Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.

The cost of IBD care - how to make it sustainable.

The rising global prevalence of inflammatory bowel diseases (IBD), such as Crohn's disease (CD) and ulcerative colitis (UC), underscores the need to examine current and future IBD care costs. Direct healthcare expenses, including ambulatory visits, hospitalizations, and medications, are substantial, averaging $9,000 to $12,000 per person annually in high-income regions. However, these estimates do not fully account for factors such as disease severity, accessibility, and variability in healthcare infrastructure among regions. Indirect costs, predominantly stemming from loss in productivity due to absenteeism, presenteeism, and other intangible costs, further contribute to the financial burden of IBD. Despite efforts to quantify indirect costs, many aspects remain poorly understood, leading to an underestimation of their actual impact. Challenges to achieving cost sustainability include disparities in access, treatment affordability, and the absence of standardized cost-effective care guidelines. Strategies for making IBD care sustainable include early implementation of biologic therapies, focusing on cost-effectiveness in settings with limited resources, and promoting the uptake of biosimilars to reduce direct costs. Multidisciplinary care teams leveraging technology and patient-reported outcomes also hold promise in reducing both direct and indirect costs associated with IBD. Addressing the increasing financial burden of IBD requires a comprehensive approach that tackles disparities, enhances access to cost-effective therapeutics, and promotes collaborative efforts across healthcare systems. Embracing innovative strategies can pave the way for personalized, cost-effective care accessible to all individuals with IBD, ensuring better outcomes and sustainability.

Legalization of Cannabis Does Not Reduce Opioid Prescribing in Patients With Inflammatory Bowel Disease: A Difference-in-Difference Analysis.

INTRODUCTION: Cannabis may provide inflammatory bowel disease (IBD) patients with an alternative to opioids for pain. METHODS: We conducted a difference-in-difference analysis using MarketScan. Changes over time in rates of opioid prescribing were compared in states with legalized cannabis to those without. RESULTS: We identified 6,240 patients with IBD in states with legalized cannabis and 79,272 patients with IBD in states without legalized cannabis. The rate of opioid prescribing decreased over time in both groups and were not significantly different (attributed differential = 0.34, confidence interval -13.02 to 13.70, P = 0.96). DISCUSSION: Opioid prescribing decreased from 2009 to 2016 among patients with IBD in both states with legalized and state without legalized cannabis, similar to what has been observed nationally across a variety of diseases. Cannabis legalization was not associated with a lower rate of opioid prescribing for patients with IBD.

Improving Adherence to Clinical Practice Guidelines for Managing Gastric Intestinal Metaplasia Among Gastroenterologists at a US Academic Institution.

BACKGROUND: Clinical guidelines reserve endoscopic surveillance after a gastric intestinal metaplasia (GIM) diagnosis for high-risk patients. However, it is unclear how closely guidelines are followed in clinical practice. We examined the effectiveness of a standardized protocol for the management of GIM among gastroenterologists at a US hospital. METHODS: This was a preintervention and postintervention study, which included developing a protocol and education of gastroenterologists on GIM management. For the preintervention study, 50 patients with GIM were randomly selected from a histopathology database at the Houston VA Hospital between January 2016 and December 2019. For the postintervention study, we assessed change in GIM management in a cohort of 50 patients with GIM between April 2020 and January 2021 and surveyed 10 gastroenterologists. The durability of the intervention was assessed in a cohort of 50 GIM patients diagnosed between April 2021 and July 2021. RESULTS: In the preintervention cohort, GIM location was specified (antrum and corpus separated) in 11 patients (22%), and Helicobacter pylori testing was recommended in 11 of 26 patients (42%) without previous testing. Gastric mapping biopsies were recommended in 14% and surveillance endoscopy in 2%. In the postintervention cohort, gastric biopsy location was specified in 45 patients (90%, P <0.001) and H. pylori testing was recommended in 26 of 27 patients without prior testing (96%, P <0.001). Because gastric biopsy location was known in 90% of patients ( P <0.001), gastric mapping was not necessary, and surveillance endoscopy was recommended in 42% ( P <0.001). One year after the intervention, all metrics remained elevated compared with the preintervention cohort. CONCLUSIONS: GIM management guidelines are not consistently followed. A protocol for GIM management and education of gastroenterologists increased adherence to H. pylori testing and GIM surveillance recommendations.

