/324), p < 0.001], drug withdrawal [28.6% (43/149) vs. 9.3% (30/324), p < 0.001], delayed biologics infusions [60.4% (90/149) vs. 19.1% (62/324), p < 0.001], and postponed elective surgery [16.1% (24/149) vs. 3.7% (12/324), p < 0.001]. There was an increased use of telemedicine after the outbreak compared to before the outbreak in Hubei province [38.9% (58/149) vs. 15.4% (23/149), p < 0.001], while such a significant increase was not observed in Guangdong province [21.9% (71/324) vs. 18.8% (61/324), p = 0.38]. Approximately two-thirds of IBD patients from both sites agreed that telemedicine should be increasingly used in future medical care. Conclusions: Our patient-based survey study in a real-world setting showed that COVID-19 resulted in a great impact on the healthcare of patients with IBD, and such an impact was more obvious in the epicenter compared to the non-epicenter area of COVID-19. Telemedicine offers a good solution to counteract the challenges in an unprecedented situation such as COVID-19.

Down-Regulation of Colonic ACE2 Expression in Patients With Inflammatory Bowel Disease Responding to Anti-TNF Therapy: Implications for COVID-19.

Background and Aims: Angiotensin-converting enzyme II (ACE2) is the key molecule for understanding the pathophysiology of COVID-19. The risk of COVID-19 and impact of immunosuppressive treatment on disease course in patients with inflammatory bowel disease (IBD) remain controversial. We aimed to determine the change of intestinal ACE2 expression before and after biologics treatment including anti-tumor necrosis factor α (anti-TNFα), anti-integrin, and anti-interleukin (IL)12/23 in IBD patients. Methods: We analyzed the ACE2 expression through the public database of paired intestinal biopsies from IBD patients before and after biologic therapy. Change of ACE2 RNA and protein expression were validated in two independent cohorts (Birmingham cohort and Guangzhou cohort). The correlation between ACE2 expression and disease activity was also analyzed. Results: Mining information from the GEO database showed that compared with healthy control, intestinal ACE2 expression was downregulated in ileum of CD patients, while upregulated in colon of both CD and UC patients. Colonic ACE2 RNA expression was decreased significantly in patients responding to anti-TNFα but not anti-integrin and anti-IL12/23, which was validated in the Birmingham cohort. Using the Guangzhou cohort including 53 patients matched by pre- and post-anti-TNFα therapy, colonic ACE2 protein expression was significantly downregulated after anti-TNFα treatment in responders (P < 0.001) rather than non-responders. Colonic ACE2 expression was significantly higher in patients with severe histologically active disease compared with those with moderate (P < 0.0001) and mild (P = 0.0002) histologically active disease. Conclusion: Intestinal inflammation influences the expression of intestinal ACE2 in IBD patients, with different alterations in the ileum and colon. Colonic ACE2 expression was downregulated after anti-TNFα therapy in IBD patients responding to treatment. This might provide new clues regarding the risk of SARS-CoV-2 infection and the potential benefit of sustaining anti-TNFα treatment in patients with IBD.