Mucosal Healing Research Articles

Naltrexone accelerated oral traumatic ulcer healing and downregulated TLR-4/NF-kB pathway in Wistar rats

ObjectiveTo assess the effect of naltrexone on oral mucosal healing using a traumatic ulcer model DesignWistar rats (n = 112) received distilled water (control) or naltrexone (0.5, 10, or 50 mg/kg/day). Ulcers were induced on the buccal mucosa using a round skin biopsy punch (diameter 6 mm). Euthanasia was performed on days 1, 3, 7, and 14. Healing was assessed by ulcer area, histological scores, histomorphometric analysis (number of polymorphonuclears, mononuclears, and fibroblasts), and collagen percentage. Immunohistochemistry for TLR-2, TLR-4, NF-kB, and CD31 was evaluated. Nociceptive threshold was measured daily. ResultsThe 50 mg/kg group showed reduced ulcer area on days 1 (p < 0.001), 3 (p < 0.05), and 14 (p < 0.01). In this group, there was, on day 14, an increase in the percentage of reepithelization (p = 0.043) and collagen (p < 0.05), an increase in connective tissue maturation (p = 0.016), and on day 7 an increase in fibroblasts (p < 0.001). The 10 mg/kg dose reduced the ulcer area on day 1 (p < 0.001). The 50 mg/kg group showed lower expression of TLR-4 (p < 0.001) on day 1, NF-kB on days 1 (p < 0.05) and 14 (p < 0.05), and CD31 on day 14 (p < 0.05). The 0.5 and 10 mg/kg doses reduced TLR-4 expression on day 1 (p < 0.05; p < 0.01, respectively). Nociceptive threshold increased in the 50 mg/kg group (p < 0.01). ConclusionNaltrexone enhanced traumatic oral ulcer healing by reducing TLR-4/NF-kB signaling and promoting fibroblast proliferation and collagen deposition. Additionally, naltrexone reduced pain in rats.

Real-life effectiveness and safety of vedolizumab in moderate-to-severe ulcerative colitis: A single-center experience in Northern China.

Vedolizumab (VDZ), a monoclonal antibody to α4β7 integrin, is available for patients with moderate-to-severe ulcerative colitis (UC). This study planned to assess the real-world effectiveness and safety of VDZ for UC patients in Northern China. We enrolled patients with moderate-to-severe UC who underwent VDZ induction therapy from March 2021 to November 2022 at the Affiliated Hospital of Qingdao University. The primary outcome was clinical remission at weeks 14 and 52 after the initial VDZ therapy. Overall adverse events and risk factors associated with loss of response (LOR) were also evaluated. Seventy-three UC patients receiving VDZ therapy were included in this study. The rates of clinical response, clinical remission, and steroid-free clinical remission were 69.9%, 39.7%, and 34.2% at week 14 and 90.5%, 66.7%, and 64.4% at week 52, respectively. The mucosal remission rates were 37.5% (18/48) at week 14 ± 8 and 27.3% (9/33) at week 52 ± 16, while only 2 and 3 patients achieved mucosal healing at weeks 14 ± 8 and 52 ± 16, respectively. Of the UC patients, 23.3% experienced adverse events associated with VDZ, most of which were mild and self-limiting. Until the last follow-up, 37 of 73 UC patients experienced LOR during the maintenance period. Patients with a higher ulcerative colitis endoscopic severity index (UCEIS), partial Mayo scores (PMS), or hemoglobin below 120 g/L at baseline were more likely to experience LOR after VDZ induction therapy. VDZ is an effective and safe agent for patients with moderate-to-severe UC in Northern China. A high baseline UCEIS, PMS, or hemoglobin < 120 g/L may be an independent risk factor for LOR during the maintenance period.

