Mild Colitis Research Articles

S3389 Segmental Colitis Associated With Diverticulosis Mimicking Inflammatory Bowel Diseases

INTRODUCTION: Segmental colitis associated with diverticulosis (SCAD) is defined by active chronic inflammation in colonic segments affected by diverticular disease. It was previously thought to be a complication of inflammatory bowel disease (IBD) and was not considered a distinct entity until 1983. We present two cases of SCAD that were initially diagnosed as IBD. CASE DESCRIPTION/METHODS: Case 1: 59-year-old male with presumed left-sided ulcerative colitis presented to us with intermittent hematochezia for months. Physical exam was unremarkable. Laboratory work-up was significant for elevated fecal calprotectin at 1543μg/mg. Colonoscopy revealed moderate sigmoid diverticulosis with surrounding erythema and erosions, but otherwise normal rectum, colon and terminal ileum. Biopsies from the affected sigmoid colon showed moderate active colitis and crypt abscesses. Small bowel imaging was unremarkable. The prior IBD diagnosis was changed to SCAD and the patient started a Mediterranean diet and has remained asymptomatic on follow-up. Case 2: 39-year-old male with a history of sigmoid diverticulosis with associated wall thickening and recurrent episodes of left lower quadrant abdominal pain with non-bloody diarrhea came to our clinic for suspected Crohn’s disease. Physical exam and laboratory workup were unremarkable. A colonoscopy ten years prior revealed sigmoid diverticulosis with associated erythema and edema. Biopsies showed mild active colitis. We repeated a colonoscopy that revealed mild inflammatory changes in the sigmoid colon surrounding the diverticula, but otherwise normal rectum, colon and terminal ileum. Biopsies from the affected sigmoid colon showed lymphoplasmacytic expansion of the lamina propria but no active colitis. Small bowel imaging was unremarkable. The prior IBD diagnosis was changed to SCAD and the patient started a Mediterranean diet and has remained asymptomatic on follow-up. DISCUSSION: These two cases highlight the importance of accurately diagnosing SCAD as it impacts the disease management and prognosis. SCAD and IBD share many overlapping features; however, SCAD typically spares the rectum and the diverticular orifices, and has a lower rate of relapse.SCAD can be classified into four different types (A, B, C, and D) based on presentation pattern, endoscopic and pathologic features. There is limited data informing management of patients with SCAD; current treatment options include diet, mesalamines, antibiotics, steroids, probiotics and in some cases anti-TNF therapy or surgery.Figure 1.: Patchy erythema and erosions in the sigmoid colon near diverticula.Figure 2.: Mild patchy erythema in the sigmoid colon near diverticula.

Fecal Microbiota Transplant in Two Ulcerative Colitis Pediatric Cases: Gut Microbiota and Clinical Course Correlations.

Fecal microbiota transplantation (FMT) is a promising strategy in the management of inflammatory bowel disease (IBD). The clinical effects of this practice are still largely unknown and unpredictable. In this study, two children affected by mild and moderate ulcerative colitis (UC), were pre- and post-FMT monitored for clinical conditions and gut bacterial ecology. Microbiota profiling relied on receipts’ time-point profiles, donors and control cohorts’ baseline descriptions. After FMT, the improvement of clinical conditions was recorded for both patients. After 12 months, the mild UC patient was in clinical remission, while the moderate UC patient, after 12 weeks, had a clinical worsening. Ecological analyses highlighted an increase in microbiota richness and phylogenetic distance after FMT. This increase was mainly due to Collinsella aerofaciens and Eubacterium biforme, inherited by respective donors. Moreover, a decrease of Proteus and Blautia producta, and the increment of Parabacteroides, Mogibacteriaceae, Bacteroides eggerthi, Bacteroides plebeius, Ruminococcus bromii, and B Bacteroides ovatus were associated with remission of the patient’s condition. FMT results in a long-term response in mild UC, while in the moderate form there is probably need for multiple FMT administrations. FMT leads to a decrease in potential pathogens and an increase in microorganisms correlated to remission status.

CADM1 enhances intestinal barrier function in a rat model of mild inflammatory bowel disease by inhibiting the STAT3 signaling pathway.

