Real-Life Efficacy of Tofacitinib in Various Situations in Ulcerative Colitis: A Retrospective Worldwide Multicenter Collaborative Study.

BACKGROUND AND AIMS: Tofacitinib (TFB) appears to be effective in the treatment of ulcerative colitis (UC); however, available real-world studies are limited by cohort size. TFB could be an option in the treatment of acute severe ulcerative colitis (ASUC). We aimed to investigate efficacy and safety of TFB in moderate-to-severe colitis and ASUC. METHODS: This retrospective, international cohort study enrolling UC patients with ≥6-week follow-up period was conducted from February 1 to July 31, 2022. Indications were categorized as ASUC and chronic activity (CA). Baseline demographic and clinical data were obtained. Steroid-free remission (SFR), colectomy, and safety data were analyzed. RESULTS: A total of 391 UC patients (median age 38 [interquartile range, 28-47] years; follow-up period 26 [interquartile range, 14-52] weeks) were included. A total of 27.1% received TFB in ASUC. SFR rates were 23.7% (ASUC: 26.0%, CA: 22.8%) at week 12 and 41.1% (ASUC: 34.2%, CA: 43.5%) at week 52. The baseline partial Mayo score (odds ratio [OR], 0.850; P = .006) was negatively associated with week 12 SFR, while biologic-naïve patients (OR, 2.078; P = .04) more likely achieved week 52 SFR. The colectomy rate at week 52 was higher in ASUC group (17.6% vs 5.7%; P < .001) and decreased with age (OR, 0.94; P = .013). A total of 67 adverse events were reported, and 17.9% resulted in cessation of TFB. One case of thromboembolic event was reported. CONCLUSIONS: TFB is effective in both studied indications. TFB treatment resulted in high rates of SFR in the short and long terms. Higher baseline disease activity and previous biological therapies decreased efficacy. No new adverse event signals were found.

The cost of inflammatory bowel disease in high-income settings: a Lancet Gastroenterology & Hepatology Commission.

The cost of caring for patients with inflammatory bowel disease (IBD) continues to increase worldwide. The cause is not only a steady increase in the prevalence of Crohn's disease and ulcerative colitis in both developed and newly industrialised countries, but also the chronic nature of the diseases, the need for long-term, often expensive treatments, the use of more intensive disease monitoring strategies, and the effect of the diseases on economic productivity. This Commission draws together a wide range of expertise to discuss the current costs of IBD care, the drivers of increasing costs, and how to deliver affordable care for IBD in the future. The key conclusions are that (1) increases in health-care costs must be evaluated against improved disease management and reductions in indirect costs, and (2) that overarching systems for data interoperability, registries, and big data approaches must be established for continuous assessment of effectiveness, costs, and the cost-effectiveness of care. International collaborations should be sought out to evaluate novel models of care (eg, value-based health care, including integrated health care, and participatory health-care models), as well as to improve the education and training of clinicians, patients, and policy makers.

Identifying patients with inflammatory bowel disease in the Danish National Patient Register.

INTRODUCTION: The Danish National Patient Register (NPR) is an indispensable source of data for population-based studies of inflammatory bowel disease (IBD). Current case-validation algorithms are at risk of overestimating the occurrence of IBD in Denmark. We aimed to develop a new algorithm for validating IBD patients in the Danish NPR and compared it with the algorithm currently used. METHODS: We used the Danish NPR to identify all IBD patients between 1973 and 2018. In addition, we compared the traditional two-registration validation method with a newly developed ten-step method. Data were provided by Statistics Denmark. RESULTS: In total, 69,908 IBD patients (Crohn's disease (CD): 23,500 (33.6%); ulcerative colitis (UC): 38,728 (55.4%); IBD unclassified (IBDU): 7,680 (11.0%)) and 84,872 (UC: 51,304 (60.4%), CD: 20,637 (24.3%), IBDU: 9,931 (11.7%)) were identified using the new and the traditional algorithm, respectively, yielding 21.4% more patients. The sensitivity of each algorithm was 98%; however, the new algorithm demonstrated a superior positive predictive value (PPV) (69% (95% confidence interval (CI): 66-72%) versus 57% (95% CI: 54-59%), p less-than 0.05). The overall incidence rate in 2017 was 44.36 (95% CI: 42.66-46.11) versus 53.41 (95% CI: 51.54-55.33, p less-than 0.0001) for the new and the traditional method, respectively. CONCLUSION: We developed a new and more refined algorithm for validating IBD patients in the Danish NPR. The algorithm will ensure that new studies based upon one of the world's most comprehensive registers will be of an even higher quality. We recommend that all future studies of IBD in Denmark use the new algorithm. FUNDING: none. TRIAL REGISTRATION: not relevant.