Assessment of Physician Needs and Access to Inflammatory Bowel Disease Specialty Care Resources in a National Integrated Health System.

BACKGROUND: The barriers to providing high-quality inflammatory bowel disease (IBD) care go beyond educational needs alone to include access to IBD-related resources such as medications, laboratory testing, and multidisciplinary teams. We assessed the needs and resource constraints of physicians caring for Veterans with IBD to inform efforts to improve access to high-quality care. METHODS: We conducted a national observational survey study in July 2021 of gastroenterologists (GIs) and primary care providers (PCPs) caring for Veterans with IBD within the Veterans Health Administration with the intent of including physicians from all 18 Veterans Integrated Service Networks (VISN). We reported descriptive statistics and compared responses between gastroenterologists (GIs) and primary care providers (PCPs), practice locations, and years of experience using χ2 tests. RESULTS: Overall, 173 of 2241 eligible physicians completed the survey, representing an individual physician response rate of 7.7% and VISN response rate of 18 out of 18 (100%). We identified several areas of IBD care where GIs and PCPs reported discomfort including medication prescribing, treatment strategies, and special populations. Further, variability in access to IBD services and awareness of the availability of IBD-targeted medications and laboratory tests was common. This survey also highlights the frequency with which PCPs were identified among the highest volume IBD providers in their facility. CONCLUSIONS: Variation in GIs' and PCPs' comfort with IBD treatment and access to IBD resources is common and needs to be considered in leveraging virtual care and educational programs and managing the expansion of IBD support and resources within VA.

Using Natural Language Processing to Automatically Identify Dysplasia in Pathology Reports for Patients With Barrett's Esophagus.

BACKGROUND & AIMS: Identifying dysplasia of Barrett's esophagus (BE) in the electronic medical record (EMR) requires manual abstraction of unstructured data. Natural language processing (NLP) creates structure to unstructured free text. We aimed to develop and validate an NLP algorithm to identify dysplasia in BE patients on histopathology reports with varying report formats in a large integrated EMR system. METHODS: We randomly selected 600 pathology reports for NLP development and 400 reports for validation from patients with suspected BE in the national Veterans Affairs databases. BE and dysplasia were verified by manual review of the pathology reports. We used NLP software (Clinical Language Annotation, Modeling, and Processing Toolkit; Melax Tech, Houston, TX) to develop an algorithm to identify dysplasia using findings. The algorithm performance characteristics were calculated as recall, precision, accuracy, and F-measure. RESULTS: In the development set of 600 patients, 457 patients had confirmed BE (60 with dysplasia). The NLP identified dysplasia with 98.0% accuracy, 91.7% recall, and 93.2% precision, with an F-measure of 92.4%. All 7 patients with confirmed high-grade dysplasia were classified by the algorithm as having dysplasia. Among the 400 patients in the validation cohort, 230 had confirmed BE (39 with dysplasia). Compared with manual review, the NLP algorithm identified dysplasia with 98.7% accuracy, 92.3% recall, and 100.0% precision, with an F-measure of 96.0%. CONCLUSIONS: NLP yielded a high degree of sensitivity and accuracy for identifying dysplasia from diverse types of pathology reports for patients with BE. The application of this algorithm would facilitate research and clinical care in an EMR system with text reports in large data repositories.

Cardiovascular Safety of Ozanimod in Patients With Ulcerative Colitis: True North and Open-Label Extension Analyses.

