TNF promoter hypomethylation is associated with mucosal inflammation in IBD and anti-TNF response.

Background and aims: Inflammatory Bowel Diseases (IBD) are chronic inflammatory conditions influenced heavily by environmental factors. DNA methylation is a form of epigenetic regulation linking environmental stimuli to gene expression changes and inflammation. Here, we investigated how DNA methylation of the TNF promoter differs between inflamed and uninflamed mucosa of IBD patients, including anti-TNF responders and non-responders. Methods: We obtained mucosal biopsies from 200 participants (133 IBD and 67 controls) and analyzed TNF promoter methylation using bisulfite sequencing, comparing inflamed with uninflamed segments, in addition to paired inflamed/uninflamed samples from individual patients. We conducted similar analyses on purified intestinal epithelial cells from bowel resections. We also compared TNF methylation levels of inflamed and uninflamed mucosa from a separate cohort of 15 anti-TNF responders and 17 non-responders. Finally, we sequenced DNA methyltransferase genes to identify rare variants in IBD patients and functionally tested them using rescue experiments in a zebrafish genetic model of DNA methylation deficiency. Results: TNF promoter methylation levels were decreased in inflamed mucosa of IBD patients and correlated with disease severity. Isolated IECs from inflamed tissue showed proportional decreases in TNF methylation. Anti-TNF non-responders showed lower levels of TNF methylation than responders in uninflamed mucosa. Our sequencing analysis revealed two missense variants in DNMT1, one of which had reduced function in vivo. Conclusions: Our study reveals an association of TNF promoter hypomethylation with mucosal inflammation, suggesting that IBD patients may be particularly sensitive to inflammatory environmental insults affecting DNA methylation. Together, our analyses indicate that TNF promoter methylation analysis may aid in the characterization of IBD status and evaluation of anti-TNF therapy response.

Increased activity of MAPKAPK2 within mesenchymal cells as a target for inflammation associated fibrosis in Crohn's Disease.

BACKGROUND: Mesenchymal stromal cells are suggested to play a critical role in the Crohn's Disease (CD) associated fibrosis. MAPKAPK2 (MK2) has emerged as a potential therapeutic target to reduce inflammation in CD. However, cell-specific pattern of pMK2 activation and its role in the CD associated fibrosis are unknown. The objectives of this study were to evaluate cell-specific changes in MK2 activity between predominantly inflammatory CD versus CD with fibrotic complication and define the role of stromal cell-specific MK2 activation in CD-associated fibrosis. METHODS: CD tissue, CD tissue derived mesenchymal stromal cells known as myo-/fibroblasts (CD-MFs), fibroblast specific MK2 conditional KO mice were used. RESULTS: We observed that in the inflamed area of predominantly inflammatory CD, high MK2 activity was equally distributed between mesenchymal and hematopoietic cells. By contrast, in CD with fibrotic complications, high MK2 activity was mostly associated with mesenchymal stromal cells. Using ex vivo CD tissue explants and IL-10KO murine colitis model, we demonstrated that pro-fibrotic responses are significantly reduced by treatment with the MK2 inhibitor PF-3644022. Inhibition of MK2 activity in primary cultures of CD-MFs significantly reduced basal and TGF-ß1-induced profibrotic responses. Using fibroblast-specific MK2 knockout mice in chronic DSS colitis, we demonstrated that fibroblast intrinsic MK2 signaling is among the key processes involved in the chronic inflammation induced profibrotic responses. CONCLUSIONS: Our data suggest that activation of MK2 within fibroblasts contributes to the chronic inflammation induced fibrosis in CD and that targeting MK2 has potential for the development of novel therapeutic approaches for fibrosis in CD.

Vedolizumab, Adalimumab, and Methotrexate Combination Therapy in Crohn's Disease (EXPLORER).