Cell adhesion molecule 1 (CADM1) is frequently silenced in lung, prostate, liver, stomach, pancreatic and breast carcinomas and other forms of human carcinomas. However, it is unclear regarding the role of CADM1 in irritable bowel syndrome with diarrhoea (IBS-D) that is the most common gastrointestinal diagnosis and may contribute to impaired intestinal barrier function. The aim of the present study is to explore the potential mechanism of CADM1 in regulating intestinal barrier function in IBS-D. A rat model with IBS-D induced by the combination method of mother-infant separation, acetic acid and restraint stress was initially established. The defecation frequency, faecal water content (FWC), total intestinal permeability, sIgA, endotoxin, D-lactic acid and diamine oxidase (DAO) were then measured. Next, positive expression of CADM1 protein was detected in distal colonic tissue of rats by immunohistochemistry. The expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in distal colonic mucosa, CADM1, Janus kinase 1 (JAK1), STAT3, p-JAK1, p-STAT3, Claudin-1and Claudin-2 were evaluated using ELISA, RT-qPCR and western blot analysis. IBS-D rats exhibited low CADM1 expression and activated STAT3 signaling pathway. Overexpression of CADM1 in rats was shown to increase Claudin-1 expression, while decreasing expression of STAT3, Claudin-2, TNF-α and IL-6. In addition, silencing of CADM1 or inhibition of the STAT3 signaling pathway was demonstrated to improve the intestinal barrier function. Our study provides evidence that CADM1 can potentially improve intestinal barrier function in rats with IBS-D by inhibiting the STAT3 signaling pathway.

Proper E-cadherin membrane location in colon requires Dab2 and it modifies by inflammation and cancer.

We reported that Disabled-2 (Dab2) is located at the apical membrane in suckling rat intestine. Here, we discovered that, in colon of suckling and adult mouse and of adult human, Dab2 is only at lateral crypt cell membrane and colocalized with E-cadherin. Dab2 depletion in Caco-2 cells led to E-cadherin internalization indicating that its membrane location requires Dab2. In mice, we found that 3 days of dextran sulfate sodium-induced colitis increased Dab2/E-cadherin colocalization, which was decreased as colitis progressed to 6 and 9 days. In agreement, Dab2/E-cadherin colocalization increased in human mild and severe ulcerative colitis and in polyps, being reduced in colon adenocarcinomas, which even showed epithelial Dab2 absence and E-cadherin delocalization. Epithelial Dab2 decrement preceded that of E-cadherin. We suggest that Dab2, by inhibiting E-cadherin internalization, stabilizes adherens junctions, and its absence from the epithelium may contribute to development of colon inflammation and cancer.

Changes in the expression of substance P in nerve fibres of the colonic mucosa in dogs suffering from inflammatory bowel disease.

Due to its difficult diagnosis and complicated treatment, inflammatory bowel disease (IBD) in dogs is a challenge for the veterinarian. Several aspects connected with pathological changes during IBD still remain unknown. Since one of these aspects is the participation of intestinal innervation in the evolution of the disease, the aim of this study was to demonstrate changes in the number and distribution of intramucosal colonic nerve fibres immunoreactive to substance P (SP) arising as the disease progresses. SP is one of the most important neuronal factors in intestinal innervation which, among other tasks, takes part in the conduction of pain stimuli. Using routine immunofluorescence technique, the density of nerve fibres containing SP was evaluated within mucosal biopsy specimens collected from the descending colon of healthy dogs and animals suffering from IBD of varying severity. The results of the study indicate that during severe IBD the number of nerve fibres containing SP located in the colonic mucosal layer increases in comparison to control animals. The number of SP-positive intramucosal nerves amounted to 10.99 ± 2.11 nerves per observation field in healthy dogs, 14.62 ± 2.86 in dogs with mild IBD, 14.80 ± 0.91 in dogs with moderate IBD and 19.03 ± 6.11 in animals with severe IBD. The observed changes were directly proportional to the intensity of the disease process. These observations may suggest a role of this neuronal substance in pathological processes occurring during IBD. Although the exact mechanism of the observed changes has not been completely explained, the results obtained in this investigation may contribute to improving the diagnosis and treatment of this disease, as well as the staging of canine IBD in veterinary practice.

The mRNA-binding protein IGF2BP1 maintains intestinal barrier function by up-regulating occludin expression

Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an mRNA-binding protein that has an oncofetal pattern of expression. It is also expressed in intestinal tissue, suggesting that it has a possible role in intestinal homeostasis. To investigate this possibility, here we generated Villin CreERT2:Igf2bp1flox/flox mice, which enabled induction of an IGF2BP1 knockout specifically in intestinal epithelial cells (IECs) of adult mice. Using gut barrier and epithelial permeability assays and several biochemical approaches, we found that IGF2BP1 ablation in the adult intestinal epithelium causes mild active colitis and mild-to-moderate active enteritis. Moreover, the IGF2BP1 deletion aggravated dextran sodium sulfate-induced colitis. We also found that IGF2BP1 removal compromises barrier function of the intestinal epithelium, resulting from altered protein expression at tight junctions. Mechanistically, IGF2BP1 interacted with the mRNA of the tight-junction protein occludin (Ocln), stabilizing Ocln mRNA and inducing expression of occludin in IECs. Furthermore, ectopic occludin expression in IGF2BP1-knockdown cells restored barrier function. We conclude that IGF2BP1-dependent regulation of occludin expression is an important mechanism in intestinal barrier function maintenance and in the prevention of colitis.

