Healing In Ulcerative Colitis Research Articles

The effects of combustible cigarettes and electronic nicotine delivery systems on immune cell-driven inflammation and mucosal healing in ulcerative colitis.

The effects of combustible cigarettes (CCs) and electronic nicotine delivery systems (ENDS) on immune cell-driven colon inflammation and intestinal healing of patients with ulcerative colitis (UC) are still unknown and, therefore, were examined in this study. Intracellular staining and flow cytometry analysis of immune cells isolated from UC patients who used ENDS (UCENDS), CCs (UCCC) and who were non-smokers (UCAIR) were performed to elucidate cellular mechanisms which were responsible for CCs and ENDS-dependent modulation of immune response during UC progression. Additionally, dextran sulfate sodium (DSS)-colitis was induced in ENDS/CC/air-exposed mice (DSSENDS/ DSSCC/DSSAIR groups) to support clinical findings. Significantly increased number of immunosuppressive, IL-10, TGF-β and IL-35-producing, FoxP3-expressing CD3+CD4+T regulatory cells (Tregs) was observed in the blood of UCENDS patients while reduced presence of inflammatory, TNF-α and IFN-γ-producing, Tbx21-expressing CD3+CD4+ Th1, IL-4-producing Gata3-expresing Th2 and IL-17, IL-22-producing, RORγT, IL-23R-expressing Th17 cells were noticed in the blood of UCCC patients. Exposure to either CCs or ENDS was associated with enhanced mucosal healing, ameliorated spontaneous recovery and improved survival of DSS-treated mice. An expansion of immunosuppressive cells (IL-10-producing tolerogenic CD11c+ dendritic cells, alternatively activated CD206, Arginase 1-expressing, IL-10-producing F4/80+macrophages, IL-10-producing FoxP3-expressing Tregs) was noticed in the colons of DSSENDS-treated mice, while reduced number of inflammatory, IL-17- and IL-4-producing T lymphocytes was observed in the colons of DSSCC-compared to DSSAIR-treated mice. Despite different mechanisms of action, both ENDS and CCs attenuated on-going colon inflammation, enhanced healing and ameliorated recovery of injured intestines of DSS-treated mice and UC patients. This is the first study that compared the effects of CCs and ENDS on immune cells of patients suffering from ulcerative colitis, providing new information about molecular and cellular mechanisms which were responsible for ENDS and CCs-dependent modulation of immune cell-driven colon injury and inflammation. Obtained results showed that both ENDS and CCs had capacity to attenuate detrimental immune response, enhanced healing and ameliorated recovery of injured intestines.

Intestinal Ultrasound, Fecal Calprotectin, and Their Combination to Predict Endoscopic Mucosal Healing in Ulcerative Colitis: A Real-Life Cross-Sectional Study.

The development of noninvasive markers to assess mucosal healing in ulcerative colitis (UC) is essential in the treat-to-target era. The aim of this study was to evaluate the performance of intestinal ultrasound (IUS), fecal calprotectin (FC), and their combination to assess mucosal healing in UC patients. All consecutive patients between January 2021 and September 2022 with UC who underwent a complete colonoscopy and IUS and/or an FC test within 4 weeks were included in a prospective cohort. Bowel wall thickness (BWT) and the color Doppler signal (CDS) were assessed for each segment. Endoscopic mucosal healing was defined by a Mayo score of 0 to 1. A total of 61 patients were included, of whom 79% showed endoscopic healing (26 Mayo 0 and 11 Mayo 1). Among the patients, 16 (27.6%) of 58 had a BWT <3mm, and 41 (70.7%) of 58 had no CDS. The sensitivity, specificity, positive predictive value, and negative predictive value of a BWT <3mm to predict endoscopic mucosal healing were 37%, 77%, 72%, and 44%, respectively. The association of FC <150 µg/g, a BWT <3mm, and a CDS = 0 increased the specificity and positive predictive value (sensitivity 33%, specificity 94%, positive predictive value 89%, negative predictive value 48%). The combination of a normal IUS, no rectal bleeding, and an FC <172 µg/g identified all patients with mucosal healing. The combination of IUS and FC is effective in identifying mucosal healing in UC. Noninvasive evaluation of mucosal healing is possible for most UC patients.

Development and validation of a novel criterion of histologic healing in ulcerative colitis defined by inflammatory cell enumeration in lamina propria mucosa: A multicenter retrospective cohort in China.