BACKGROUND & AIMS: Although biologics have revolutionized the treatment of Crohn's disease (CD), an efficacy ceiling has been reached. Combining biologic therapies may improve remission rates. METHODS: EXPLORER, a phase 4, single-arm, open-label study, evaluated triple combination therapy with vedolizumab (300 mg on day 1, weeks 2 and 6, and then every 8 weeks), adalimumab (160 mg on day 2, 80 mg at week 2, then 40 mg every 2 weeks), and methotrexate (15 mg weekly) in biologic-naïve patients with newly diagnosed, moderate- to high-risk CD. Endoscopic remission at week 26 (primary end point; Simple Endoscopic Score for CD ≤2), clinical remission at weeks 10 and 26 (secondary end point; Crohn's Disease Activity Index <150), and incidences of adverse events and serious adverse events were evaluated. RESULTS: Among 55 enrolled patients, the mean CD duration was 0.4 years, the mean baseline Simple Endoscopic Score for CD was 12.6, and the mean baseline Crohn's Disease Activity Index was 265.5. At week 26, 19 patients (34.5%) were in endoscopic remission. At weeks 10 and 26, 34 (61.8%) and 30 patients (54.5%), respectively, were in clinical remission. Post hoc Bayesian analysis showed that the probabilities that triple combination therapy produced a higher endoscopic remission rate (33.5%; 95% credible interval, 22.4-45.7) than placebo (14%), vedolizumab monotherapy (27%), or adalimumab monotherapy (30%) were 99.9% or higher, 86.3%, and 71.4%, respectively. Six patients had serious adverse events. CONCLUSIONS: Combination therapy resulted in endoscopic and clinical remission at week 26 in 34.5% and 54.5% of patients, respectively, with no safety signal related to the treatment regimen. This supports further evaluation of combination therapy in CD. CLINICALTRIALS: gov number: NCT02764762.

Etrolizumab as induction and maintenance therapy in patients with moderately to severely active Crohn's disease (BERGAMOT): a randomised, placebo-controlled, double-blind, phase 3 trial.

