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Background Both obesity and inflammatory bowel disease (IBD) are highly prevalent in Western societies. IBD, including Crohn’s disease (CD) and ulcerative colitis (UC), has been historically associated with cachexia and malnutrition. It is uncertain how obesity, a chronic pro-inflammatory state, may impact the course of IBD. Aim The aim of this study was to report the prevalence of obesity in patients with IBD in a metropolitan US population and to assess the impact of obesity on disease phenotypes, treatment, and surgical outcomes in IBD patients. Methods We reviewed the medical records of patients identified from the IBD registries of the Dallas Veterans Affairs Medical Center and Parkland Health and Hospital Systems who were seen from January 1, 2000, to December 31, 2012. Results Of 581 identified IBD patients, 32.7 % were obese (BMI ≥ 30) and 67.6 % were non-obese (BMI < 30). There were 297 (51.1 %) patients with CD and 284 (48.9 %) patients with UC. The rate of obesity was 30.3 % among CD patients and 35.2 % among UC patients. Overall, obese patients were significantly less likely to receive anti-TNF treatment, undergo surgery, or experience a hospitalization for their IBD than their non-obese counterparts (55.8 vs. 72.1 %, p  = .0001). Conclusion Obesity is highly prevalent in our IBD patients, paralleling the obesity rates in the US population. Clinical outcomes were significantly different in obese versus non-obese patients with IBD. Despite the plausible mechanisms whereby obesity might exacerbate IBD, we have found that obesity (as defined by BMI) is a marker of a less severe disease course in IBD.

ObjectiveAlthough perturbations in mitochondrial function and structure have been described in the intestinal epithelium of Crohn’s disease and ulcerative colitis patients, the role of epithelial mitochondrial stress in the pathophysiology of inflammatory bowel diseases (IBD) is not well elucidated. Prohibitin 1 (PHB1), a major component protein of the inner mitochondrial membrane crucial for optimal respiratory chain assembly and function, is decreased during IBD.DesignMale and female mice with inducible intestinal epithelial cell deletion of Phb1 (Phb1iΔIEC ) or Paneth cell-specific deletion of Phb1 (Phb1ΔPC ) and Phb1fl/fl control mice were housed up to 20 weeks to characterise the impact of PHB1 deletion on intestinal homeostasis. To suppress mitochondrial reactive oxygen species, a mitochondrial-targeted antioxidant, Mito-Tempo, was administered. To examine epithelial cell-intrinsic responses, intestinal enteroids were generated from crypts of Phb1iΔIEC or Phb1ΔPC mice.Results Phb1iΔIEC mice exhibited spontaneous ileal inflammation that was preceded by mitochondrial dysfunction in all IECs and early abnormalities in Paneth cells. Mito-Tempo ameliorated mitochondrial dysfunction, Paneth cell abnormalities and ileitis in Phb1iΔIEC ileum. Deletion of Phb1 specifically in Paneth cells (Phb1ΔPC ) was sufficient to cause ileitis. Intestinal enteroids generated from crypts of Phb1iΔIEC or Phb1ΔPC mice exhibited decreased viability and Paneth cell defects that were improved by Mito-Tempo.ConclusionOur results identify Paneth cells as highly susceptible to mitochondrial dysfunction and central to the pathogenesis of ileitis, with translational implications for the subset of Crohn’s disease patients exhibiting Paneth cell defects.

Corticosteroids are effective for the short-term treatment of inflammatory bowel disease (IBD). Long-term use, however, is associated with significant adverse effects. To define the: (1) frequency and duration of corticosteroid use, (2) frequency of escalation to corticosteroid-sparing therapy, (3) rate of complications related to corticosteroid use, (4) rate of appropriate bone density measurements (dual energy X-ray absorptiometry [DEXA] scans), and (5) factors associated with escalation and DEXA scans. Retrospective review of Veterans Health Administration (VHA) data from 2002-2010. Of the 30,456 Veterans with IBD, 32% required at least one course of corticosteroids during the study time period, and 17% of the steroid users had a prolonged course. Among these patients, only 26.2% underwent escalation of therapy. Patients visiting a gastroenterology (GI) physician were significantly more likely to receive corticosteroid-sparing medications. Factors associated with corticosteroid-sparing medications included younger age (OR = 0.96 per year,95%CI:0.95, 0.97), male gender (OR = 2.00,95%CI:1.16,3.46), GI visit during the corticosteroid evaluation period (OR = 8.01,95%CI:5.85,10.95) and the use of continuous corticosteroids vs. intermittent corticosteroids (OR = 2.28,95%CI:1.33,3.90). Rates of complications per 1000 person-years after IBD diagnosis were higher among corticosteroid users (venous thromboembolism [VTE] 9.0%; fragility fracture 2.6%; Infections 54.3) than non-corticosteroid users (VTE 4.9%; fragility fracture 1.9%; Infections 26.9). DEXA scan utilization rates among corticosteroid users were only 7.8%. Prolonged corticosteroid therapy for the treatment of IBD is common and is associated with significant harm to patients. Patients with prolonged use of corticosteroids for IBD should be referred to gastroenterology early and universal efforts to improve the delivery of high quality care should be undertaken.