Histological healing is closely associated with improved long-term clinical outcomes and lowered relapses in patients with ulcerative colitis (UC). Here, we developed a novel diagnostic criterion for assessing histological healing in UC patients. We conducted a retrospective cohort study in UC patients, whose treatment was iteratively optimized to achieve mucosal healing at Shanghai Tenth People's Hospital of Tongji University from January 2017 to May 2022. We identified an inflammatory cell enumeration index (ICEI) for assessing histological healing based on the proportions of eosinophils, CD177 + neutrophils, and CD40L + T cells in the colonic lamina propria under high power field (HPF), and the outcomes (risks of symptomatic relapses) of achieving histological remission vs . persistent histological inflammation using Kaplan-Meier curves. Intrareader reliability and inter-reader reliability were evaluated by each reader. The relationships to the changes in the Nancy index and the Geboes score were also assessed for responsiveness. The ICEI was further validated in a new cohort of UC patients from other nine university hospitals. We developed an ICEI for clinical diagnosis of histological healing, i.e., Y=1.701X 1 + 0.758X 2 + 1.347X 3 - 7.745 (X 1 , X 2 , and X 3 represent the proportions of CD177 + neutrophils, eosinophils, and CD40L + T cells, respectively, in the colonic lamina propria under HPF). The receiver operating characteristics curve (ROC) analysis revealed that Y <-0.391 was the cutoff value for the diagnosis of histological healing and that an area under the curve (AUC) was 0.942 (95% confidence interval [CI]: 0.905-0.979) with a sensitivity of 92.5% and a specificity of 83.6% ( P <0.001). The intraclass correlation coefficient (ICC) for the intrareader reliability was 0.855 (95% CI: 0.781-0.909), and ICEI had good inter-reader reliability of 0.832 (95% CI: 0.748-0.894). During an 18-month follow-up, patients with histological healing had a substantially better outcome compared with those with unachieved histological healing ( P <0.001) using ICEI. During a 12-month follow-up from other nine hospitals, patients with histological healing also had a lower risk of relapse than patients with unachieved histological healing. ICEI can be used to predict histological healing and identify patients with a risk of relapse 12 months and 18 months after clinical therapy. Therefore, ICEI provides a promising, simplified approach to monitor histological healing and to predict the prognosis of UC. Chinese Clinical Trial Registry, No. ChiCTR2300077792.

Comparison of diagnostic accuracy between linked color imaging and autofluorescence imaging in patients with ulcerative colitis: A prospective observational study.

Image enhancement endoscopy techniques, such as linked color imaging (LCI) and autofluorescence imaging (AFI), have shown promise in diagnosing mucosal inflammation in ulcerative colitis (UC). However, no studies have directly compared the diagnostic efficacy of LCI and AFI. This prospective observational study aimed to compare their diagnostic accuracy for histological healing in UC. This study included 81 UC patients, resulting in a total of 204 endoscopic images captured using LCI and AFI, respectively. Spearman's rank correlation coefficients assessed the correlation between LCI and AFI coloration and Geboes histopathology score (GHS). Six endoscopists, who were blinded to clinicopathological features, evaluated these images, and subsequently, the diagnostic accuracy was evaluated. Spearman's rank correlation coefficients between LCI index, AFI index (reverse gamma value), and GHS were 0.324 and -0.428, respectively (P<0.001), indicating a significant correlation between LCI and AFI coloration and histological healing. In LCI and AFI classifications, mean values for diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 76.3±2.2 versus 77.8±2.7, 91.8±4.0 versus 83.2±7.6, 53.4±10.0 versus 70.0±5.3, 74.0±3.5 versus 80.0±1.6, and 82.9±5.2 versus 75.5±7.5, respectively. No significant difference in diagnostic accuracy existed between LCI and AFI classifications. However, LCI displayed higher sensitivity than AFI while AFI showed higher specificity compared with LCI (P<0.05). LCI and AFI offer comparable diagnostic accuracy for histological healing. Clinically, it is necessary to recognize diagnostic features characterized by higher sensitivity in LCI and greater specificity in AFI.

Comparative Efficacy of Subcutaneous and Intravenous Infliximab and Vedolizumab for Maintenance Treatment of TNF-naive Adult Patients with Inflammatory Bowel Disease: A Systematic Literature Review and Network Meta-analysis.

