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Background: The natural history of primary sclerosing cholangitis (PSC) among African Americans (AA) is not well understood., Methods: Transplant-free survival and hepatic decompensation-free survival were assessed using a retrospective research registry from 16 centers throughout North America. Patients with PSC alive without liver transplantation after 2008 were included. Diagnostic delay was defined from the first abnormal liver test to the first abnormal cholangiogram/liver biopsy. Socioeconomic status was imputed by the Zip code., Results: Among 850 patients, 661 (77.8%) were non-Hispanic Whites (NHWs), and 85 (10.0%) were AA. There were no significant differences by race in age at diagnosis, sex, or PSC type. Inflammatory bowel disease was more common in NHWs (75.8% vs. 51.8% p=0.0001). The baseline (median, IQR) Amsterdam-Oxford Model score was lower in NHWs (14.3, 13.4-15.2 vs. 15.1, 14.1-15.7, p=0.002), but Mayo risk score (0.03, -0.8 to 1.1 vs. 0.02, -0.7 to 1.0, p=0.83), Model for End-stage Liver Disease (5.9, 2.8-10.7 vs. 6.4, 2.6-10.4, p=0.95), and cirrhosis (27.4% vs. 27.1%, p=0.95) did not differ. Race was not associated with hepatic decompensation, and after adjusting for clinical variables, neither race nor socioeconomic status was associated with transplant-free survival. Variables independently associated with death/liver transplant (HR, 95% CI) included age at diagnosis (1.04, 1.02-1.06, p<0.0001), total bilirubin (1.06, 1.04-1.08, p<0.0001), and albumin (0.44, 0.33-0.61, p<0.0001). AA race did not affect the performance of prognostic models., Conclusions: AA patients with PSC have a lower rate of inflammatory bowel disease but similar progression to hepatic decompensation and liver transplant/death compared to NHWs., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD) 1 -a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence of IBD in industrialized countries and the augmented disease risk observed in migrants who move into areas of higher disease prevalence suggest that environmental factors are also important determinants of IBD susceptibility and severity 2 . However, the identification of environmental factors relevant to IBD and the mechanisms by which they influence disease has been hampered by the lack of platforms for their systematic investigation. Here we describe an integrated systems approach, combining publicly available databases, zebrafish chemical screens, machine learning and mouse preclinical models to identify environmental factors that control intestinal inflammation. This approach established that the herbicide propyzamide increases inflammation in the small and large intestine. Moreover, we show that an AHR-NF-κB-C/EBPβ signalling axis operates in T cells and dendritic cells to promote intestinal inflammation, and is targeted by propyzamide. In conclusion, we developed a pipeline for the identification of environmental factors and mechanisms of pathogenesis in IBD and, potentially, other inflammatory diseases., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: Bile acids, such as chenodeoxycholic acid, play an important role in digestion but are also involved in intestinal motility, fluid homeostasis, and humoral activity. Colonic delivery of sodium chenodeoxycholate (CDC) has demonstrated clinical efficacy in treating irritable bowel syndrome with constipation but was associated with a high frequency of abdominal pain. We hypothesized that these adverse effects were triggered by local super-physiological CDC levels caused by an unfavorable pharmacokinetic profile of the delayed release formulation., Methods: We developed novel release matrix systems based on hydroxypropyl methylcellulose (HPMC) for sustained release of CDC. These included standard HPMC formulations as well as bi-layered formulations to account for potential delivery failures due to low colonic fluid in constipated patients. We evaluated CDC release profiles in silico (pharmacokinetic modeling), in vitro and in vivo in swine (pharmacokinetics, rectal manometry)., Results: For the delayed release formulation in vitro release studies demonstrated pH triggered dose dumping which was associated with giant colonic contractions in vivo. Release from the bi-layered HPMC systems provided controlled release of CDC while minimizing the frequency of giant contractions and providing enhanced exposure as compared to standard HPMC formulations in vivo., Discussion: Bi-phasic CDC release could help treat constipation while mitigating abdominal pain observed in previous clinical trials. Further studies are necessary to demonstrate the therapeutic potential of these systems in humans.