The Incidence and Prevalence of Paediatric- and Adult-Onset Inflammatory Bowel Disease in Denmark During a 37-Year Period: A Nationwide Cohort Study (1980-2017).

BACKGROUND: Incidence rates of inflammatory bowel disease [IBD] reported from developed countries are rising, with some levelling out. The aim of this study was to assess the disease burden of IBD by estimating the incidence and prevalence across age groups and projecting these to 2030 in a high-incidence country. METHODS: Using an algorithm [incorporating ICD codes, medications and histopathology], patients [n = 69 862] diagnosed with Crohn's disease [CD] or ulcerative colitis [UC] between 1980 and 2017 were identified in the Danish National Patient Registry and included in a nationwide cohort. RESULTS: From 1980 to 2017 the overall incidence of CD increased from 5.1 [95% CI: 4.5-5.8] to 15.6 [95% CI: 14.6-16.6] per 100 000, while the incidence of UC increased from 6.2 [95% CI: 5.5-6.9] to 27.2 [95% CI: 25.9-28.6] per 100 000. For paediatric-onset CD [pCD], the incidence increased from 1.9 [95% CI: 1.2-2.8] to 9.9 [95% CI: 8.1-11.8] per 100 000 and from 1.8 [95% CI: 1.2-2.8] to 8.7 [95% CI: 7.1- 10.5] per 100 000 for paediatric-onset UC [pUC]. In 2017, the prevalence of CD and UC was 293 [95% CI: 288-297] and 523 [95% CI: 517-528] per 100 000. For pCD and pUC, the prevalence was 35 [95% CI: 31-38] and 28 [95% CI: 26-32] per 100 000. CONCLUSIONS: The incidence of paediatric- and adult-onset IBD in Denmark continues to increase and is among the highest in the world.

Therapeutic management and outcomes in inflammatory bowel diseases, 2010 to 2017 in cohorts from Denmark, Sweden and Norway.

BACKGROUND: Despite the increasing use of biologics in patients with inflammatory bowel disease (IBD), real-world data about outcomes in the era of biologics remain inconclusive. AIMS: To investigate trends in surgeries, hospitalisations and medication use in patients with IBD in a multinational, population-based cohort METHODS: We included 42,894 patients with ulcerative colitis (UC) and 24,864 with Crohn's disease (CD) who were diagnosed between 2010 and 2017 in Denmark, Norway and Sweden. We extracted data about surgeries, hospitalisations and medications from national registries and compared across countries and diagnosis years. RESULTS: Between 2010 and 2017, 2-year surgery rates were 4-7% in UC and 10-15% in CD and were stable over time. Two-year hospitalisation rates increased in Denmark (UC: 20% to 35%; CD: 27% to 32%) but were stable in Norway and Sweden (fluctuating between 33% and 37% in UC, and 46% and 52% in CD). Two-year rates of biologic use increased in both UC (7% to 16% in Denmark, 8% to 18% in Norway) and CD (22% to 26% in Denmark; 21% to 35% in Norway). Two-year rates of immunomodulator use increased in Norway (from 14% to 23% in UC; 37% to 45% in CD) and Sweden (from 41% to 52% in CD), but were stable in Denmark (between 17% and 21% in UC; 39% to 46% in CD). CONCLUSION: Between 2010 and 2017, surgery rates among Scandinavian patients with IBD remained stable, with no clear changes in hospitalisation rates despite the increasing use of immunomodulators and biologics.

