Chronic IBD Research Articles

Multiplex spatial omics reveals changes in immune-epithelial crosstalk during inflammation and dysplasia development in chronic IBD patients

Patients with long-standing inflammatory bowel disease (IBD) face an increased risk of developing colitis-associated cancer (CAC). Although IBD-induced prolonged inflammation seems to be involved in CAC pathogenesis, the specific molecular changes that contribute remain unknown. Here, we applied digital spatial RNA profiling, RNAscope, and imaging mass cytometry to examine paired uninflamed, inflamed, and early dysplastic mucosa of patients with IBD. We observed robust type 3 (IL-17) responses during inflammation, accompanied by elevated JAK-STAT signaling and phosphorylated STAT3 (P-STAT3) levels, with both inflamed and dysplastic mucosa displaying immune cell activation. Higher stromal P-STAT3 was detected in uninflamed and inflamed mucosa of patients who eventually developed dysplasia. CD8a+ Tcells did not infiltrate inflamed or dysplastic epithelial regions in these patients, while control patients showed elevated CD8a in inflamed mucosa. Our study reveals distinct inflammatory patterns throughout CAC development, marked by an activated IL-17 pathway, engaged STAT3, and diminished cytotoxic Tcell infiltration.

Distal cap–assisted EMR allows the safe and effective resection of adherent dysplastic lesions in the setting of inflammatory bowel disease: a multicenter retrospective study (with video)

Endoscopic mucosal resection (EMR) is established as the primary approach for large/complex dysplastic lesions. However, submucosal fibrosis caused by previous attempts at removal, biopsy, inflammation, or tattoo can cause a benign "negative lift sign" and create difficulty for EMR. Here, we present the use of distal-cap assisted EMR (EMR-DC) specifically for the use of resecting dysplastic colon lesions when submucosal fibrosis is present in IBD patients. 16 IBD patients were retrospectively evaluated from two high volume centers. The patient demographics, lesion pathology and classification, outcomes including time and success of resection, SAEs within 30 days of the procedure, and efficacy were measured. 75% of patients treated with EMR-DC achieved complete resection with 0 serious adverse events within 30 days of the procedure. EMR-DC represents an attractive option for the resection of adherent dysplastic lesions in chronic IBD which is effective, safe, and inexpensive.

Dopamine β-hydroxylase shapes intestinal inflammation through modulating T cell activation

BackgroundInflammatory bowel disease (IBD) is a chronic and relapsing disease characterized by immune-mediated dysfunction of intestinal homeostasis. Alteration of the enteric nervous system and the subsequent neuro-immune interaction are thought to contribute to the initiation and progression of IBD. However, the role of dopamine beta-hydroxylase (DBH), an enzyme converting dopamine into norepinephrine, in modulating intestinal inflammation is not well defined. MethodsCD4+CD45RBhighT cell adoptive transfer, and 2,4-dinitrobenzene sulfonic acid (DNBS) or dextran sodium sulfate (DSS)-induced colitis were collectively conducted to uncover the effects of DBH inhibition by nepicastat, a DBH inhibitor, in mucosal ulceration, disease severity, and T cell function. ResultsInhibition of DBH by nepicastat triggered therapeutic effects on T cell adoptive transfer induced chronic mouse colitis model, which was consistent with the gene expression of DBH in multiple cell populations including T cells. Furthermore, DBH inhibition dramatically ameliorated the disease activity and colon shortening in chemically induced acute and chronic IBD models, as evidenced by morphological and histological examinations. The reshaped systemic inflammatory status was largely associated with decreased pro-inflammatory mediators, such as TNF-α, IL-6 and IFN-γ in plasma and re-balanced Th1, Th17 and Tregs in mesenteric lymph nodes (MLNs) upon colitis progression. Additionally, the conversion from dopamine (DA) to norepinephrine (NE) was inhibited resulting in increase in DA level and decrease in NE level and DA/NE showed immune-modulatory effects on the activation of immune cells. ConclusionModulation of neurotransmitter levels via inhibition of DBH exerted protective effects on progression of murine colitis by modulating the neuro-immune axis. These findings suggested a promising new therapeutic strategy for attenuating intestinal inflammation.

IL-22 regulates MASTL expression in intestinal epithelial cells.