Assessment the Role of Non Invasive Biomarkers as an Early Predictors of Mucosal Healing in Ulcerative Colitis Patients Treated with the Biological Therapy

Abstract Background Ulcerative colitis (UC) is characterized by confluent mucosal inflammation and erosions starting from the anal verge and extending to a variable extent, where patients often complain of diarrhea associated with rectal bleeding, abdominal tenderness, and weight loss. Numerous disease biomarkers have been studied in ulcerative colitis (UC) such as Erythrocyte sedimentation rate(ESR) and C- reactive protein(CRP). On the other hand, fecal calprotectin and Lactoferrin are more specific and sensitive but expensive and still not commonly used in clinical practice due to the need for on demand specimen collection. Objective To evaluate the role of the non-invasive biomarkers as an early predictor of mucosal healing in ulcerative colitis patients treated with biological therapy. Methods Twenty adult patients with ulcerative colitis who received biological therapy (after adequate screening) were included in our study. The patients met the indications for treatment with biological therapy according to European Crohn and Colitis Organization guidelines. The patients were presented to our IBD clinic at tropical medicine department, Ain shams university in the period from 1/2018 to 9/2021. Results There is a strong relationship between clinical response and mucosal healing at 6 months of starting biological therapy as 100% of patients who achieved mucosal healing showed clinical response. Median N/L ratio, median PLT/L ratio and CRP/albumin ratio were 1.58, 425 and 1.19 respectively in patients who achieved mucosal healing at 6 months after 3 months of starting biological therapy with statistical significance (p-value = 0.019, 0.019 and 0.008) respectively in comparison to the patients who didn’t achieve mucosal healing. Both median of L/M ratio and PLT/M ratio were decreased in patients achieved mucosal healing at 6 months after 3 months of starting biological therapy (3.43 and 660) respectively in comparison to patients who didn’t achieve mucosal healing but it didn’t reach any statistical significance. Conclusion Non invasive biomarkers at 3 months like N/L ratio, PLT/L ratio, L/M ratio and PLT/M ratio may be used as non invasive predictors of mucosal healing at 6 months after starting treatment with biological treatment.

Mucosal Healing with Vedolizumab in Patients with Chronic Pouchitis: EARNEST, a Randomized, Double-Blind, Placebo-Controlled Trial

BACKGROUND & AIMSVedolizumab is indicated for the treatment of chronic pouchitis in the EU. We assessed whether vedolizumab induced mucosal healing (MH) and if MH was associated with clinical improvements. METHODSEARNEST, a randomized, double-blind, placebo-controlled study, evaluated vedolizumab efficacy and safety in adults with chronic pouchitis. Centrally read endoscopic and histological evaluation was performed at baseline, week (W)14, and W34. Ulcer count, adapted Simple Endoscopic Score for Crohn’s Disease (SES-CD) in the pouch, and Pouchitis Disease Activity Index (PDAI) histological component were evaluated. PDAI and Inflammatory Bowel Disease Questionnaire (IBDQ) remission at W14 and W34 were compared by MH status at W14. RESULTSFollowing treatment, mean (SD) number of ulcers in vedolizumab-treated patients reduced from 15.1 (16.4) to 5.0 (4.9) at W14 and 2.7 (3.2) at W34 vs placebo-treated patients with corresponding values of 11.8 (11.3), 13.4 (18.4), and 9.7 (13.8) (vedolizumab vs placebo difference [95% CI]: W14:−8.4 [−14.3,−2.6]; W34:−7.0 [−12.0,−2.0]). More patients receiving vedolizumab vs placebo achieved reduction in ulcerated pouch surface area (W14: 52.4% vs 20.0%; difference 32.4p.p [9.7, 51.4]; W34: 52.1% vs 12.9%; difference 40.2p.p [15.6, 60.3]), absence of ulceration (W14: 23.8% vs 7.5%; difference 16.3p.p [1.1, 31.6]; W34: 34.4% vs 15.6%; difference 18.8p.p [-2.0, 39.5]), SES-CD remission (W14: 23.8% vs 7.5%; difference 16.3p.p [1.1, 31.6]; W34: 34.4% vs 15.6%; difference 18.8p.p [-2.0, 39.5]) and MH (W14: 16.7% vs 2.5%; difference 14.2p.p [1.9, 26.4]). Patients with MH at W14 had higher rates of PDAI and IBDQ remission at W14 and W34 than those without. CONCLUSIONVedolizumab induced endoscopic improvements in patients with chronic pouchitis, which was associated with improved outcomes at W34, particularly in patients achieving MH at W14. ClinicalTrials.gov number, NCT02790138.