[Practical guide to the use of thiopurinesin patients with inflammatory bowel diseases].

Despite the increasing availability of biological treatment in recent years, thiopurines remain an important treatment option in patients with inflammatory bowel diseases (IBD) both as monotherapy and in combination therapy with biologicals. Pre-treatment screening of thiopurine-methyltransferase activity and monitoring of thiopurine metabolites during treatment are essential to optimize the effectiveness and safety of thiopurines. This review provides an evidence-based practical guide to prescribing and monitoring thiopurines in patients with IBD.

Trends in the use of biologicals and their treatment outcomes among patients with inflammatory bowel diseases - a Danish nationwide cohort study.

BACKGROUND: Therapeutic management of inflammatory bowel diseases (IBD) is rapidly evolving, with an expanding armoury of biological drugs at our disposal. However, real-world findings about treatment persistence and the impact of biologicals on surgery remain inconsistent. AIMS: This study aimed to investigate trends in biological use and surgery rates in a nationwide cohort of biological-naïve IBD patients. METHODS: Patients with IBD who initiated biological treatment between 2011 and 2018 were identified in the Danish National Patient Registry. Data on use of biologicals, surgeries and healthcare costs were retrieved and analysed for time trends. RESULTS: Between 2011 and 2018, a total of 6,036 IBD (51% ulcerative colitis (UC), 49% Crohn's disease (CD)) patients received biological treatment for the first time. Cumulative use of biologicals increased from 5.0% to 10.8% among UC and 8.9%-14.5% among CD patients. Infliximab remained the most-prescribed first-line biological for UC and CD. Treatment persistence was 44.3% and 16.9% after 1 and 3 years in UC, compared to 59.9% and 33.6% in CD patients. Overall, 32.8% of patients switched to a second biological. Surgery rates decreased in both UC (P = 0.015) and CD (P = 0.008) patients and remained significant for UC in the Cox regression model (P = 0.002). Outpatient and surgical costs also fell among both UC and CD patients. CONCLUSIONS: Persistence rates for first-line biologicals among IBD patients were low and one-third switched treatment. Surgery rates and direct costs decreased over time, but whether this is related to the use of biologicals has yet to be determined.

Systematic review and meta-analysis: the impact of co-occurring immune-mediated inflammatory diseases on the disease localization and behavior of Crohn's disease.

BACKGROUND: Patients with Crohn's disease (CD) are at increased risk of co-occurring immune-mediated inflammatory diseases (IMIDs). As discrepancy exists regarding the phenotypic presentation of CD among patients with such co-occurring IMIDs, we aimed to conduct a systematic review with meta-analysis characterizing the phenotype of CD among this subgroup of patients. METHODS: PubMed, Embase, and Scopus were searched from their earliest records to October 2019 for studies reporting the behavior and localization of CD according to the Vienna or Montreal Classifications and CD-related surgery in patients with co-occurring IMIDs. These studies were the subject of a random effect meta-analysis. RESULTS: After reviewing 24,413 studies, we identified a total of 23 studies comprising 1572 and 35,043 CD patients with and without co-occurring IMIDs, respectively, that fulfilled our inclusion criteria. Overall, patients with co-occurring IMIDs were more likely to have upper gastrointestinal inflammation than were patients without co-occurring IMIDs [relative risk (RR) = 1.49 (95% confidence interval (CI) 1.09-2.04), p = 0.01, I 2 = 7%]. In addition, presence of primary sclerosing cholangitis (PSC) was associated with a lower occurrence of ileal affection [RR = 0.44 (95% CI 0.24-0.81), p < 0.01, I 2 = 32%], increased occurrence of colonic affection [RR = 1.78 (95% CI 1.33-2.38), p < 0.01, I 2 = 32%] and an increased likelihood of non-stricturing and non-penetrating behavior [RR = 1.43 (95% CI 0.97-2.11), p = 0.07, I 2 = 86%]. The latter reached significance when cumulating different IMIDs [RR = 1.30 (95% CI 1.09-1.55), p < 0.01, I 2 = 88%]. CD patients with PSC also underwent fewer CD-related surgeries [RR = 0.55 (95% CI 0.34-0.88), p = 0.01, I 2 = 0%], irrespective of CD location or behavior. CONCLUSION: This study emphasizes that CD patients with co-existing PSC are likely to have a unique inflammatory distribution primarily confined to the colon, while patients with IMIDs in general have higher likelihood of affection of upper gastrointestinal tract and a non-stricturing and non-penetrating behavior. As such a phenotype of CD is typically associated with a milder disease course; future studies are needed to confirm these results.