Microtubule-associated serine-threonine kinase-like (MASTL) has recently been identified as an oncogenic kinase given its overexpression in numerous cancers. Our group has shown that MASTL expression is upregulated in mouse models of sporadic colorectal cancer and colitis-associated cancer (CAC). CAC is one of the most severe complications of chronic inflammatory bowel disease (IBD), but a limited understanding of the mechanisms governing the switch from normal healing to neoplasia in IBD underscores the need for increased research in this area. However, MASTL levels in patients with IBD and its molecular regulation in IBD and CAC have not been studied. This study reveals that MASTL is upregulated by the cytokine interleukin (IL)-22, which promotes proliferation and has important functions in colitis recovery; however, IL-22 can also promote tumorigenesis when chronically elevated. Upon reviewing the publicly available data, we found significantly elevated MASTL and IL-22 levels in the biopsies from patients with late-stage ulcerative colitis compared with controls, and that MASTL upregulation was associated with high IL-22 expression. Our subsequent in vitro studies found that IL-22 increases MASTL expression in intestinal epithelial cell lines, which facilitates IL-22-mediated cell proliferation and downstream survival signaling. Inhibition of AKT activation abrogated IL-22-induced MASTL upregulation. We further found an increased association of carbonic anhydrase IX (CAIX) with MASTL in IL-22-treated cells, which stabilized MASTL expression. Inhibition of CAIX prevented IL-22-induced MASTL expression and cell survival. Overall, we show that IL-22/AKT signaling increases MASTL expression to promote cell survival and proliferation. Furthermore, CAIX associates with and stabilizes MASTL in response to IL-22 stimulation.NEW & NOTEWORTHY MASTL is upregulated in colorectal cancer; however, its role in colitis and colitis-associated cancer is poorly understood. This study is the first to draw a link between MASTL and IL-22, a proinflammatory/intestinal epithelial recovery-promoting cytokine that is also implicated in colon tumorigenesis. We propose that IL-22 increases MASTL protein stability by promoting its association with CAIX potentially via AKT signaling to promote cell survival and proliferation.

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

ObjectiveIntestinal 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...

N45 Nurse intervention in patients with Inflammatory bowel disease: impact in their quality of life

Abstract Background Physical inactivity is considered as a modifiable risk factor in chronic diseases1 and IBD. Regular physical activity could help patients with IBD by reducing some IBD complications, such as improving immune response, increasing muscle mass and strength, and improving bone density. The aim of this study is to determine the impact of a Nurse intervention, on Physical Activity, in quality of life of IBD patients. Methods Quasi-experimental study before and after. 20 patients, both sex, with IBD from Hospital Universitario del Henares, 18-65 years old, in clinical remission or mild activity; IBD ≥ 6 months. Exclusion: physical impairment for daily activities (cardiac, orthopedic or cognitive impairment); pregnancy; surgery < 3 months. Nurse intervention on physical exercise: 4 group sessions of 60 minutes, 10 months follow-up. Training on strength and endurance exercises by a physiotherapist adapted to each patient’s special needs. Data were collected in Inflammatory Bowel Disease Questionnaire 32 (IBDQ-32), Rapid Assessment of Physical Activity (RAPA), Hospital Anxiety and Depression Scale (HADS). Variables: quality of life, physical activity, IBD activity, socio-demographic, health status and lifestyle. A descriptive analysis was carried out with qualitative and quantitative variables. Four dimensions of quality of life index and impact of exercise on quality of life were calculated, before and after intervention with Students-T. Results Quasi-experimental study before and after. 20 patients, both sex, with IBD from Hospital Universitario del Henares, 18-65 years old, in clinical remission or mild activity; IBD ≥ 6 months. Exclusion: physical impairment for daily activities (cardiac, orthopedic or cognitive impairment); pregnancy; surgery < 3 months. Nurse intervention on physical exercise: 4 group sessions of 60 minutes, 10 months follow-up. Training on strength and endurance exercises by a physiotherapist adapted to each patient’s special needs. Data were collected in Inflammatory Bowel Disease Questionnaire 32 (IBDQ-32), Rapid Assessment of Physical Activity (RAPA), Hospital Anxiety and Depression Scale (HADS). Variables: quality of life, physical activity, IBD activity, socio-demographic, health status and lifestyle. A descriptive analysis was carried out with qualitative and quantitative variables. Four dimensions of quality of life index and impact of exercise on quality of life were calculated, before and after intervention with Students-T. Conclusion There are non-significative differences in quality of life before and after intervention. Patients increased their physical activity after intervention. Regular physical activity is a useful tool for improving quality of life in patients with IBD.