BACKGROUND & AIMS: Evaluating cardiovascular safety of sphingosine 1-phosphate (S1P) receptor modulators is warranted due to S1P receptor expression on cardiomyocytes and vascular endothelial cells. This analysis reports the cardiovascular safety of ozanimod, an S1P receptor modulator, in patients with moderately to severely active ulcerative colitis from the phase 3 True North (TN) and open-label extension (OLE). METHODS: All patients who received ozanimod in TN (n = 796) and all eligible TN patients who entered the OLE (n = 823) were included. Cardiovascular-related adverse events were evaluated in patients with up to 146 weeks of ozanimod exposure (2219 patient-years), which included 52 weeks during TN. RESULTS: On TN day 1, first-dose ozanimod resulted in a 0.2 beats per minute mean decrease in heart rate from pretreatment to hour 6; 2 patients experienced bradycardia, which resolved without treatment modification. Mean systolic and diastolic blood pressure increases of 5.1 and 2.2 mm Hg, respectively, were observed at TN week 52. No second-degree Mobitz type II atrioventricular block events were reported; 1 third-degree atrioventricular block unrelated to ozanimod occurred in the OLE. Cardiac and vascular treatment-emergent adverse events were infrequent (3.8% [31 of 823] and 8.5% [70 of 823]); no ozanimod-related cardiovascular deaths occurred. The incidences of deep-vein thrombosis (0.2%; 2 of 823), pulmonary embolism (0.2%; 2 of 823), and ischemic stroke (0.4%; 3 of 823) in the OLE were low. CONCLUSIONS: No new cardiovascular safety signals were identified, consistent with findings from previous ozanimod studies. There were few major adverse cardiovascular events or thromboembolic events, which were unrelated or unlikely related to ozanimod. Ozanimod has a well-tolerated cardiovascular safety profile when prescribed in accordance with the label. Clinical trial registry website and trial numbers: ClinicalTrials.gov numbers: NCT02435992 and NCT02531126.

Comparative Effectiveness of Surveillance Colonoscopy Intervals on Colorectal Cancer Outcomes in a National Cohort of Patients with Inflammatory Bowel Disease.

BACKGROUND & AIMS: Surveillance colonoscopy is recommended to reduce colorectal cancer (CRC)-related morbidity and mortality in patients with inflammatory bowel disease (IBD). The comparative effectiveness of varying colonoscopy intervals on CRC outcomes among patients with IBD is unknown. METHODS: We performed a retrospective cohort study of patients with confirmed CRC within a cohort of 77,824 patients with IBD during 2000 to 2015 in the National Veterans Health Administration. We examined the association between colonoscopy surveillance intervals on CRC stage, treatment, or all-cause and cancer-specific mortality. The interval of colonoscopy prior to CRC diagnosis was categorized as those performed within <1 year, 1 to 3 years, 3 to 5 years, or none within 5 years. RESULTS: Among 566 patients with CRC-IBD, most (69.4%) did not have colonoscopy within 5 years prior to CRC diagnosis, whereas 9.7% had colonoscopy within 1 year prior to diagnosis, 17.7% within 1 to 3 years, and 3.1% between 3 and 5 years. Compared with no surveillance, colonoscopy within 1 year (adjusted odds ratio, 0.40; 95% confidence interval [CI], 0.20-0.82), and 1 to 3 years (adjusted odds ratio, 0.56; 95% CI, 0.32-0.98) were less likely to be diagnosed at late stage. Regardless of IBD type and duration, colonoscopy within 1 year was associated with a lower all-cause mortality (adjusted hazard ratio, 0.56; 95% CI, 0.36-0.88). CONCLUSIONS: In a national cohort of patients with CRC-IBD, colonoscopy within 3 years prior to CRC diagnosis was associated with early tumor stage at diagnosis, and colonoscopy within 1 year was associated with a reduced all-cause mortality compared with no colonoscopy. Our findings support colonoscopy intervals of 1 to 3 years in patients with IBD to reduce late-stage CRC and all-cause mortality.

The Association Between Nonsteroidal Anti-Inflammatory Drug Use and Inflammatory Bowel Disease Exacerbations: A True Association or Residual Bias?

