Genetics and Therapeutics in Pediatric Ulcerative Colitis: the Past, Present and Future [version 1; referees: 2 approved]

Ulcerative colitis (UC) is a relapsing and remitting disease with significant phenotypic and genotypic variability. Though more common in adults, UC is being increasingly diagnosed in childhood. The subsequent lifelong course of disease results in challenges for the patient and physician. Currently, there is no medical cure for UC. Even though surgical removal of the colon can be curative, complications including infertility in females make colectomy an option often considered only when the disease presents with life-threatening complications or when medical management fails. One of the greatest challenges the clinician faces in the care of patients with UC is the inability to predict at diagnosis which patient is going to respond to a specific therapy or will eventually require surgery. This therapeutic conundrum frames the discussion to follow, specifically the concept of individualized or personalized treatment strategies based on genetic risk factors. As we move to therapeutics, we will elucidate traditional approaches and discuss known and novel agents. As we look to the future, we can expect increasing integrated approaches using several scientific disciplines to inform how genetic interactions shape and mold the pathogenesis and therapeutics of UC

Editing of the gut microbiota reduces carcinogenesis in mouse models of colitis-associated colorectal cancer.

Chronic inflammation and gut microbiota dysbiosis, in particular the bloom of genotoxin-producing E. coli strains, are risk factors for the development of colorectal cancer. Here, we sought to determine whether precision editing of gut microbiota metabolism and composition could decrease the risk for tumor development in mouse models of colitis-associated colorectal cancer (CAC). Expansion of experimentally introduced E. coli strains in the azoxymethane/dextran sulfate sodium colitis model was driven by molybdoenzyme-dependent metabolic pathways. Oral administration of sodium tungstate inhibited E. coli molybdoenzymes and selectively decreased gut colonization with genotoxin-producing E. coli and other Enterobacteriaceae. Restricting the bloom of Enterobacteriaceae decreased intestinal inflammation and reduced the incidence of colonic tumors in two models of CAC, the azoxymethane/dextran sulfate sodium colitis model and azoxymethane-treated, Il10-deficient mice. We conclude that metabolic targeting of protumoral Enterobacteriaceae during chronic inflammation is a suitable strategy to prevent the development of malignancies arising from gut microbiota dysbiosis

Microbial Sensing by Intestinal Myeloid Cells Controls Carcinogenesis and Epithelial Differentiation.

Physiologic microbe-host interactions in the intestine require the maintenance of the microbiota in a luminal compartment through a complex interplay between epithelial and immune cells. However, the roles of mucosal myeloid cells in this process remain incompletely understood. In this study, we identified that decreased myeloid cell phagocytic activity promotes colon tumorigenesis. We show that this is due to bacterial accumulation in the lamina propria and present evidence that the underlying mechanism is bacterial induction of prostaglandin production by myeloid cells. Moreover, we show that similar events in the normal colonic mucosa lead to reductions in Tuft cells, goblet cells, and the mucus barrier of the colonic epithelium. These alterations are again linked to the induction of prostaglandin production in response to bacterial penetration of the mucosa. Altogether, our work highlights immune cell-epithelial cell interactions triggered by the microbiota that control intestinal immunity, epithelial differentiation, and carcinogenesis

A predictive density for semiparametric scale and location models

COMMD1 deficiency results in defective copper homeostasis, but the mechanism for this has remained elusive. Here we report that COMMD1 is directly linked to early endosomes through its interaction with a protein complex containing CCDC22, CCDC93, and C16orf62. This COMMD/CCDC22/CCDC93 (CCC) complex interacts with the multisubunit WASH complex, an evolutionarily conserved system, which is required for endosomal deposition of F-actin and cargo trafficking in conjunction with the retromer. Interactions between the WASH complex subunit FAM21, and the carboxyl-terminal ends of CCDC22 and CCDC93 are responsible for CCC complex recruitment to endosomes. We show that depletion of CCC complex components leads to lack of copper-dependent movement of the copper transporter ATP7A from endosomes, resulting in intracellular copper accumulation and modest alterations in copper homeostasis in humans with CCDC22 mutations. This work provides a mechanistic explanation for the role of COMMD1 in copper homeostasis and uncovers additional genes involved in the regulation of copper transporter recycling.Christine A. Phillips-Krawczak, Amika Singla, Petro Starokadomskyy, Zhihui Deng, Douglas G. Osbornea, Haiying Li, Christopher J. Dick, Timothy S. Gomez, Megan Koenecke, Jin-San Zhang, Haiming Dai, Luis F. Sifuentes-Dominguez, Linda N. Geng, Scott H. Kaufmann, Marco Y. Hein, Mathew Wallis, Julie McGaughran, Jozef Gecz, Bart van de Sluis, Daniel D. Billadeau and Ezra Burstei

Precision editing of the gut microbiota ameliorates colitis

Inflammatory diseases of the gastrointestinal tract are frequently associated with dysbiosis, characterized by changes in gut microbial communities that include an expansion of facultative anaerobic bacteria of the Enterobacteriaceae family (phylum Proteobacteria). Here we show that a dysbiotic expansion of Enterobacteriaceae during gut inflammation could be prevented by tungstate treatment, which selectively inhibited molybdenum-cofactor-dependent microbial respiratory pathways that are operational only during episodes of inflammation. By contrast, we found that tungstate treatment caused minimal changes in the microbiota composition under homeostatic conditions. Notably, tungstate-mediated microbiota editing reduced the severity of intestinal inflammation in mouse models of colitis. We conclude that precision editing of the microbiota composition by tungstate treatment ameliorates the adverse effects of dysbiosis in the inflamed gut