Paradoxical interaction between cancer and long-term postsepsis disorder: impairment of de novo carcinogenesis versus favoring the growth of established tumors.

BackgroundPrevious data have reported that the growth of established tumors may be facilitated by postsepsis disorder through changes in the microenvironment and immune dysfunction. However, the influence of postsepsis disorder in initial carcinogenesis remains elusive.MethodsIn the present work, the effect of postsepsis on inflammation-induced early carcinogenesis was evaluated in an experimental model of colitis-associated colorectal cancer (CAC). We also analyzed the frequency and role of intestinal T regulatory cells (Treg) in CAC carcinogenesis.ResultsThe colitis grade and the tumor development rate were evaluated postmortem or in vivo through serial colonoscopies. Sepsis-surviving mice (SSM) presented with a lower colonic DNA damage, polyp incidence, reduced tumor load, and milder colitis than their sham-operated counterparts. Ablating Treg led to restoration of the ability to develop colitis and tumor polyps in the SSM, in a similar fashion to that in the sham-operated mice. On the other hand, the growth of subcutaneously inoculated MC38luc colorectal cancer cells or previously established chemical CAC tumors was increased in SSM.ConclusionOur results provide evidence that postsepsis disorder has a dual effect in cancer development, inhibiting inflammation-induced early carcinogenesis in a Treg-dependent manner, while increasing the growth of previously established tumors.

Infectious and digestive complications in glycogen storage disease type Ib: Study of a French cohort

Glycogenosis type Ib (GSD1B) causes not only hypoglycemia but also infections and “Crohn's disease like” inflammatory bowel disease (IBD) that can significantly impair patient's quality of life. We retrospectively evaluated infectious and digestive complications in 9 French patients (3 girls, 6 boys) diagnosed at 0.8 years on average, with a mean follow-up of 19.1 years. Infections occurred earlier than IBD, at mean ages of 1.7 and 3.8 years, respectively. The number of acute hospitalizations was 0.7/year due to infectious (0.4/year) or digestive symptoms (0.4/year). Clinical presentations allowed separating patients into mild (n = 5) and severe (n = 4) intestinal involvement. Patients in the severe group had more serious digestive symptoms but also earlier neutropenia (median 0.3 vs. 1.5 years, p =0 .046) with a tendency to a lower neutrophil count (NC) during follow-up, and a higher number of acute hospitalizations (median 1.3/year vs. 0.2/year, p =0 .014) due to digestive symptoms (median 0.6/year vs. 0.05/year, p = 0,012) and infections (median 0.8/year vs. 0.2/year, p =0 .014). Treatments included G-CSF and cotrimoxazole (n = 7), 5-aminosalicylic acid (n = 2), and a polymeric solution enriched in the anti-inflammatory cytokine TGF-β (n = 4, “severe” group), and immunomodulatory treatment (n = 1). In conclusion, infections and IBD are rare but severe complications in GSD1B. Neutropenia tended to be more prevalent in the severe IBD group than in the mild IBD group. Dietetic treatment with specific anti-inflammatory solutions seems particularly appropriate in these patients.

Pregnancy outcomes in women with inflammatory bowel disease: a 10-year nationwide population-based cohort study.

Data relating to the association between inflammatory bowel disease (IBD) and pregnancy outcomes are lacking in Korea. To determine the incidence rates of pregnancy outcomes in women with IBD. A nationwide population study was performed using the Korean National Health Insurance claims database. A total of 2058 women with IBD consisting of ulcerative colitis (UC, n=1469) and Crohn's disease (CD, n=589) were pregnant between 2007 and 2016. We compared their incidence of pregnancy outcomes with 20580 age-matched controls without IBD. We also stratified the patients into those with quiescent to mild and moderate to severe IBD and compared the outcomes between them. The pregnancy rate of women with IBD was lower than that of women without (25.7% vs 32.3%, P<0.001). Caesarean section (46.5% vs 38.8%, odds ratio [OR] 1.43, 95% confidence interval [CI]: 1.17-1.75), and intrauterine growth retardation (IUGR) (3.0% vs 1.0%, OR 2.89, 95% CI: 1.59-5.26) were increased in CD patients than the controls. In regards to disease severity, there were no significant differences in pregnancy outcomes between patients with quiescent to mild IBD and the controls. However, the live birth rate of patients with moderate to severe IBD was lower than that of the controls (65.0% vs 69.9%, OR 0.79, 95%CI: 0.66-0.94). In addition, moderate to severe IBD was significantly associated with spontaneous abortion (14.9% vs 11.9%, OR 1.33, 95% CI: 1.04-1.68), caesarean section (46.4% vs 38.8%, OR 1.41, 95% CI: 1.14-1.74) and IUGR (3.4% vs 1.0%, OR 3.20, 95% CI: 1.75-5.84). With the exception of moderate to severe disease, the incidences of adverse pregnancy outcomes in women with IBD are similar to that of the general population.