INTRODUCTION: Studies suggest that nonsteroidal anti-inflammatory drugs (NSAID) may contribute to inflammatory bowel disease (IBD) exacerbations. We examined whether variation in the likelihood of IBD exacerbations is attributable to NSAID. METHODS: In a cohort of patients with IBD (2004-2015), we used 3 analytic methods to examine the likelihood of an exacerbation after an NSAID exposure. First, we matched patients by propensity for NSAID use and examined the association between NSAID exposure and IBD exacerbation using an adjusted Cox proportional hazards model. To assess for residual confounding, we estimated a previous event rate ratio and used a self-controlled case series analysis to further explore the relationship between NSAID and IBD exacerbations. RESULTS: We identified 15,705 (44.8%) and 19,326 (55.2%) IBD patients with and without an NSAID exposure, respectively. Findings from the Cox proportional hazards model suggested an association between NSAID and IBD exacerbation (hazard ratio 1.24; 95% confidence interval 1.16-1.33). However, the likelihood of an IBD exacerbation in the NSAID-exposed arm preceding NSAID exposure was similar (hazard ratio 1.30; 95% confidence interval 1.21-1.39). A self-controlled case series analysis of 3,968 patients who had both an NSAID exposure and IBD exacerbation demonstrated similar exacerbation rates in the 1 year preceding exposure, 2-6 weeks postexposure, and 6 weeks to 6 months postexposure, but a higher incidence in 0-2 weeks postexposure, suggesting potential confounding by reverse causality. DISCUSSION: While we see an association between NSAID and IBD exacerbations using traditional methods, further analysis suggests this may be secondary to residual bias. These findings may reassure patients and clinicians considering NSAID as a nonopioid pain management option.

Spatial Characteristics of Colonic Mucosa-Associated Gut Microbiota in Humans.

Limited data exist on the spatial distribution of the colonic bacteria in humans. We collected the colonic biopsies from five segments of 27 polyp-free adults and collected feces from 13 of them. We sequenced the V4 region of the bacterial 16S rRNA gene using the MiSeq platform. The sequencing data were assigned to the amplicon sequence variant (ASV) using SILVA. Biodiversity and the relative abundance of the ASV were compared across the colonic segments and between the rectal and fecal samples. Bacterial functional capacity was assessed using Tax4fun. Each individual had a unique bacterial community composition (Weighted Bray-Curtis P value = 0.001). There were no significant differences in richness, evenness, community composition, and the taxonomic structure across the colon segments in all the samples. Firmicutes (47%), Bacteroidetes (39%), and Proteobacteria (6%) were the major phyla in all segments, followed by Verrucomicrobia, Fusobacteria, Desulfobacterota, and Actinobacteria. There were 15 genera with relative abundance > 1%, including Bacteroides, Faecalibacterium, Escherichia/Shigella, Sutterella, Akkermansia, Parabacteroides, Prevotella, Lachnoclostridium, Alistipes, Fusobacterium, Erysipelatoclostridium, and four Lachnospiraceae family members. Intra-individually, the community compositional dissimilarity was the greatest between the cecum and the rectum. There were significant differences in biodiversity and the taxonomic structure between the rectal and fecal bacteria. The bacterial community composition and structure were homogeneous across the large intestine in adults. The inter-individual variability of the bacteria was greater than inter-segment variability. The rectal and fecal bacteria differed in the community composition and structure.

Correction: Lu et al. Periodontal Pathogen Adhesion, Cytotoxicity, and Surface Free Energy of Different Materials for an Implant Prosthesis Screw Access Hole. Medicina 2022, 58, 329.

In the original publication [...].

Periodontal Pathogen Adhesion, Cytotoxicity, and Surface Free Energy of Different Materials for an Implant Prosthesis Screw Access Hole.