Using MR elastography to assess portal hypertension and response to beta-blockers in patients with cirrhosis.

BACKGROUND: MR elastography can determine organ-related stiffness, which reflects the degree of fibrosis. Liver stiffness increases in cirrhosis, and stiffness increases further post-prandially due to increased portal blood in-flow. Non-selective beta-blockers (NSBB) reduce the portal venous inflow, but their effect on liver and spleen stiffness are disputed. AIMS: To assess whether MR elastography of the liver or spleen reflects the severity of cirrhosis, whether treatment with NSBB changes liver and spleen stiffness and whether changes in stiffness can predict the effect of NSBB on portal pressure. METHODS: Fifty-two patients with cirrhosis underwent liver vein catheterization and two-dimensional (2D) MR elastography on separate days. Thirty-six of the patients had a hepatic venous pressure gradient (HVPG) of ≥12 mmHg and were tested prior to, and after, intravenous infusion of NSBB using HVPG measurement and MR elastography. RESULTS: HVPG showed a strong, positive, linear relationship with liver stiffness (r2  = 0.92; P < .001) and spleen stiffness (r2  = 0.94; P < .001). The cut-off points for identifying patients with a HVPG ≥ 12 mmHg were 7.7 kPa for liver stiffness (sensitivity 0.78, specificity 0.64) and 10.5 kPa for spleen stiffness (sensitivity 0.8, specificity 0.79). Intravenous administration of NSBB significantly decreased spleen stiffness by 6.9% (CI: 3.5-10.4, P < .001), but NSBB had no consistent effect on liver stiffness. However, changes in spleen stiffness were not related to the HVPG response (P = .75). CONCLUSIONS: Two-dimensional MR elastographic estimation of liver or spleen stiffness reflects the degree of portal hypertension in patients with liver cirrhosis, but changes in stiffness after NSBB do not predict the effect on HVPG.

The Burden of Inflammatory Bowel Disease in Europe in 2020.

New data suggest that incidence and prevalence of inflammatory bowel diseases [IBD] are still increasing worldwide, and approximately 0.2% of the European population suffer from IBD at the present time. Medical therapy and disease management have evolved significantly in recent decades, with an emphasis on tight objective monitoring of disease progression and a treat-to-target approach in Europe and also worldwide, aiming to prevent early bowel damage and disability. Surgery rate declined over time in Europe, with 10-30% of CD and 5-10% of UC patients requiring a surgery within 5 years. The health economic burden associated with IBD is high in Europe. Direct health care costs [approximately €3500 in CD and €2000 in UC per patient per year] have shifted from hospitalisation and surgery towards drug-related expenditures with the increasing use of biologic therapy and other novel agents, and substantial indirect costs arise from work productivity loss [approximately €1900 per patient yearly]. The aim of this paper is to provide an updated review of the burden of IBD in Europe by discussing current data on epidemiology, disease course, risk for surgery, hospitalisation, and mortality and cancer risks, as well as the economic aspects, patient disability, and work impairment, by discussing the latest population-based studies from the region.

The Risk of Extraintestinal Cancer in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis of Population-based Cohort Studies.