Background: Anti-TNFα agents have revolutionised management of chronic inflammatory diseases. Paradoxically, these agents might provoke development of de novo autoimmune diseases., Aim: To examine whether there is an increased risk of developing Crohn's disease (CD) and ulcerative colitis (UC) while under treatment with anti-TNFα agents for diseases other than inflammatory bowel disease (IBD) METHODS: A nationwide cohort study, based on Danish health registries, of all patients who utilised anti-TNFα agents for non-IBD indications. Included were patients, who had diseases for which anti-TNFα agent is indicated (rheumatoid arthritis, psoriasis/psoriatic arthritis, ankylosing spondylitis, others). The observation period for development of de novo IBD started from 2004. Exposed patients had received at least one dose of anti-TNFα., Results: In total 17 018 individuals with autoimmune diseases were exposed to anti-TNFα (the vast majority had infliximab, etanercept and adalimumab), and 63 308 individuals were not. Patients treated with etanercept had an increased risk of being diagnosed with CD and UC while under treatment, adjusted hazard ratio 2.0 [95% CI: 1.4-2.8] and 2.0 [95% CI: 1.5-2.8], respectively. The corresponding hazards ratios for infliximab were 1.3 [95% CI: 0.8-2.2] and 1.0 [95% CI:0.6-1.6], and for adalimumab 1.2 [95% CI: 0.8-1.8] and 0.6 [95% CI: 0.3-1.0]., Conclusions: Patients treated for autoimmune diseases with anti-TNFα had an increased risk of being diagnosed with CD or UC while under treatment with etanercept. The nature of this association is uncertain. This finding has relevance to clinical care and insights into common mechanisms of the pathophysiology of these diseases., (© 2019 John Wiley & Sons Ltd.)

Introduction: Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD) can profoundly affect quality of life and are influenced by stress and resiliency. The impact of mind-body interventions (MBIs) on IBS and IBD patients has not previously been examined., Methods: Nineteen IBS and 29 IBD patients were enrolled in a 9-week relaxation response based mind-body group intervention (RR-MBI), focusing on elicitation of the RR and cognitive skill building. Symptom questionnaires and inflammatory markers were assessed pre- and post-intervention, and at short-term follow-up. Peripheral blood transcriptome analysis was performed to identify genomic correlates of the RR-MBI., Results: Pain Catastrophizing Scale scores improved significantly post-intervention for IBD and at short-term follow-up for IBS and IBD. Trait Anxiety scores, IBS Quality of Life, IBS Symptom Severity Index, and IBD Questionnaire scores improved significantly post-intervention and at short-term follow-up for IBS and IBD, respectively. RR-MBI altered expression of more genes in IBD (1059 genes) than in IBS (119 genes). In IBD, reduced expression of RR-MBI response genes was most significantly linked to inflammatory response, cell growth, proliferation, and oxidative stress-related pathways. In IBS, cell cycle regulation and DNA damage related gene sets were significantly upregulated after RR-MBI. Interactive network analysis of RR-affected pathways identified TNF, AKT and NF-κB as top focus molecules in IBS, while in IBD kinases (e.g. MAPK, P38 MAPK), inflammation (e.g. VEGF-C, NF-κB) and cell cycle and proliferation (e.g. UBC, APP) related genes emerged as top focus molecules., Conclusions: In this uncontrolled pilot study, participation in an RR-MBI was associated with improvements in disease-specific measures, trait anxiety, and pain catastrophizing in IBS and IBD patients. Moreover, observed gene expression changes suggest that NF-κB is a target focus molecule in both IBS and IBD-and that its regulation may contribute to counteracting the harmful effects of stress in both diseases. Larger, controlled studies are needed to confirm this preliminary finding., Trial Registration: ClinicalTrials.Gov NCT02136745.

Background: The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis result from alterations in intestinal microbes and the immune system. However, the precise dysfunctions of microbial metabolism in the gastrointestinal microbiome during IBD remain unclear. We analyzed the microbiota of intestinal biopsies and stool samples from 231 IBD and healthy subjects by 16S gene pyrosequencing and followed up a subset using shotgun metagenomics. Gene and pathway composition were assessed, based on 16S data from phylogenetically-related reference genomes, and associated using sparse multivariate linear modeling with medications, environmental factors, and IBD status., Results: Firmicutes and Enterobacteriaceae abundances were associated with disease status as expected, but also with treatment and subject characteristics. Microbial function, though, was more consistently perturbed than composition, with 12% of analyzed pathways changed compared with 2% of genera. We identified major shifts in oxidative stress pathways, as well as decreased carbohydrate metabolism and amino acid biosynthesis in favor of nutrient transport and uptake. The microbiome of ileal Crohn's disease was notable for increases in virulence and secretion pathways., Conclusions: This inferred functional metagenomic information provides the first insights into community-wide microbial processes and pathways that underpin IBD pathogenesis.

