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The Oxysterol Synthesising Enzyme CH25H Contributes to the Development of Intestinal Fibrosis

Intestinal fibrosis and stenosis are common complications of Crohn's disease [CD], frequently requiring surgery. Anti-inflammatory strategies can only partially prevent fibrosis; hence, anti-fibrotic therapies remain an unmet clinical need. Oxysterols are oxidised cholesterol derivatives with important roles in various biological processes. The enzyme cholesterol 25-hydroxylase [CH25H] converts cholesterol to 25-hydroxycholesterol [25-HC], which modulates immune responses and oxidative stress. In human intestinal samples from CD patients, we found a strong correlation of CH25H mRNA expression with the expression of fibrosis markers. We demonstrate reduced intestinal fibrosis in mice deficient for the CH25H enzyme, using the sodium dextran sulphate [DSS]-induced chronic colitis model. Additionally, using a heterotopic transplantation model of intestinal fibrosis, we demonstrate reduced collagen deposition and lower concentrations of hydroxyproline in CH25H knockouts. In the heterotopic transplant model, CH25H was expressed in fibroblasts. Taken together, our findings indicate an involvement of oxysterol synthesis in the pathogenesis of intestinal fibrosis

The EBI2-oxysterol axis promotes the development of intestinal lymphoid structures and colitis.

The gene encoding for Epstein-Barr virus-induced G-protein-coupled receptor 2 (EBI2) is a risk gene for inflammatory bowel disease (IBD). Together with its oxysterol ligand 7α,25-dihydroxycholesterol, EBI2 mediates migration and differentiation of immune cells. However, the role of EBI2 in the colonic immune system remains insufficiently studied. We found increased mRNA expression of EBI2 and oxysterol-synthesizing enzymes (CH25H, CYP7B1) in the inflamed colon of patients with ulcerative colitis and mice with acute or chronic dextran sulfate sodium (DSS) colitis. Accordingly, we detected elevated levels of 25-hydroxylated oxysterols, including 7α,25-dihydroxycholesterol in mice with acute colonic inflammation. Knockout of EBI2 or CH25H did not affect severity of DSS colitis; however, inflammation was decreased in male EBI2 <sup>-/-</sup> mice in the IL-10 colitis model. The colonic immune system comprises mucosal lymphoid structures, which accumulate upon chronic inflammation in IL-10-deficient mice and in chronic DSS colitis. However, EBI2 <sup>-/-</sup> mice formed significantly less colonic lymphoid structures at baseline and showed defects in inflammation-induced accumulation of lymphoid structures. In summary, we report induction of the EBI2-7α,25-dihydroxycholesterol axis in colitis and a role of EBI2 for the accumulation of lymphoid tissue during homeostasis and inflammation. These data implicate the EBI2-7α,25-dihydroxycholesterol axis in IBD pathogenesis

Optimal diet selection by white-tailed deer: Balancing reproduction with starvation risk

Energy intake rates of wintering deer vary over time because of variation in the abundance and quality of their natural foods. Accordingly, there is a chance that energy requirements will not be satisfied in a feeding period. This is especially critical because deer are reproductive during winter; hence selecting diets to minimize the risk of starvation may not maximize fitnss. I examined diet selection by white-tailed deer ( Odocoileus virginianus ) using a risk-sensitive foraging model which predicts the optimal diet when foragers face starvation risks during a reproductive period. Optimal diets were estimated by quantifying the mean and variance in energy intake rate deer could obtain when selecting different potential diets and substituting these values into functions for estimating offspring production and starvation risk. I conducted a field experiment to ask whether deer selected deciduous and coniferous twigs according to model predictions. Starvation risk was manipulated by providing deer supplemental feed. When faced with starvation risks, deer appeared to select diets that balanced offspring production with starvation risk. When starvation risk was climinated, deer tended to select diets that simply maximized their mean energy intake rates.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42743/1/10682_2005_Article_BF02270707.pd

Transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND-study)

Background: Recent non-randomized studies suggest that extended endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM). If equally effective, EMR might be a more cost-effective approach as this strategy does not require expensive equipment, general anesthesia and hospital admission. Furthermore, EMR appears to be associated with fewer complications. The aim of this study is to compare the cost-effectiveness and cost-utility of TEM and EMR for the resection of large rectal adenomas. Methods/design. Multicenter randomized trial among 15 hospitals in the Netherlands. Patients with a rectal adenoma 3 cm, located between 115 cm ab ano, will be randomized to a TEM- or EMR-treatment strategy. For TEM, patients will be treated under general anesthesia, adenomas will be dissected en-bloc by a full-thickness excision, and patients will be admitted to the hospital. For EMR, no or conscious sedation is used, lesions will be resected through the submucosal plane i

Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Abstract: Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10−10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10−10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis

Optimal foraging and community structure: implications for a guild of generalist grassland herbivores

A particular linear programming model is constructed to predict the diets of each of 14 species of generalist herbivores at the National Bison Range, Montana. The herbivores have body masses ranging over seven orders of magnitude and belonging to two major taxa: insects and mammals. The linear programming model has three feeding constraints: digestive capacity, feeding time and energy requirements. A foraging strategy that maximizes daily energy intake agrees very well with the observed diets. Body size appears to be an underlying determinant of the foraging parameters leading to diet selection. Species that possess digestive capacity and feeding time constraints which approach each other in magnitude have the most generalized diets. The degree that the linear programming models change their diet predictions with a given percent change in parameter values (sensitivity) may reflect the observed ability of the species to vary their diets. In particular, the species which show the most diet variability are those whose diets tend to be balanced between monocots and dicots. The community-ecological parameters of herbivore body-size ranges and species number can possibly be related to foraging behavior.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47765/1/442_2004_Article_BF00377109.pd

Metabolizable energy and biomass of plants consumed by caribou (Rangifer tarandus) in tundra communities of northern Alaska and deer (Odocoileus spp.) in forests and grasslands of Washington, United States of America

&lt;p&gt;A ubiquitous interaction operates at the base of food webs in many terrestrial ecosystems of the world, creating the foundation for bottom-up regulation of consumers. This interaction plays out as follows. Populations of herbivores deplete plant biomass by foraging. Increasing herbivore population size intensifies this depletion, which in turn, creates a negative feedback regulating herbivore population growth. Large herbivores and the plants they consume offer a useful system for studying this interaction because populations of large herbivores are often regulated by density dependence, defined as the reduction in the per-capita growth rate that occurs as populations grow. Diminished body mass of individuals has been repeatedly observed in high-density populations, implicating plant-mediated, diminished nutrition as the primary cause of density dependence. However, there is no general explanation for why these nutritional deficiencies occur.  The data deposited here were used to demonstrate fit new model of the feedbacks from plant biomass to herbivores. The model shows how reduced nutrition of herbivores can result from increased dilution of metabolizable energy in the plant tissue they consume as populations grow even when a large fraction of the consumable plant biomass remains uneaten. This result provides a tidy, mechanistic explanation for bottom-up control of population dynamics of primary consumers in a "green world." &lt;/p&gt;&lt;p&gt;R code is included in the repository.&lt;/p&gt;&lt;p&gt;Funding provided by: National Science Foundation&lt;br&gt;Crossref Funder Registry ID: http://dx.doi.org/10.13039/501100008982&lt;br&gt;Award Number: 5352167&lt;/p&gt