LMT503, A NOVEL THERAPY FOR INFLAMMATORY BOWEL DISEASE THROUGH MACROPHAGE POLARIZATIONS BY METABOLIC REPROGRAMMING OF ACTIVATED MACROPHAGE

Abstract Macrophages are the first line of defense against self-stimuli and non-self-pathogens and adopt diverse activation states by reprogramming their cell metabolism and thereby polarizing their phenotypes in order to drive their pro-inflammatory or pro-resolving responses. As the key gatekeeper of intestinal immune homeostasis, macrophage polarization has an important effect on maintaining tissue homeostasis with inducing resolution, and therefore macrophages phenotype alteration by modulating their cellular metabolism might be a novel therapeutic approach in IBD. LMT503 is an orally available organic small molecule and exerted the macrophage polarization from M1-like inflammatory macrophage to M2-like anti-inflammatory macrophages in LPS-induced bone marrow-derived macrophage in vitro experiment. The expression level of M1-related intracellular functional marker iNOS was suppressed by LMT503, while Arg-1 which is M2-associated marker was increased. LMT503 also performed metabolic reprogramming with decreasing anabolic metabolism but enhancing catabolic metabolism including mitochondrial metabolism. In the therapeutic settings using various IBD in vivo models such as DSS-induced acute/chronic mice models and adoptive T cell transfer mice model, LMT503 exerted macrophage polarization with showing reduced expression level of M1 markers such as iNOS, CD80, and CD86 but increased expression of M2 markers like Arg-1, CD168, and CD206. LMT503 mitigated inflammation with decreased production of inflammatory cytokines (TNF-a, IL-6, IL-1b, IL-18), increased anti-inflammatory cytokines (IL-10, IL-22), and reduced neutrophil infiltrations. In the addition to increased ratio of M2/M1 macrophages, LMT503 increased ratio of Treg/Th17. LMT503 also induced epithelial restitution with increased number of goblet cells, and showed decreased bacterial translocation from gut to mesenteric lymph node. In a chronic IBD mice model, LMT503 showed reduced intestinal fibrotic marker a-SMA which is one of critical complications for patients with long-term IBD. Mode of action through macrophage polarization was proved by using a macrophage-depleted IBD in vivo model, and LMT503 did not improve the disease associate index or inflammation. Also LMT503 showed re-storing immunity in an in vivo study of challenging pathogen to LMT503-treated and washed-out model, which avoids the possibility of an opportunistic infections. In summary, LMT503 was very efficacious in various IBD in vivo models with showing the resolution of intestinal inflammation and mucosal healing through improved epithelial restitution via macrophage polarizations, and this approach can be a very effective and safe therapy for multifaceted IBD. The first in human study with LMT503 will be initiating in 4Q 2022.

Network pharmacology and molecular docking reveal zedoary turmeric-trisomes in Inflammatory bowel disease with intestinal fibrosis.

BACKGROUNDInflammatory bowel disease (IBD) is a complex chronic IBD that is closely associated with risk factors such as environment, diet, medications and lifestyle that may influence the host microbiome or immune response to antigens. At present, with the increasing incidence of IBD worldwide, it is of great significance to further study the pathogenesis of IBD and seek new therapeutic targets. Traditional Chinese medicine (TCM) treatment of diseases is characterized by multiple approaches and multiple targets and has a long history of clinical application in China. The mechanism underlying the effect of zedoary turmeric-trisomes on inducing mucosal healing in IBD is not clear.AIMTo explore the effective components and potential mechanism of zedoary turmeric-trisomes in the treatment of IBD with intestinal fibrosis using network pharmacology and molecular docking techniques.METHODSThe chemical constituents and targets of Rhizoma zedoary and Rhizoma sanarum were screened using the TCMSP database. The GeneCards database was searched to identify targets associated with intestinal fibrosis in IBD. The intersection of chemical component targets and disease targets was obtained using the Venny 2.1 online analysis platform, and the common targets were imported into the STRING 11.0 database to construct a protein interaction regulatory network. A “zedoary turmeric-trisomes-chemical composition-target-disease” network diagram was subsequently constructed using Cytoscape 3.7.2 software, and the topological properties of the network were analyzed using the “Network Analysis” plug-in. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the common targets were performed using the DAVID 6.8 database to elucidate the mechanism of zedoary turmeric-trisomes in the treatment of IBD. Subsequently, molecular docking of the compounds and targets with the highest intermediate values in the “zedoary turmeric-trisomes-chemical composition-target-disease” network was performed using Sybyl-x 2.1.1 software.RESULTSA total of 5 chemical components with 60 targets were identified, as well as 3153 targets related to IBD and 44 common targets. The protein-protein interaction network showed that the core therapeutic targets included JUN, MAPK14, CASP3, AR, and PTGS2. The GO enrichment analysis identified 759 items, and the KEGG enrichment analysis yielded 52 items, including the cancer pathway, neuroactive ligand-receptor interaction, hepatitis B, and the calcium signaling pathway, reflecting the complex biological processes of the multicomponent, multitarget and multipathway treatment of diseases with zedoary turmeric-trisomes. Molecular docking showed that the compound bonded with the target through hydrogen bond interactions and exhibited good docking activity.CONCLUSIONThis study identified the potential mechanism of action of zedoary turmeric-trisomes in the treatment of inflammatory bowel fibrosis using network pharmacology and molecular docking technology, providing a scientific basis for further expansion of their clinical use.