A Comprehensive Review on the Efficacy and Safety of Vonoprazan in the Management of Gastric Acid-Related Diseases.

Gastric acid-related diseases, including gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), and Helicobacter pylori(H. pylori) infection, present significant clinical challenges due to their prevalence and potential for severe complications. Effective management of these conditions is essential for symptom relief, mucosal healing, and prevention of complications. This review aims to evaluate the efficacy and safety of vonoprazan, a novel potassium-competitive acid blocker (P-CAB), in the treatment of gastric acid-related diseases and to compare it with traditional proton pump inhibitors (PPIs). A comprehensive analysis of clinical trials and studies was conducted to assess the effectiveness of vonoprazan in managing GERD, PUD, and H. pylori infection. The safety profile of vonoprazan was also reviewed, and comparisons were made to PPIs and other gastric acid suppressants. Vonoprazan demonstrates superior and more consistent acid suppression thanPPIs, resulting in rapid and sustained symptom relief and mucosal healing. Clinical trials have shown its efficacy in treating GERD, PUD, and H. pylori infection, with higher eradication rates for H. pylori when used in combination therapies. The safety profile of vonoprazan is favorable, with fewer adverse effects and drug interactions compared to PPIs. Vonoprazan offers a promising alternative to traditional PPIs for the management of gastric acid-related diseases. Its unique mechanism of action and superior efficacy make it a valuable option for patients requiring effective and reliable acid suppression. Further research is warranted to explore its potential in broader clinical applications and to establish long-term safety data.

Effectiveness of adalimumab in severe ulcerative colitis: A systematic review and a meta-analysis.

Ulcerative colitis (UC) causes chronic inflammation in the digestive tract, leading to abdominal pain and diarrhea. Adalimumab, a monoclonal antibody, is used to treat moderate to severe cases. This review and meta-analysis evaluated adalimumab's effectiveness for severe UC, considering patient age, disease duration, and gender. This study was designed as a systematic review and a meta-analysis. Articles were searched in PubMed, Scopus, and Web of Science databases based on the keywords of adalimumab and UC. The titles, the abstracts, and, if necessary, the full texts of the articles were read. Then for further review, the full texts of the related articles were carefully examined, and the final articles were selected. Seventy-eight articles were searched based on the keywords, and after reading the articles, 50 articles were related to the topic of the dissertation. The 50 articles were evaluated critically based on a checklist prepared by a statistical consultant and four articles with a score above 70% were selected. In the four articles, the main indicators of the effectiveness of adalimumab, including mucosal healing, clinical remission, and clinical response, were evaluated. The effectiveness of adalimumab on the mucosal healing index was 75.40%, the clinical remission index was 70.79%, and the clinical response index was 83.02%, based on different doses and treatment durations in the study. In the four meta-analysis studies on adalimumab's effectiveness, 1613 UC patients were treated with varying doses over 8 and 52 weeks. Based on a meta-analysis over 8 and 52 weeks for treating moderate to severe UC, adalimumab's effectiveness was 70%-83%. The highest effectiveness, based on three main indices, was with a 40 mg dose over 52 weeks. According to the meta-analysis, the effectiveness of adalimumab for treating moderate to severe UC over 8 and 52 weeks was 70%-83%. The highest effectiveness, based on three main indices, was with a 40 mg dose over 52 weeks.

Evaluación de la sensibilidad y especificidad de la sigmoidoscopia en comparación con la colonoscopia en la detección de actividad inflamatoria intestinal en el seguimiento de pacientes con colitis ulcerosa