Infliximab and vedolizumab are widely used to treat Crohn's disease (CD) and ulcerative colitis (UC). This systematic review and network meta-analysis evaluated comparative efficacy of various regimens for intravenous or subcutaneous infliximab and vedolizumab during maintenance treatment in CD and UC. Parallel-group randomized controlled trials (RCTs) were identified by a systematic literature review (CRD42022383401) and included if they evaluated therapeutics of interest for maintenance treatment of adults with moderate-to-severe luminal CD or UC and assessed clinical remission between Weeks 30 and 60. Clinical remission rates in CD or UC and mucosal healing rates in UC were analyzed in a Bayesian network meta-analysis model. Endoscopic outcomes in CD were synthesized by proportional meta-analysis. Overall, 13 RCTs were included in the analyses. All vedolizumab studies randomized induction responders to maintenance treatment; infliximab studies used a treat-through design. Subcutaneous infliximab 120 mg every 2 weeks had the highest odds ratio (OR) [95% credible interval] versus placebo for clinical remission during the maintenance phase (CD: 5.90 [1.90-18.2]; UC: 5.45 [1.94-15.3]), with surface under the cumulative ranking curve (SUCRA) values of 0.91 and 0.82, respectively. For mucosal healing in UC, subcutaneous infliximab 120 mg every 2 weeks showed the highest OR (4.90 [1.63-14.1]), with SUCRA value of 0.73, followed by intravenous vedolizumab 300mg every 4 weeks (SUCRA value, 0.70). Endoscopic outcomes in CD were better with subcutaneous infliximab 120 mg every 2 weeks than intravenous infliximab 5 mg/kg every 8 weeks. Subcutaneous infliximab showed a favorable efficacy profile for achieving clinical remission and endoscopic outcomes during maintenance treatment in CD or UC.

Are we ready to use new endoscopic scores for ulcerative colitis?

For ulcerative colitis (UC), the variability in inflammatory activity along the colon poses a challenge in management. The focus on achieving endoscopic healing in UC is evident, where the UC Endoscopic Index of Severity and Mayo Endoscopic Subscore are commonly used for evaluation. However, these indices primarily consider the most severely affected region. Liu et al recent study validates the Toronto Inflammatory Bowel Disease Global Endoscopic Reporting (TIGER) score offering a comprehensive assessment of inflammatory activity across diverse segments of the colon and rectum and a reliable index correlating strongly with UC Endoscopic Index of Severity and moderately with Mayo Endoscopic Subscore (MES). Despite recommendation, certain aspects warrant further investigation. Fecal calprotectin, an intermediate target, correlates with TIGER and should be explored. Determining TIGER scores defining endoscopic remission and response, evaluating agreement with histological activity, and assessing inter-endoscopist agreement for TIGER require scrutiny. Exploring the correlation between TIGER and intestinal ultrasound, akin to MES, adds value.

The ERK-cPLA2-ACSL4 axis mediating M2 macrophages ferroptosis impedes mucosal healing in ulcerative colitis

Ulcerative colitis (UC) is a chronic gastrointestinal disease that can be managed with 5-aminosalicylic acid (5-ASA), the standard treatment for UC. However, the effectiveness of 5-ASA is not always optimal. Our study revealed that despite 5-ASA treatment, cells continued to experience excessive ferroptosis, which may hinder mucosal healing in UC and limit the success of this treatment approach in achieving disease remission. We found that combining 5-ASA with the ferroptosis inhibitor Fer-1 led to a significant inhibition of ferroptosis in macrophages present in the colon tissue, along with an increase in the proportion of M2 macrophages, suggesting that targeting ferroptosis in M2 macrophages could be a potential therapeutic strategy for alleviating UC. Our study also demonstrated that M2 macrophages are more susceptible to ferroptosis compared to M1 macrophages, and this susceptibility is associated with the activated arachidonic acid (AA) metabolism pathway mediated by ERK-cPLA2-ACSL4. Additionally, we found that the expression of cPLA2 gene pla2g4a was increased in the colon of UC patients compared to healthy controls. Furthermore, targeted metabolomics analysis revealed that the combination treatment group, as opposed to the 5-ASA treatment group, exhibited the ability to modulate AA metabolism. Overall, our findings emphasize the importance of addressing macrophage ferroptosis in order to enhance macrophage anti-inflammation, improve mucosal healing, and achieve better therapeutic outcomes for patients with UC.

P267 Prospective validation of the IBD - Distribution, Chronicity, Activity (DCA) histological score for Ulcerative Colitis and correlation with UCEIS and MES