BACKGROUND: Etrolizumab is a gut-targeted anti-ß7 monoclonal antibody targeting α4ß7 and αEß7 integrins. We aimed to compare the safety and efficacy of two doses of etrolizumab with placebo in patients with Crohn's disease. METHODS: BERGAMOT was a randomised, placebo-controlled, double-blind, phase 3 study done at 326 treatment centres worldwide. We included patients aged 18-80 years with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] score of 220-480, and a mean daily stool frequency score of ≥6 or a mean daily stool frequency score of >3, and a mean daily abdominal pain score of >1, as well as the presence of active inflammation on screening ileocolonoscopy) who had intolerance, inadequate response, or no response to one or more of corticosteroids, immunosuppressants, or anti-TNF therapy within the past 5 years. BERGAMOT consisted of three induction cohorts (a placebo-controlled, double-blind exploratory cohort [cohort 1]; an active treatment cohort not containing a placebo control [cohort 2]; and a placebo-controlled, double-blind pivotal cohort [cohort 3]) and one maintenance cohort. In induction cohort 3, during the 14-week induction, patients were randomly assigned (2:3:3) to receive matched placebo, 105 mg etrolizumab subcutaneously every 4 weeks (at weeks 0, 4, 8, and 12) or 210 mg etrolizumab subcutaneously (at weeks 0, 2, 4, 8, and 12), stratified by concomitant treatment with oral corticosteroids, concomitant treatment with immunosuppressants, baseline disease activity, and previous exposure to anti-TNF therapy. To preserve masking, all patients received two injections at weeks 0, 4, 8, and 12 and one injection at week 2. Week 14 etrolizumab responders from all cohorts were re-randomly assigned (1:1) to receive 105 mg etrolizumab (etrolizumab maintenance group) or placebo (placebo maintenance group) every 4 weeks for 52 weeks; patients in the induction placebo group underwent a sham re-randomisation to preserve masking. During maintenance, randomisation was stratified by CDAI remission status, concomitant treatment with oral corticosteroids, induction dose regimen, and previous exposure to anti-TNF therapy. All participants and study site personnel were masked to treatment assignment for both induction and maintenance. Co-primary induction endpoints at week 14 (placebo vs 210 mg etrolizumab) were clinical remission (mean stool frequency ≤3 and mean abdominal pain ≤1, with no worsening) and endoscopic improvement (≥50% reduction in Simple Endoscopic Score for Crohn's Disease [SES-CD]). Co-primary maintenance endpoints at week 66 (placebo vs etrolizumab) were clinical remission and endoscopic improvement. Efficacy was analysed using a modified intention-to-treat (mITT) population, defined as all randomised patients who received at least one dose of study drug (induction) and as all patients re-randomised into maintenance who received at least one dose of study drug in the maintenance phase (maintenance). Safety analyses included all patients who received at least one dose of study drug. Maintenance safety analyses include all adverse events occurring in both induction and maintenance. This trial is registered with ClinicalTrials.gov, NCT02394028, and is closed to recruitment. FINDINGS: Between March 20, 2015, and Sept 7, 2021, 385 patients (209 [54%] male and 326 [85%] white) were randomly assigned in induction cohort 3 to receive placebo (n=97), 105 mg etrolizumab (n=143), or 210 mg etrolizumab (n=145). 487 patients had a CDAI-70 response in any of the induction cohorts and were enrolled into the maintenance cohort, of whom 434 had a response to etrolizumab and were randomly assigned to placebo (n=217) or 105 mg etrolizumab (n=217). At week 14, 48 (33%) of 145 patients in the 210 mg induction etrolizumab group versus 28 (29%) of 96 patients in the placebo induction group were in clinical remission (adjusted treatment difference 3·8% [95% CI -8·3 to 15·3]; p=0·52), and 40 (27%) versus 21 (22%) showed endoscopic improvement (5·8% [-5·4 to 17·1]; p=0·32). At week 66, a significantly higher proportion of patients receiving etrolizumab than those receiving placebo had clinical remission (76 [35%] of 217 vs 52 [24%] of 217; adjusted treatment difference 11·3% [95% CI 2·7-19·7]; p=0·0088) and endoscopic improvement (51 [24%] vs 26 [12%]; 11·5% [4·1-18·8]; p=0·0026). Similar proportions of patients reported one or more adverse events during induction (95 [66%] of 143 in the 105 mg etrolizumab group, 85 [59%] of 145 in the 210 mg etrolizumab group, and 51 [53%] of 96 in the placebo group) and maintenance (189 [87%] of 217 in the etrolizumab group and 190 [88%] of 217 in the placebo group). During induction, the most common treatment-related adverse events were injection site erythema (six [4%] of 143 in the 105 mg etrolizumab group, four [3%] of 145 in the 210 mg etrolizumab group, and none of 96 in the placebo group), and arthralgia (two [1%], one [1%], and four [4%]). In the maintenance cohort, the most common treatment-related adverse events were injection site erythema (six [3%] of 217 in the etrolizumab group vs 14 [6%] of 217 in the placebo: group), arthralgia (five [2%] vs eight [4%]), and headache (five [2%] vs seven [3%]). The most common serious adverse event was exacerbation of Crohn's disease (14 [6%] of 217 patients taking placebo and four [2%] of 217 patients taking 105 mg etrolizumab in the maintenance cohort). INTERPRETATION: A significantly higher proportion of patients with moderately to severely active Crohn's disease achieved clinical remission and endoscopic improvement with etrolizumab than placebo during maintenance, but not during induction. FUNDING: F Hoffmann-La Roche.

MK2 Inhibitors as a Potential Crohn's Disease Treatment Approach for Regulating MMP Expression, Cleavage of Checkpoint Molecules and T Cell Activity.

Crohn's Disease (CD) and Ulcerative Colitis (UC) are the two major forms of inflammatory bowel disease (IBD), which are incurable chronic immune-mediated diseases of the gastrointestinal tract. Both diseases present with chronic inflammation that leads to epithelial barrier dysfunction accompanied by loss of immune tolerance and inflammatory damage to the mucosa of the GI tract. Despite extensive research in the field, some of the mechanisms associated with the pathology in IBD remain elusive. Here, we identified a mechanism by which the MAPK-activated protein kinase 2 (MK2) pathway contributes to disease pathology in CD by regulating the expression of matrix metalloproteinases (MMPs), which cleave checkpoint molecules on immune cells and enhance T cell activity. By utilizing pharmaceuticals targeting MMPs and MK2, we show that the cleavage of checkpoint molecules and enhanced T cell responses may be reduced. The data presented here suggest the potential for MK2 inhibitors as a therapeutic approach for the treatment of CD.