The microenvironment of solid tumors is characterized by oxygen and glucose deprivation. Acss2/HIF-2 signaling coordinates essential genetic regulators including acetate-dependent acetyl CoA synthetase 2 (Acss2), Creb binding protein (Cbp), Sirtuin 1 (Sirt1), and Hypoxia Inducible Factor 2α (HIF-2α). We previously shown in mice that exogenous acetate augments growth and metastasis of flank tumors derived from fibrosarcoma-derived HT1080 cells in an Acss2/HIF-2 dependent manner. Colonic epithelial cells are exposed to the highest acetate levels in the body. We reasoned that colon cancer cells, like fibrosarcoma cells, may respond to acetate in a pro-growth manner. In this study, we examine the role of Acss2/HIF-2 signaling in colon cancer. We find that Acss2/HIF-2 signaling is activated by oxygen or glucose deprivation in two human colon cancer-derived cell lines, HCT116 and HT29, and is crucial for colony formation, migration, and invasion in cell culture studies. Flank tumors derived from HCT116 and HT29 cells exhibit augmented growth in mice when supplemented with exogenous acetate in an Acss2/HIF-2 dependent manner. Finally, Acss2 in human colon cancer samples is most frequently localized in the nucleus, consistent with it having a signaling role. Targeted inhibition of Acss2/HIF-2 signaling may have synergistic effects for some colon cancer patients.

Cronkhite-Canada Syndrome (CCS) is a rare, noninherited polyposis syndrome affecting 1 in every million individuals. Despite over 50 years of CCS cases, the etiopathogenesis and optimal treatment for CCS remains unknown due to the rarity of the disease and lack of model systems. To better understand the etiology of CCS, we generated human intestinal organoids (HIOs) from intestinal stem cells isolated from 2 patients. We discovered that CCS HIOs are highly proliferative and have increased numbers of enteroendocrine cells producing serotonin (also known as 5-hydroxytryptamine or 5HT). These features were also confirmed in patient tissue biopsies. Recombinant 5HT increased proliferation of non-CCS donor HIOs and inhibition of 5HT production in the CCS HIOs resulted in decreased proliferation, suggesting a link between local epithelial 5HT production and control of epithelial stem cell proliferation. This link was confirmed in genetically engineered HIOs with an increased number of enteroendocrine cells. This work provides a new mechanism to explain the pathogenesis of CCS and illustrates the important contribution of HIO cultures to understanding disease etiology and in the identification of novel therapies. Our work demonstrates the principle of using organoids for personalized medicine and sheds light on how intestinal hormones can play a role in intestinal epithelial proliferation.

Early reports suggested that the risk of gastrointestinal bleeding (GIB) was higher for patients on non-vitamin K antagonist oral anticoagulants (NOACs) than for those on warfarin. We compared the incidence of GIB in our patients on NOACs with those on warfarin. We used our VA pharmacy database to identify patients taking NOACs (dabigatran, rivaroxaban, and apixaban) or warfarin between January 2011 and June 2015, and used the VistA system to identify those who were hospitalized for GIB. We included only patients with clinically significant GIB, defined as documented GI blood loss with a hemoglobin drop ≥2 g/dl, hemodynamic instability, and/or need for endoscopic evaluation, angiography, or surgery. We identified 803 patients on NOACs and 6,263 on warfarin. One hundred and fifty-eight patients on warfarin had GIB (2.5%), compared with only five patients (0.6%) on NOACs (odds ratio=4.13; 95% confidence interval: 1.69-10.09). Blood transfusion for GIB was significantly more common in patients on warfarin than on NOACs (64.6% vs. 20%, P=0.04). Within 90 days of GIB hospitalization, 12 patients (7.6%) in the warfarin group died, whereas there were no deaths in the NOAC group. In our patients, the incidence of GIB for those on warfarin was more than four times that for those on NOACs. Blood transfusions for GIB were more common in warfarin patients, and no NOAC patients died of GIB. In contrast to early reports, our findings suggest that the risk of GIB and subsequent complications is considerably lower for patients on NOACs than for patients on warfarin.