Care of Women with Chronic Inflammatory Bowel Disease (Chronic IBD) During Pregnancy

The incidence of chronic inflammatory bowel disease (chronic IBD) in persons of reproductive age is high. Chronic IBD does not typically lead to impaired fertility. Nevertheless, the percentage of women suffering from chronic IBD who have children is lower than that of the general population, due to self-imposed childlessness. Providing women with open, unbiased information and, if necessary, helping them to overcome baseless fears should therefore be an essential part of preconception counseling. With the exception of methotrexate, most standard drugs can and should be continued during pregnancy. If the pregnancy occurs during an inactive phase of disease, the rate of complications in pregnancy should, in principle, not be higher than normal. Nevertheless, pregnant women with chronic IBD are classed as high-risk pregnancies. Organ screening in accordance with DEGUM II criteria should be carried out in every case, and women must be monitored for the potential development of placental insufficiency. Any flare-ups which occur during pregnancy should be treated in full. Vaginal delivery can be considered if there is no perianal manifestation of disease; however, the individual risk must be carefully weighed up.

P029 Activation of FXR restores expression of genes dysregulated in human IBD and suppresses TNFa and IL-6 signaling pathways in adoptive transfer colitis model

Abstract Background Farnesoid X receptor (FXR) is a ligand-activated nuclear hormone receptor highly expressed in the gastrointestinal tract. We have shown that FXR agonists improve disease in multiple chronic IBD models (Adoptive transfer (AT) colitis, Mdr1a-/- colitis, and SAMP1/YitFc ileitis) with efficacy similar to anti-IL-12/23. To explore the mechanisms by which FXR agonists reduce colitis in these models and the relevance to human IBD, we identified the genes and pathways regulated by FXR in the AT colitis mice, and compared them with the gene expression profile in human IBD patients. Methods Colitis was induced by transplanting CD4+CD45RBhi T-cells to C.B-17 SCID mice. Mice were treated with vehicle (n=10), an FXR agonist (p.o. daily, n=10) or anti-IL-12p40 (i.p., weekly, n=5) in therapeutic mode (started 21 days post AT) for 4 weeks. Efficacy was assessed by colon histopathology of inflammation, erosion, gland loss and hyperplasia (0–5 each). RNAseq was performed on colon RNAs (n=5–7 samples/group). Genes differentially regulated by the FXR agonist were compared with published FXR ChIPSeq data (Thomas et al 2010 Hepatology) and a IBD patients’ gene expression dataset (GSE73661) to identify FXR target genes associated with human IBD. Gene set enrichment analysis (GSEA) was performed to identify enriched pathways. Results Direct FXR target genes were identified by comparing genes upregulated by the FXR agonist in the AT mice with FXR ChIPSeq data. Further comparison with GSE73661 identified FXR target genes relevant to human IBD. The majority of these genes are down-regulated in diseased mice and IBD patients compared to healthy controls. Importantly, in GSE73661 dataset, those genes were upregulated in patients that responded to therapy, while remained down-regulated in refractory patients. The function of those genes includes reducing inflammation, improving gut healing and transporter activities. Further pathway analysis by GSEA identified a number of inflammatory pathways significantly upregulated in AT mice and IBD patients, many of which show reduction with the FXR agonist treatment. Of note, TNFα/NF-κB and IL-6/STAT3 pathways, targeted by approved IBD therapies, were significantly elevated in AT mice but reduced by the FXR agonist or anti-IL-12/23. Conclusion Activation of FXR directly induces IBD-dysregulated genes that can suppress inflammation, promote gut healing and transporter functions. In addition, FXR activation reduced TNFα/NF-κB and IL-6/STAT3 pathways in AT colitis model. These findings support further development of novel FXR agonists as a potential oral therapy for IBD.

Hepatitis B (HBV) reactivation in patients receiving biologic therapy for chronic inflammatory diseases in clinical practice.

