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Ulcerative Colitis: HELP
Articles from University of Michigan
Based on 57 articles published since 2008
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These are the 57 published articles about Colitis, Ulcerative that originated from University of Michigan during 2008-2019.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Editorial Miles to Go on the SCENIC Route: Should Chromoendoscopy Become the Standard of Care in IBD Surveillance? 2015

Higgins, Peter D R. ·Department of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA. ·Am J Gastroenterol · Pubmed #26148262.

ABSTRACT: The recent SCENIC Consensus statement has raised questions about which patients with chronic colitis should receive chromoendoscopic surveillance. Two papers in this issue of the American Journal of Gastroenterology provide more evidence and context, and this editorial discusses the current evidence base, which patients might benefit from chromoendoscopy, and what more evidence is needed before chromoendoscopy can be considered a possible new standard of care in all patients with chronic colitis.

2 Editorial Pushing the pedal to the metal: should we accelerate infliximab therapy for patients with severe ulcerative colitis? 2015

Herfarth, Hans H / Rogler, Gerhard / Higgins, Peter D R. ·Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina. · Division of Gastroenterology and Hepatology, University of Zurich, Zurich, Switzerland. · Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan. ·Clin Gastroenterol Hepatol · Pubmed #25285408.

ABSTRACT: -- No abstract --

3 Editorial The IBD drug pipeline-ready to deliver? 2014

Higgins, Peter Dr. ·Department of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA. ·Am J Gastroenterol · Pubmed #24989095.

ABSTRACT: The study of modified-release phosphatidylcholine in this issue of the American Journal of Gastroenterology by Karner et al. is a substantial step forward for a mucosal barrier agent in inflammatory bowel disease (IBD). It is the first agent in a novel class to demonstrate clinical efficacy in a phase 2 study. There are a number of new agents with new mechanisms of action that are rapidly advancing through the IBD drug development pipeline. This article reviews the promising candidates and mechanisms of action in late-phase trials in IBD.

4 Review Chronic Colitis in Biopsy Samples: Is It Inflammatory Bowel Disease or Something Else? 2017

Choi, Eun-Young Karen / Appelman, Henry D. ·Department of Pathology, University of Michigan, 5231B Medical Science I, 1301 Catherine Street, SPC 5602, Ann Arbor, MI 48109-5602, USA. Electronic address: ekchoi@med.umich.edu. · Department of Pathology, University of Michigan, 5220 Medical Science I, 1301 Catherine Street, SPC 5602, Ann Arbor, MI 48109-5602, USA. ·Surg Pathol Clin · Pubmed #29103536.

ABSTRACT: Chronic colitis, regardless of type, is defined histologically by chronic inflammation, mainly plasmacytosis, in the lamina propria. Specific diagnosis of chronic colitides in biopsies can be challenging for practicing pathologists. This article focuses on discussing specific histologic features in biopsies of the inflammatory bowel diseases (IBDs), including ulcerative colitis, Crohn colitis, and colitis of indeterminate type. It also offers suggestions as to how to separate the IBDs from other chronic colitides, such as lymphocytic colitis, collagenous colitis, diverticular disease-associated colitis, diversion colitis, and chronic colitides that are due to drugs. Normal histology in colon biopsies is also briefly discussed.

5 Review Risk for Overall Infection with Anti-TNF and Anti-integrin Agents Used in IBD: A Systematic Review and Meta-analysis. 2017

Shah, Eric D / Farida, Jeremy P / Siegel, Corey A / Chong, Kelly / Melmed, Gil Y. ·*Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan; †Section of Gastroenterology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; ‡Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico; and §Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California. ·Inflamm Bowel Dis · Pubmed #28230558.

ABSTRACT: BACKGROUND: The overall risk for infection with contemporary biological agents in treating Crohn's disease (CD) and ulcerative colitis (UC) has not been systematically assessed. METHODS: We performed a PubMed and Cochrane database literature search to evaluate randomized, placebo-controlled trials of biologics in treating UC and CD. Meta-analysis was performed using a DerSimonian and Laird random effects model. We determined relative risk (RR) of harm against placebo; number needed to harm (NNH) was reported when appropriate. Heterogeneity and publication bias were assessed. RESULTS: Fourteen trials (6 UC and 8 CD) evaluating 5107 patients were included. For anti-tumor necrosis factor agents used in the treatment of UC, golimumab {NNH of 9.3, RR = 1.4 (95% confidence interval [CI], 1.04-1.8)} and pooled studies of infliximab and adalimumab (NNH = 17.2, RR = 1.2 [95% CI, 1.0-1.3]) had a statistically significant higher risk for any infection versus placebo. Risk was not significantly increased in anti-tumor necrosis factor trials in CD (RR = 1.1 [95% CI, 0.8-1.5]). By contrast, anti-integrin agents in UC (RR = 1.0 [95% CI, 0.9-1.2]) or CD (RR = 1.1 [95% CI, 0.97-1.3]) did not confer a statistically significant excess risk of infection versus placebo. CONCLUSIONS: Anti-tumor necrosis factor therapy but not anti-integrin therapy is associated with a greater infection risk than placebo in treating UC. Neither class of therapy is associated with increased infection risk over placebo in treating CD. Our findings can help guide patient-centered discussions regarding the risk for infection with biological agents.

6 Review Factors associated with poor outcomes in adults with newly diagnosed ulcerative colitis. 2015

Reinisch, Walter / Reinink, Andrew R / Higgins, Peter D R. ·Department of Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address: reinisw@mcmaster.ca. · Department of Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan. ·Clin Gastroenterol Hepatol · Pubmed #24887059.

