A Novel CRISPR/Cas9-mediated Mouse Model of Colon Carcinogenesis.

Background & Aims: Human sporadic colorectal cancer (CRC) results from a multistep pathway with sequential acquisition of specific genetic mutations in the colorectal epithelium. Modeling CRC in vivo is critical for understanding the tumor microenvironment. To accurately recapitulate human CRC pathogenesis, mouse models must include these multi-step genetic abnormalities.

Fecal microbiome and bile acid metabolome in adult short bowel syndrome.

Loss of functional small bowel surface area causes short bowel syndrome (SBS), intestinal failure, and parenteral nutrition (PN) dependence. The gut adaptive response following resection may be difficult to predict, and it may take up to 2 yr to determine which patients will wean from PN. Here, we examined features of gut microbiota and bile acid (BA) metabolism in determining adaptation and ability to wean from PN.

Stem cell and niche regulation in human short bowel syndrome.

Loss of functional small bowel surface area following surgical resection for disorders such as Crohn's disease, intestinal ischemic injury, radiation enteritis, and in children, necrotizing enterocolitis, atresia, and gastroschisis, may result in short bowel syndrome, with attendant high morbidity, mortality, and health care costs in the United States. Following resection, the remaining small bowel epithelium mounts an adaptive response, resulting in increased crypt cell proliferation, increased villus height, increased crypt depth, and enhanced nutrient and electrolyte absorption. Although these morphologic and functional changes are well described in animal models, the adaptive response in humans is less well understood.

Increased Adiposity and Reduced Lean Body Mass in Patients with Short Bowel Syndrome.

Background: Few studies have examined the metabolic consequences of short bowel syndrome (SBS) and its effects on body composition in adults. We hypothesized that body composition of SBS patients is altered compared to a normal age-, race-, and sex-matched population, regardless of parenteral nutrition (PN) dependence.

Aim: To compare the body composition of adult patients with SBS to age-, sex-, and race-matched healthy controls.

Epimorphin regulates the intestinal stem cell niche via effects on the stromal microenvironment.

Stem cell therapy is a potential therapeutic approach for disorders characterized by intestinal injury or loss of functional surface area. Stem cell function and proliferation are mediated by the stem cell niche. Stromal cells such as intestinal subepithelial myofibroblasts (ISEMFs) are important but poorly studied components of the stem cell niche.

Increased IFRD1 Expression in Human Colon Cancers Predicts Reduced Patient Survival.

Background: Colon cancer (CRC) is the third most common cancer worldwide. CRC develops through combinations of genetic and epigenetic changes. However, there is marked heterogeneity in the "driver gene" mutational profiles within and among colon cancers from individual patients, and these are not sufficient to explain differences in colon cancer behavior and treatment response.

Mechanisms of intestinal adaptation.

Following loss of functional small bowel surface area due to surgical resection for therapy of Crohn's disease, ischemia, trauma or other disorders, the remnant gut undergoes a morphometric and functional compensatory adaptive response which has been best characterized in preclinical models. Increased crypt cell proliferation results in increased villus height, crypt depth and villus hyperplasia, accompanied by increased nutrient, fluid and electrolyte absorption. Clinical observations suggest that functional adaptation occurs in humans.

Proline Absorption and SGK1 Expression are Inhibited in Intestinal Tis7 Transgenic Mice.

Background/aims: Expression of the transcriptional co-regulator tis7 is markedly increased in the adaptive small intestine in a mouse model of short bowel syndrome. Transgenic mice with enterocytic overexpression of tis7 (tis7tg) have accelerated triglyceride absorption, with increased adiposity yet reduced skeletal muscle mass. To further explore this phenotype, we examined whether tis7 also regulates amino acid and carbohydrate absorption.

Tis7 deletion reduces survival and induces intestinal anastomotic inflammation and obstruction in high-fat diet-fed mice with short bowel syndrome.

Effective therapies are limited for patients with parenteral nutrition-dependent short bowel syndrome. We previously showed that intestinal expression of the transcriptional coregulator tetradecanoyl phorbol acetate-induced sequence 7 (tis7) is markedly increased during the adaptive response following massive small bowel resection and tis7 plays a role in normal gut lipid metabolism. Here, we further explore the functional implications of tis7 deletion in intestinal lipid metabolism and the adaptive response following small bowel resection.