Biologic treatment - particularly with the anti-TNF molecules - is frequently used in clinical practice to treat the severe form for both chronic rheumatic diseases and inflammatory bowel diseases. The immunosuppression induced by biologic therapies increases the risk of infections, including tuberculosis, as well as hepatitis B virus (HBV) reactivation may occur in inactive carriers or occult HBV infection (OBI) subjects during biologic therapy. This study aimed to update data on HBV prevalence and reactivation in patients receiving biologic therapy for either chronic rheumatic diseases or IBD, and to describe their management in clinical practice. This study was performed in 6 Italian centers (3 Rheumatology Units and 3 Gastroenterology Units). Clinical, biochemical and virological data, as well as follow up information, were recorded and analyzed. 984 patients were considered, including 817 with rheumatic disease and 167 with IBD. A total of 43 showed HBV infection (38 OBI and 5 carriers) accounting for a prevalence of 4%. Among OBI patients, 1 (2.6%) case of HBV reactivation occurred in a male patient with Crohn disease. Among the 5 HBV carriers, two patients (1 with spondyloarthritis and 1 with rheumatoid arthritis) did not received HBV antiviral therapy, and both experienced flare of hepatitis at 47 and 49 months following biologic therapy starting. Data of our study highlight that guidelines on management of HBV patients treated with biologic therapies should be still implemented in clinical practice when considering that, although infrequent, HBV reactivation could be potentially life-threatening.

Vitexin prevents colitis-associated carcinogenesis in mice through regulating macrophage polarization

BackgroundPatients with inflammatory bowel disease are at increased risks of developing ulcerative colitis-associated colorectal cancer (CAC). Vitexin can suppress the proliferation of colorectal carcinoma cells in vitro orin vivo. However, different from colorectal carcinoma, CAC is more consistent with the transformation from inflammation to cancer in clinical chronic IBD patients. Therefore, we aim to investigated that vitexin whether possess benefic effects on CAC mice. PurposeWe aimed to determine the beneficial effects of vitexin on CAC mice and reveal its underlying mechanism. MethodsThe mouse CAC model was induced by Azoxymethane and dextran sodium sulfate (AOM/DSS) and CAC mice were treated with vitexin. At the end of this study, inflammatory cytokines of IL-1β, IL-6, TNF-α, IL-10 as well as nitric oxide (NO) were detected by kits after long-term treatment of vitexin. Pathological changes and macrophage polarization were determined by H&E and immunofluorescence in adjacent noncancerous tissue and carcinomatous tissue respectively of CAC mice. ResultsOur results showed that oral administration of vitexin could significantly improve the clinical signs and symptoms of chronic colitis, relieve colon damage, regulate colonic inflammatory cytokines, as well as suppress tumor incidence and tumor burden. Interesting, vitexin caused a significant increase in serum level of NO and a higher content of NO in tumor tissue. In addition, vitexin significantly decreased M1 phenotype macrophages in the adjacent noncancerous tissue, while markedly up-regulated M1 macrophage polarization in the tumor tissue in the colon of CAC mice. ConclusionVitexin can attenuate chronic colitis-associated carcinogenesis induced by AOM/DSS in mice and its protective effects are partly associated with its alternations in macrophage polarization in the inflammatory and tumor microenvironment .

S3321 Recurrent Acute Pancreatitis Secondary to Pancreatic Divisum Anomaly

INTRODUCTION: Pancreatic divisum (PD) is a congenital malformation that occurs when the ventral and dorsal ducts of the pancreas fail to fuse. Inadequate drainage of pancreatic secretions from the minor papilla results in ductal distension and recurrent pancreatitis. We present a patient with PD who developed acute necrotizing pancreatitis (ANP) complicated by walled off pancreatic necrosis (WOPN). CASE DESCRIPTION/METHODS: 64-year-old female with history of chronic alcohol abuse and IBD presented with epigastric abdominal pain and emesis. Labs showed normal triglycerides, elevated lipase and amylase. Abdominal US ruled out gallstones. Abdominal CT showed pancreatic inflammation with several cystic-appearing fluid collections. She was treated conservatively. Repeat abdominal CT showed multiple increased peripancreatic fluid collections with mass effect on the stomach (Figure 1). Persistent abdominal pain led to ERCP which displayed complete PD and high-grade pancreatic duct fistula in the body and tail. Ventral and dorsal duct sphincterotomies were done with stent deployment in each duct. EUS revealed 3 peripancreatic fluid collections (consistent with WOPN); the largest was adjacent to the gastric antrum. Purulent drainage was noted after 3 cystogastrostomy incisions. Antibiotics were initiated. Patient eventually had recurrent pancreatitis, requiring repeat minor papilla sphincterotomy with dorsal pancreatic duct stent exchange. DISCUSSION: WOPN is a late complication of ANP, occurring more than 4 weeks after the initial attack. It can cause obstruction and fistula. Due to her PD anatomy, we suspect the patient had previous indolent acute pancreatitis episodes however they were falsely attributed to her IBD. Thus, delaying diagnosis of acute pancreatitis and leading to ANP and WOPN. The lifetime risk of pancreatitis in PD patients is similar to the general population. Consider PD in young, female patients in whom etiologies such as, gallstones and alcohol use, have been excluded. Alcohol abuse in context of her PD anatomy could have amplified our patient’s risk of acute pancreatitis. CT and MRI scans do not reliably detect PD thus ERCP remains the diagnostic test. Minor papilla sphincterotomy, papillary dilatation, stent insertion and pancreatic resection are treatment options. Since recurrent acute pancreatitis can lead to chronic pancreatitis, it is important to detect PD early. Follow up imaging in 3-6 months after pancreatitis resolution is vital, especially in patients with WOPN, to exclude neoplasm.Figure 1Figure 2.: Fig 1. and 2: CT abdomen and pelvis with contrast showing significantly compressed gastric lumen and multiloculated collections surrounding the pancreas, along the fundus of the stomach measuring 8 × 4.3 cm with mass effect, slightly inferiorly along the fundus and body measuring 7.7 × 4.2 cm, and along the antrum measuring 7.9 × 4.3 cm with surrounding fat stranding and mass effect.