ABSTRACT: It is a challenge to accurately identify patients with early stage ulcerative colitis (UC) who are at highest risk for a poor outcome and therefore might require salvage therapy. Several epidemiologic and clinical studies have analyzed factors associated with poor prognosis and increased risk for colectomy. We review prognostic factors for adults with newly diagnosed UC and discuss which patients might benefit from rapid and progressive therapy. Patients with poor prognoses tend to be young nonsmokers with high levels of inflammatory biomarkers, low levels of hemoglobin, and extensive disease, based on colonoscopy. We examine these risk factors in 2 hypothetical patients who have been newly diagnosed with UC.

7 Review Vedolizumab: an α4β7 integrin inhibitor for inflammatory bowel diseases. 2014

Smith, Michael A / Mohammad, Rima A. ·University of the Sciences, Philadelphia, PA, USA mic.smith@usciences.edu. · University of Michigan College of Pharmacy, University of Michigan Health Systems, Ann Arbor, MI, USA. ·Ann Pharmacother · Pubmed #25186623.

ABSTRACT: OBJECTIVES: To review the pharmacology, efficacy, and safety of vedolizumab in the treatment of patients with ulcerative colitis (UC) and Crohn's disease (CD). DATA SOURCES: A literature search through clinicialtrials.gov, EMBASE and MEDLINE was conducted (January 1966-June 2014) using the terms vedolizumab and MLN0002. References from retrieved articles were reviewed for any additional material. Additionally, the prescribing information was retrieved. STUDY SELECTION/DATA EXTRACTION: Phase 1, 2, and 3 human and animal studies describing the pharmacology, pharmacokinetics, efficacy, and safety of vedolizumab were identified. DATA SYNTHESIS: Vedolizumab, an α4β7 integrin inhibitor, was recently approved for adult patients with moderate to severe active UC or CD who are refractory or intolerant to standard therapies or who are dependent on corticosteroids. Trial data have demonstrated that vedolizumab 300 mg at weeks 0, 2, and 6 followed by every 8 weeks is effective at inducing and maintaining clinical response and remission, improving mucosal appearance, and achieving corticosteroid-free remission in patients with UC. This regimen is also effective at achieving clinical response, remission, and corticosteroid-free remission in patients with CD. Patients treated with vedolizumab, unadjusted for exposure, reported experiencing nasopharyngitis, headache, nausea, arthralgias, pyrexia, upper-respiratory-tract infections, fatigue, and cough. CONCLUSIONS: Vedolizumab is an effective agent at inducing and maintaining remission in patients with UC or CD. Vedolizumab is generally well tolerated and has not been associated with progressive multifocal leukoencephalopathy.

8 Review Systematic review with network meta-analysis: the efficacy of anti-tumour necrosis factor-alpha agents for the treatment of ulcerative colitis. 2014

Stidham, R W / Lee, T C H / Higgins, P D R / Deshpande, A R / Sussman, D A / Singal, A G / Elmunzer, B J / Saini, S D / Vijan, S / Waljee, A K. ·Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA. ·Aliment Pharmacol Ther · Pubmed #24506179.

ABSTRACT: BACKGROUND: Antibodies against tumour necrosis factor-alpha (anti-TNF) are effective therapies in the treatment of ulcerative colitis (UC), but their comparative efficacy is unknown. AIM: To perform a network meta-analysis comparing the efficacy of anti-TNF agents in UC. METHODS: After screening 506 studies, reviewers extracted information on seven studies. Traditional meta-analysis (TMA) was used to compare each anti-TNF agent to placebo. Bayesian network meta-analysis (NMA) was performed to compare the effects of anti-TNF agents to placebo. In addition, sample sizes for comparative efficacy trials were calculated. RESULTS: Compared to placebo, TMA revealed that anti-TNF agents result in a higher likelihood of induction of remission and response (RR: 2.45, 95% CI: 1.72-3.47 and RR: 1.65, 95% CI: 1.37-1.99 respectively) as well as maintenance of remission and response (RR: 2.00, 95% CI: 1.52-2.62 and RR: 1.76, 95% CI: 1.46-2.14 respectively). Individually, infliximab, adalimumab and goliumumab resulted in a higher likelihood of induction and maintenance for both remission and response. NMA found nonsignificant trends in comparisons of the individual agents. The required sample sizes for direct head-to-head trials between infliximab and adalimumab for induction and maintenance are 174 and 204 subjects respectively. CONCLUSIONS: This study demonstrates that, compared to placebo, infliximab, adalimumab and golimumab are all effective for the induction and maintenance of remission in ulcerative colitis. However, network meta-analysis demonstrates that no single agent is clinically superior to the others and therefore, other factors such as cost, safety, route of administration and patient preference should dictate our choice of anti-TNF agents. A randomised comparative efficacy trial between infliximab and adalimumab in UC is of practical size and should be performed.

9 Review Voting With their Feet (VWF) endpoint: a meta-analysis of an alternative endpoint in clinical trials, using 5-ASA induction studies in ulcerative colitis. 2009

Rangwalla, Sujal C / Waljee, Akbar K / Higgins, Peter D R. ·Division of Gastroenterology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA. ·Inflamm Bowel Dis · Pubmed #19058232.