An Unusual Cause of Chronic Diarrhea

Question: A male patient presented with recurrent episodes of diarrhea that developed after a Caribbean cruise 1 year ago. He also complained of severe epigastric pain, arthralgias, myalgias, significant weight loss, and ocular symptoms, which were diagnosed as iritis. He had undergone an extensive workup at an outside hospital including a colonoscopy, which showed colonic mucosal congestion, loss of vascular architecture, and diverticulosis. Biopsies were interpreted as mild active chronic colitis and the possibility of inflammatory bowel disease was raised.

AB037. Probiotics in paediatric practice

: The first consensus on definitions in the field of probiotics between the FAO (Food and Agriculture Organization of the United Nations) and the World Health Organization (WHO) was adopted in 2001. Then, probiotics were defined as “live microorganisms, which, when administered in adequate amounts, confer a health benefit on the host” but already in the following year, in 2002, the FAO/WHO working group issued more detailed instructions on the interpretation of the document produced. Several professional associations reached the agreement on the assessment of probiotics based on the results from available clinical studies according to “evidence-based medicine” which lead to the clinical recommendation. They refer to specific clinical indications such as the treatment and prevention of acute gastroenteritis (AG) in children and adults (Lactobacillus rhamnosus LGG, Lactobacillus casei, Lactobacillus reuteri, Saccharomyces boulardi), necrotizing enterocolitis (NEC), antibiotic-associated diarrhoea (LGG, L. casei, Saccharomyces boulardi), irritable colon, infant colic (Bacillus infantis and L. reuteri), in the case of H. pylori eradication, mild ulcerative colitis (UC) with the probiotic VSL#3, but with disappointing results in the remission of Crohn’s disease and prevention of food allergy. The capacity of probiotics to cure illnesses and relieve symptoms varies between different strains, drawing the conclusion of their uneven efficacy and appropriateness in the treatment of every illness conditions. Special caution is advised in immunocompromised and severely ill patients in the intensive care unit (ICU).

P052 VALIDITY AND INTERPRETABILITY OF PROMIS PEDIATRIC PATIENT-REPORTED OUTCOMES FOR CHILDREN WITH INFLAMMATORY BOWEL DISEASE

Abstract Introduction Patient-Reported Outcome Measurement Information System (PROMIS) instruments were developed using rigorous psychometric methods to assess health and quality of life across the life course. In two studies, we aimed to evaluate the clinical validity of PROMIS measures for children with inflammatory bowel disease (IBD) and to increase the interpretability of scores on these measures. Methods Study 1 recruitment and clinical data collection took place within 14 pediatric gastroenterology practices located across the United States. PROMIS Pediatric measures of Pain Interference, Fatigue, Psychological Stress Experiences, Global Health, and Life Satisfaction were completed by 1,049 children and youth (8–24 years old) with IBD and linked to an IBD registry that included disease activity measures. Study 2 utilized baseline data from a large, multi-center clinical trial to compare the effectiveness of anti-TNF monotherapy versus combination therapy with methotrexate. A total of 199 participants (8–20 years old) across 35 sites completed PROMIS Pediatric measures of Pain Interference, Fatigue, and Positive Affect. PROMIS measures were scored on a T-score metric (mean = 50; standard deviation = 10). Scores on symptom measures were classified as “severe” if they were at or above the 95th percentile, and scores on positive health measures were classified as “poor” if they were at or below the 5th percentile, relative to the United States general population of children ages 8–17. Results For nearly all domains across both studies, PROMIS scores were significantly associated with clinical measures of IBD severity. PROMIS measures indicated worse health and/or functioning with corresponding increases in disease activity (inactive to mild to moderate/severe). Comparisons between inactive and mild IBD groups resulted in medium or large effect sizes (Cohen’s d = 0.5 – 0.96) for Pain Interference, Fatigue, Psychological Stress, Global Health, and Life Satisfaction (Table 1). Proportions of children with IBD who were classified as “severe” or “poor” were higher than in the general population and increased with increasing levels of IBD severity (Table 2). Conclusions These studies support the clinical validity of PROMIS instruments for assessing the lived experiences of children with IBD. Effect sizes associated with differences between inactive and mild IBD translate to 5–10 points on the PROMIS T-scale, suggesting that 5–10 points is a clinically important difference between group average scores. To aid interpretation of an individual’s score, percentiles derived from the general population may be used to determine whether the score falls within the range of severe/poor scores for the measure.