IntroductionUlcerative colitis (UC) is a chronic disease characterized by periods of inflammatory activity and remission, which vary from the rectum to the proximal colon. Currently, mucosal healing is a long-term goal in the management of inflammatory bowel disease, with colonoscopy and sigmoidoscopy being the recommended tools for evaluation. ObjectiveTo assess the effectiveness of both examinations in determining the presence of inflammatory activity in the follow-up of patients with UC. MethodsRetrospective observational study analyzing colonoscopies performed as part of the follow-up of UC patients between January 2021 and July 2023 by gastroenterologists from the Inflammatory Bowel Disease Program at the Clínica Universidad de los Andes. The study compared endoscopic and histological activity observed in the rectosigmoid region with that found in the rest of the colon. Sensitivity and specificity were determined using concordance and correlations tests. ResultsA very good concordance and correlation were observed regarding endoscopic findings, with a Kappa index of 0.97 and a Spearman coefficient of 0.97. The Positive Predictive Value (PPV) of sigmoidoscopy for endoscopic activity was 1, and the Negative Predictive Value (NPV) was 0.96. In relation to histological activity, the concordance had a Kappa index of 0.93 and a Spearman coefficient of 0.93, with a PPV of sigmoidoscopy for histological activity being 1 and an NPV of 0.91. ConclusionThis cohort suggests that sigmoidoscopy is a cost-effective option for evaluating mucosal healing in UC patients in symptomatic and biomarker remission. However, complete colonoscopy should be considered in cases of discrepancies with the clinical picture or in colorectal cancer surveillance.

Risk factors for clinical relapse in patients with ulcerative colitis who are in clinical remission but with endoscopic activity.

The treatment strategy for patients with ulcerative colitis (UC) in clinical remission who have not achieved mucosal healing is unclear. This study aimed to determine the risk factors of relapse in patients in clinical remission with endoscopic activity. This retrospective, single-center study included patients with UC who underwent colonoscopy (CS) and were in clinical remission with endoscopic activity. Characteristics were compared between patients who relapsed within 2 years after CS and those who did not. A Cox proportional hazards regression model was used to identify risk factors contributing to clinical relapse. Recent worsening in bowel symptoms was defined as increase in bowel frequency and/or increase in abdominal pain within approximately 1 month based on the descriptions in the medical charts. This study regarded 142 patients in clinical remission with an endoscopic activity of Mayo endoscopic subscore (MES) of ≥1 as eligible, and 33 (23%) patients relapsed during the observation period. Recent worsening of bowel symptoms was a significant risk factor for clinical relapse (hazard ratio [HR]: 3.02, 95% confidence interval [CI]: 1.34-6.84). This was particularly evident in patients with MES of 2 (HR: 5.16, 95% CI: 1.48-18.04), whereas no risk factors were identified in patients with MES of 1. The presence or absence of therapeutic intervention just after CS did not significantly affect clinical relapse. Recent worsening in bowel symptoms was a significant risk factor for clinical relapse in patients with UC who were in clinical remission with endoscopic activity.

Fecal calprotectin and endoscopic scores: The cornerstones in clinical practice for evaluating mucosal healing in inflammatory bowel disease

Managing inflammatory bowel disease (IBD) is becoming increasingly complex and personalized, considering the advent of new advanced therapies with distinct mechanisms of action. Achieving mucosal healing (MH) is a pivotal therapeutic goal in IBD management and can prevent IBD progression and reduce flares, hospitalization, surgery, intestinal damage, and colorectal cancer. Employing proactive disease and therapy assessment is essential to achieve better control of intestinal inflammation, even if subclinical, to alter the natural course of IBD. Periodic monitoring of fecal calprotectin (FC) levels and interval endoscopic evaluations are cornerstones for evaluating response/remission to advanced therapies targeting IBD, assessing MH, and detecting subclinical recurrence. Here, we comment on the article by Ishida et al Moreover, this editorial aimed to review the role of FC and endoscopic scores in predicting MH in patients with IBD. Furthermore, we intend to present some evidence on the role of these markers in future targets, such as histological and transmural healing. Additional prospective multicenter studies with a stricter MH criterion, standardized endoscopic and histopathological analyses, and virtual chromoscopy, potentially including artificial intelligence and other biomarkers, are desired.