ABSTRACT: BACKGROUND: Strict clinical remission endpoints in ulcerative colitis (UC) trials produce low remission rates and do not reflect the good outcomes of UC therapy. We proposed the use of the VWF (Voting With their Feet) endpoint, the percentage of subjects leaving a randomized controlled trial (RCT) arm for lack of efficacy). The aims were 1) to determine if the VWF endpoint can be extracted from 5-aminosalicylate (5-ASA) RCTs in UC; 2) to perform meta-analyses of VWF and clinical remission (CR) endpoints; and 3) to determine the statistical power of the VWF endpoint. METHODS: Fixed effects meta-analysis and power calculations were used. RESULTS: In 5 studies, including 1048 subjects, 9.5% of patients left 5-ASA study arms for lack of efficacy, versus 28.3% leaving placebo. The rate of failure to achieve CR was 68.2% with 5-ASA, versus 86.9% with placebo. The relative risk (RR) of treatment failure for 5-ASA using the VWF endpoint was 0.33 (95% confidence interval [CI] 0.24-0.44), which was significantly smaller than with the CR endpoint (RR 0.81, 95% CI 0.76-0.88). The statistical power of VWF was slightly greater than CR. CONCLUSIONS: VWF is inexpensive, intuitive, and has similar statistical power to CR. The VWF endpoint can confirm the validity of outcome measures in clinical trials, and estimate real-world clinical efficacy.

10 Review Systematic review: impact of non-adherence to 5-aminosalicylic acid products on the frequency and cost of ulcerative colitis flares. 2009

Higgins, P D R / Rubin, D T / Kaulback, K / Schoenfield, P S / Kane, S V. ·Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. phiggins@umich.edu ·Aliment Pharmacol Ther · Pubmed #18945258.

ABSTRACT: BACKGROUND: Ulcerative colitis (UC) can be maintained in remission with 5-aminosalicylic acid (5-ASA) medications, but frequent non-adherence by patients who are feeling well has been associated with more frequent flares of colitis. AIM: To perform a systematic review of the published literature and unpublished randomized clinical trials (RCTs) regarding the impact of non-adherence with 5-ASA medications on the incidence of UC flares and costs of care. METHODS: A search of MEDLINE, EMBASE and the Cochrane databases was performed. Prospective studies of UC maintenance with 5-ASAs in adults were selected if they included data on adherence and disease flares. Studies using insurance claims data to estimate the impact of non-adherence on cost of care were included. Data from unpublished RCTs were obtained from the FDA with a request under the Freedom of Information Act. RESULTS: The relative risk for flare in non-adherent vs. adherent patients ranged from 3.65 to infinity. Data were obtained from six unpublished 5-ASA RCTs, but none measured the impact of adherence on disease activity. The comorbidity-adjusted annual costs of care in adherent patients were 12.5% less than in non-adherent patients, despite increased medication expenditures. CONCLUSIONS: A substantial proportion of UC flares and medical costs of UC are attributable to 5-ASA non-adherence. As non-adherence to 5-ASA medications is common, cost-effective strategies to improve adherence are needed. The impact of adherence on disease activity should be measured in RCTs of all inflammatory bowel disease treatments.

11 Article Methotrexate Is Not Superior to Placebo in Maintaining Steroid-Free Response or Remission in Ulcerative Colitis. 2018

Herfarth, Hans / Barnes, Edward L / Valentine, John F / Hanson, John / Higgins, Peter D R / Isaacs, Kim L / Jackson, Susan / Osterman, Mark T / Anton, Kristen / Ivanova, Anastasia / Long, Millie D / Martin, Christopher / Sandler, Robert S / Abraham, Bincy / Cross, Raymond K / Dryden, Gerald / Fischer, Monika / Harlan, William / Levy, Campbell / McCabe, Robert / Polyak, Steven / Saha, Sumona / Williams, Emmanuelle / Yajnik, Vijay / Serrano, Jose / Sands, Bruce E / Lewis, James D / Anonymous6650953. ·Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina; University of North Carolina Multidisciplinary Center for Inflammatory Bowel Diseases, Chapel Hill, North Carolina. Electronic address: hherf@med.unc.edu. · Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina; University of North Carolina Multidisciplinary Center for Inflammatory Bowel Diseases, Chapel Hill, North Carolina. · Division of Gastroenterology, Hepatology and Nutrition, University of Utah, Salt Lake City, Utah. · Atrium Health, Charlotte, North Carolina. · Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan. · Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. · Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina; Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina; Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. · Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina. · Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina. · Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina; Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina. · Division of Gastroenterology and Hepatology, Houston Methodist-Weill Cornell, Houston, Texas. · Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland. · Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, Kentucky. · Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana. · Asheville Gastroenterology Associates, Asheville, North Carolina. · Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. · Minnesota Gastroenterology, Plymouth, Minnesota. · Division of Gastroenterology, Hepatology and Nutrition, University of Iowa, Iowa City, Iowa. · Division of Gastroenterology and Hepatology, University of Wisconsin, Madison, Wisconsin. · Division of Gastroenterology and Hepatology, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania. · Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. · Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York. · Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. · see sites and investigators in Supplementary Material. ·Gastroenterology · Pubmed #29964043.

