Selective oxidative protection leads to tissue topological changes orchestrated by macrophage during ulcerative colitis

Background and Aims: Ulcerative colitis(UC) is a chronic inflammatory bowel disorder with highly cellular heterogeneity. Mass cytometry(Cy-TOF) and single-cell RNA sequencing (scRNA-seq) have revealed cellular heterogeneity of UC. However, comprehensive elucidation of tissue topological changes within the UC ecosystem is still missing. And we aimed to illustrate compositional and spatial changes of the UC ecosystem.Methods: Imaging mass cytometry (IMC) and scRNA-seq were applied to depict the single-cell landscape of colon ecosystem.Results: We noticed tissue topological changes featured with macrophage disappearance reaction (MDR) in UC region. MDR only occurred for CD163+ tissue-resident macrophages. We found reactive oxygen species (ROS) level were higher in UC region but ROS scavenging enzyme SOD1/2 were barely detected in resident macrophages, resulting selective oxidative protection for inflammatory macrophages and resident macrophage disappearance reaction. Furthermore, inflammatory macrophages replaced resident macrophages during UC, which played a key role in forming the inflammatory cellular network by producing TNF-α and IL-1β. Conclusions: Our study dissected the microenvironment of UC lesions at single-cell resolution while preserving its architecture, based on which, we discovered the mechanism of MDR in UC region and resident macrophage specific MDR resulted in infiltration of inflammatory macrophage, which formed the cytokine producing network within the local cellular neighborhood.

Comparative Transcriptomic Analysis Reveals the Immunosuppressive Targets of Mesalazine in Dextran Sulfate Sodium-Induced Ulcerative Colitis

Ulcerative colitis (UC) is a complex inflammatory bowel disorder that can induce colonic and rectal dysfunction. Mesalazine, a first-line medicine, is routinely prescribed for UC treatment. However, the pharmacological targets of mesalazine against UC are not detailed in current publications. In the current study, a transcriptomics strategy was applied to reveal the therapeutic targets and molecular mechanisms of mesalazine for treating dextran sulfate sodium (DSS)-induced UC in mice. Compared with the UC group, a total of 1,663 differentially expressed genes were identified in mesalazine-treated mice, of which 262 were upregulated and 1,401 were downregulated. GO and KEGG enrichment analyses indicated that the protective actions of mesalazine for treating UC were related to the functional regulation of immune inflammatory response, such as the regulation of T cells, white blood cells, and cytokine receptor pathways. In addition, ingenuity pathway analysis of the gene network further revealed the inhibitory action of mesalazine on C–C motif chemokine ligands (CCL11 and CCL21) and C–X–C motif chemokine ligands (CXCL3 and CXCR2). Taken together, the current transcriptomic findings revealed anti-UC pharmacological targets, including the newly discovered biotargets CCL11, CCL21, CXCL3, and CXCR2, of mesalazine against DSS-induced intestinal inflammation.

P471 Predictors of bowel damage in long term progression of Crohn’s disease

Background Crohn’s disease is a chronic inflammatory bowel disorder that progresses to bowel damage over time. An image-based index, the Lémann Index, has been developed to measure the cumulative bowel damage. AIMS To characterize the long-term progression of bowel damage in Crohn’s disease based on changes in the Lémann Index and to determine risk factors for long term progression. Methods This was a single-center longitudinal cohort study. Patients who had participated in prospective studies on the accuracy of magnetic resonance imaging using endoscopy as gold standard and had a follow-up of at least 5 years were reevaluated after 5–12 years. Results Seventy-two patients were included. Lémann Index increased in 38 patients (52.8%), remained unchanged in 9 patients (12.5%) and decreased in 25 patients (34.7%). Small bowel score and surgery subscale significantly increased (p=0.002 and p=0.0001), whereas fistulizing subscale significantly decreased (p=0.001). Baseline parameters associated with bowel damage progression were ileum location (p=0.026), phenotype (stricturing, fistulizing or both with p=0.007, p=0.006 and p=0.035), disease duration >10 years (p=0.019) and baseline Lémann Index stricturing score (p=0.049). No correlation was observed between bowel damage progression and baseline clinical activity, biological markers or endoscopic lesions. Need of surgery during follow-up was a major determinant of bowel damage progression (p=0.0001). Baseline stricturing Lémann Index score was associated with the risk of future surgery (p=0.02). Conclusion Bowel damage, assessed by the Lémann Index, progresses in half of the patients with Crohn’s disease over a period of 5–12 years. The main determinants of bowel damage progression are ileum location, stricturing/fistulizing phenotype and disease duration.