Intestinal mRNA expression profiles associated with mucosal healing in ustekinumab-treated Crohn's disease patients: bioinformatics analysis and prospective cohort validation

BackgroundVariations exist in the response of patients with Crohn’s disease (CD) to ustekinumab (UST) treatment, but the underlying cause remains unknown. Our objective was to investigate the involvement of immune cells and identify potential biomarkers that could predict the response to interleukin (IL) 12/23 inhibitors in patients with CD.MethodsThe GSE207022 dataset, which consisted of 54 non-responders and 9 responders to UST in a CD cohort, was analyzed. Differentially expressed genes (DEGs) were identified and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Least absolute shrinkage and selection operator (LASSO) regression was used to screen the most powerful hub genes. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performances of these genes. Single-sample Gene Set Enrichment Analysis (ssGSEA) was used to estimate the proportions of immune cell types. These significantly altered genes were subjected to cluster analysis into immune cell-related infiltration. To validate the reliability of the candidates, patients prescribed UST as a first-line biologic in a prospective cohort were included as an independent validation dataset.ResultsA total of 99 DEGs were identified in the integrated dataset. GO and KEGG analyses revealed significant enrichment of immune response pathways in patients with CD. Thirteen genes (SOCS3, CD55, KDM5D, IGFBP5, LCN2, SLC15A1, XPNPEP2, HLA-DQA2, HMGCS2, DDX3Y, ITGB2, CDKN2B and HLA-DQA1), which were primarily associated with the response versus nonresponse patients, were identified and included in the LASSO analysis. These genes accurately predicted treatment response, with an area under the curve (AUC) of 0.938. T helper cell type 1 (Th1) cell polarization was comparatively strong in nonresponse individuals. Positive connections were observed between Th1 cells and the LCN2 and KDM5D genes. Furthermore, we employed an independent validation dataset and early experimental verification to validate the LCN2 and KDM5D genes as effective predictive markers.ConclusionsTh1 cell polarization is an important cause of nonresponse to UST therapy in patients with CD. LCN2 and KDM5D can be used as predictive markers to effectively identify nonresponse patients.Trial registration: Trial registration number: NCT05542459; Date of registration: 2022-09-14; URL: https://www.clinicaltrials.gov.

The Protective Role of IL-17 and IL-22 in COVID-19 Infection.

The development of a cytokine storm in Coronavirus Disease 2019 (COVID-19) infection can make the disease fatal. We hypothesize that this excessive cytokine production impairs mucosal healing. IL-17 and IL-22 are cytokines that play a key role in protecting and regenerating mucosal tissues.IL-17 and IL-22 support each other and the imbalance between them plays a role in the pathogenesis of many rheumatologic diseases. To investigate whether COVID-19 severity is related to IL17, IL-22, and the IL-17/IL-22 ratio. The study was planned prospectively and included 69 patients with active COVID-19 infection.Three groups were created: patients with upper respiratory tract infection, pneumonia, and cytokine storm. Blood samples were taken from the patients upon their first admission and serum levels of IL-17 and IL-22 were measured using the enzyme-linked immunosorbent assay (ELISA). We assessed the relationship between IL17, IL22, IL17/IL22 ratio, clinical and lung involvement by comparing them with the healthy group. The levels of IL-17 were significantly higher in COVID-19 patients with upper respiratory tract infection compared to the control group (p=0.027). IL17/IL-22 ratio significantly increased in patients with cytokine storm compared to the healthy controls (p=0.027). Serum levels of IL-22 were negatively correlated with the CO-RADS score (r=-0.31, p=0.004), while IL-17/IL-22 ratio was positively correlated with the CO-RADS score (r= 0.29, p=0.008). Levels of IL-17, IL-22 and IL-17/IL-22 may provide valuable insights into the progression of COVID-19.

Gastroduodenal injury and repair mechanisms.