ABSTRACT: BACKGROUND & AIMS: Parenteral methotrexate induces clinical remission but not endoscopic improvement of mucosal inflammation in patients with ulcerative colitis (UC). We performed a randomized, placebo-controlled trial to assess the efficacy of parenteral methotrexate in maintaining steroid-free response or remission in patients with UC after induction therapy with methotrexate and steroids. METHODS: We performed a 48-week trial, from February 2012 through May 2016, of 179 patients with active UC (Mayo score of 6-12 with endoscopy subscore ≥ 2) despite previous conventional or biological therapy. The study comprised a 16-week open label methotrexate induction period followed by a 32-week double-blind, placebo-controlled maintenance period. Patients were given subcutaneous methotrexate (25 mg/wk) and a 12-week steroid taper. At week 16, steroid-free responders were randomly assigned to groups that either continued methotrexate (25 mg/wk, n = 44) or were given placebo (n = 40) until week 48. We compared the efficacy of treatment by analyzing the proportion of patients who remained relapse free and were in remission at week 48 without use of steroids or other medications to control disease activity. RESULTS: Ninety-one patients (51%) achieved response at week 16, and 84 patients were included in the maintenance period study. During this period, 60% of patients in the placebo group (24/40) and 66% in the methotrexate group (29/44) had a relapse of UC (P = .75). At week 48, 30% of patients in the placebo group (12/40) and 27% of patients in the methotrexate group (12/44) were in steroid-free clinical remission without need for additional therapies (P = .86). No new safety signals for methotrexate were detected. CONCLUSIONS: Parenteral methotrexate (25 mg/wk) was not superior to placebo in preventing relapses of UC in patients who achieved steroid-free response during induction therapy. ClinicalTrials.gov, Number: NCT01393405.

12 Article Systemic Inflammatory Responses in Ulcerative Colitis Patients and Clostridium difficile Infection. 2018

Limsrivilai, Julajak / Rao, Krishna / Stidham, Ryan W / Govani, Shail M / Waljee, Akbar K / Reinink, Andrew / Johnson, Laura / Briggs, Emily / Higgins, Peter D R. ·Division of Gastroenterology, Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA. · Internal Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand. · VA Center for Clinical Management Research, Ann Arbor, MI, USA. · Gastroenterology, Veterans Affairs Medical Center, Minneapolis, MN, USA. · Brown University, Providence, RI, USA. · Division of Gastroenterology, Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA. phiggins@med.umich.edu. ·Dig Dis Sci · Pubmed #29644517.

ABSTRACT: BACKGROUND/AIMS: Finding differences in systemic inflammatory response in ulcerative colitis (UC), UC with Clostridium difficile infection (CDI), and CDI could lead to a better ability to differentiate between UC with symptomatic CDI and UC with C. difficile colonization, and could identify specific inflammatory pathways for UC or CDI, which could be therapeutic targets. METHODS: We prospectively collected sera from symptomatic UC patients whose stools were tested for toxigenic C. difficile, and from CDI patients who did not have UC (CDI-noUC). The UC patients with positive tests (UC-CDI) were further categorized into responders to CDI treatment (UC-CDI-R) and non-responders (UC-CDI-NR). We compared serum inflammatory mediators among groups using unadjusted and adjusted multivariable statistics. RESULTS: We included 117 UC [27 UC-CDI, 90 UC without CDI (UC-noCDI)] and 16 CDI-noUC patients. Principal component analysis (PCA) did not reveal significant differences either between UC-CDI and UC-noCDI groups, or between UC-CDI-R and UC-CDI-NR groups. In contrast, the PCA showed significant separation between the UC and CDI-noUC groups (P = 0.002). In these two groups, hepatocyte growth factor (HGF) and chemokine (C-C motif) ligand 2 (CCL2) levels were significantly lower and IL-23 levels were higher in UC patients in multivariable analyses. The model to distinguish UC from CDI including IL-23, HGF, CCL2, age, gender, and HGB had an AuROC of 0.93. CONCLUSION: Inflammatory profiles could not distinguish UC-CDI from UC-noCDI, and UC-CDI-R from UC-CDI-NR. However, the UC and CDI-noUC groups were significantly different. Future work should examine whether therapeutic agents inhibiting IL-23 or stimulating HGF can treat UC.

13 Article Expression and regulation of proton-coupled oligopeptide transporters in colonic tissue and immune cells of mice. 2018

Wang, Yuqing / Hu, Yongjun / Li, Ping / Weng, Yayun / Kamada, Nobuhiko / Jiang, Huidi / Smith, David E. ·Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA; Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China. · Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. · Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China. · Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA. · Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China. Electronic address: hdjiang@zju.edu.cn. · Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. Electronic address: smithb@umich.edu. ·Biochem Pharmacol · Pubmed #29305856.

ABSTRACT: A number of studies have implicated proton-coupled oligopeptide transporters (POTs) in the initiation and/or progression of inflammatory bowel disease and immune cell signaling. With this in mind, the aim of this study was to delineate the expression of POTs in mouse colonic tissues and immune cells, and characterize the potential role of these transporters in nucleotide-binding oligomerization domain (NOD) signaling. Using a dextran sodium sulfate (DSS)-induced colitis mouse model, we found that DSS down regulated Pht1 gene expression and up regulated Pht2 gene expression in colonic tissue and immune cells. In contrast, PEPT1 protein was absent from the colonic tissue and immune cells of normal and DSS-treated mice. NOD ligands, muramyl dipeptide (MDP) and l-Ala-γ-d-Glu-meso-diaminopimelic acid (tri-DAP), were shown to be substrates of PHT2 in MDCK-hPHT2

14 Article Reduced paraspinous muscle area is associated with post-colectomy complications in children with ulcerative colitis. 2018

Dedhia, Priya H / White, Yasmine / Dillman, Jonathan R / Adler, Jeremy / Jarboe, Marcus D / Teitelbaum, Daniel H / Hirschl, Ronald B / Gadepalli, Samir K. ·Department of Surgery, Division of General Surgery, University of Michigan, Ann Arbor, MI. Electronic address: pdedhia@med.umich.edu. · Department of Surgery, Division of General Surgery, University of Michigan, Ann Arbor, MI. · Department of Radiology, University of Michigan Ann Arbor, MI. · Department of Pediatrics and Communicable Diseases, Division of Pediatric Gastroenterology, University of Michigan, Ann Arbor, MI; Children's Health Evaluation and Research Unit, University of Michigan, Ann Arbor, MI. · Department of Surgery, Division of Pediatric Surgery, University of Michigan, Ann Arbor, MI. · Children's Health Evaluation and Research Unit, University of Michigan, Ann Arbor, MI; Department of Surgery, Division of Pediatric Surgery, University of Michigan, Ann Arbor, MI. ·J Pediatr Surg · Pubmed #29103786.