IN SILICO MOLECULAR DOCKING STUDY OF CONSTITUENTS FROM APPLE AND PASSION FRUIT FOR THE TREATMENT OF INFLAMMATORY BOWEL DISORDER TARGETING INFLAMMATORY PATHWAY

Inflammatory bowel disorder is a group of inflammatory conditions of the colon and small intestine with greater prevalence among the Indian population. Our focus is to explore and compare the therapeutic potential of phytoconstituents from apple and passion fruit by assessing the affinity with the target sites such as JAK/STAT, MPO and iNOS by molecular docking studies. ADMET prediction and drug-likeness were also conducted to screen out the best-fit ligands, whic are expected to be biologically effective. Few selected constituents displayed considerable binding affinity with the selected targets in our docking study. Interestingly, ligands of phenolic nature displayed the highest inhibitory activity by forming strong hydrogen bonding and van der Waals force with the amino acid residues of the target protein. Comparative study proves that constituents of apple showed better effect than passion fruit. It helps to give the existing information to identify precise targets for the selected drugs. However, the results are preliminary and experimental evaluation needs to be done for obtaining the confirmatory results.

Butyrate Mitigates Weanling Piglets From Lipopolysaccharide-Induced Colitis by Regulating Microbiota and Energy Metabolism of the Gut–Liver Axis

Inflammatory bowel disorder is accompanied by the destruction of immunity homeostasis, gut microbiota perturbation, and chronic inflammatory liver diseases. Butyrate is known as a primary energy source for colonocytes and functional substances for mitigating pathological features of colitis. However, it is still unclear whether butyrate alleviates colitis progression by regulation of microbiota and metabolism in the gut–liver axis. In the present study, we aimed to determine the role of microbiota and metabolism of the gut–liver axis in ameliorating lipopolysaccharide (LPS)-induced colitis in piglets using protected butyrate administration. Eighteen crossbred male piglets were weaned at 30 days old and were randomly allocated to three treatments, with CON (basal diet), LPS (basal diet + LPS), and BT-LPS (basal diet + 3.0 g/kg protected butyrate + LPS). On days 19 and 21, piglets in the LPS and BT-LPS groups were intraperitoneally challenged with LPS at 100 μg/kg body weight. Butyrate administration significantly decreased LPS-induced rise in the clinical score of piglets and colonic histological scores and reduced the susceptibility to LPS-induced severe inflammatory response by decreasing proinflammatory (IL-1β, IL-6, IL-8, and TNF-α) cytokines. Butyrate supplementation accelerated the prevalence of Faecalibacterium and Lactobacillus by enhancing the tricarboxylic acid (TCA) cycle of colonocytes. Dietary supplementation with protected butyrate significantly targeted increased concentrations of butyric acid in the colon and portal venous circulation, and enhanced the TCA cycle in the gut–liver axis by mobilizing amino acid and vitamin B group as a coenzyme. Meanwhile, during this progress, LPS increased fatty acid synthesis that was reversed by butyrate treatment, which was reflected by decreased acylcarnitines. Butyrate-reshaped colonic microbial community and metabolism in the gut–liver axis contributed to morphology integrity and immunity homeostasis by promoting anti-inflammatory (IL-10 and TGF-β) cytokines and suppressing inflammatory mediator hypoxia-inducible factor 1α and its downstream response elements cyclooxygenase 2 and inducible nitric oxide synthase. These results identified the pivotal role of colonic microbiota and metabolism in the gut–liver axis for alleviating inflammatory progression and possible therapeutic targets.