P153 MET642, AN ORAL FXR AGONIST, IMPROVES COLITIS INDUCED BY ADOPTIVE T-CELL TRANSFER

Abstract Introduction Farnesoid X receptor (FXR) is a ligand-activated nuclear hormone receptor expressed in the gastrointestinal tract, with high expression levels in the intestinal epithelium. Previously we have shown that FXR agonists with sustained activity decreased colitis in multiple chronic IBD models (i.e. Adoptive transfer colitis, Mdr1a-/- colitis, and SAMP1/YitFc ileitis). Because FXR agonists are dosed orally and do not have systemic immunosuppressive properties, they represent a novel and differentiated therapeutic approach for IBD. MET642 is an optimized, potent non-bile acid FXR agonist with sustained FXR activation. In this study, we examined the efficacy of MET642 in therapeutic treatment mode in adoptive T-cell transfer model. Methods Colitis was induced by transplanting CD4+CD45RBhi T-cells to recipient C.B-17 SCID mice. Body weights were monitored throughout study duration. Staring 21 days after T-cell transfer, mice were treated with vehicle (n=10), MET642 (0.1, 0.3 or 1 mg/kg p.o., daily, n=10), or anti-IL-12p40 (neutralizing both IL-12 and IL-23, 0.5mg/mouse, i.p., weekly, n=5) for 4 weeks. Terminal endpoints included colon weight to length ratio (W/L), colon histopathology and gene expression. Histopathology scores were determined for inflammation, erosion, gland loss and hyperplasia, each with a score of 0–5, and cumulative sum score of 0–20. Results CD4+CD45RBhi T-cell transfer led to a significant reduction in body weight and increase in colon W/L ratio; both were reversed by MET642 and anti-IL-12p40. All dose levels of MET642 significantly improved the histopathology sum score relative to vehicle treatment, with maximal efficacy reached at 0.3mg/kg. Similar to anti-IL-12p40, MET642 showed improvements across all individual histopathology endpoints. Gene expression analysis suggests FXR activation increases anti-microbial activity, improves gut barrier and transporter function, and suppresses inflammation. Conclusion MET642, an oral once daily FXR agonist, significantly improved colitis in the adoptive T-cell transfer model. Activation of FXR by MET642 potentially promotes pathways of gut anti-microbial function, barrier function, and suppression of inflammation. These findings support further development of MET642 as a novel oral therapeutic for treating IBD.