Autophagy is an adaptive response to extracellular and intracellular stress by which cytoplasmic components and organelles, including damaged mitochondria, are degraded to promote cell survival and restore cell homeostasis. Certain genes involved in autophagy confer susceptibility to Crohn's disease. Reactive oxygen species and pro-inflammatory cytokines such as tumor necrosis factor α (TNFα), both of which are increased during active inflammatory bowel disease, promote cellular injury and autophagy via mitochondrial damage. Prohibitin (PHB), which plays a role in maintaining normal mitochondrial respiratory function, is decreased during active inflammatory bowel disease. Restoration of colonic epithelial PHB expression protects mice from experimental colitis and combats oxidative stress. In this study, we investigated the potential role of PHB in modulating mitochondrial stress-related autophagy in intestinal epithelial cells. We measured autophagy activation in response to knockdown of PHB expression by RNA interference in Caco2-BBE and HCT116 WT and p53 null cells. The effect of exogenous PHB expression on TNFα- and IFNγ-induced autophagy was assessed. Autophagy was inhibited using Bafilomycin A(1) or siATG16L1 during PHB knockdown and the affect on intracellular oxidative stress, mitochondrial membrane potential, and cell viability were determined. The requirement of intracellular ROS in siPHB-induced autophagy was assessed using the ROS scavenger N-acetyl-L-cysteine. TNFα and IFNγ-induced autophagy inversely correlated with PHB protein expression. Exogenous PHB expression reduced basal autophagy and TNFα-induced autophagy. Gene silencing of PHB in epithelial cells induces mitochondrial autophagy via increased intracellular ROS. Inhibition of autophagy during PHB knockdown exacerbates mitochondrial depolarization and reduces cell viability. Decreased PHB levels coupled with dysfunctional autophagy renders intestinal epithelial cells susceptible to mitochondrial damage and cytotoxicity. Repletion of PHB may represent a therapeutic approach to combat oxidant and cytokine-induced mitochondrial damage in diseases such as inflammatory bowel disease.

Understanding the role of diet in the management of IBD is important to both patients and physicians. This review provides a summary to improve understanding and promote discussions on diet with the goal of improving patient care and satisfaction.AbstractInflammatory bowel diseases (IBDs) are chronic immune-related diseases hypothesized to be a sequela of an interplay of genetic predisposition and environmental exposures. The global incidence of IBD is increasing, and more patients are exploring diet as a means to explain and treat their IBD. In fact, many patients strongly believe diet plays a fundamental role in the onset and management of their IBD. However, a significant proportion of patients report limited nutritional education from their provider, and providers report limited nutritional resources to aid in discussions with patients. This imbalance between supply and demand likely reflects the previous paucity of available literature characterizing the influence of diet in IBD. To address this gap in knowledge, we review the available literature to characterize the role of diet in the pathogenesis, exacerbation, and treatment of IBD. We aim to provide patients and providers with resources to better understand and discuss the role of diet in IBD, with the overall goal of improving patient care and satisfaction.Video Abstract 10.1093/ibd/izz268_video1Video Abstractizz268_video16099349078001

Background With the recent, widespread availability of endoscopic hemoclips, it has become common clinical practice to apply hemoclips to some non-bleeding polypectomy sites “prophylactically” to prevent delayed post-polypectomy bleeding (PPB). Few published data support this practice, however. Aim The aim of this study was to compare rates of delayed PPB in matched patients who had polypectomies performed with and without the prophylactic placement of hemoclips. Methods We reviewed medical records of patients who had elective colonoscopy at our VA Medical Center between July 2008 and December 2009. We identified patients who had hemoclips applied prophylactically (cases) and compared their rate of delayed PPB within 30 days to that of patients who had polypectomy without hemoclipping (controls). Controls were matched 1:1 to cases based on age and on factors known to contribute to the risk of PPB including polyp size, morphology, technique of polyp removal, number of polyps removed, and use of anticoagulants. Results We identified 184 patients (cases) who underwent prophylactic hemoclipping and 184 well-matched controls. An average of 3.8 polyps per patient were removed in the case group compared to 3.3 polyps per patient in controls ( p  = 0.6). Delayed PPB occurred in three patients in the prophylactic hemoclip group and in one patient in the control group (1.6 vs. 0.5 %, p  = 0.62). Conclusions We found no significant difference in the rate of delayed PPB between patients who had prophylactic hemoclipping of polypectomy sites and a well-matched control group of patients who had polypectomy without prophylactic hemoclipping. These data call into question the expensive practice of prophylactic hemoclipping.

Corticosteroids are effective rescue therapies for patients with inflammatory bowel disease (IBD), but have significant side effects, which may be amplified in the growing population of elderly patients with IBD. We aimed to compare the use of steroids and steroid-sparing therapies (immunomodulators and biologics) and rates of complications among elderly (≥65) and younger patients in a national cohort of veterans with IBD.MethodsWe used national Veterans Health Administrative data to conduct a retrospective study of veterans with IBD between 2002 and 2010. Medications and the incidence of complications were obtained from the Veterans Health Administrative Decision Support Systems. Multivariate logistic regression accounting for facility-level clustering was used to identify predictors of use of steroid-sparing medications.ResultsWe identified 30,456 veterans with IBD. Of these, 94% were men and 40% were more than 65, and 32% were given steroids. Elderly veterans were less likely to receive steroids (23.8% versus 38.3%, P < 0.001) and were less likely to be prescribed steroid-sparing medications (25.5% versus 46.9%, respectively, P < 0.001). In multivariate analysis controlling for sex, age <65 (odds ratio, 2.19; 95% CI, 1.54–3.11) and gastroenterology care (odds ratio, 8.42; 95% CI, 6.18–11.47) were associated with initiation of steroid-sparing medications. After starting steroids, fracture rates increased in the elderly patients with IBD, whereas increases in venous thromboembolism and infections after starting steroids affected both age groups.ConclusionsElderly veterans are less likely to receive steroids and steroid-sparing medications than younger veterans; elderly patients exposed to steroids were more likely to have fractures than the younger population.