Although the mucosal barrier serves as a primary interface between the environment and host, little is known about the repair of acute, superficial lesions or deeper, persistent lesions that if not healed, can be the site of increased permeability to luminal antigens, inflammation, and/or neoplasia development. Studies on acute superficial lesions have been sparse in the past year, with more focus given to novel mechanisms of mucosal protection, and the way in which mature epithelial cells or committed stem cells dedifferentiate, reprogram, proliferate, and then regenerate the gastroduodenal mucosa after injury. For this, adenoviral therapy showed organ specific targeting with mRNA and protein expression of effectors to protect against mucosal injury and ulceration. A large database of plant-based agents known to protect against injury and ulceration was published, along with studies using plant-based compounds delivered with alginates, polysaccharide/gel floating rafts, or incorporated into nanoparticles or green carbon dots to improve targeting and retention at the ulcerated lesion. With RNA technology developing rapidly, particularly single-cell RNA sequencing, important and novel data was forthcoming on mucosal regeneration. In particular, the role of interleukin-17 hub proteins in mucosal healing was highlighted. The presence and role of injury reserve cells was determined, as was the composition of ligand gradients for cell differentiation in both stomach and duodenum. The role of amphiregulin in parietal cell differentiation from lineage-restricted stem cells and the Yap1 gene signature in metaplasia vs. healing ulcers were of particular importance. Additionally, studies unveiled the important role of mesenchymal stromal cells in differentiation and repair mechanisms, in Muse cells as an exciting new therapy for mucosal repair after injury, and the role of sympathetic neurons in activating the immune system to regulate mucosal repair mechanisms. Recent studies highlight novel mechanisms that promote mucosal regeneration after injury of the gastroduodenal mucosa.

Vonoprazan: a promising advancement in proton pump inhibitor therapy

Vonoprazan, a potent potassium-competitive acid blocker (P-CAB), has emerged as a potential therapeutic option for acid-related disorders, particularly gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD). This comprehensive review aims to provide an overview of the efficacy, safety profile, and clinical implications of vonoprazan based on current literature. Efficacy studies have demonstrated vonoprazan's superiority over proton pump inhibitors (PPIs) in achieving effective acid suppression, rapid symptom relief, and promoting mucosal healing in patients with GERD and PUD. Moreover, its long-lasting acid suppression properties offer protection against Helicobacter pylori (H. pylori) infection, presenting it as a potential alternative to traditional triple H. pylori eradication regimens. Safety evaluations reveal a favourable tolerability profile with minimal adverse effects and a lower risk of drug interactions compared to PPIs. However, concerns regarding long-term safety, such as hypomagnesemia and the potential for rebound acid hypersecretion, necessitate further investigation. Additionally, the role of vonoprazan in special populations, such as the elderly and those with renal impairment, warrants exploration. Overall, vonoprazan represents a promising advancement in acid suppression therapy, offering efficacy, safety, and potential advantages over traditional agents.

Risks of Cancer Associated with Therapeutic Drugs for Inflammatory Bowel Disease

Crohn's disease and ulcerative colitis are lifelong chronic inflammatory conditions, with many patients requiring ongoing immunomodulatory drug therapy for maintenance treatment. Recent therapeutic goals in inflammatory bowel disease (IBD) are not only aimed at symptomatic remission but also at achieving mucosal healing to improve the natural course of the disease. In this context, therapeutic approaches are being applied in clinical settings that involve early and appropriate use of drugs, such as immunomodulators or biologics, that have the potential to induce healing of the inflamed intestine before irreversible intestinal damage occurs. All drugs that continuously control intestinal inflammation in IBD can heal the mucosa and potentially reduce the incidence of colitis-associated bowel cancer; however, the continuous use of immunosuppressants can potentially increase the risk of malignancies. The safety issues of the drugs used in clinical practice are partly confirmed during their development processes or shortly after initial marketing, but in other cases, they are estimated through post-marketing case reports or epidemiological studies, sometimes decades after drug approval. This review explores the risks associated with malignancies related to the treatment of IBD, focusing on drugs currently approved in Republic of Korea.

Deciphering Microbial Composition in Patients with Inflammatory Bowel Disease: Implications for Therapeutic Response to Biologic Agents.