Abstract Background Histological assessment is not currently recognised as an independent parameter to guide personalised treatment for patients with ulcerative colitis (UC). The development of the Inflammatory Bowel Disease – Distribution, Chronicity, Activity (IBD-DCA) score allows a pragmatic approach to quantitatively evaluate mucosal injury and healing in UC, compared with other pre-existing histological scores (Lang-Schwarz et al., J Crohns Colitis, 2021). This scoring system facilitates a template-based reporting to produce consistent reports with information representing UC severity. Each domain of the IBD-DCA is scored as one of 0 (normal), 1 (mild), or 2 (moderate to severe) based on the presence of established histological UC findings (Figure 1). This project aims to prospectively validate the IBD-DCA score for routine clinical deployment and correlate with endoscopic scores – UC Endoscopic Index of Severity (UCEIS) and Mayo Endoscopic Score (MES). Methods Colonoscopic biopsies from patients with a previously confirmed diagnosis of UC attending one of four hospitals in a single healthcare group from August 2022 to January 2023 were reported using the IBD-DCA histological score, and the corresponding, clinician-reported UCEIS and MES scores were recorded. The histopathology reports were assessed based on the completeness of information in their respective D, C, and A domains. The proportion of reports with information fully represented by the IBD-DCA reporting template and the distribution of biopsy sites were described. The correlation between IBD-DCA with UCEIS and MES was quantified via Kendall’s tau (τ) using the R statistical package v4.3.2. Results Of the 151 cases reported, 70 (46.4%) patients were female and 81 (53.6%) were male. 12 patients (7.9%) had full colonic biopsies, while the remaining cases were assessed with selective biopsies. Rectal biopsy was most often performed (83.4%). The IBD-DCA components were reported for every biopsied sites in 133 (88.1%) cases. Notable correlations included UCEIS vascular pattern with histological chronicity (τ = 0.3891), UCEIS erosions/ulceration with histological activity (τ = 0.3252), and histological activity with the total UCEIS score (τ = 0.3450). MES showed the strongest correlation with histological disease distribution (τ = 0.3450)(Table 1). All p-values &amp;lt; 0.001. Conclusion These data show encouraging uptake of this simple histological reporting template in UC in daily routine use. The findings suggest that the IBD-DCA score may be a useful addition in the clinical management in patients with UC.

P855 Have biological agents changed the need for abdominal surgery in inflammatory bowel disease over time?

Abstract Background Inflammatory bowel disease (IBD) is a chronic relapsing-remitting inflammatory intestinal disorder with two main categories: Crohn’s disease (CD) and ulcerative colitis (UC). CD patients can develop strictures and penetrating complications over time, that can lead to an increased number of bowel resections which, if extensive, can end up as short bowel syndromes. Aggresive UC is related to an increased colectomy rate. Controlling flares in CD and achieving mucosal healing in UC may decrease the need for abdominal surgery. Irruption of biological agents at the begining of the twenty-first century could be related to the fulfillment of both objectives decreasing number of surgeries. Our aim was to analyze the impact of biological treatment in abdominal surgery among patients with CD and UC. Methods We conducted a retrospective two cohort study of patients with IBD and abdominal surgery, using our prospectively collected ENEIDA data base. Patients were included in two periods of time, before and after biological irruption. The first cohort included all the patients operated between 1993 and 1998 (before biologics) and the second one between 2013 and 2018. We analyzed differences in the number of surgeries per patient and time between IBD diagnosis and first surgery, among other variables. Results We included 55 patients (89.1% CD and 10.9% UC) in the first cohort and 69 patients (82.6% CD and 17.4% UC) in the second one. 44 patients in the second cohort (63.8%) received biological agents before first surgery. There were no significant differences in the number of surgeries (two or more) per patient in both periods of time (10.9% vs 7.3%, p 0.69). The main indication of surgery was strictures (44.6% vs 46.6%) followed by penetrating complications (25.0% vs 30.1%) and medical refractoriness (21.4% vs 15.1%). No differences were observed in the reason to indicate surgery (p 0.78). The main surgical procedure was ileocecal resection (60.0% vs 54.1%), followed by small bowel resection (11.7% vs 17.6%) and proctocolectomy (10.0% vs 5.4%), without significant differences over time (p 0.67). There were 7 immediate post-surgical complications in both cohorts (11.3% vs 9.5%) without significant differences between them (p 0.94). The median time between IBD diagnosis and first surgery was greater among patients in the second cohort who had received any biological agent (19.0 vs 71.2 months, p&amp;lt;0.05), [image 1]. Conclusion Biological treatment considerably increases the time between IBD diagnosis and the first surgery. Future research will allow us to determine if this is associated to less surgeries in each patient and a reduction in long-term post-surgery complications (short-bowel syndrome, abdominal adhesions, eventrations, etc).

Deep mucosal healing in ulcerative colitis: how deep is better?