Metabolic targeting of NRF2 potentiates the efficacy of the TRAP1 inhibitor G-TPP through reduction of ROS detoxification in colorectal cancer.

Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial homolog of HSP90 chaperones. It plays an important role in protection against oxidative stress and apoptosis by regulating reactive oxidative species (ROS). To further elucidate the mechanistic role of TRAP1 in regulating tumor cell survival, we used gamitrinib-triphenylphosphonium (G-TPP) to inhibit TRAP1 signaling pathways in colon cancer. Inhibition of TRAP1 by G-TPP disrupted redox homeostasis and induced cell death. However, colon cancers show a wide range of responses to G-TPP treatment through the induction of variable ER stress responses and ROS accumulation. Interestingly, a strong inverse correlation was observed between the expression of TRAP1 and antioxidant genes in colon tumor tissues using the GSE106582 database. Using a luciferase reporter assay, we detected increased transcriptional activation of antioxidant response elements (AREs) in G-TPP-treated DLD1 and RKO cells but not in SW48 cells. We found that G-TPP induced upregulation of GRP78, CHOP and PARP cleavage in G-TPP-sensitive cells (SW48). In contrast, G-TPP treatment of G-TPP-resistant cells (DLD1 and RKO) resulted in excessive activation of the antioxidant gene NRF2, leading to ROS detoxification and improved cell survival. The NRF2 target genes HO1 and NQO1 were upregulated in G-TPP-treated DLD1 cells, making the cells more resistant to G-TPP treatment. Furthermore, treatment with both a NRF2 inhibitor and a TRAP1 inhibitor led to excessive ROS production and exacerbated G-TPP-induced cell death in G-TPP-resistant cells. Taken together, dual targeting of TRAP1 and NRF2 may potentially overcome colon cancer resistance by raising cellular ROS levels above the cytotoxic threshold.

Biodiversity influences the effects of oil disturbance on coastal ecosystems.

Biodiversity can enhance the response of ecosystems to disturbance. However, whether diversity can reduce the ecological effect of human-induced novel and extreme disturbances is unclear. In April 2010, the Deepwater Horizon (DwH) platform exploded, allowing an uncontrolled release of crude oil into the northern Gulf of Mexico. Initial surveys following the spill found that ecological impacts on coastal ecosystems varied greatly across habitat-type and trophic group; however, to date, few studies have tested the influence of local biodiversity on these responses. We used a meta-analytic approach to synthesize the results of 5 mesocosm studies that included 10 independent oil experiments and 5 independent oil + dispersant experiments. We tested whether biodiversity increased the resistance and/or resilience of coastal ecosystems to oil disturbance and whether a biodiversity effect depended on the type of diversity present (taxonomic or genetic) and/or the response type measured (population, community, or ecosystem level). We found that diversity can influence the effects of oiling, but the direction and magnitude of this diversity effect varied. Diversity reduced the negative impact of oiling for within-trophic-level responses and tended to be stronger for taxonomic than genetic diversity. Further, diversity effects were largely driven by the presence of highly resistant or quick to recover taxa and genotypes, consistent with the insurance hypothesis. However, we found no effect of diversity on the response to the combination of oil and dispersant exposure. We conclude that areas of low biodiversity may be particularly vulnerable to future oil disturbances and provide insight into the benefit of incorporating multiple measures of diversity in restoration projects and management decisions.

Adaptive immunity induces mutualism between commensal eukaryotes.