P156 ALPN-101, A FIRST-IN-CLASS DUAL ICOS/CD28 ANTAGONIST, DEMONSTRATES EFFICACY IN PATIENT-DERIVED PBMC IN VITRO AND IN AN IN VIVO T CELL TRANSFER MODEL OF CHRONIC INFLAMMATORY BOWEL DISEASE (IBD)

Abstract Background T cell costimulation has been strongly implicated in the pathogenesis of IBD, yet CD28 costimulatory pathway inhibitors (e.g. abatacept, CTLA4-Fc) have not proven clinically efficacious, implicating an alternative costimulatory pathway. ICOS is a costimulatory receptor highly related to CD28, upregulated upon T cell activation and mediating costimulatory signals in post-activation T cells - suggesting ICOS may be more relevant in active disease. In contrast, CD28 predominates in naïve T cells and is less critical in activated, effector and/or memory T cells. ALPN-101 is an Fc fusion protein of a human inducible T cell costimulator ligand (ICOSL) variant immunoglobulin domain (vIgDTM) engineered to inhibit simultaneously the CD28 and ICOS pathways. It has been shown to have potent in vitro immunosuppressive activity and in vivo efficacy in models of disease for which implication of CD28 and ICOS has been reported (e.g. aGvHD, inflammatory arthritis, Sjögren’s, lupus, MS). Its safety, tolerability, and dose-dependent pharmacokinetics/dynamics are under study in a Ph1 healthy volunteer study. Here, we evaluate ALPN-101 in vitro using PBMC from Crohn’s and ulcerative colitis patients demonstrating superior suppression of T cell activation and cytokine release and show its efficacy to both prevent and treat disease in a mouse T cell transfer model of chronic colitis. Methods Primary cell assays were performed with PBMC stimulated with K562 cells (CD80+, CD86+, ICOSL+, anti-CD3 (OKT3) +) to evaluate suppression of cytokine release and compare to single pathway inhibition. ALPN-101 was assessed in the CD4+CD45RBhigh T cell-induced colitis model either singly dosed on Day 0 or 14 or repeat dosed 2x/week starting at Day 0 or 14 through Day 41, respectively. Serum cytokine and flow analysis of blood was performed throughout the study. Clinical presence of colitis was assessed using a disease activity index based on weight loss and stool consistency. At end of study, colons were measured and assessed histologically. Results ALPN-101 suppressed cytokine release (IFNγ, IL-2) from healthy or IBD patient PBMCs superior to single pathway inhibitors. In vivo, preventively or therapeutically, a single dose of ALPN-101 was efficacious to significantly improve multiple colitis readouts. Repeat dosing completely prevented onset of colitis. ALPN-101-treated mice gained weight and had colon weight-to-length ratios similar to the no-colitis cohort and demonstrated significant suppression of T cells and pro-inflammatory cytokines (e.g. TNFα, IL-12/23, IL-6). Conclusion Dual pathway inhibitor ALPN-101 is superior to single pathway inhibition in human in vitro and mouse in vivo translational studies and may be a novel therapeutic candidate for the treatment of IBD. Clinical trials for ALPN-101 in multiple inflammatory diseases are planned and underway. Consistent with clinical findings, histological analysis confirms efficacy of ALPN-101 in reducing colitis. All ALPN-101 treated groups had lower histological scores compared to the Fc control treated group (B). Mice treated from Day 0 to the end of the study had no pathological colon findings (C), 4/12 mice treated from Day 14 to end of study had no signs of colitis (D). None of the mice in these groups had their muscularis layer of colon affected by inflammation. Mice treated with a single dose at day 0 or day 14 had milder colitis than Fc control-treated mice, although the differences were not statistically significant.