ABSTRACT: BACKGROUND AND OBJECTIVES: Sarcopenia, defined as reduced muscle mass, is typically assessed by CT scans, which are infrequently performed in children. Using MRI to measure sarcopenia, we determined the association with postoperative complications after colectomy for ulcerative colitis (UC). METHODS: Clinical and preoperative MRI data for 13-18-year-old UC patients who underwent colectomy were retrospectively reviewed. Bilateral paraspinous muscle area (PSMA) and psoas muscle area (PMA) at L3 vertebra were measured and averaged. Composite complications were infection, wound dehiscence, postoperative leak/abscess, prolonged ileus, pulmonary embolism, venous thromboembolism, or readmission. RESULTS: Twenty-nine patients with average age 15.9±1.36years and weight 61.5±19.8kg had a preoperative MRI. The 18/29(62%) with complications had significantly reduced PSMA (4.71±1.44 vs 5.64±1.38cm2, p=0.04) and PMA (7.16±2.60 vs 8.93±2.44, p=0.04). When stratified and compared to highest PSMA, patients with lowest PSMA had increased complication rates (88% vs 29%, p=0.04). There were no differences in age, BMI, albumin, CRP, ESR, or preoperative steroid or anti-TNFα use. Odds of complication in the lowest tertile were 25.0-fold higher than the highest tertile (p=0.04, 95% CI=1.2-520.73). CONCLUSION: This is the first study to show low PSMA on MRI is associated with complications and increased hospital stay after colectomy in children with UC. LEVELS OF EVIDENCE: Level III retrospective comparative study.

15 Article Route Connection: Mouth to Intestine in Colitis. 2017

Inohara, Naohiro. ·Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: ino@umich.edu. ·Cell Host Microbe · Pubmed #29241039.

ABSTRACT: In a recent study published in Science, Atarashi et al. (2017) showed that Klebsiella strains isolated from the saliva of Crohn's disease patients can induce Th1 cell responses to promote colitis. Their findings highlight the importance of the oral cavity as a potential reservoir for bacteria that can promote intestinal disease.

16 Article Longitudinal Patterns of Medication Nonadherence and Associated Health Care Costs. 2017

Hommel, Kevin A / McGrady, Meghan E / Peugh, James / Zacur, George / Loreaux, Katherine / Saeed, Shehzad / Williams, Elizabeth / Denson, Lee A. ·*Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; †Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio; and ‡Department of Pediatrics, University of Michigan School of Medicine, Ann Arbor, Michigan. ·Inflamm Bowel Dis · Pubmed #28617754.

ABSTRACT: BACKGROUND: Nonadherence to treatment recommendations is associated with poorer outcomes in inflammatory bowel disease and may increase the cost of care. We examined the longitudinal relationship between nonadherence and health care costs and hypothesized that at least 3 distinct trajectories of nonadherence would be observed and that increasing nonadherence would account for significantly greater health care costs after controlling for disease activity. METHODS: Ninety-nine patients aged 2 to 21 years with inflammatory bowel disease were recruited into this 2-year longitudinal study. Medication possession ratios were calculated from pharmacy refill data, disease activity ratings were obtained from medical charts, and hospital and physician charges associated with an International Classification of Diseases, Ninth Revision code for ulcerative colitis or Crohn's disease were obtained from the hospital's accounting database. RESULTS: An average total cost effect size of d = 0.68 was observed between the increasing severity and stable low severity groups, but the confidence intervals overlap. Conversely, patients with increasing nonadherence demonstrated significantly higher health care costs than patients with stable ≤10%, stable 11% to 20%, or decreasing nonadherence. CONCLUSIONS: Medication nonadherence is related to increased health care costs after controlling for disease severity. Patients with increasing nonadherence over time demonstrate more than a 3-fold increase in costs compared with adherent patients. In addition, patients whose adherence improves over time incur approximately the same costs as those who are consistently adherent. This suggests that, in addition to leveraging prevention efforts to keep patients from becoming more nonadherent as treatment continues, efforts aimed at modifying adherence behavior may result in significant cost savings over time.

17 Article IL-36γ signaling controls the induced regulatory T cell-Th9 cell balance via NFκB activation and STAT transcription factors. 2017

Harusato, A / Abo, H / Ngo, V L / Yi, S W / Mitsutake, K / Osuka, S / Kohlmeier, J E / Li, J D / Gewirtz, A T / Nusrat, A / Denning, T L. ·Center for Inflammation, Immunity, &Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA. · Department of Neurosurgery, Emory University, Atlanta, Georgia, USA. · Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, USA. · Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. ·Mucosal Immunol · Pubmed #28327619.