BACKGROUND & AIMS: Patients with Crohn's disease (CD) and ulcerative colitis (UC) are at increased risk of developing intestinal cancer. However, less is known about the risk of extraintestinal cancers (EICs). The aim of this study was to conduct a systematic review and meta-analysis of population-based cohorts assessing the risk of EICs in inflammatory bowel disease (IBD) patients. METHODS: Only population-based studies reporting on the prevalence or incidence of EICs were included. In total, 884 studies were screened and those included were assessed for quality. Eligible studies were pooled for length of follow-up evaluation, events in the IBD population, and events or expected events in a control population for the meta-analyses. RESULTS: In total, 40 studies were included in the systematic review and 15 studies were included in the meta-analysis. The overall risk of EICs was found to be increased in both CD (incidence rate ratio [IRR]: 1.43 [CI, 1.26, 1.63]) and UC (IRR: 1.15 [1.02, 1.31]) patients. Both CD and UC patients presented with an increased risk of skin (IRR: CD, 2.22 [1.41-3.48]; UC, 1.38 [1.12-1.71]) and hepatobiliary (IRR: CD, 2.31 [1.25-4.28]; UC, 2.05 [1.52-2.76]) malignancies. Furthermore, CD patients showed an increased risk of hematologic (IRR, 2.40 [1.81-3.18]) and lung (IRR, 1.53 [1.23-1.91]) cancers. These increased risks were present despite treatment with immunosuppressives. CONCLUSIONS: This systematic review and meta-analysis shows that both CD and UC patients are at an increased risk of developing EICs, both overall and at specific sites. However, additional studies with longer follow-up evaluation are needed to assess the true risk of EICs posed by IBD.

Systematic Review with Meta-analysis: The Impact of Co-occurring Immune-mediated Inflammatory Diseases on the Disease Course of Inflammatory Bowel Diseases.

BACKGROUND AND AIMS: Patients with inflammatory bowel diseases (IBDs) are at risk of developing a variety of other immune-mediated inflammatory diseases (IMIDs). The influence of co-occurring IMIDs on the disease course of IBD remains unknown. The aim of this study was therefore to conduct a systematic review and meta-analysis of the impact of IMIDs on phenotypic presentation and outcome in patients with IBD. METHODS: PubMed and Embase were searched from their earliest records through December 2018 and updated in October 2019 for studies reporting proportions or ratios of IBD-related disease outcomes in patients with and without co-occurring IMIDs. Meta-analyses were performed to estimate summary proportions and risks of the main outcomes. PRISMA guidelines were used, and study quality was assessed according to the Newcastle-Ottawa Scale. RESULTS: A total of 93 studies were identified, comprising 16,064 IBD patients with co-occurring IMIDs and 3,451,414 IBD patients without IMIDs. Patients with IBD and co-occurring IMIDs were at increased risk of having extensive colitis or pancolitis (risk ratio, 1.38; 95% Cl, 1.25-1.52; P < 0.01, I2 = 86%) and receiving IBD-related surgeries (risk ratio, 1.17; 95% Cl, 1.01-1.36; P = 0.03; I2 = 85%) compared with patients without IMIDs. Co-occurrence of IMIDs other than primary sclerosing cholangitis in patients with IBD was associated with an increased risk of receiving immunomodulators (risk ratio, 1.15; 95% Cl, 1.06-1.24; P < 0.01; I2 = 60%) and biologic therapies (risk ratio, 1.19; 95% Cl, 1.08-1.32; P < 0.01; I2 = 53%). CONCLUSION: This meta-analysis found that the presence of co-occurring IMIDs influences the disease course of IBD, including an increased risk of surgery and its phenotypical expression.

Predictors of response and disease course in patients with inflammatory bowel disease treated with biological therapy-the Danish IBD Biobank Project: protocol for a multicentre prospective cohort study.

