BACKGROUND & AIMS Activation of the transcription factor NFκB has been associated with development of inflammatory bowel disease (IBD). COMMD1, a regulator of various transport pathways, has been shown to limit NFκB activation. We investigated the roles of COMMD1 in the pathogenesis of colitis in mice and IBD in humans. METHODS We created mice with specific disruption of Commd1 in myeloid cells (Mye-K/O mice); we analyzed immune cell populations and functions and expression of genes regulated by NFκB. Sepsis was induced in Mye-K/O and wild-type mice by cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide (LPS), colitis was induced by administration of dextran sodium sulfate (DSS), and colitis-associated cancer was induced by administration of DSS and azoxymethane. We measured levels of COMMD1 mRNA in colon biopsies from 29 patients with IBD and 16 patients without (controls), and validated findings in an independent cohort (17 patients with IBD and 22 controls). We searched for polymorphisms in or near COMMD1 that were associated with IBD using data from the International IBD Genetics Consortium and performed quantitative trait locus analysis. RESULTS In comparing gene expression patterns between myeloid cells from Mye-K/O and wild-type mice, we found that COMMD1 represses expression of genes induced by LPS. Mye-K/O mice had more intense inflammatory responses to LPS and developed more severe sepsis and colitis, with greater mortality. More Mye-K/O mice with colitis developed colon dysplasia and tumors than wild-type mice. We observed reduced expression of COMMD1 in colon biopsies and circulating leukocytes from patients with IBD. We associated single nucleotide variants near COMMD1 with reduced expression of the gene and linked them with increased risk for ulcerative colitis. CONCLUSIONS Expression of COMMD1 by myeloid cells has anti-inflammatory effects. Reduced expression or function of COMMD1 could be involved in the pathogenesis of IBD.

Inflammatory bowel disease (IBD) affects 1.5–3.0 million people in the United States. IBD is genetically determined and many common risk alleles have been identified. Yet, a large proportion of genetic predisposition remains unexplained. In this study, we report the identification of an ultra rare missense variant (NM_006998.3:c.230G > A;p.Arg77His) in the SCGN gene causing Mendelian early-onset ulcerative colitis. SCGN encodes a calcium sensor that is exclusively expressed in neuroendocrine lineages, including enteroendocrine cells and gut neurons. SCGN interacts with the SNARE complex, which is required for vesicle fusion with the plasma membrane. We show that the SCGN mutation identified impacted the localization of the SNARE complex partner, SNAP25, leading to impaired hormone release. Finally, we show that mouse models of Scgn deficiency recapitulate impaired hormone release and susceptibility to DSS-induced colitis. Altogether, these studies demonstrate that functional deficiency in SCGN can result in intestinal inflammation and implicates the neuroendocrine cellular compartment in IBD.

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percutaneous transhepatic biliary drainage (PTBD) may be more appropriate in this setting [1]. The purpose of this study is to identify the influence of cholangiocarcinoma location on therapy outcomes. Materials: Records of 122 patients with newly diagnosed cholangiocarcinoma requiring biliary decompression from 2007 to 2016 were retrospectively reviewed. Preprocedural MRI was used to classify tumor location for 84% of patients. When this was not available, fluoroscopic procedural images were used. Hilar cholangiocarcinoma (Klatskin tumor) was present in 74 patients, and 41 had tumor involving the common hepatic and/or common bile ducts but not the hilum. PTBD was the initial therapy for 57 patients, and 65 were initially treated by ERCP. Therapeutic success was defined as resolution of hyperbilirubinemia to below 2.5 mg/ dL, a level at which systemic chemotherapy can be safely administered. Results: Of the group receiving initial ERCP treatment, 18/33 (55%) patients with hilar cholangiocarcinoma required conversion to PTBD within 30 days, compared to 4/28 (14%) with cholangiocarcinoma of the common hepatic or common bile ducts. Patients with hilar tumors are therefore over three times more likely to fail endoscopic management (p ¼ 0.001). Immediately apparent technical failure of ERCP stent placement occurred in 9/33 (27%) patients with hilar tumors. The ERCP and PTBD treatment groups had average pretreatment serum total bilirubin concentrations of 17.5 and 17.4 mg/dl, respectively. In both treatment groups, half of the patients reached therapeutic success within the period of available follow-up data. The PTBD group had a shorter mean time to therapeutic success of 33 days vs. 41 days for the ERCP group. Conclusions: Hilar location of cholangiocarcinoma is a strong predictor of failure of endoscopic management. PTBD as the firstline therapy for these patients could minimize the number of procedures performed and the associated complication risks. MRI is useful to determine which treatment best suits a patient.

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