Pathogenic fungi reside in the intestinal microbiota but rarely cause disease. Little is known about the interactions between fungi and the immune system that promote commensalism. Here we investigate the role of adaptive immunity in promoting mutual interactions between fungi and host. We find that potentially pathogenic Candida species induce and are targeted by intestinal immunoglobulin A (IgA) responses. Focused studies on Candida albicans reveal that the pathogenic hyphal morphotype, which is specialized for adhesion and invasion, is preferentially targeted and suppressed by intestinal IgA responses. IgA from mice and humans directly targets hyphal-enriched cell-surface adhesins. Although typically required for pathogenesis, C. albicans hyphae are less fit for gut colonization1,2 and we show that immune selection against hyphae improves the competitive fitness of C. albicans. C. albicans exacerbates intestinal colitis3 and we demonstrate that hyphae and an IgA-targeted adhesin exacerbate intestinal damage. Finally, using a clinically relevant vaccine to induce an adhesin-specific immune response protects mice from C. albicans-associated damage during colitis. Together, our findings show that adaptive immunity suppresses harmful fungal effectors, with benefits to both C. albicans and its host. Thus, IgA uniquely uncouples colonization from pathogenesis in commensal fungi to promote homeostasis.

A Randomized Trial Comparing the Specific Carbohydrate Diet to a Mediterranean Diet in Adults With Crohn's Disease.

BACKGROUND & AIMS: This study compared the effectiveness of the Specific Carbohydrate Diet (SCD) to the Mediterranean diet (MD) as treatment for Crohn's disease (CD) with mild to moderate symptoms. METHODS: Adult patients with CD and with mild-to-moderate symptoms were randomly assigned 1:1 to consume the MD or SCD for 12 weeks. For the first 6 weeks, participants received prepared meals and snacks according to their assigned diet. After 6 weeks, participants were instructed to follow the diet independently. The primary outcome was symptomatic remission at week 6. Key secondary outcomes at week 6 included fecal calprotectin (FC) response (FC <250 µg/g and reduction by >50% among those with baseline FC >250 µg/g) and C-reactive protein (CRP) response (high-sensitivity CRP <5 mg/L and >50% reduction from baseline among those with high-sensitivity CRP >5 mg/L). RESULTS: The study randomized 194 patients, and 191 were included in the efficacy analyses. The percentage of participants who achieved symptomatic remission at week 6 was not superior with the SCD (SCD, 46.5%; MD, 43.5%; P = .77). FC response was achieved in 8 of 23 participants (34.8%) with the SCD and in 4 of 13 participants (30.8%) with the MD (P = .83). CRP response was achieved in 2 of 37 participants (5.4%) with the SCD and in 1 of 28 participants (3.6%) with the MD (P = .68). CONCLUSIONS: The SCD was not superior to the MD to achieve symptomatic remission, FC response, and CRP response. CRP response was uncommon. Given these results, the greater ease of following the MD and other health benefits associated with the MD, the MD may be preferred to the SCD for most patients with CD with mild to moderate symptoms. ClinicalTrials.gov Identifier: NCT03058679.

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.

Disturbance-driven changes to northern Gulf of Mexico nekton communities following the Deepwater Horizon oil spill.

The 2010 Deepwater Horizon (DwH) oil spill in the Gulf of Mexico discharged ~3.19 million barrels of oil into Gulf waters, making it one of the largest marine disasters in history in terms of volume. We report on the results of a study to assess oil impacts to coastal fishes and invertebrates. Using two-decades of fisheries-independent data in coastal Alabama and Mississippi, we document variability following both natural and anthropogenic disturbances from two periods pre-DwH (1997-2001 and 2007-2009), one intra-spill period for acute DwH effects (2010-2012) and one period post-spill for chronic, longer-term impacts (2014-2017). Results indicated significant changes to community structure, relative abundance, and diversity in the intra-spill period. Causation for changes is confounded by variables such as behavioral emigration, altered freshwater inflow, death of consumers, and the mandated fishery closure. Results highlight the need for long-term, comprehensive monitoring/observing systems to provide adequate background for assessing future disturbances.

Expansion of Bacteriophages Is Linked to Aggravated Intestinal Inflammation and Colitis.