Ulcerative colitis (UC), characterized by its recurrent nature, imposes a significant disease burden and compromises the quality of life. Emerging evidence suggests that achieving clinical remission is not sufficient for long-term remission. In pursuit of a favorable prognosis, mucosal healing (MH) has been defined as the target of therapies in UC. This paradigm shift has given rise to the formulation of diverse endoscopic and histological scoring systems, providing distinct definitions for MH. Endoscopic remission (ER) has been widely employed in clinical practice, but it is susceptible to subjective factors related to endoscopists. And there's growing evidence that histological remission (HR) might be associated with a lower risk of disease flares, but the incorporation of HR as a routine therapeutic endpoint remains a debate. The integration of advanced technology has further enriched the definition of deep MH. Up to now, a universal standardized definition for deep MH in clinical practice is currently lacking. This review will focus on the definition of deep MH, from different dimensions, and analyze strengths and limitations, respectively. Subsequent multiple large-scale trials are needed to validate the concept of deep MH, offering valuable insights into potential benefits for UC patients.

Leaving behind the Mucosa: Advances and Future Directions of Intestinal Ultrasound in Ulcerative Colitis.

Inflammatory Bowel Diseases (IBD), mainly Ulcerative Colitis (UC) and Crohn's Disease (CD), are disorders characterized by chronic inflammation with severe morbidity and long-term disabling quality of life outcomes. UC mainly affects the mucosal and sub-mucosal layers of the colon, without embracing the peri-intestinal structures. Considering the predominant mucosal location of UC inflammation, the implementation of transmural evaluation by cross-sectional imaging techniques, mainly Intestinal Ultrasound (IUS), has been left behind for ages, especially if compared to CD. Nevertheless, studies analyzing intestinal ultrasound parameters accuracy in disease activity detection reported a good-to-optimal correlation of IUS markers with colonic inflammation, suggesting comparable feasibility of IUS monitoring in UC as in CD. The easy-to-use, costless and point-of-care available status of IUS is therefore crucial in order to improve the diagnostic process and, according to the recent literature, to monitor the response to treatment leading to speeding up decision making and therapy adjustments. Recent studies have demonstrated the correlation between transmural healing in UC with favorable outcomes even in the long term. An evidence gap still exists in the assessment of the rectum, with trans-perineal ultrasound (TPUS) a potential answer to reach a more precise evaluation of rectal inflammation. Eventually, IUS is also increasingly showing promises in emergent or post-surgical UC settings, considering various efforts put in line to demonstrate its feasibility in predicting response to salvage therapy for surgery avoidance and in studying inflammation relapse after procto-colectomy with ileo-pouch-anal anastomosis (IPAA) creation.

Regulation of epithelial cell differentiation by the Ubiquitous expressed transcript isoform 1 in ulcerative colitis.

Mucosal healing has emerged as a desirable treatment goal for patients with ulcerative colitis (UC). Healing of mucosal wounds involves epithelial cell proliferation and differentiation, and Y-box transcription factor ZONAB has recently been identified as the key modulator of intestinal epithelial restitution. We studied the characteristics of UXT-V1 expression in UC patients using immunohistochemistry and qPCR. The functional role of UXT-V1 in the colonic epithelium was investigated using lentivirus-mediated shRNA in vitro and ex vivo. Through endogenous Co-immunoprecipitation and LC-MS/MS, we identified ZONAB as a UXT-V1-interactive protein. Herein, we report that UXT-V1 promotes differentiation of intestinal epithelial cells by regulating the nuclear translocation of ZONAB. UXT-V1 was upregulated in the intestinal epithelia of UC patients compared with that of healthy controls. Knocking down UXT-V1 in NCM-460 cells led to the enrichment of pathways associated with proliferation and differentiation. Furthermore, the absence of UXT-V1 in cultured intestinal epithelial cells and colonic organoids inhibited differentiation to the goblet cell phenotype. Mechanistically, the loss of UXT-V1 in the intestinal epithelial cells allowed nuclear translocation of ZONAB, wherein it regulated the transcription of differentiation-related genes, including AML1 and KLF4. Taken together, our study reveals a potential role of UXT-V1 in regulating epithelial cell differentiation, proving a molecular basis for mucosal healing in UC.

Mirikizumab-Induced Transcriptome Changes in Ulcerative Colitis Patient Biopsies at Week 12 Are Maintained Through Week 52.