1557 Not Your Average Colon Cancer: Diffuse Large B-Cell Lymphoma in a Terminal Ileum Mass and Colon Polyp

INTRODUCTION: Although the GI tract is a common site of extranodal non-Hodgkin lymphoma, primary ileocolonic lymphoma is rare among GI malignancies. Here, we report the case of a man presenting with abdominal pain diagnosed with diffuse large B-cell lymphoma (DLBCL) in his terminal ileum and sigmoid colon on colonoscopy. CASE DESCRIPTION/METHODS: A 72 year-old male with type 2 diabetes mellitus and recurrent UTIs presented with several weeks of abdominal pain and rectal bleeding. A colonoscopy 7 years prior showed diverticulosis. He had a 10 pack-year smoking history (quit 35 years prior). Family history was notable for a father with prostate cancer. Exam showed abdominal tenderness in the right lower quadrant. Laboratory work-up was only notable for ESR 25 and CRP 1.1. CT abdomen/pelvis demonstrated wall thickening in the cecum/ascending colon with surrounding inflammatory change and reactive adenopathy. Colonoscopy showed an ulcerated 2.0 × 1.8 cm mass in the terminal ileum, involving one-third of the lumen circumference (Figure 1). A 1.0 cm semi-pedunculated polyp was found in the sigmoid colon (Figure 2). Pathology of the ileal mass was consistent with DLBCL, non-germinal center B cell origin; pathology of the sigmoid polyp was tubular adenoma with large atypical lymphoid submucosal cells, suggestive of lymphatic involvement. DISCUSSION: The ileocolonic area is the least common site of primary GI lymphoma, accounting for only 0.3-0.5% of malignancies found there. Most patients present with abdominal pain, lower GI bleeding, or weight loss. GI lymphoma is more common in men, age 60-70s. Other risk factors are immunosuppression, chronic viral illness, H. Pylori, IBD, and Celiac disease. CT is the mainstay in diagnostic imaging. However, radiographic and endoscopic appearance cannot differentiate GI lymphoma from other malignancy; biopsy is the only way to confirm diagnosis. DLBCL is the most common subtype, with mantle cell and follicular lymphoma less prevalent. There is no standard treatment, although surgery is generally performed given risk of spontaneous perforation. Chemotherapy is often offered alone or adjuvantly as disease usually extends beyond local fields. Though our case has some typical features of GI lymphoma, ileocolonic involvement is very uncommon, and occurrence in multiple areas is rare, found in less than 10% of primary GI lymphomas. Thus, this case is unique, as the patient had an ileal mass as the primary site of DLBCL with a polyp in the sigmoid, suggesting lymphatic spread.

750 Incidence and Risk Factors of Constipation in Inflammatory Bowel Disease Patients During Remission

INTRODUCTION: The incidence of constipation in long term follow-up of chronic IBD patients during remission hasn't been studied. Though constipation was observed in patients with proctitis, and hard stools reported in 27% of patients with active UC (1), constipation was not the focus of IBD studies in the past. The overlap of IBS with IBD was studied, a small and similar incidence of constipation was reported in both groups (2). This five-year follow-up study documented the incidence of constipation in IBD patients during remission, analyzing the risk factors related to the IBD Illness. METHODS: 259 Patients with IBD in the GI clinic were followed for 5 years, between 2013-2018. Patients who developed constipation during the remission period were studied to find the incidence of constipation and risk factors related to IBD. The remission was identified as clinical remission for more than 6 mo, or by endoscopic or histologic remission. All patients had KUB documented the high fecal load without obstruction at the time of clinical presentation with constipation. Factors related to IBD illness were analyzed, including gender, type of IBD, period of illness, and intestinal involvement. Those with Proctitis only and those with previous surgeries were extracted. RESULTS: 89/259 patients (34%) developed constipation. 43/89 with UC vs 41/89 with CD (P > 0.1). No statistical significance also found for the gender (54M Vs 35F) and the period of the illness (52 < 5 years, vs 37 > 5 years). The involvement of the distal colon including pancolitis involvement was significantly higher than the involvement of the right side of the colon (67/89 had distal involvement vs 3/89 proximal involvement), to the point of statistical significance (P < 0.05). Patients with skipping lesions with distal involvement were 19/89. CONCLUSION: This study showed a high incidence of constipation in patients with inactive IBD (34%), it was higher than the incidence of patients with hard stools at the time of diagnosis (4/50). The clinical setting of this study with long term observation was different from the clinical setting of the 2 surveillance that reported constipation in IBD patients in the medical literature. Though constipation is a functional symptom, the risk factor of IBD involvement is not related to the IBS. The successful treatment of constipation in this group impacted the quality of life and the management of IBD with medications, only 3 patients in this group required treatment with immunosuppressive or biologic medications.

P140 Challenges in colonoscopic surveillance in chronic IBD

P140 Challenges in colonoscopic surveillance in chronic IBD

Divergent Innate and Epithelial Functions of the RNA-Binding Protein HuR in Intestinal Inflammation.