ABSTRACT: Regulatory and effector T helper (Th) cells are abundant at mucosal surfaces, especially in the intestine, where they control the critical balance between tolerance and inflammation. However, the key factors that reciprocally dictate differentiation along these specific lineages remain incompletely understood. Here we report that the interleukin-1 (IL-1) family member IL-36γ signals through IL-36 receptor, myeloid differentiation primary response gene 88, and nuclear factor-κBp50 in CD4

18 Article NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth. 2017

Chen, Liang / Wilson, Justin E / Koenigsknecht, Mark J / Chou, Wei-Chun / Montgomery, Stephanie A / Truax, Agnieszka D / Brickey, W June / Packey, Christopher D / Maharshak, Nitsan / Matsushima, Glenn K / Plevy, Scott E / Young, Vincent B / Sartor, R Balfour / Ting, Jenny P-Y. ·Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA. · Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. · Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, New York, USA. · Department of Gastroenterology, Tel-Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. · UNC Neuroscience Center and Integrative Program for Biological Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. · Immunology Research and Development, Janssen Pharmaceuticals, Spring House, Pennsylvania, USA. · Center for Gastrointestinal Biology and Disease and the Departments of Medicine, of Microbiology and of Immunology, University of North Carolina, Chapel Hill, North Carolina, USA. ·Nat Immunol · Pubmed #28288099.

ABSTRACT: Inflammatory bowel diseases involve the dynamic interaction of host genetics, the microbiome and inflammatory responses. Here we found lower expression of NLRP12 (which encodes a negative regulator of innate immunity) in human ulcerative colitis, by comparing monozygotic twins and other patient cohorts. In parallel, Nlrp12 deficiency in mice caused increased basal colonic inflammation, which led to a less-diverse microbiome and loss of protective gut commensal strains (of the family Lachnospiraceae) and a greater abundance of colitogenic strains (of the family Erysipelotrichaceae). Dysbiosis and susceptibility to colitis associated with Nlrp12 deficency were reversed equally by treatment with antibodies targeting inflammatory cytokines and by the administration of beneficial commensal Lachnospiraceae isolates. Fecal transplants from mice reared in specific-pathogen-free conditions into germ-free Nlrp12-deficient mice showed that NLRP12 and the microbiome each contributed to immunological signaling that culminated in colon inflammation. These findings reveal a feed-forward loop in which NLRP12 promotes specific commensals that can reverse gut inflammation, while cytokine blockade during NLRP12 deficiency can reverse dysbiosis.

19 Article Subcorneal pustular dermatosis and episcleritis associated with poorly controlled ulcerative colitis. 2017

Wargo, Jeffrey J / Adams, Megan / Trevino, Julian. ·Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA. · Department of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan, USA. · Department of Dermatology, Wright State University Boonshoft School of Medicine, Dayton, Ohio, USA. ·BMJ Case Rep · Pubmed #28137903.

ABSTRACT: A man aged 56 years with a history of ulcerative colitis (UC) status postsubtotal colectomy was hospitalised with fevers, dry cough, eye redness and a new bloody, mucoid rectal discharge. 2 months prior to admission, the dermatologist had started him on dapsone for subcorneal pustular dermatosis but did not recognise that he had recently self-discontinued mesalamine enemas, inducing a flare of his UC. After a thorough inpatient evaluation, including flexible sigmoidoscopy, active UC involving the rectal stump was determined to be driving his dermatological and ophthalmological findings. By reinstituting mesalamine enemas, control of his UC was achieved and the extraintestinal manifestations of his inflammatory bowel disease (IBD) resolved. This case illustrates the importance of careful history taking and of early recognition of extraintestinal manifestations of IBD in order to appropriately target treatment and prevent unnecessary morbidity.

20 Article The anti-inflammatory drug mesalamine targets bacterial polyphosphate accumulation. 2017

Dahl, Jan-Ulrik / Gray, Michael J / Bazopoulou, Daphne / Beaufay, Francois / Lempart, Justine / Koenigsknecht, Mark J / Wang, Ying / Baker, Jason R / Hasler, William L / Young, Vincent B / Sun, Duxin / Jakob, Ursula. ·Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Internal Medicine/Division of Infectious Diseases &Department of Microbiology and Immunology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ·Nat Microbiol · Pubmed #28112760.

ABSTRACT: Mesalamine serves as the gold standard in treating ulcerative colitis. However, its precise mechanism(s) of action remains unclear. Here, we show that mesalamine treatment rapidly decreases polyphosphate levels in diverse bacteria, including members of the human gut microbiome. This decrease sensitizes bacteria towards oxidative stress, reduces colonization and attenuates persister cell and biofilm formation, suggesting that mesalamine aids in diminishing the capacity of bacteria to persist within chronically inflamed environments.

21 Article Characteristics and Behavior of Elderly-onset Inflammatory Bowel Disease: A Multi-center US Study. 2016

Hou, Jason K / Feagins, Linda A / Waljee, Akbar K. ·*Houston VA HSR&D Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; †Department of Medicine, Baylor College of Medicine, Houston, Texas; ‡Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; §Department of Medicine, VA North Texas Healthcare System, Dallas, Texas; ‖Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; ¶Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, Michigan; and **VA Center for Clinical Management Research, Ann Arbor, Michigan. ·Inflamm Bowel Dis · Pubmed #27482973.