P104 PEDIATRIC CROHN’S DISEASE PRESENTINAG AS GENITAL EDEMA

Abstract Two 12 year old boys presented to pediatric urology with chief complaints of genital swelling who were eventually diagnosed with Crohn’s disease. Patient 1 presented with swelling, erythema and discomfort of his penis. He did not respond to topical hydrocortisone or oral antibiotics. With history of short stature he was referred to pediatric GI. He had oral ulcerations and perianal skin tag, but denied abdominal pain or diarrhea. Weight was at the 3rd percentile height was at the 2nd percentile. He had Hgb of 12.2, and iron saturation of 8 with normal ESR and CRP. ASCA IgA was normal but IgG was elevated at 66 (normal &amp;lt;20). Endoscopy revealed erythema with linear ulcerations in the stomach and aphthous ulcerations of the colon with erythema and edema of the ileocecal valve with inability to intubate it. Pathology demonstrated mild chronic active gastritis and mild chronic active colitis with granulomas. Magnetic resonance enterography (MRE) showed mild enhancement at the ileocecal area. Budesonide improved the penile erythema but did not change the edema. He was then started on methotrexate and infliximab with no improvement of the edema. Topical tacrolimus did not resolve edema. At age 15 he had surgical resection of the indurated subcuticular penile tissues with pathology revealing fibrotic stroma with lymphoplasmacytic inflammation and rare granulomas. He has recovered well from his penile procedure with a dramatic improvement in the cosmetic appearance, with no recurrence of the penile edema. Patient 2 had scrotal edema, erythema, and discomfort. A scrotal ultrasound demonstrated moderate to severe scrotal edema without epididymitis, orchitis, or abscess. He was prescribed a dose of prednisone and diphenhydramine. Swelling improved but he presented a month later with recurrent scrotal edema and pain and was prescribed doxycycline for a presumed diagnosis of cellulitis along with recommendations for ice, compression and elevation. He returned to the ER the next day due to serous seepage from the scrotum. Upon follow up in urology, a pediatric gastroenterology referral was performed as a family history of Crohn’s disease in the mother, maternal aunt, and maternal grandmother was noted. Labs revealed a slightly elevated ESR of 17, elevated CRP of 7.3 (normal &amp;lt;0.5), negative ASCA, and mildly elevated fecal calprotectin of 193. Endoscopy revealed aphthous ulcerations in the duodenal bulb and patchy erythema of the terminal ileum. Pathology revealed mild reflux esophagitis, mild reactive changes in the stomach, mild chronic duodenitis, and mild active ileitis. MRE was normal. He was treated with budesonide and mesalamine with subsequent improvement in the scrotal edema. Patients presenting as genital edema as their initial Crohn’s presentation is rare and it is important for providers to be aware of this rare manifestation. Epitheliod granuloma in the bowel. Epitheliod granuloma in penile tissue.

Activity of Inflammatory Bowel Disease After Liver Transplantation for Primary Sclerosing Cholangitis Predicts Poorer Clinical Outcomes.

The impact of inflammatory bowel disease (IBD) activity on long-term outcomes after liver transplantation (LT) for primary sclerosing cholangitis (PSC) is unknown. We examined the impact of post-LT IBD activity on clinically significant outcomes. One hundred twelve patients undergoing LT for PSC from 2 centers were studied for a median of 7 years. Patients were divided into 3 groups according to their IBD activity after LT: no IBD, mild IBD, and moderate to severe IBD. Patients were classified as having moderate to severe IBD if they met at least 1 of 3 criteria: (i) Mayo 2 or 3 colitis or Simple Endoscopic Score-Crohn's Disease ≥7 on endoscopy; (ii) acute flare of IBD necessitating steroid rescue therapy; or (iii) post-LT colectomy for medically refractory IBD. Moderate to severe IBD at any time post-transplant was associated with a higher risk of Clostridium difficile infection (27% vs 8% mild IBD vs 8% no IBD; P = 0.02), colorectal cancer/high-grade dysplasia (21% vs 3% both groups; P = 0.004), post-LT colectomy (33% vs 3% vs 0%) and rPSC (64% vs 18% vs 20%; P < 0.001). Multivariate analysis revealed that moderate to severe IBD increased the risk of both rPSC (relative risk [RR], 8.80; 95% confidence interval [CI], 2.81-27.59; P < 0.001) and colorectal cancer/high-grade dysplasia (RR, 10.45; 95% CI, 3.55-22.74; P < 0.001). Moderate to severe IBD at any time post-LT is associated with a higher risk of rPSC and colorectal neoplasia compared with mild IBD and no IBD. Patients with no IBD and mild IBD have similar post-LT outcomes. Future prospective studies are needed to determine if more intensive treatment of moderate to severe IBD improves long-term outcomes in patients undergoing LT for PSC.

Exploratory clinical characterization of experimentally-induced ulcerative colitis nonhuman primates

A limitation of currently used preclinical models of colitis is that disease and treatment assessment methods differ from clinically used methods. Thus, a modified Mayo score and an endoscopic index (EI) were developed for use in cynomolgus macaques with 0.25% dextran sulfate sodium (DSS)-induced ulcerative colitis. Macaques were treated with water with DSS for two weeks followed by water without DSS for two weeks. Disease activity was classified according to a modified Mayo score: stool consistency, rectal bleeding, colonoscopy examination and global assessment. Findings on colonoscopy were further graded according the Rachmilewitz EI. To demonstrate the sensitivity of the modified Mayo score and EI to therapeutic intervention, macaques were treated with the anti-inflammatory steroid prednisolone followed eight weeks later by the integrin antibody vedolizumab. Before DSS treatment, normal stool consistency and no rectal bleeding were observed. Colonoscopy demonstrated no mucosal abnormalities. Following the first DSS treatment, Mayo score and EI indicated signs of mild colitis. Following subsequent DSS treatments, mild to moderate colitis emerged with each DSS treatment and reduced signs of colitis were observed 2 weeks after DSS treatment termination. Prednisolone treatment during DSS treatment suppressed the emergence of colitis. Vedolizumab reduced signs of colitis during DSS treatment and further reduced signs of colitis that persisted after termination of DSS treatment. The current study demonstrated the potential of utilizing clinical outcome measures to assess experimentally-induced colitis in the macaque. Furthermore, signs of colitis, as assessed with the current methods, were reduced following therapeutic treatment. The current findings suggest that clinically relevant outcome measures in the macaque model of ulcerative colitis could be used to test novel treatments.