Background and Objectives: Oral implant restorations are an excellent treatment option for edentulous patients; however, periodontopathogenic bacteria have been found in the microgaps between implant-abutment junctions. Implant designs to limit the microgaps have been extensively studied. However, studies have shown microgaps continue to exist, allowing for the leakage of bacteria into the implant system. Screw access hole materials are used to fill the access hole void. The use of materials with beneficial properties could provide bacterial leakage prevention. The aim of this study was to examine the surface free energy, cytotoxicity, and bacterial adhesion of selected screw access hole materials such as cotton, polytetrafluoroethylene (PTFE) tape, paraffin wax-polyolefin thermoplastic (PF), paraffin wax (Wax), gutta-percha (GP), and caviton EX (CE). Materials and Methods: A sessile drop test was performed to observe the contact angle and calculate the surface free energy of each material in order to determine the level of hydrophobicity. Cytotoxicity was examined in a mouse gingival epithelial cell line for day 1 and day 3. Bacterial adhesion was tested with Porphyromonas gingivalis, Fusobacterium nucleatum, and Aggregatibacter actinomycetemcomitans. Results: PTFE, PF, and wax presented low surface free energies of 19.34, 23.041, and 24.883 mN.m-1, respectively. No cytotoxicity was observed, except for GP and CE. Concurrently, the bacterial adhesion was also the lowest in PTFE and PF. Conclusions: Within the limits of this study, PTFE and PF showed an excellent biocompatibility with few bacterial adhesions. These materials could be potential screw access hole materials in clinical settings.

Quality of Care Program Reduces Unplanned Health Care Utilization in Patients With Inflammatory Bowel Disease.

INTRODUCTION: There is significant variation in processes and outcomes of care for patients with inflammatory bowel disease (IBD), suggesting opportunities to improve quality of care. We aimed to determine whether a structured quality of care program can improve IBD outcomes, including the need for unplanned health care utilization. METHODS: We used a structured approach to improve adult IBD care in 27 community-based gastroenterology practices and academic medical centers. Patient-reported outcomes (PRO) and health care utilization were collected at clinical visits. Outcomes were monitored monthly using statistical process control charts; improvement was defined by special cause (nonrandom) variation over time. Multivariable logistic regression was applied to patient-level data. Nineteen process changes were offered to improve unplanned health care utilization. Ten outcomes were assessed, including disease activity, remission status, urgent care need, recent emergency department use, hospitalizations, computed tomography scans, health confidence, corticosteroid or opioid use, and clinic phone calls. RESULTS: We collected data prospectively from 20,382 discrete IBD visits. During the 15-month project period, improvement was noted across multiple measures, including need for urgent care, hospitalization, steroid use, and opioid utilization. Adjusted multivariable modeling showed significant improvements over time across multiple outcomes including urgent care need, health confidence, emergency department utilization, hospitalization, corticosteroid use, and opioid use. Attendance at monthly coached webinars was associated with improvement. DISCUSSION: Outcomes of IBD care were improved using a structured quality improvement program that facilitates small process changes, sharing of best practices, and ongoing feedback. Spread of these interventions may facilitate broad improvement in IBD care when applied to a large population.

Health Economic Impact of a Multicenter Quality-of-Care Initiative for Reducing Unplanned Healthcare Utilization Among Patients With Inflammatory Bowel Disease.

INTRODUCTION: A multicenter adult inflammatory bowel disease learning health system (IBD Qorus) implemented clinical care process changes for reducing unplanned emergency department visits and hospitalizations using a Breakthrough Series Collaborative approach. METHODS: Using Markov decision models, we determined the health economic impact of participating in the Collaborative from the third-party payer perspective. RESULTS: Across all 23 sites, participation in the Collaborative was associated with lower annual costs by an average of $2,528 ± $233 per patient when compared with the baseline period. DISCUSSION: Implementing clinical care process changes using a Collaborative approach was associated with overall cost savings. Future work should examine which specific interventions are most effective and whether such cost savings are sustainable.