ABSTRACT: BACKGROUND: Existing data conflict regarding differences in inflammatory bowel disease (IBD) characteristics between adult-onset and elderly-onset IBD. IBD extent and behavior are strong predictors of IBD-related surgery and complications. The aim of this study was to compare disease characteristics and behavior of adult- and elderly-onset IBD in a multi-center US study. METHODS: We performed a multi-center retrospective cohort study of patients with IBD. Chart review was performed to confirm IBD diagnoses and extract data regarding IBD characteristics, medications, surgery, cancer, and death. Patients were classified based on age at IBD diagnosis as adult onset (18-64 years) or elderly onset (≥65 years). RESULTS: A total of 1665 patients were confirmed to have IBD; 272 patients were ≥65 years at IBD diagnosis. Whites were more likely than non-whites to have elderly-onset IBD (adjusted odds ratio 2.26, 95% confidence interval 1.36-3.76). Patients with ulcerative colitis were more likely than CD patients to have elderly-onset IBD (aOR 1.50, 95% confidence interval 1.11-2.03). Compared with patients with adult-onset CD, patients with elderly-onset CD were more likely to have isolated colonic disease and nonstricturing, nonpenetrating phenotype, but less likely to have perianal complications or receive immunosuppressants. Rates of bowel resection, and both colonic and extra-colonic malignancies did not differ based on age of IBD onset. CONCLUSIONS: There are several significant differences in the disease characteristics between adult- and late-onset IBD; these differences may reflect differences in natural history of IBD and influence approaches to management among patients with elderly-onset IBD.

22 Article Neurotensin Promotes the Development of Colitis and Intestinal Angiogenesis via Hif-1α-miR-210 Signaling. 2016

Bakirtzi, Kyriaki / Law, Ivy Ka Man / Xue, Xiang / Iliopoulos, Dimitrios / Shah, Yatrik M / Pothoulakis, Charalabos. ·Inflammatory Bowel Disease Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095; · Division of Gastroenterology, Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109; · Division of Digestive Diseases, Center for Systems Biomedicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095; and. · Division of Gastroenterology, Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109; Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109. · Inflammatory Bowel Disease Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095; cpothoulakis@mednet.ucla.edu. ·J Immunol · Pubmed #27076683.

ABSTRACT: Neurotensin (NT) via its receptor 1 (NTR1) modulates the development of colitis, decreases HIF-1α/PHD2 interaction, stabilizes and increases HIF-1α transcriptional activity, and promotes intestinal angiogenesis. HIF-1α induces miR-210 expression, whereas miR-210 is strongly upregulated in response to NT in NCM460 human colonic epithelial cells overexpressing NTR1 (NCM460-NTR1). In this study, we examined whether NT activates a NTR1-HIF-1α-miR-210 cascade using in vitro (NCM460-NTR1 cells) and in vivo (transgenic mice overexpressing [HIF-1α-OE] or lacking HIF-1α [HIF-1α-knockout (KO)] in intestinal epithelial cells and mice lacking NTR1 [NTR1-KO]) models. Pretreatment of NCM460-NTR1 cells with the HIF-1α inhibitor PX-478 or silencing of HIF-1α (small interfering HIF-1α) attenuated miR-210 expression in response to NT. Intracolonic 2,4,6-trinitrobenzenesulfonic acid (TNBS) administration (2-d model) increased colonic miR-210 expression that was significantly reduced in NTR1-KO, HIF-1α-KO mice, and wild-type mice pretreated intracolonically with locked nucleic acid anti-miR-210. In contrast, HIF-1α-OE mice showed increased miR-210 expression at baseline that was further increased following TNBS administration. HIF-1α-OE mice had also exacerbated TNBS-induced neovascularization compared with TNBS-exposed wild-type mice. TNBS-induced neovascularization was attenuated in HIF-1α-KO mice, or mice pretreated intracolonically with anti-miR-210. Intracolonic anti-miR-210 also reduced colitis in response to TNBS (2 d). Importantly, miR-210 expression was increased in tissue samples from ulcerative colitis patients. We conclude that NT exerts its proinflammatory and proangiogenic effects during acute colitis via a NTR1-prolyl hydroxylase 2/HIF-1α-miR-210 signaling pathway. Our results also demonstrate that miR-210 plays a proinflammatory role in the development of colitis.

23 Article Effect of Psychotherapy on Health Care Utilization in Children With Inflammatory Bowel Disease and Depression. 2016

Keerthy, Divya / Youk, Ada / Srinath, Arvind I / Malas, Nasuh / Bujoreanu, Simona / Bousvaros, Athos / Keljo, David / DeMaso, David R / Szigethy, Eva M. ·*University of Pittsburgh School of Medicine †Department of Biostatistics, University of Pittsburgh ‡Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC §Departments of Psychiatry and Pediatrics, University of Michigan Health System ||Department of Psychiatry, Boston Children's Hospital ¶Division of Gastroenterology, Hepatology, & Nutrition, Boston Children's Hospital #Division of Pediatric Gastroenterology, Children's Hospital of Pittsburgh of UPMC **Department of Psychiatry, University of Pittsburgh. ·J Pediatr Gastroenterol Nutr · Pubmed #27035372.