Budesonide ММХ in the treatment of ulcerative colitis: real world clinical practice

Rationale: Mild and moderate ulcerative colitis (UC) is conventionally treated with oral and rectal 5-aminosalicylic acid (5-ASA) formulations and, if ineffective, with systemic glucocorticosteroids. A huge disadvantage of systemic steroids is that with highly efficacy they have severe side effects and the development of hormone-dependency requiring their withdrawal. The main goal of UC treatment is to achieve clinical and endoscopic remission, and possibility to stop steroids. The introduction of multimatrix (MMX) budesonide (Cortiment®), a new topical steroid for UC treatment, widens the therapeutic armamentarium and allows in some cases to refrain from systemic agents, avoiding their side effects and achieving the necessary treatment goals.Aim: To evaluate the efficacy of topical steroid budesonide MMX for remission induction of UC in the real clinical practice.Materials and methods: We have analyzed 122 specially designed case report forms filled in from September 2018 to March 2019 in healthcare centers of Moscow, Voronezh, Lipetsk, Krasnodar, and Krasnoyarsk Regions of Russian Federation. The case report forms included anonymized data on the UC patients treated with budesonide MMX. The results of treatment were analyzed for various severity and extension of UC and depending on budesonide MMX monotherapy or combined therapy with rectal 5-ASA formulations. Treatment was considered effective if clinical and endoscopic remission was achieved.Results: Total efficacy in terms of improvement of clinical parameters (improvement/remission) after 4 weeks of treatment was 95% (118 patients), with clinical remission induced in 42.6% (52 patients). Positive changes over time in the endoscopic findings (improvement/remission) within the same time period were observed in 93% (60 patients), with endoscopic remission in 24.1% (21 patients).Conclusion: Budesonide MMX allows for a rapid clinical improvement and/or clinical remission in the majority of the patients with mild and moderate UC of predominantly left-sided location.

Fli-1 Regulates Multiple T-Cell Subsets during Inflammatory Responses and Experimental Graft-Versus-Host Disease

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a procedure undertaken to cure hematological malignancies, especially leukemia. Graft-Versus-Host Disease (GVHD) is a serious condition that often appears following allo-HCT. Friend Leukemia Virus Integration 1 (Fli-1) is a transcription factor highly expressed in cancers including erythroleukemia and acute myeloid leukemia while also implicated in pathogenesis of systemic lupus. We have interrogated the role of Fli-1 in T-cell responses by generating a novel T-cell specific conditional disruption of fli-1 where essential exons 3 and 4 of the gene are floxed and excised in the presence of CD4-Cre recombinase. Models of acute GVHD (aGVHD) and chronic GVHD (cGVHD) were tested utilizing hematopoietic cells from mice with a heterozygous (fli-1-/+ or Het) or homozygous (fli-1-/-or Null) disruption of the fli-1 gene, or from wild-type (fli-1+/+ or WT) littermate controls. At baseline, T cells among each of these three mouse strains showed no significant difference in CD44/CD62L expression or CD4+FoxP3+ (nTreg) frequencies. In the cGVHD model, BALB/c (H2Kd) recipients were infused with allogeneic B6 (H2Kb) genotype-respective bone marrow and splenocytes in order to induce cGVHD. Recipients that received fli-1-/+CD4Cre+ marrow and splenocytes demonstrated improved survival and mild cGVHD, whereas those that received fli-1-/-CD4Cre+ or WT donor cells developed serve cGVHD (Fig. 1 a-f). Cellular studies from lymphoid organs of cGVHD allo-HCT recipients revealed that disruption of fli-1 was associated with decreased frequencies of donor CD4+ cells expressing IL-17A, IFN-γ, T follicular-like (TFH-like) cell markers, and CD8+ cells expressing PD-1. In aGVHD settings, donor fli-1-/+CD4Cre+ T cells had a decreased ability to induce aGVHD compared to WT donor T cells and fli-1-/- donor T cells (Fig. 2 a-b). When investigating cellular mechanisms in aGVHD settings, we found that fli-1-/+CD4Cre+ T cells produced significantly lower IFN-γ early after T-cell activation in vivo compared to WT and fli-1-/-CD4Cre+ T cells (Fig. 2 c). To then investigate the role of Fli-1 in T cells beyond GVHD, we utilized a colitis model by transferring naïve CD4+ T cells (CD44-CD25-) into Rag2-/- syngeneic recipients. While fli-1+/+ T cells induced severe colitis as expected, fli-1-/- and fli--/+ T cells caused moderate and mild colitis, respectively. These results were consistent with those observed in GVHD models. To elucidate underlying mechanisms, we tested the effects of Fli-1 on antigen-specific T-cells using a MHC-II restricted TCR transgenic (Tg) mouse strain specific for HY-peptide. CD4+CD25- T cells from fli-1+/+, fli-1-/+, or fli-1-/- CD4Cre+ TCR-Tg mice were polarized in vitro with endogenous antigen presenting cells from spleen in presence of HY-peptide under iTreg- or Th17-polarizing conditions. Both fli-1-/+ and fli-1-/- TCR-tg T cells exhibited significant increases in iTreg (CD4+FoxP3+) frequencies and surface expression of iTreg functional markers (CD25, CD39, CD73, NRP-1), while also having significantly decreased frequencies of IL-17A producing T cells compared to WT-TCR-tg T cells. To further explore the molecular mechanisms, we retrieved fli-1+/+, fli-1-/+, or fli-1-/- donor T cells from recipient spleens after allo-HCT and did RNAseq analysis on these cells. RNAseq data reveals significant differences in mRNA expression within acute inflammatory response and positive regulation of the immune response enrichment pathways between fli-1-/+ T cells and littermate fli-1+/+ T cells, and to a lesser extent in fli-1-/- T cells (Fig. 2 d-f). Thus, reducing Fli-1 transcriptional activity represents a potential therapeutic concept toward ameliorating GVHD after allo-HCT, while simultaneously targeting cancers such as leukemia which typically overexpress Fli-1. Disclosures No relevant conflicts of interest to declare.