Prevalence of Advanced Colorectal Neoplasia in Veterans: Effects of Age, Sex, and Race/Ethnicity.

GOAL: We sought to quantify the independent effects of age, sex, and race/ethnicity on risk of colorectal cancer (CRC) and advanced neoplasia (AN) in Veterans. STUDY: We conducted a retrospective, cross-sectional study of Veterans aged 40 to 80 years who had diagnostic or screening colonoscopy between 2002 and 2009 from 1 of 14 Veterans Affairs Medical Centers. Natural language processing identified the most advanced finding and location (proximal, distal). Logistic regression was used to examine the adjusted, independent effects of age, sex, and race, both overall and in screening and diagnostic subgroups. RESULTS: Among 90,598 Veterans [mean (SD) age 61.7 (9.4) y, 5.2% (n=4673) were women], CRC and AN prevalence was 1.3% (n=1171) and 8.9% (n=8081), respectively. Adjusted CRC risk was higher for diagnostic versus screening colonoscopy [odds ratio (OR)=3.79; 95% confidence interval (CI), 3.19-4.50], increased with age, was numerically (but not statistically) higher for men overall (OR=1.53; 95% CI, 0.97-2.39) and in the screening subgroup (OR=2.24; 95% CI, 0.71-7.05), and was higher overall for Blacks and Hispanics, but not in screening. AN prevalence increased with age, and was present in 9.2% of men and 3.9% of women [adjusted OR=1.90; 95% CI, 1.60-2.25]. AN risk was 11% higher in Blacks than in Whites overall (OR=1.11; 95% CI, 1.04-1.20), was no different in screening, and was lower in Hispanics (OR=0.74; 95% CI, 0.55-0.98). Women had more proximal CRC (63% vs. 39% for men; P=0.03), but there was no difference in proximal AN (38.3% for both genders). CONCLUSIONS: Age and race were associated with AN and CRC prevalence. Blacks had a higher overall prevalence of both CRC and AN, but not among screenings. Men had increased risk for AN, while women had a higher proportion of proximal CRC. These findings may be used to tailor when and how Veterans are screened for CRC.

Recommendations for Successful Transition of Adolescents With Inflammatory Bowel Diseases to Adult Care.

Adolescents and young adults diagnosed with inflammatory bowel diseases (IBDs) in pediatric care are vulnerable during their transition to adult care. There are 6 core elements of transition from pediatric to adult IBD care. We identified gaps in this transition and make recommendations for clinical practice and research. There have been few studies of transition policy (core element 1) or studies that tracked and monitored patients through the transition (core element 2). Several studies have assessed transition readiness (core element 3), but instruments for assessment were not validated using important outcomes such as disease control, health care use, adherence, quality of life, or continuity of care. There have been no studies of best practices for transition planning (core element 4), including how to best educate patients and facilitate gradual shifts in responsibility. A small number of longitudinal studies have investigated transfer of care (core element 5), but these were conducted outside of the United States; these studies found mixed results in short- and intermediate-term outcomes after transition completion (core element 6). We discuss what is known about the transition from pediatric to adult care for IBD, make recommendations to improve this process, and identify areas for additional research.

Association Between Inflammatory Bowel Disease and Colorectal Cancer Stage of Disease and Survival.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer (CRC). However, there are few data comparing outcomes between IBD and non-IBD-associated CRC. METHODS: Retrospective cohort study of patients with CRC identified from the Veteran Affairs (VA) Central Cancer Registry from 1998 to 2012 linked to national VA administrative claims to identify patients with IBD using a previously validated algorithm. The association between IBD status and stage of disease and overall risk of death were evaluated using multivariable logistic and Cox regression, respectively. RESULTS: Among 34,570 CRC patients, 217 had IBD. IBD patients were significantly younger for both colon and rectal cancer. IBD patients who developed rectal cancer were significantly more likely to present with locally advanced or metastatic disease (P = 0.007), but there was no difference in stage among patients with colon cancer. This difference persisted after multivariable adjustment (overall-odds ratio [OR] 1.40, 95% confidence interval [1.03-1.90]; colon-OR 1.22 [0.84-1.78]; rectum-OR 2.04 [1.22-3.40]). Total colectomy was more commonly performed among IBD patients. Overall, IBD was associated with a 52% increased risk of death (hazard ratio 1.52 [1.21-1.91]). CONCLUSIONS: Although IBD is associated with more advanced stage at diagnosis for rectal cancer, it is associated with a worse survival primarily in patients with colon cancer. Further work is needed to better understand the reason for these observed differences between IBD and non-IBD patients and to better delineate the impact of endoscopic surveillance on CRC care and outcomes in IBD patients.