ABSTRACT: OBJECTIVES: Pediatric patients with inflammatory bowel disease (IBD) are at an increased risk of developing depression compared with community controls. Depression often negatively influences illness behaviors such as resource utilization. We sought to investigate the effects of treating depression on utilization of medical resources in depressed pediatric patients with IBD by comparing rates of health care utilization 1 year before and after psychotherapy. METHOD: Two hundred seventeen subjects ages 9 to 17 years with IBD and depression received 3 months of psychotherapy for depression as part of a multicenter randomized controlled trial. Of these 217 subjects, 70 had utilization data available 1 year prior and 1 year after receiving 3 months of psychotherapy. Primary outcomes included frequency of hospitalizations, inpatient hospital days, outpatient gastrointestinal visits, and number of emergency room visits, radiological examinations, and endoscopies. Within subject analyses were completed comparing health care utilization 12 months before psychotherapy compared with the 12 months after the conclusion of psychotherapy. RESULTS: Fifty-one and 19 patients had CD and UC, respectively. A total of 55.7% of patients had major depression and 44.3% had minor depression. Overall, all study measures of health care utilization were significantly reduced after psychotherapy (P < 0.01)-including gastrointestinal-related (mean values) hospitalization frequency, inpatient days, outpatient visit, emergency room visits, radiological examinations, and endoscopies. CONCLUSIONS: Psychotherapy for comorbid depression in pediatric patients with IBD is associated with decreased GI-related health care utilization. The present study highlights the importance of screening for depression in a pediatric population with IBD, and that psychotherapy may be a reasonable adjunctive treatment for pediatric patients with IBD and comorbid depression.

24 Article Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. 2016

Ellinghaus, David / Jostins, Luke / Spain, Sarah L / Cortes, Adrian / Bethune, Jörn / Han, Buhm / Park, Yu Rang / Raychaudhuri, Soumya / Pouget, Jennie G / Hübenthal, Matthias / Folseraas, Trine / Wang, Yunpeng / Esko, Tonu / Metspalu, Andres / Westra, Harm-Jan / Franke, Lude / Pers, Tune H / Weersma, Rinse K / Collij, Valerie / D'Amato, Mauro / Halfvarson, Jonas / Jensen, Anders Boeck / Lieb, Wolfgang / Degenhardt, Franziska / Forstner, Andreas J / Hofmann, Andrea / Anonymous3910861 / Anonymous3920861 / Anonymous3930861 / Anonymous3940861 / Anonymous3950861 / Schreiber, Stefan / Mrowietz, Ulrich / Juran, Brian D / Lazaridis, Konstantinos N / Brunak, Søren / Dale, Anders M / Trembath, Richard C / Weidinger, Stephan / Weichenthal, Michael / Ellinghaus, Eva / Elder, James T / Barker, Jonathan N W N / Andreassen, Ole A / McGovern, Dermot P / Karlsen, Tom H / Barrett, Jeffrey C / Parkes, Miles / Brown, Matthew A / Franke, Andre. ·Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany. · Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. · Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford, UK. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. · Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea. · Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. · Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. · Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Division of Rheumatology, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. · Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. · Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. · Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway. · K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway. · Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway. · Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. · Estonian Genome Center, University of Tartu, Tartu, Estonia. · Division of Endocrinology, Boston Children's Hospital, Cambridge, Massachusetts, USA. · Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge, Massachusetts, USA. · University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands. · Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. · Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. · Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands. · Department of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden. · BioCruces Health Research Institute and Ikerbasque, Basque Foundation for Science, Bilbao, Spain. · Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden. · Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Institute of Epidemiology, University Hospital Schleswig-Holstein, Kiel, Germany. · PopGen Biobank, University Hospital Schleswig-Holstein, Kiel, Germany. · Institute of Human Genetics, University of Bonn, Bonn, Germany. · Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany. · Department of General Internal Medicine, Universitätsklinikum Schleswig-Holstein Campus Kiel, Kiel, Germany. · Department of Dermatology, University Hospital, Schleswig-Holstein, Christian Albrechts University of Kiel, Kiel, Germany. · Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester, Minnesota, USA. · Department of Radiology, University of California, San Diego, La Jolla, California, USA. · Division of Genetics and Molecular Medicine, King's College London, London, UK. · Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA. · Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA. · St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, King's College London, London, UK. · NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Division of Mental Health and Addiction, Oslo University Hospital, Ullevål, Oslo, Norway. · F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, California, USA. · Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK. · University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. · Institute of Health and Biomedical Innovation (IHBI), Faculty of Health, Queensland University of Technology (QUT), Translational Research Institute, Brisbane, Queensland, Australia. ·Nat Genet · Pubmed #26974007.

ABSTRACT: We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.

25 Article Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis. 2016

Ro, Seung-Hyun / Xue, Xiang / Ramakrishnan, Sadeesh K / Cho, Chun-Seok / Namkoong, Sim / Jang, Insook / Semple, Ian A / Ho, Allison / Park, Hwan-Woo / Shah, Yatrik M / Lee, Jun Hee. ·Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States. · Department of Biochemistry, University of Nebraska, Lincoln, United States. · Department of Cell Biology, College of Medicine, Konyang University, Daejeon, Republic of Korea. · Myung-Gok Eye Research Institute, Konyang University, Seoul, Republic of Korea. ·Elife · Pubmed #26913956.

ABSTRACT: The mTOR complex 1 (mTORC1) and endoplasmic reticulum (ER) stress pathways are critical regulators of intestinal inflammation and colon cancer growth. Sestrins are stress-inducible proteins, which suppress both mTORC1 and ER stress; however, the role of Sestrins in colon physiology and tumorigenesis has been elusive due to the lack of studies in human tissues or in appropriate animal models. In this study, we show that human SESN2 expression is elevated in the colon of ulcerative colitis patients but is lost upon p53 inactivation during colon carcinogenesis. In mouse colon, Sestrin2 was critical for limiting ER stress and promoting the recovery of epithelial cells after inflammatory injury. During colitis-promoted tumorigenesis, Sestrin2 was shown to be an important mediator of p53's control over mTORC1 signaling and tumor cell growth. These results highlight Sestrin2 as a novel tumor suppressor, whose downregulation can accelerate both colitis and colon carcinogenesis.

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