Joel Pekow

Background: Alcohol consumption has been found to worsen the pathology of colitis. To elucidate the underlying mechanism, we performed both miRNA and mRNA sequencing of the large intestinal epithelial cells derived from a murine model of alcohol‐induced colitis. Methods: Mice received Dextran Sulfate Sodium (DSS) for 5 days to induce colitis and were gavaged with alcohol (~3 g/kg) or water for 3 days. Three hours after the final gavage, mice were euthanized, and colon lengths were measured, followed by epithelial cell isolation. RNA, including miRNA, was isolated from the colonic epithelial cells and sent to Novogene for mRNA and miRNA sequencing. Results: Analysis comparing DSS Ethanol vs. Sham Vehicle mice showed 3931 significantly upregulated genes and 3788 significantly downregulated genes. Functional enrichment analysis of GO and KEGG pathways showed enrichment of positive regulation of superoxide anion generation and HIF‐1 signaling pathways, both related to oxidative stress. DSS Ethanol compared to DSS Vehicle resulted in 921 significantly upregulated and 1072 significantly downregulated genes ( P _adj < 0.05), with functional enrichment analysis showing the term with the highest fold enrichment was superoxide anion generation. We further confirmed the RNA expression of NOS2, CYBB, and NCF1, which are involved in nitric oxide and superoxide production. miRNA sequencing revealed 84 differentially expressed miRNAs comparing DSS Ethanol to DSS Vehicle. Functional enrichment analysis of predicted targets of these miRNAs also showed enrichment in superoxide anion generation. Conclusion: These results suggest that combined ethanol and DSS exposure may increase the production of reactive oxygen species, which further damages the intestinal lining and potentially contributes to the ethanol exacerbation of colitis.

Purpose: The fucosyltransferase 2 gene (FUT2) is responsible for the regulation of mucosal blood type antigens which can act as receptors for bacterial adhesion and regulate intestinal flora. A homozygous nonsense mutation in this gene leads to the absence of these antigens, termed FUT2 non-secretor status, and is associated with the development of Crohn’s disease (CD). The mechanism of this association is likely via changes in homeostatic symbiosis, thus promoting development of inflammation. However, the impact of FUT2 genotype on CD phenotype and outcomes is not known. Methods: Subjects were prospectively enrolled into a single-center translational IBD registry. All patients with CD who had available DNA extracted from peripheral blood for genotyping were included. Genotyping was performed using the rs601338-AA SNP, which represents the nonsense mutation (428GA) shown to be causing non-secretor status. Baseline demographics, disease phenotype, CD-related surgeries, and hospitalizations were also assessed retrospectively and statistically compared based on FUT2 genotype. Results: 635 patients with CD were included in the analysis, including 178 FUT2 wild-type (WT), 314 heterozygous (HET) and 143 homozygous (O) patients. The mean duration of follow-up was 8 years and 2 months. There were no statistically significant differences detected between genotypes when comparing sex, race, smoking status, body-mass index, and age of onset. Presence of extra-intestinal manifestations including arthritis, uveitis, erythema nodosum, pyoderma gangrenosum and primary sclerosing cholangitis, as well as disease location and behavior were also found to be similar when compared between O and WT, O and HET, and O and HET plus WT populations. The mean number of biologics used between groups was 1.50 (O), 1.39 (HET)and 1.42 (WT) (P = .55), with no difference in total duration of biologic therapy between groups. 60.8% of O patients used immunomodulators compared to 54.8% of HET and 59.6% of WT patients. In addition, there were no differences between groups in the number of patients who required more than one CD-related hospitalization (O = 30.1%, HET = 34.1%, WT = 30.3%) or surgery (O = 32.2%, HET = 39.5%, WT = 32%). Conclusion: In this single-center analysis of 635 patients with CD, the FUT2 genotype was not associated with disease phenotype, disease severity, or clinical outcomes. These data suggest that while lack of fucosylation is associated with developing CD, it does not play a major role in driving disease progression.

INTRODUCTION: Regulatory safety warnings for Janus kinase inhibitors, based on increased cardiovascular events in the rheumatoid arthritis populations, have raised concern regarding their use in inflammatory bowel disease (IBD) patients with cardiovascular risk factors. METHODS: Patients 50 years and older with IBD initiating upadacitinib were studied. Lipids, atherosclerotic cardiovascular disease risk scores, and adverse events were longitudinally assessed. RESULTS: Low-density lipoprotein increased early but stabilized, whereas high-density lipoprotein increased, with no change in low-density lipoprotein:high-density lipoprotein ratio. Atherosclerotic cardiovascular disease risk increased modestly (+1.2%). No major adverse cardiovascular events occurred. Two venous thromboembolism events occurred during active disease. DISCUSSION: In older patients with IBD and baseline cardiovascular risk, upadacitinib was not associated with cardiovascular events over 188 patient-years, supporting appropriate clinical use with risk monitoring.