Bacteriophages are the most abundant members of the microbiota and have the potential to shape gut bacterial communities. Changes to bacteriophage composition are associated with disease, but how phages impact mammalian health remains unclear. We noted an induction of host immunity when experimentally treating bacterially driven cancer, leading us to test whether bacteriophages alter immune responses. Treating germ-free mice with bacteriophages leads to immune cell expansion in the gut. Lactobacillus, Escherichia, and Bacteroides bacteriophages and phage DNA stimulated IFN-γ via the nucleotide-sensing receptor TLR9. The resultant immune responses were both phage and bacteria specific. Additionally, increasing bacteriophage levels exacerbated colitis via TLR9 and IFN-γ. Similarly, ulcerative colitis (UC) patients responsive to fecal microbiota transplantation (FMT) have reduced phages compared to non-responders, and mucosal IFN-γ positively correlates with bacteriophage levels. Bacteriophages from active UC patients induced more IFN-γ compared to healthy individuals. Collectively, these results indicate that bacteriophages can alter mucosal immunity to impact mammalian health.

Family History Associates With Increased Risk of Colorectal Cancer in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Individuals with inflammatory bowel diseases (IBDs) have an increased risk of developing colorectal cancer (CRC). Although family history of CRC is a well-established risk factor in healthy individuals, its role in patients with IBD is less clear. We aimed to estimate the risk of CRC in a cohort of patients with IBD from Utah and the significance of family history of CRC in a first-degree relative (FDR). METHODS: We identified Utah residents with IBD, using the Intermountain Healthcare and University of Utah Health Sciences databases, from January 1, 1996, through December 31, 2011. CRCs were identified using the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. CRC incidence was compared with that of the state population by standardized incidence ratios (SIRs). RESULTS: A cohort of 9505 individuals with IBD was identified and 101 developed CRC during the study period. The SIR for CRC in patients with Crohn's disease was 3.4 (95% CI, 2.3-4.4), and in patients with ulcerative colitis was 5.2 (95% CI, 3.9-6.6). Patients with IBD and a concurrent diagnosis of primary sclerosing cholangitis had the greatest risk of CRC (SIR, 14.8; 95% CI, 8.3-21.2). A history of CRC in a FDR was associated with a nearly 8-fold increase in risk of CRC in patients with IBD (SIR, 7.9; 95% CI, 1.6-14.3), compared with the state population. CONCLUSIONS: Patients with IBD have a 3- to 5-fold increase in risk of CRC, and those with CRC in a FDR have an almost 8-fold increase in risk. Family history may act as a simple measure to identify individuals with IBD at highest risk for CRC and indicates the need for enhanced surveillance in this population.

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

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.

Chromoendoscopy for Dysplasia Surveillance in Inflammatory Bowel Disease.

Long-standing ulcerative colitis (UC) and extensive Crohn's colitis confer increased risk for development of colorectal cancer. Screening and surveillance colonoscopy programs aim to identify, resect, or detect dysplasia or colorectal cancer. Dysplastic lesions can be removed by endoscopic resection and patients with unresectable lesions can be referred for colectomy at an earlier stage, with the goal of reducing overall morbidity and mortality from colorectal cancer. Surveillance colonoscopy for patients with inflammatory bowel disease (IBD) is endorsed by multiple specialty societies. High-definition endoscopy systems provide improved image resolution, and application of dilute indigo carmine or methylene blue for chromoendoscopy can provide increased contrast. International specialty society guidelines differ in their recommendations regarding use of chromoendoscopy for dysplasia surveillance, with some guidelines advocating a risk-stratified surveillance strategy. In this review, we discuss chromoendoscopy technique, training, implementation, yield as compared with standard-definition and high-definition white light colonoscopy, and positioning of this technique in clinical practice.

Colorectal Cancer in Inflammatory Bowel Diseases: A Population-Based Study in Utah.