Growing evidence suggests that alterations in the gut microbiome impact the development of inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC). Although IBD often requires the use of immunosuppressant drugs and biologic therapies to facilitate clinical remission and mucosal healing, some patients do not benefit from these drugs, and the reasons for this remain poorly understood. Despite advancements, there is still a need to develop biomarkers to help predict prognosis and guide treatment decisions. The aim of this study was to investigate the gut microbiome of IBD patients using biologics to identify microbial signatures associated with responses, following standard accepted criteria. Microbiomes in 66 stool samples from 39 IBD patients, comprising 20 CD and 19 UC patients starting biologic therapies, and 29 samples from healthy controls (HCs) were prospectively analyzed via NGS and an ensemble of metagenomics analysis tools. At baseline, differences were observed in alpha and beta metrics among patients with CD, UC and HC, as well as between the CD and UC groups. The degree of dysbiosis was more pronounced in CD patients, and those with dysbiosis exhibited a limited response to biological drugs. Pairwise differential abundance analyses revealed an increasing trend in the abundance of an unannotated genus from the Clostridiales order, Gemmiger genus and an unannotated genus from the Rikenellaceae family, which were consistently identified in greater abundance in HC. The Clostridium genus was more abundant in CD patients. At baseline, a greater abundance of the Odoribacter and Ruminococcus genera was found in IBD patients who responded to biologics at 14 weeks, whereas a genus identified as SMB53 was more enriched at 52 weeks. The Collinsella genus showed a higher prevalence among non-responder IBD patients. Additionally, a greater abundance of an unclassified genus from the Barnesiellaceae family and one from Lachnospiraceae was observed in IBD patients responding to Vedolizumab at 14 weeks. Our analyses showed global microbial diversity, mainly in CD. This indicated the absence or depletion of key taxa responsible for producing short-chain fatty acids (SCFAs). We also identified an abundance of pathobiont microbes in IBD patients at baseline, particularly in non-responders to biologic therapies. Furthermore, specific bacteria-producing SCFAs were abundant in patients responding to biologics and in those responding to Vedolizumab.

G Protein-Coupled Estrogen Receptor-Mediated Anti-Inflammatory and Mucosal Healing Activity of a Trimethylpyridinol Analogue in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is characterized by abnormal immune responses, including elevated proinflammatory cytokines, such as tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) in the gastrointestinal (GI) tract. This study presents the synthesis and anti-inflammatory evaluation of 2,4,5-trimethylpyridin-3-ol analogues, which exhibit dual inhibition of TNFα- and IL-6-induced inflammation. Analysis using in silico methods, including 3D shape-based target identification, modeling, and docking, identified G protein-coupled estrogen receptor 1 (GPER) as the molecular target for the most effective analogue, 6-26, which exhibits remarkable efficacy in ameliorating inflammation and restoring colonic mucosal integrity. This was further validated by surface plasmon resonance (SPR) assay results, which showed direct binding to GPER, and by the results showing that GPER knockdown abolished the inhibitory effects of 6-26 on TNFα and IL-6 actions. Notably, 6-26 displayed no cytotoxicity, unlike G1 and G15, a well-known GPER agonist and an antagonist, respectively, which induced necroptosis independently of GPER. These findings suggest that the GPER-selective compound 6-26 holds promise as a therapeutic candidate for IBD.

Baseline Assessment of Serum Cytokines Predicts Clinical and Endoscopic Response to Ustekinumab in Patients With Crohn's Disease: A Prospective Pilot Study.

No biomarkers are currently available to predict therapeutic response to ustekinumab (UST) in Crohn's disease (CD). The aim of this prospective study was to identify 1 or more cytokines able to predict mucosal healing in patients with CD treated with UST. We prospectively enrolled consecutive CD patients treated with UST. At weeks 0 (baseline), 24, and 48, a panel of serum cytokines was measured by a fluorescence assay. At the same time points, fecal calprotectin (FC) was assessed. A colonoscopy was performed at baseline and at week 48, where therapeutic outcome was evaluated in terms of mucosal healing. Out of 44 patients enrolled, 22 (50%) achieved mucosal healing at the end of follow-up. Response was associated with higher interleukin (IL)-23 levels (P < .01). Fecal calprotectin levels decreased over time in responders but did not change in nonresponders (test for the interaction between time and mucosal healing, P < .001). This pilot study showed that IL-23 and FC could be reliable biomarkers in predicting therapeutic outcome to UST therapy in CD. In particular, the correlation between baseline serum levels of IL-23 and mucosal healing at 48 weeks is particularly strong, paving the way for its use to drive therapeutic decisions.