Villin-1 and Gelsolin Regulate Changes in Actin Dynamics That Affect Cell Survival Signaling Pathways and Intestinal Inflammation.

BACKGROUND & AIMS: Cell stress signaling pathways result in phosphorylation of the eukaryotic translation initiation factor 2 subunit alpha (EIF2S1 or EIF2A), which affects regulation of protein translation. Translation reprogramming mitigates stress by activating pathways that result in autophagy and cell death, to eliminate damaged cells. Actin is modified during stress and EIF2A is dephosphorylated to restore homeostasis. It is not clear how actin affects EIF2A signaling. We studied the actin-binding proteins villin 1 (VIL1) and gelsolin (GSN) in intestinal epithelial cells (IECs) to determine whether they respond to cell stress response and affect signaling pathways. METHODS: We performed studies with mice with disruptions in Vil1 and Gsn (double-knockout mice). Wild-type (WT) mice either were or were not (controls) exposed to cell stressors such as tumor necrosis factor and adherent-invasive Escherichia coli. Distal ileum tissues were collected from mice; IECs and enteroids were cultured and analyzed by histology, immunoblots, phalloidin staining, immunohistochemistry, electron microscopy, and flow cytometry. HT-29 cells were incubated with cell stressors such as DTT, IFN, and adherent-invasive E coli or control agents; cells were analyzed by immunoblots and quantitative polymerase chain reaction. Green fluorescent protein and green fluorescent protein tagged mutant EIF2A were expressed from a lentiviral vector. The mouse immunity-related GTPase (IRGM1) was overexpressed in embryonic fibroblasts from dynamin1 like (DNM1L) protein-knockout mice or their WT littermates. IRGM1 was overexpressed in embryonic fibroblasts from receptor interacting serine/threonine kinase 1-knockout mice or their WT littermates. Human IRGM was overexpressed in human epithelial cell lines incubated with the DNM1L-specific inhibitor Mdivi-1. Mitochondria were analyzed by semi-quantitative confocal imaging. We performed immunohistochemical analyses of distal ileum tissues from 6-8 patients with Crohn's disease (CD) and 6-8 individuals without CD (controls). RESULTS: In IECs exposed to cell stressors, EIF2A signaling reduced expression of VIL1 and GSN. However, VIL1 and GSN were required for dephosphorylation of EIF2A and recovery from cell stress. In mouse and human IECs, prolonged, unresolved stress was accompanied by continued down-regulation of VIL1 and GSN, resulting in constitutive phosphorylation of EIF2A and overexpression of IRGM1 (or IRGM), which regulates autophagy. Overexpression of IRGM1 (or IRGM) induced cell death by necroptosis, accompanied by release of damage-associated molecular patterns (DAMPs). In double-knockout mice, constitutive phosphorylation of EIF2A and over-expression of IRGM1 resulted in spontaneous ileitis that resembled human CD in symptoms and histology. Distal ileum tissues from patients with CD had lower levels of VIL1 and GSN, increased phosphorylation of EIF2A, increased levels of IRGM and necroptosis, and increased release of nuclear DAMPs compared with controls. CONCLUSIONS: In studies of intestinal epithelial tissues from patients with CD and embryonic fibroblasts from mice, along with enteroids and human IEC lines, we found that induction of cell stress alters the cytoskeleton in IECs via changes in the actin-binding proteins VIL1 and GSN. Acute changes in actin dynamics increase IEC survival, whereas long-term changes in actin dynamics lead to IEC death and intestinal inflammation. IRGM regulates necroptosis and release of DAMPs to induce gastrointestinal inflammation, linking IRGM activity with CD.