Mirikizumab, an anti-interleukin-23p19 monoclonal antibody, demonstrated efficacy in phase 2 and 3 randomized clinical trials of patients with moderate-to-severe ulcerative colitis (UC). Previous results have shown that 12 weeks of mirikizumab treatment downregulated transcripts associated with UC disease activity and tumor necrosis factor inhibitor resistance. We assessed week-52 gene expression from week-12 responders receiving mirikizumab or placebo. In the phase 2 AMAC study (NCT02589665), mirikizumab-treated patients achieving week-12 clinical response were rerandomized to mirikizumab 200 mg subcutaneous every 4 or 12 weeks through week 52 (N = 31). Week-12 placebo responders continued placebo through week 52 (N = 7). The limma R package clustered transcript changes in colonic mucosa biopsies from baseline to week 12 into differentially expressed genes (DEGs). Among DEGs, similarly expressed genes (DEGSEGs) maintaining week-12 expression through week 52 were identified. Of 89 DEGSEGs, 63 (70.8%) were present only in mirikizumab induction responders, 5 (5.6%) in placebo responders, and 21 (23.6%) in both. Week-12 magnitudes and week-52 consistency of transcript changes were greater in mirikizumab than in placebo responders (log2FC > 1). DEGSEG clusters (from 84 DEGSEGs identified in mirikizumab and mirikizumab/placebo responders) correlated to modified Mayo score (26/84 with Pearson correlation coefficient [PCC] >0.5) and Robarts Histopathology Index (55/84 with PCC >0.5), sustained through week 52. Mirikizumab responders had broader, more sustained transcriptional changes of greater magnitudes at week 52 vs placebo. Mirikizumab responder DEGSEGs suggest a distinct molecular healing pathway associated with mirikizumab interleukin-23 inhibition. The cluster's correlation with disease activity illustrates relationships between clinical, endoscopic, and molecular healing in UC.

Single-cell and bulk transcriptomics reveals M2d macrophages as a potential therapeutic strategy for mucosal healing in ulcerative colitis.

Mucosal healing is essential for treating ulcerative colitis (UC), which results from imbalanced macrophage polarization and dysregulated inflammatory responses. However, the mechanisms of cellular communication and signal transduction that regulate mucosal healing among macrophage subtypes require further investigation. We use bulk and single-cell RNA sequencing analysis to reveal that macrophage subtypes vary in different UC states. At the same time, chemokine and angiogenesis signaling is strongly associated with M2 macrophage's infiltrated proportion. To get more insight into subtypes of macrophages in mucosal healing, we divided macrophages into M1, M2b, and M2d macrophages. Based on the differentially expressed genes (DEGs) between M2d and M1 macrophages, KEGG and GO analysis highlights M2d macrophages' ability to alleviate inflammation and promote epithelial healing. Trajectory analysis revealed opposite differentiation of macrophage subsets between UC and healthy groups, with M1 and M2d macrophages coexisting in the same differentiation branch under UC conditions. Along the pseudotime axis, CCL3 and VEGFA expression increased in UC, while IL10RA remained stable in UC but increased in healthy controls. CellChat identified CCL3-CCR1 has strong communication between M1 and M2d macrophages, while the IL10 signaling pathway is activated explicitly in M2d macrophages to mitigate inflammation and promote epithelial healing. We also speculate that high levels of VEGFA activate endothelial cells expressing VEGFR and worsen inflammation. To conclude, we suggested IL10 and VEGF signaling in M2d macrophages as potential therapeutic targets for mucosal healing. However, it is necessary to establish reliable methods for isolating and purifying M2d macrophages before these targets can be effectively utilized.

Evaluation of Mucosal Healing in Ulcerative Colitis by Fecal Calprotectin vs. Fecal Immunochemical Test: A Systematic Review and Meta-analysis.

Mucosal healing has been considered a treatment goal for patients with inflammatory bowel disease. To compare the accuracy of fecal immunochemical test and fecal calprotectin in the judgment of mucosal healing in ulcerative colitis, a meta-analysis was performed. We searched the PubMed, Cochrane Library, Web of Science, and Embase for the studies on fecal immunochemical test and fecal calprotectin predicting mucosal healing in ulcerative colitis. The comprehensive sensitivity, specificity, diagnostic odds ratio, positive likelihood ratio, and negative likelihood ratio were calculated to evaluate the accuracy. By analyzing 22 publications, we found that the combined sensitivity and specificity of fecal immunochemical test were 0.87 (95% CI, 0.80-0.92) and 0.73 (95% CI, 0.62-0.81), respectively. The combined sensitivity and specificity of fecal calprotectin were 0.76 (95% CI, 0.70-0.80) and 0.80 (95% CI, 0.76-0.84), respectively. The area under the curve values of the fecal immunochemical test and fecal calprotectin summary receiver operating characteristic (SROC) curves were 0.88 and 0.85, respectively. Consequently, fecal immunochemical test had higher sensitivity in predicting mucosal healing in ulcerative colitis patients, while fecal calprotectin had higher specificity. Compared with fecal calprotectin, fecal immunochemical test was more accurate in judging mucosal healing in ulcerative colitis.