Inflammatory bowel diseases (IBD), principally Crohn’s disease (CD) and ulcerative colitis (UC), are common chronic disorders involving inflammation and often progressive tissue damage. Genome-wide association studies have mapped many risk signals, but the causal variants, effector genes and relevant cellular contexts remain difficult to resolve, limiting mechanistic interpretation and therapeutic translation. Here we performed a multi-ancestry GWAS meta-analysis of 125,992 individuals with IBD and more than 1.2 million controls, identifying 619 independent association signals (374 novel) at 420 IBD regions that account for 77–80% of SNP-based heritability. Fine-mapping resolved 81 high-confidence variants, 41 not previously reported. Although most signals were shared between CD and UC, 39% showed IBD subtype specificity, with UC signals showing stronger enrichment in functional annotations from intestinal epithelial, secretory and enteroendocrine cells, and CD showing stronger genetic correlations with circulating inflammatory biomarkers, including C-reactive protein and glycoprotein acetylation. Latent causal modelling supported a causal effect of decreased high-density lipoprotein on CD risk. By integrating bulk and single-cell eQTL and pQTL resources using colocalisation and Mendelian randomisation, together with coding-variant evidence from exome sequencing, we prioritised 664 candidate effector genes across 341 signals, including 390 newly implicated IBD genes, revealing new biological mechanisms and candidate therapeutic targets supported by human genetics.

Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation ^1,2 . Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.

Cutaneous Crohn's disease (CD) is a rare manifestation of inflammatory bowel disease characterized by cutaneous lesions that are noncontiguous with gastrointestinal tissue yet share similar histopathologic features with gastrointestinal CD. To our knowledge, there are no published data on the use of guselkumab for cutaneous CD. We discuss a case of concomitant pyoderma gangrenosum and cutaneous CD treated with a novel combination of guselkumab, antimicrobial agents, and corticosteroids.

We assessed the predictive value of MAdCAM‐1 expression on response to vedolizumab in patients with inflammatory bowel disease. This was a retrospective, single‐center, cohort study including 109 patients with pretreatment inflammation who completed at least three doses of vedolizumab. We described clinical and endoscopic outcomes of patients based on MAdCAM‐1 expression. There was no significant difference in MAdCAM‐1 expression when stratified by histology. Patients in clinical remission at 14 weeks had significantly lower median baseline MAdCAM‐1 expression (37425.3 vs. 46278.9, p < 0.015). There was no difference in pretreatment MAdCAM‐1 expression among patients who later achieved endoscopic or biologic response. In the posttreatment cohort, lower MAdCAM‐1 expression was associated with an increased likelihood of endoscopic or biologic response (36719.5 vs. 44229.9, p < 0.038). However, posttreatment MAdCAM‐1 expression did not significantly differ when stratified for clinical remission at 14 weeks. Ultimately, MAdCAM‐1 immunohistochemistry has limited utility as a predictive biomarker but may provide insights into vedolizumab‐associated bowel healing.

The association of chronic inflammation with colorectal carcinoma (CRC) development is well known in ulcerative colitis (UC). However, the role of inflammatory changes in sporadic CRC pathogenesis is less widely appreciated. In this study, in the first step using RNA-seq, we identified gene-pathway-level changes in UC-associated CRC (UC CRC, n = 10) and used the changes as a proxy for inflammation in human colon to ask if there were associations of inflammatory pathway dysregulations in sporadic CRC pathogenesis (n = 8). We found down-regulations of several inflammation-related metabolic pathways (nitrogen metabolism, sulfur metabolism) and other pathways (bile secretion, fatty acid degradation) in sporadic CRC. Non-inflammation-related changes included up-regulation of the proteasome pathway. In the next step, from a larger number of paired samples from sporadic CRC patients (n = 71) from a geographically and ethnically different population and using a different platform (microarray), we asked if the inflammation-CRC association could be replicated. The associations were significant even after stratification by sex, tumor stage, grade, MSI status, and KRAS mutation status. Our findings have important implications to widen our understanding of inflammatory pathogenesis of sporadic CRC. Furthermore, targeting of several of these dysregulated pathways could provide the basis for improved therapies for CRC.

Background: Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) have an increased risk of developing colorectal neoplasia (CRN) in the proximal colon. Objectives: To evaluate whether duration and severity of inflammation are linked to the development of CRN in this population. Design: Retrospective, case–control chart review of patients with PSC and IBD at a tertiary care center. Methods: Disease activity was scored per colonic segment at each colonoscopy prior to the first instance of observed CRN using a modified Mayo endoscopic sub-score and histologic assessment. Patients in the CRN-positive group were compared to controls that did not. Results: In all, 72 PSC-IBD patients with no history of CRN were identified, 13 of whom developed CRN after at least one colonoscopy at our institution. Patients in the CRN-positive group had significantly more endoscopic ( p < 0.01) and histologic ( p < 0.01) inflammation in the right compared to the control group prior to the development of dysplasia. There was significantly greater endoscopic inflammation in the segment of the colon with a dysplastic lesion than other segments of the colon ( p = 0.018). Patients with moderate/severe lifetime endoscopic ( p = 0.02) or histologic inflammation ( p = 0.04) score had a lower probability of remaining free of dysplasia during follow-up. Nearly half of the patients with dysplasia had invisible lesions found on random biopsy. Conclusions: Endoscopic and histologic inflammation in the proximal colon are risk factors for CRN in patients with PSC-IBD. PSC-IBD patients frequently have subclinical inflammation, and these findings support the practice of regular assessment of disease activity and random biopsy of inflamed and uninflamed areas in patients with PSC with the goal of reducing inflammation to prevent the development of CRN.