BACKGROUND AND AIMS: The molecular, endoscopic, and histological features of IBD-associated CRC differ from sporadic CRC. The objective of this study was to describe the prevalence, clinical features, and prognosis of IBD-associated CRC compared to patients with sporadic CRC in a US statewide population-based cohort. METHODS: All newly diagnosed cases of CRC between 1996 and 2011 were obtained from Utah Cancer Registry. IBD was identified using a previously validated algorithm, from statewide databases of Intermountain Healthcare, University of Utah Health Sciences, and the Utah Population Database. Logistic regression was performed to identify risk factors associated with IBD-associated cancer and Cox regression for differences in survival. RESULTS: Among 12,578 patients diagnosed with CRC, 101 (0.8%) had a prior history of IBD (61 ulcerative colitis and 40 Crohn's disease). The mean age at CRC diagnosis was greater for patients without IBD than those with IBD (67.1 vs 52.8 years, P < 0.001). Individuals with IBD-associated CRC were more likely to be men (odds ratio [OR] 1.90, 95% CI 1.23-2.92), aged less than 65 years (OR 6.77, 95% CI 4.06-11.27), and have CRC located in the proximal colon (OR 2.79, 95% CI 1.85-4.20) than those with sporadic CRC. Nearly 20% of the IBD-associated CRCs had evidence of primary sclerosing cholangitis. After adjustment for age, gender, and stage at diagnosis, the excess hazard of death after CRC diagnosis was 1.7 times higher in IBD than in non-IBD patients (95% CI 1.27-2.33). CONCLUSIONS: The features of patients with CRC and IBD differ significantly from those without IBD and may be associated with increased mortality.

Update on the Diagnosis and Management of Colon Ischemia.

OPINION STATEMENT: Colonic ischemia is the most common ischemic disorder of the gastrointestinal tract. The condition occurs more commonly in women, and risk increases with advancing age. Presenting symptoms include abdominal pain, bowel urgency, and passage of bloody diarrhea; however, nearly one half of patients do not present with this classic triad of symptoms. Abdominal pain without bloody diarrhea or non-bloody diarrhea should raise concern for an isolated right colon pattern of ischemia. An isolated right colon distribution is associated with more severe outcomes, including need for surgical intervention and increased mortality. Patients that present with symptoms concerning for ischemia should undergo computed tomography (CT) scan of the abdomen and pelvis with oral and IV contrast and laboratory testing. Colonoscopy should be performed in patients without evidence of peritonitis. Medical history should be obtained to identify possible etiologies of ischemia. Thrombophilia workup should be considered in young patients and those with recurrent ischemia, but is not required universally. In cases of isolated right colon ischemia, evaluation of the mesenteric vasculature is particularly important, for exclusion of concurrent acute mesenteric ischemia. Treatment of ischemic colitis is supportive in less severe cases, with intravenous fluids and bowel rest. Broad-spectrum antibiotics should be initiated, and surgical consultation should be obtained in cases of severe disease, pancolonic ischemia, and isolated right colonic ischemia. Surgery should be performed for peritonitis, hemodynamic instability, or failure of non-operative management. This article will review colonic ischemia diagnosis, evaluation, and treatment.

MicroRNA-146a constrains multiple parameters of intestinal immunity and increases susceptibility to DSS colitis.

Host-microbial interactions within the mammalian intestines must be properly regulated in order to promote host health and limit disease. Because the microbiota provide constant immunological signals to intestinal tissues, a variety of regulatory mechanisms have evolved to ensure proper immune responses to maintain homeostasis. However, many of the genes that comprise these regulatory pathways, including immune-modulating microRNAs (miRNAs), have not yet been identified or studied in the context of intestinal homeostasis. Here, we investigated the role of microRNA-146a (miR-146a) in regulating intestinal immunity and barrier function and found that this miRNA is expressed in a variety of gut tissues in adult mice. By comparing intestinal gene expression in WT and miR-146a-/- mice, we demonstrate that miR-146a represses a subset of gut barrier and inflammatory genes all within a network of immune-related signaling pathways. We also found that miR-146a restricts the expansion of intestinal T cell populations, including Th17, Tregs, and Tfh cells. GC B cells, Tfh ICOS expression, and the production of luminal IgA were also reduced by miR-146a in the gut. Consistent with an enhanced intestinal barrier, we found that miR-146a-/- mice are resistant to DSS-induced colitis, a model of Ulcerative Colitis (UC), and this correlated with elevated colonic miR-146a expression in human UC patients. Taken together, our data describe a role for miR-146a in constraining intestinal barrier function, a process that alters gut homeostasis and enhances at least some forms of intestinal disease in mice.