Lower ultra-short-term heart rate variability can predict worse mucosal healing in ulcerative colitis

BackgroundPsychological stress has been proved to be a risk factor for exacerbation for ulcerative colitis (UC). However, traditional approaches of quantifying psychological stress using psychological scales are time-consuming and the results may not be comparable among patients with different educational levels and cultural backgrounds. Alternatively, heart rate variability (HRV) is an indicator for psychological stress and not biased by educational and cultural backgrounds.AimsIn this study, we try to explore the relationship between psychological stress and UC by analyzing the effect of ultra-short-term HRV on mucosal and histological remission status of UC.MethodsThis is a retrospective case–control study on UC inpatients from 2018 through 2020. Ultra-short-term HRV were calculated using baseline electrocardiography. Patients were divided intocase and control groups according to their Mayo endoscopic scores or histological Geboes scores. Three variables of ultra-short-term HRV (the standard deviation of normal to normal R-R intervals (SDNN), the standard deviation of successive differences between adjacent normal to normal R-R intervals (SDSD), the root mean square of successive differences of normal to normal R-R intervals (RMSSD)) were compared between different groups. And for those variables with significant differences, we built univariate and multivariate logistic regressions to depict the relationship between HRV variables and remission status of UC.ResultsAll three HRV variables showed significant differences between the mucosal groups. However, none of them showed significant difference between the histological groups. In further logistic regression analyses, smaller RMSSD can predict severe mucosal healing status (OR = 5.21).ConclusionsLower ultra-short-term HRV (i.e. smaller RMSSD) is shown to positively correlate with worse mucosal healing status. However, ultra-short-term HRV cannot predict histological healing status according to our data.

A Comparative Evaluation of the Measurement Properties of Three Histological Indices of Mucosal Healing in Ulcerative Colitis: Geboes Score, Robarts Histopathology Index and Nancy Index.

To inform their future use in regulated clinical trials to evaluate treatment efficacy hypotheses, the measurement properties of three histological indices, Geboes Score [GS], Robarts Histopathology Index [RHI] and Nancy Index [NI], were evaluated among patients with ulcerative colitis. Analyses were conducted on data from a Phase 3 clinical trial of adalimumab [M14-033, n = 491] and focused on evaluating the measurement properties of the GS, RHI and NI. Specifically, internal consistency and inter-rater reliability, convergent, discriminant and known-group validity, and sensitivity to change were assessed at Baseline, and at Weeks 8 and 52. Internal consistency for the RHI showed lower alpha [α] values at Baseline [α = 0.62] relative to Weeks 8 [α = 0.82] and 52 [α = 0.81]. The inter-rater reliability values of RHI [0.91], NI [0.64] and GS [0.53] were excellent, good and fair, respectively. Regarding validity, Week 52 correlations were moderate to strong between full and partial Mayo scores and Mayo subscale scores and the RHI and GS, and were weak to moderate for the NI. Significant differences between mean scores of all three histological indices were observed across known-groups based on Mayo endoscopy subscores and full Mayo scores at Weeks 8 and 52 [p < 0.001]. The GS, RHI and NI are each capable of producing reliable and valid scores that are sensitive to changes in disease activity over time, in patients with moderately to severely active ulcerative colitis. While all three indices demonstrated relatively acceptable measurement properties, the GS and RHI performed better than the NI.

Diallyl Trisulfide, A Major Bioactive Constituent Of The Garlic, Promotes Colonic Mucosal Healing In Ulcerative Colitis Through Accelerating Focal Adhesion Assembly And Consequent Epithelial Cell Migration Via The Rab21-Integrin Β1-Fak Pathway.

Colonic mucosal healing is the terminal goal for the treatment of ulcerative colitis (UC), but there is currently no specific drug available. This study investigated the beneficial effect of diallyl trisulfide (DATS) on the colonic mucosal healing. Dextran sulfate sodium (DSS) was used to induce colitis in female C57BL/6 mice, and DATS was orally administered during the recovery period. DATS hardly impacted the inflammation of the colonic tissues, but significantly promoted the mucosal repair. DATS promoted the migration but not proliferation of colonic epithelial cells in the colitis mice. In addition, DATS accelerated the wound healing, cell migration, focal adhesion assembly and phosphorylation of focal adhesion kinase (FAK) of colonic epithelial cells in vitro, which were evidently reversed by combined use of FAK inhibitor PF-573228. Similar results were shown in colitis mice. Mechanically, DATS promoted the binding of Rab21 to integrin β1 and accelerated the endocytosis of integrin β1, which was significantly attenuated by the knockdown of Rab21. DATS promotes the binding of Rab21 to integrin β1 and the endocytosis of integrin β1, thereby increases FAK phosphorylation and focal adhesion assembly, finally accelerates the migration of colonic epithelial cells and mucosal healing. This article is protected by copyright. All rights reserved.