Sialic acid acetylesterase (SIAE) is an enzyme that negatively regulates B lymphocyte antigen receptor signalling and is required for the maintenance of immunological tolerance in mice. Heterozygous loss-of-function germline rare variants and a homozygous defective polymorphic variant of SIAE were identified in 24/923 subjects of European origin with relatively common autoimmune disorders and in 2/648 controls of European origin. All heterozygous loss-of-function SIAE mutations tested were capable of functioning in a dominant negative manner. A homozygous secretion-defective polymorphic variant of SIAE was catalytically active, lacked the ability to function in a dominant negative manner, and was seen in eight autoimmune subjects but in no control subjects. The odds ratio for inheriting defective SIAE alleles was 8.6 in all autoimmune subjects, 8.3 in subjects with rheumatoid arthritis, and 7.9 in subjects with type I diabetes. Functionally defective SIAE rare and polymorphic variants represent a strong genetic link to susceptibility in relatively common human autoimmune disorders.

Background & Aims: The practice of dosing mesalamines in divided doses for the treatment of ulcerative colitis (UC) began with sulfasalazine and was driven by sulfapyridine toxicity. This convention and the assumption that dosing multiple times a day is necessary to treat UC had not been challenged until recently. This study was conducted to determine the efficacy and safety of once-daily dosing of delayed-release mesalamine (Asacol 400-mg tablets) compared with twice-daily dosing for maintaining remission in UC patients., Methods: A multicenter, randomized, investigator-blinded, 12-month, active-control trial was conducted to assess the noninferiority of delayed-release mesalamine 1.6-2.4 g/day administered once daily compared with twice daily in patients with mild-to-moderate UC currently in clinical remission. The primary end point was maintenance of clinical remission at month 6., Results: A total of 1023 patients were randomized and dosed. The primary objective of noninferiority was met. At month 6, 90.5% of patients receiving once-daily dosing had maintained clinical remission, compared with 91.8% of patients receiving twice-daily dosing (95% confidence interval for twice daily - once daily, -2.3 to 4.9). At month 12, 85.4% of patients receiving once-daily dosing had maintained clinical remission, compared with 85.4% of patients receiving twice-daily dosing (95% confidence interval for twice daily - once daily, -4.6 to 4.7). Both regimens had low rates of withdrawals as a result of adverse events and serious adverse events., Conclusions: Once-daily dosing of delayed-release mesalamine at doses of 1.6-2.4 g/day was shown to be as effective as twice-daily dosing for maintenance of clinical remission in patients with UC., (2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Postoperative morbidity and mortality following a colectomy for ulcerative colitis (UC) has been primarily reported from tertiary care referral centers that perform a high volume of operations; however, the postoperative outcomes among nonselected hospitals are not known. We set out to evaluate postoperative morbidity and mortality using a nationally representative database and to determine the factors that influenced outcomes., Methods: We analyzed the 1995-2005 Nationwide Inpatient Sample to identify 7108 discharges for UC patients who underwent a total abdominal colectomy. The effects of hospital volume on postoperative morbidity and mortality were evaluated in logistic regression models adjusting for demographic and clinical factors., Results: Postoperative mortality and morbidity rates were 2.3% and 30.8%, respectively. Most operations were performed in low-volume hospitals that had an increased risk of death (adjusted odds ratio [aOR], 2.42; 95% confidence interval [CI]: 1.26-4.63). In-hospital mortality was increased in patients who were admitted emergently (aOR, 5.40; 95% CI: 3.48-8.40), aged 60-80 years (aOR, 8.70; 95% CI: 3.30-22.92), and those with Medicaid (aOR, 4.29; 95% CI: 2.13-8.66). Emergently admitted UC patients whose surgery was performed 6 days after their admission had significantly increased likelihood of in-hospital death (aOR, 2.12; 95% CI: 1.13-3.97)., Conclusions: Postoperative mortality was lowest in hospitals that performed the highest volume of operations. Increasing the proportion of total colectomies performed in high-volume hospitals may improve clinical outcomes for patients with UC.