Interleukin-37 Inhibits Colon Carcinogensis During Chronic Colitis.

Inflammatory bowel disease increases the risk of developing colon cancer. Interleukin (IL-) 37 is a fundamental inhibitor of innate immunity by reducing systemic and local inflammation. IL-37 protein is expressed in healthy and diseased bowel and liver tissue. Here, we tested whether transgenic expression of human IL-37 protects IL-10 deficient (IL-10KO) mice from chronic colitis. IL-37tg mice were crossbred with IL-10KO mice. Homozygous IL-10KO/IL-37tg and IL10KO drank 2% dextran sulfate sodium (DSS) in water for 5 days to induce mild colitis. Colon carcinogenesis was triggered by intragastric administration of celecoxib. Endpoints were clinical parameters of colitis, cytokine responses in LPS-stimulated whole blood and explanted colon specimen and qPCR analysis of colon biopsies. Colon inflammation and number of adenoma—carcinoma were analyzed by histology. During the DSS-induction phase IL-10KO and IL-10KO/IL-37tg mice had a similar weight loss due to mild acute colitis. From day 115 there was a significantly improved weight gain in IL-10KO/IL37-tg mice, though colon length was similar. After ex vivo LPS stimulation whole blood of IL-10KO/IL-37tg compared to IL-10KO mice released less IL-6, IL-17, IFNγ, and TNFα and ex vivo colon cultures showed reduced IL-6 production both indicative of reduced inflammatory conditions under the influence of IL-37. Six out of 10 IL-10KO mice developed colon adenoma and carcinoma. Only one adenoma but no carcinoma was detected in colons of IL-10KO/IL-37tg mice. In conclusion, IL-37 transgene expression protects IL-10KO mice from colon carcinogenesis. It remains unclear whether IL-37 has direct tumor suppressing properties.

DSS-induced colitis produces inflammation-induced bone loss while irisin treatment mitigates the inflammatory state in both gut and bone

Chronic pediatric inflammatory bowel disease (IBD) leads to lack of bone accrual, bone loss, and increased fractures. Presently there is no cure, and many IBD treatments incur negative side effects. We previously discovered treatment with exogenous irisin resolved inflammatory changes in the colon, gut lymphatics, and bone in a mild IBD rodent model. Here we assess irisin treatment in severe IBD induced via dextran sodium sulfate (DSS). Male Sprague Dawley rats (2-mo-old) were untreated (Con) or given 2% DSS in drinking water. In week two, half of each group (Con + Ir and DSS + Ir) received injections of recombinant irisin (i.p., 2x/wk). After 4 weeks, gut inflammation was associated with declines in bone mineral density and cancellous bone volume. Furthermore, elevated osteocyte TNF-α, interleukin-6, RANKL, OPG, and sclerostin corresponded with higher osteoclast surfaces and lower bone formation rate in DSS animals as well as lower ultimate load. While irisin treatment improved colon inflammation, there were no improvements in bone density or bone mechanical properties; however, irisin elevated bone formation rate, decreased osteoclast surfaces, and reduced osteocyte pro-inflammatory factors. These data highlight the negative impact of chronic gut inflammation on bone as well as the therapeutic potential of irisin as an anti-inflammatory treatment.