P130 Intestinal ultrasound combined to fecal calprotectin is effective to predict endoscopic mucosal healing in ulcerative colitis: a cross-sectional study

Abstract Background In the “treat-to-target” era, the development of non-invasive markers to assess endoscopic healing in ulcerative colitis (UC) is essential. Fecal calprotectin (FC) and intestinal ultrasound (IUS) are alternatives to colonoscopy to assess UC activity. The objective of this study was to evaluate the performance of IUS and FC to assess endoscopic mucosal healing in UC patient. Methods All consecutive patients between January 2021 and August 2022 with UC who underwent (1) a complete colonoscopy (2) an intestinal ultrasound and/or (3) a fecal calprotectin (4) within 4 weeks were included in a prospective cohort. Bowel wall thickness (BWT) and color doppler signal (CDS) were assessed on each segment. Endoscopic mucosal healing was defined by a MAYO score of 0-1. Results A total of 57 patients were included, 57.9% had endoscopic healing (22/57 MAYO 0 and 11/57 MAYO 1). Thirty-two (56.1%) were female, the median age and disease duration were respectively 43 years (IQR, 30-58) and 29 years (IQR, 18-39). Respectively 16 (16/57, 28.1%) and 41 (41/57, 71.9%) patients had BWT &amp;lt; 3 mm and an absence of Doppler signal. The sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of BWT &amp;lt; 3 mm to predict endoscopic mucosal healing were 37%, 77%, 72% and 44%. The association of the absence of CDS with normal BWT did not modify these performances. The same values for fecal calprotectin &amp;lt; 150 µg/g were respectively 81%, 78%, 84% and 74%. The association of a fecal calprotectin &amp;lt; 150 µg/g, with a BWT &amp;lt; 3mm and the absence of Doppler signal increased the specificity and the PPV (Se 33%, Sp 94%, PPV 89%, VPN 48%). The same values were found for patients classified as MAYO 0 or MAYO 0-1 (Table 1). Conclusion The combination of intestinal ultrasound and fecal calprotectin is effective to identify endoscopic mucosal healing in UC.

P304 Leucine-rich alpha 2 glycoprotein reduces the necessity for endoscopic examination for activity evaluation

Abstract Background Leucine-rich alpha 2 glycoprotein (LRG) reflects mucosal healing in ulcerative colitis (UC) and is useful for assessing mucosal healing. In this study, we hypothesized that endoscopy for activity evaluation may be unnecessary depending on LRG levels, and investigated the relationship between LRG and endoscopic findings. Methods Patients who underwent endoscopy for UC from April 2021 to August 2022, when LRG measurement became available, and whose LRG was measured within a month, were included in the study. The relationship between Mayo endoscopic subscore (MES) and LRG was evaluated and symptoms were also reviewed to examine these relationships. Endoscopic remission was defined as MES 1 or less. Results The mean (range) LRG values per MES and the percentage of patients with a cutoff value of less than 16 μg/mL were MES 0 (n=86): 11.3±2.8 (6.0-24.2) μg/mL, 96.5%; MES 1 (n=56): 13.3±6.0 (7.7-43.8) μg/mL, 79.2%; MES 2(n=53): 21.7±11.5(8.1~65.1) μg/mL, 34.0%, MES 3(n=19): 26.4±9.3(12.3~42.9) μg/mL, 25.0%, and AUC 0.856 in ROC analysis, higher than other markers (CRP, Alb, WBC) LRG Even below the cutoff value, 15.0% (22/147) were in endoscopic non-remission. Even when patients have neither diarrhea 3 or more times a day nor bloody stool, 7.4% (9/122) were still in endoscopic non-remission. However, there were no cases in endoscopic non-remission when the LRG was below the cutoff value and there were no such symptoms. In multivariate analysis using binomial logistic regression analysis, LRG (p=0.028) was an independent predictor of endoscopic remission, in addition to diarrhea (p=0.003) and bloody stool (p&amp;lt;0.001). Conclusion LRG was a useful tool for predicting endoscopic activity in ulcerative colitis, but LRG alone could not exclude non-remitting cases. However, LRG was considered to be an independent predictor of endoscopic remission, and all patients who had less than the LRG cutoff value and no diarrhea or bloody stool more than 3 times a day showed endoscopic remission, suggesting that endoscopy for activity evaluation may be unnecessary in such cases.