Rapamycin promotes the intestinal barrier repair in ulcerative colitis via the mTOR/PBLD/AMOT signaling pathway

Intestinal barrier dysfunction characterized by the functional loss of the intestinal epithelium's tight junction (TJ) barrier is a key factor in the pathogenesis of ulcerative colitis (UC). Although rapamycin, an mTOR (mechanistic target of rapamycin) inhibitor, has shown promise in inducing clinical remission and mucosal healing in inflammatory bowel disease, its underlying mechanism remains elusive. Thus, this study investigated the role of the mTOR pathway in regulating the intestinal barrier. To investigate the molecular mechanism regulating the intestinal barrier, specific intestinal epithelial phenazine biosynthesis-like domain-containing protein (PBLD)-deficient (PBLDIEC−/−) mice and control wild-type (WT) mice were intraperitoneally injected with rapamycin or MHY1485. To determine the relevance of the findings for UC, we analyzed transcriptome data and single-cell expression profiles from public databases and intestinal mucosal tissues obtained from patients with active UC or colon cancer. We observed that mTOR activation in the intestinal epithelium of patients with active UC. Moreover, in vivo, rapamycin markedly increased the expressions of PBLD and TJ proteins and reduced intestinal inflammation in mice with dextran sulfate sodium-induced enteritis. However, the therapeutic efficacy of rapamycin was notably reduced in PBLDIEC−/− mice. In vitro, rapamycin influenced PBLD expression by modulating the nuclear transcription of transcription factor EB (TFEB). Angiomotin (AMOT) could directly bind to PBLD, and rapamycin could not effectively increase the expression of TJ proteins after the knockdown of PBLD or AMOT. In summary, the administration of rapamycin is a potential treatment for UC, and targeting the mTOR/PBLD/AMOT axis is a potential novel approach for UC treatment.

Latest Intestinal Ultrasound Advancements In Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) treatment has evolved from monitoring clinical symptoms to targeting objective measurements of mucosal healing with endoscopic and radiologic imaging. It is well known that clinical symptoms do not match disease severity. Frequent evaluation with radiologic imaging is now the standard of care. Although Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) recommendations do not list radiographic targets as an endpoint due to the “limited ability of the currently available treatments to achieve transmural healing,” this will likely evolve over time particularly with the rapidly growing uptake of intestinal ultrasound (IUS) in clinical trials. For the time being, imaging is considered as an “adjuvant assessment rather than a formal treatment target.”

The reparative immunologic consequences of stem cell transplantation as a cellular therapy for refractory Crohn's disease.

Treatment strategies for Crohn's disease (CD) suppress diverse inflammatory pathways but many patients remain refractory to treatment. Autologous hematopoietic stem cell transplantation (SCT) has emerged as a therapy for medically refractory CD. SCT was developed to rescue cancer patients from myelosuppressive chemotherapy but its use for CD and other immune diseases necessitates reimagining SCT as a cellular therapy that restores appropriately responsive immune cell populations from hematopoietic progenitors in the stem cell autograft (i.e. immune "reset"). Here we present a paradigm to understand SCT as a cellular therapy for immune diseases and reveal how SCT re-establishes cellular immunity utilizing high-dimensional cellular phenotyping and functional studies of the stem cell grafts. Immunophenotyping using CyTOF, single cell RNA sequencing (scRNA-seq) and T cell receptor (TCR) sequencing was performed on peripheral blood and intestinal tissue samples from refractory CD patients who underwent SCT. The stem cell graft from these patients was analyzed using flow cytometry and functionally interrogated using a murine model for engraftment. Our study revealed a remodeling of intestinal macrophages capable of supporting mucosal healing that was independently validated using multimodal studies of immune reconstitution events including CyTOF and scRNA-seq. Functional interrogation of hematopoietic stem cells (HSCs) using a xenograft model demonstrated that HSCs shape the timing of immune reconstitution, the selected reconstitution of specific cell lineages and potentially the clinical efficacy of SCT. These studies indicate that SCT serves as a myeloid-directed cellular therapy re-establishing homeostatic intestinal macrophages that support intestinal healing and suggest refractory CD evolves from impairment of restorative functions in myeloid cells. Furthermore, we report heterogeneity among HSCs from CD patients which may drive SCT outcomes and suggests an unrecognized impact of CD pathophysiology on HSC in the marrow niche.