Proinflammatory Sulfur-Reducing Bacteria Are More Abundant in Colonic Biopsies of Patients with Microscopic Colitis Compared to Healthy Controls.

BACKGROUND: Microscopic colitis (MC), a subtype of inflammatory bowel disease, is a chronic condition of unknown etiology. Recent evidence has linked MC with intriguing changes in the stool microbiota, which may be linked to disease pathogenesis. The composition of the mucosal microbiome in patients with MC remains unclear. METHODS: We performed a cross-sectional study comparing colonic tissue samples from patients with MC to those of healthy controls at the Michael E. DeBakey VA Medical Center. We included adults older than 18 who underwent a colonoscopy with biopsies to evaluate chronic diarrhea. Cases were defined by histology consistent with MC and controls by the absence of histologic disease. We conducted structured chart review to exclude other gastrointestinal diseases and obtain demographic (age, sex, race) and clinical (duration of symptoms and concurrent medications) information for cases and controls. We extracted bacterial DNA from formalin-fixed paraffin-embedded tissue samples and sequenced the v4 region of the 16S rRNA gene. Operational taxonomic unit (OTU) clustering was performed using UPARSE, and OTUs were assigned using the SILVA database. Statistical analysis was performed in QIIME and LEfSe. Comparisons with FDR-adjusted p values of less than 0.05 were considered statistically significant. RESULTS: We included 20 MC patients and 20 controls with mean ages of 62 and 54, respectively. Most cases were White (95%), 60% had symptoms for greater than 12 months, and 50% were taking PPIs and NSAIDs at the time of their diagnosis. Compared to controls, MC patients had a significant increase in the proinflammatory sulfur-reducing bacterial family Desulfovibrionales. The Coriobacteriaceae family, abundant in the healthy gut, was significantly decreased in MC cases. There was also an increase in the genus Actinomyces in MC patients on PPI and an increase in the class Bacilli among those taking NSAIDs. DISCUSSION: Patients with MC have an increase in the proinflammatory family Desulfovibrionales. Actinomyces and Bacilli were associated with medications (PPI and NSAID) known to increase the risk of MC. Our findings may have important implications for understanding the pathogenesis of MC.

Improving Anemia in Inflammatory Bowel Disease: Impact of the Anemia Care Pathway.

BACKGROUND: Anemia is a common complication of inflammatory bowel disease (IBD). Despite existing guidelines for anemia in IBD, it is frequently under-treated and the prevalence of anemia has remained high. To address this gap, the Crohn's and Colitis Foundation developed the Anemia Care Pathway (ACP). AIMS: To implement the ACP in a managed care setting and identify where it improves practice habits and where barriers remain. METHODS: The ACP was implemented from July 2016 through June 2017 and retrospectively studied. Run charts were used to identify shifts in iron deficiency screening and treatment as well as anemia prevalence. Results were compared to those of other providers in the same center not using the ACP. RESULTS: 640 IBD encounters were studied. In the ACP clinic (n = 213), anemics received iron therapy in only 30% of encounters at baseline but improved to 80%. Concurrently, anemia prevalence decreased from 48 to 25%. Screening for iron deficiency, however, did not improve. No shifts were seen in the non-ACP clinics (n = 427) across the same period despite awareness of the ACP and other guidelines. CONCLUSIONS: Across 1 year, we observed gaps in the screening and treatment of anemia in IBD. Although screening rates did not improve, the ACP appeared to reduce missed opportunities for iron therapy by about half. Most importantly, this was associated with an overall decrease in anemia prevalence. Future refinements to the ACP should be focused on enhanced screening and follow-up.