INTRODUCTION: Inflammatory bowel diseases (IBDs) are chronic diseases of unknown cause characterised by a progressive and unpredictable disease course. In the last decade, biological treatment has become a cornerstone in the treatment of IBD. However, one-in-three-to-four patients do not respond to first-line biological agents and another third of patients see their response diminish over time. This highlights an unmet need for optimising the use of biologicals and the prediction of treatment response. Considering the multifaceted nature of IBD, we hypothesise that multiomics profiling of sequential samples from single patients could facilitate the discovery of predictive biomarkers of response to biological therapy and disease course. METHODS: This is a multicentre prospective cohort study which will enrol 840 biological-naïve patients with IBD who initiate biological therapy in a 3-year period. Primary outcomes are the occurrence of primary non-response (evaluated at weeks 14-16) and loss of response (evaluated during entire follow-up in patients who obtain partial or full response after induction period). Each patient will be followed up for their clinical data for at least 1 year or till the end of study period (up to 4 years). Blood and stool samples will be collected sequentially during the first year of biological treatment. Intestinal tissue will be sampled after 1 year of treatment and whenever an endoscopy is performed. Samples will undergo transcriptomic, proteomic and microbial DNA analyses. Omics data will be integrated with clinical data to identify a panel of predictive biomarkers of response to biological therapy and disease behaviour in patients with IBD. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Danish Ethics Committee (H-18064178). Inclusion is ongoing at three study centres and will be initiated in two additional centres. Both positive and negative study results will be disseminated through peer-reviewed journals according to Strengthening the Reporting of Observational Studies in Epidemiology guidelines, as well as presented at international conferences.

The epidemiology of inflammatory bowel disease: East meets west.

The incidence of inflammatory bowel diseases (IBD) in East has risen over the past decade to become a global disease. The increasing number of studies on the incidence and course of IBD in East has enabled us to explore East versus West differences in the epidemiology of IBD which could enhance our understanding of the heterogeneity of the disease and eventually assist in the discovery of novel therapeutic targets and design of preventive strategies. Comparison of population-based data in East and West reveals that the incidence of IBD has risen rapidly in East while plateauing in West. Furthermore, the clinical presentation and course of IBD differs between East and West with more patients in East presenting with complicated disease. Considering the scarcity of population-based data from East and the lack of studies with long durations of follow-up, it remains to be clarified whether these differences reflect true differences in disease presentation. The effects of genetic and environmental risk factors contributing to IBD also differ between Eastern and Western populations. Considering the differential effects of genetic and environmental risk factors in East and West, future studies should seek to discover novel genetic and environmental risk factors which might specifically apply to eastern populations. In this narrative review, we compare the epidemiology of IBD between eastern and western countries by summarizing evidence from population-based cohort studies in the last ten years. Furthermore, we look at differences in genetic susceptibility and environmental triggers of IBD between East and West.

Impact of Genes and the Environment on the Pathogenesis and Disease Course of Inflammatory Bowel Disease.

Crohn's disease and ulcerative colitis constitute two major subgroups of inflammatory bowel diseases (IBD), a group of complex polygenic diseases characterized by chronic and progressive inflammation in the gastrointestinal tract. In recent years, methodological advances in genetic analysis have greatly expanded our understanding of the genetic background of IBD. So far, more than 240 genetic risk loci have been identified for IBD. However, these risk alleles explain less than 30% of the susceptibility to disease development, suggesting that environmental factors contribute considerably. The increasing occurrence of IBD in Eastern countries following their 'westernization', as well as the increased risk of disease among those who migrate to high-incidence regions, also suggest that the environment is key in the pathogenesis of IBD. In this review, we summarize the current evidence on the role of genetic and environmental factors in the susceptibility to, and disease course of, IBD, and we suggest how these findings might be applied to clinical practice.

A 10-Year Follow-up Study of the Natural History of Perianal Crohn's Disease in a Danish Population-Based Inception Cohort.