Diet Advice for Crohn’s Disease: FODMAP and Beyond

Crohn’s disease (CD) is a chronic, progressive, and destructive granulomatous inflammatory bowel disorder that can involve any part of the gastrointestinal tract. It has been presumed that different types of diet might improve gastrointestinal symptoms in CD patients. The aim of this review was to clarify the efficiency and indications of a low-“fermentable oligo-, di-, mono-saccharides and polyols” (FODMAP) diet (LFD) in CD and to further analyze the available data on other types of diets. PubMed, Cochrane Library, EMBASE and WILEY databases were screened for relevant publications regarding the effect of FODMAP diets on CD. Our search identified 12 articles analyzing the effect of an LFD in CD, 5 articles analyzing the effect of a Mediterranean diet (MD), 2 articles analyzing the effect of a vegetarian diet (VD), and 2 articles analyzing the effect of a low-lactose diet (LLD). The majority of the studies included in this review show the significant efficiency of the LFD in CD patients. We found significant evidence demonstrating that the LFD has a favorable impact on gastrointestinal symptoms in CD patients. Notwithstanding the evidence, it remains to be established if an LFD is more efficient than other types of diets in the short term and especially in the long term.

Progressive Primary Appendiceal Crohn’s Disease in a 21-Year-old Female

Crohn’s disease is an inflammatory bowel disorder that can affect any portion of the gastrointestinal tract, most commonly the terminal ileum near the ileocecal valve. Crohn’s disease can be characterized by transmural inflammation and deep fissuring ulcers that predispose to fistula formation and “skip” lesions separated by normal segments of bowel. While often affecting the terminal ileum near the ileocecal valve, Crohn’s disease presenting primarily in the appendix is a rare entity. In part due to its low prevalence, cases of appendiceal Crohn’s disease can be confused for acute, non-Crohn’s-related appendicitis on initial presentation. Although there are published cases of primary appendiceal Crohn’s disease in the medical literature, in most cases the diagnosis is made retrospectively following appendectomy for presumed appendicitis. We report on a case of Crohn’s disease that was diagnosed pre-operatively, primarily involved the appendix, and which progressed radiographically despite medical therapy and resolution of clinical symptoms. Unique management issues related to this case include the appropriateness of systemic therapy for disease isolated to the appendix, an inability to endoscopically obtain tissue for a definitive diagnosis, and the decision to proceed with surgery in an asymptomatic patient with progressive disease on imaging. Intraoperatively, the appendix was severely inflamed and densely adherent to the left pelvic side wall and adjacent to the left ovary and fallopian tube. A laparoscopic appendectomy was performed. Pathology demonstrated acute appendicitis as well as marked mural chronic inflammation and epithelioid granulomas, consistent with Crohn’s disease. Surgical resection may be the most appropriate treatment for Crohn’s disease primarily involving the appendix, obviating the need for systemic therapy and minimizing the risk for appendiceal perforation and fistula formation.

Endoscopic surveillance strategies for dysplasia in ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disorder with an increased risk of colorectal cancer (CRC). This has led to the implementation of surveillance programmes to minimise this risk. Overall, these proactive programmes in association with better medical therapies have reduced the incidence of CRC in this population. Specific populations remain at increased risk, such as younger age at diagnosis, primary sclerosing cholangitis, colonic strictures and pseudopolyps. The majority of gastrointestinal international societies favour chromoendoscopy with targeted biopsies or random biopsies. The aim of this review is to present the current literature on dysplasia surveillance, the methodology and endoscopic technology available to assess dysplasia in UC.