HuR is an abundant RNA-binding protein acting as a post-transcriptional regulator of many RNAs including mRNAs encoding inflammatory mediators, cytokines, death signalers and cell cycle regulators. In the context of intestinal pathologies, elevated HuR is considered to enhance the stability and the translation of pro-tumorigenic mRNAs providing the rationale for its pharmacological targeting. However, HuR also possesses specific regulatory functions for innate immunity and cytokine mRNA control which can oppose intestinal inflammation and tumor promotion. Here, we aim to identify contexts of intestinal inflammation where the innate immune and the epithelial functions of HuR converge or diverge. To address this, we use a disease-oriented phenotypic approach using mice lacking HuR either in intestinal epithelia or myeloid-derived immune compartments. These mice were compared for their responses to (a) Chemically induced Colitis; (b) Colitis- associated Cancer (CAC); (c) T-cell mediated enterotoxicity; (d) Citrobacter rodentium-induced colitis; and (e) TNF-driven inflammatory bowel disease. Convergent functions of epithelial and myeloid HuR included their requirement for suppressing inflammation in chemically induced colitis and their redundancies in chronic TNF-driven IBD and microbiota control. In the other contexts however, their functions diversified. Epithelial HuR was required to protect the epithelial barrier from acute inflammatory or infectious degeneration but also to promote tumor growth. In contrast, myeloid HuR was required to suppress the beneficial inflammation for pathogen clearance and tumor suppression. This cellular dichotomy in HuR's functions was validated further in mice engineered to express ubiquitously higher levels of HuR which displayed diminished pathologic and beneficial inflammatory responses, resistance to epithelial damage yet a heightened susceptibility to CAC. Our study demonstrates that epithelial and myeloid HuR affect different cellular dynamics in the intestine that need to be carefully considered for its pharmacological exploitation and points toward potential windows for harnessing HuR functions in intestinal inflammation.

Ankylosing Spondylitis and Axial Spondyloarthritis in Patients With Long-term Inflammatory Bowel Disease: Results From 20 Years of Follow-up in the IBSEN Study.

Patients with inflammatory bowel disease [IBD] often suffer from rheumatic manifestations, including inflammatory back disorders. The prevalence of these disorders late in the course of IBD is poorly investigated. The aim of this study was to estimate the prevalence of inflammatory back disorders in patients with IBD 20 years after diagnosis, and to investigate possible associations with IBD severity, HLA-B27, and the NOD2 genotype. A population-based cohort [the IBSEN study] was followed prospectively for 20 years. Information covering IBD activity and rheumatic diseases was collected at the regular follow-ups. HLA-B27 and NOD2 were analysed as present or absent. At 20 years, 599 members of the original cohort were alive, of whom 470 [78.5%] were investigated [314 ulcerative colitis and 156 Crohn's disease patients]. Ankylosing spondylitis was diagnosed in 21 patients [4.5%], axial spondyloarthritis was diagnosed in 36 patients [7.7%], and inflammatory back pain was diagnosed in 54 patients [11.5%]. Chronic back pain [back pain > 3 months] was present in 220 patients [46.8%]. HLA-B27 was associated with ankylosing spondylitis, axial spondyloarthritis, and inflammatory back pain, whereas no significant association was found for NOD2. A more chronic IBD course was associated with axial spondyloarthritis. Our data revealed a high prevalence of ankylosing spondylitis, axial spondyloarthritis, and inflammatory back pain 20 years after the IBD diagnosis. HLA-B27 but not NOD-2 was a predisposing factor for the inflammatory back disorders in IBD patients. Axial spondyloarthritis was associated with a more chronic active IBD disease course.

Sofosbuvir and Ledipasvir in IBD Patients Treated With Advanced Biologics Including Ribavirin Eradicating Chronic Hepatitis C: Solataire C Trial: A Multicenter Clinical Prospective Pilot Study

Introduction: The prevalence and concomitant treatment of chronic HCV and IBD has not been elucidated. IBD and CHC of >20 years duration may have more fibrosis due to immune suppression. Treatment of IBD often requires biological therapies to achieve longer disease-free remission, which further accelerates higher HCV replication. Thus effective therapy for IBD patients requiring immunosuppressive therapy is needed. To evaluate the role and efficacy of new NS5A + NS5B inhibitors with and without RBV in treating CHC in moderate to severe IBD requiring biologic therapy Methods: 35 patients were recruited from the Kings County Hospital Medical Center, Brooklyn. Inclusion criteria CHC with IBD, Age: >18, HCV Viral Load: > 400,000IU/mL, Genotype 1. Fibrotic Score: Metavir F1 to F4. Primary End Point: SVR12 Secondary End Point: IBD activity index, sustained control of symptoms SVR 24 and complete IBD remission at 30 weeks (endoscopy at 30 weeks). The patients were divided into two groups: Group A (n=17)- RBV 1000 mg + LDV and SOF; for 8 weeks Group B (n=18): LDV and SOF; for 12 weeks All will have base line RAV and ETRAV's and SVR 24. RAVs 5A polymorphism by Quest. Viral loads 0, 7, 14 days; 4th, 8th, 12th and 24th weeks. Results: see table. Conclusion: This study demonstrates that DAA's for HCV appear to have similar efficacy and safety in the presence of active IBD therapy withTNF Alfa antagonists while keeping the IBD in uninterrupted remission.Table 1: Results