BACKGROUND: Perianal complications in patients with Crohn's disease are common and have a negative impact on the patients' quality of life. Data about the long-term disease course of perianal Crohn's disease in the era of biological treatment are limited. In this population-based cohort study, we sought to investigate the occurrence, clinical risk factors, and disease course of perianal disease. METHODS: A total of 213 Crohn's disease patients were included in a prospective population-based inception cohort. Data were retrieved from medical records and national health administrative databases. Perianal disease was defined as a perianal fistula and/or abscess. Associations between outcomes and covariates were analyzed by Cox regression analysis. RESULTS: A total of 48 (22.5%) patients developed perianal disease after 10 years. Colonic disease location (hazard ratio [HR], 1.99; 95% confidence interval [CI], 1.01-3.92) and penetrating behavior (HR, 5.65; 95% CI, 2.65-12.03) were associated with the development of perianal disease. The cumulative risk of undergoing abdominal surgery was 51% after 10 years. Patients with perianal disease had a higher rate of resection (HR, 3.92; 95% CI, 1.86-8.67) and hospitalization (HR, 1.01; 95% CI, 1.00-1.01). There was no significant difference in the rate of sick leave, unemployment, or disability pension between patients with and without perianal disease. CONCLUSIONS: Patients with perianal disease carry a higher risk of surgery and hospitalization, and this suggests a more severe disease course and poorer prognosis among these patients, even in the era of biological treatment. These findings underline the importance of optimizing treatment strategies for patients with perianal disease.

Diabetes-induced mechanophysiological changes in the small intestine and colon.

The disorders of gastrointestinal (GI) tract including intestine and colon are common in the patients with diabetes mellitus (DM). DM induced intestinal and colonic structural and biomechanical remodeling in animals and humans. The remodeling is closely related to motor-sensory abnormalities of the intestine and colon which are associated with the symptoms frequently encountered in patients with DM such as diarrhea and constipation. In this review, firstly we review DM-induced histomorphological and biomechanical remodeling of intestine and colon. Secondly we review motor-sensory dysfunction and how they relate to intestinal and colonic abnormalities. Finally the clinical consequences of DM-induced changes in the intestine and colon including diarrhea, constipation, gut microbiota change and colon cancer are discussed. The final goal is to increase the understanding of DM-induced changes in the gut and the subsequent clinical consequences in order to provide the clinicians with a better understanding of the GI disorders in diabetic patients and facilitates treatments tailored to these patients.

Transcriptional and Functional Characterization of the G Protein-Coupled Receptor Repertoire of Gastric Somatostatin Cells.

In the stomach, somatostatin (SST) acts as a general paracrine negative regulator of exocrine secretion of gastric acid and pepsinogen and endocrine secretion of gastrin, ghrelin, and histamine. Using reporter mice expressing red fluorescent protein (RFP) under control of the SST promotor, we have characterized the G protein-coupled receptors expressed in gastric Sst-RFP-positive cells and probed their effects on SST secretion in primary cell cultures. Surprisingly, besides SST, amylin and PYY were also highly enriched in the SST cells. Several receptors found to regulate SST secretion were highly expressed and/or enriched. 1) The metabolite receptors calcium-sensing receptor and free fatty acid receptor 4 (GPR120) functioned as positive and negative regulators, respectively. 2) Among the neurotransmitter receptors, adrenergic receptors α1a, α2a, α2b, and ß1 were all highly expressed, with norepinephrine and isoproterenol acting as positive regulators. The muscarinic receptor M3 acted as a positive regulator, whereas M4 was conceivably a negative regulator. 3) Of the hormone receptors, the GLP-1 and GIP receptors, CCKb (stimulated by both CCK and gastrin) and surprisingly the melanocortin MC1 receptor were all positive regulators. 4) The neuropeptide receptors for calcitonin gene-related peptide, adrenomedullin, and vasoactive intestinal peptide acted as positive regulators, no effect was observed using galanin and nociceptin although transcripts for the corresponding receptors appeared highly expressed. 5) The SST receptors 1 and 2 functioned in an autocrine negative feedback loop. Thus, the article provides a comprehensive map of receptors through which SST secretion is regulated by hormones, neurotransmitters, neuropeptides and metabolites that act directly on the SST cells in the gastric mucosa.