Epimorphin(-/-) mice are protected, in part, from acute colitis via decreased interleukin 6 signaling.

Epimorphin (Epim), a member of the syntaxin family of membrane-bound, intracellular vesicle-docking proteins, is expressed in intestinal myofibroblasts and macrophages. We demonstrated previously that Epimorphin(-/-)(Epim(-/-)) mice are protected, in part, from dextran sodium sulfate (DSS)-induced colitis. Although interleukin (IL)-6/p-Stat3 signaling has been implicated in the pathogenesis of colitis, the myofibroblast contribution to IL-6 signaling in colitis remains unexplored.

Epimorphin deletion inhibits polyposis in the Apcmin/+ mouse model of colon carcinogenesis via decreased myofibroblast HGF secretion.

Interactions between the epithelium and surrounding mesenchyme/stroma play an important role in normal gut morphogenesis, the epithelial response to injury, and epithelial carcinogenesis. The tumor microenvironment, composed of stromal cells including myofibroblasts and immune cells, regulates tumor growth and the cancer stem cell niche. Deletion of epimorphin (Epim), a syntaxin family member expressed in myofibroblasts and macrophages, results in partial protection from colitis and from inflammation-induced colon cancer in mice.

Chronic intestinal inflammation: inflammatory bowel disease and colitis-associated colon cancer.

The inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the intestine. The prevalence in the United States is greater than 200 cases per 100,000, with the total number of IBD patients between 1 and 1.5 million.

Epithelial expression of the cytosolic retinoid chaperone cellular retinol binding protein II is essential for in vivo imprinting of local gut dendritic cells by lumenal retinoids.

Dendritic cells (DCs) use all-trans retinoic acid (ATRA) to promote characteristic intestinal responses, including Foxp3(+) Treg conversion, lymphocyte gut homing molecule expression, and IgA production. How this ability to generate ATRA is conferred to DCs in vivo remains largely unstudied. Here, we observed that among DCs, retinaldehyde dehydrogenase (ALDH1), which catalyzes the conversion of retinal to ATRA, was preferentially expressed by small intestine CD103(+) lamina propria (LP) DCs.

Deletion of Tis7 protects mice from high-fat diet-induced weight gain and blunts the intestinal adaptive response postresection.

After loss of intestinal surface area, the remaining bowel undergoes a morphometric and functional adaptive response. Enterocytic expression of the transcriptional coregulator tetradecanoyl phorbol acetate induced sequence 7 (Tis7) is markedly increased in a murine model of intestinal adaptation. Mice overexpressing Tis7 in intestine have greater triglyceride absorption and weight gain when fed a high-fat diet (42% energy) than their wild-type (WT) littermates fed the same diet.

Epimorphin deletion protects mice from inflammation-induced colon carcinogenesis and alters stem cell niche myofibroblast secretion.

Epithelial-mesenchymal interactions regulate normal gut epithelial homeostasis and have a putative role in inflammatory bowel disease and colon cancer pathogenesis. Epimorphin is a mesenchymal and myofibroblast protein with antiproliferative, promorphogenic effects in intestinal epithelium. We previously showed that deletion of epimorphin partially protects mice from acute colitis, associated with an increase in crypt cell proliferation.

Intestinal redox status of major intracellular thiols in a rat model of chronic alcohol consumption.

Background: Alcohol consumption is associated with oxidative stress in multiple tissues in vivo, yet the effect of chronic alcohol intake on intestinal redox state has received little attention. In this study, we investigated the redox status of 2 major intracellular redox regulating couples: glutathione (GSH)/glutathione disulfide (GSSG) and cysteine (Cys)/cystine (CySS) in a rat model of chronic alcohol ingestion.

Methods: Sprague-Dawley rats were fed the liquid Lieber-DeCarli diet consisting of 36% ethanol of total calories for 6 weeks.

Chronically administered retinoic acid has trophic effects in the rat small intestine and promotes adaptation in a resection model of short bowel syndrome.

Following the loss of functional small bowel surface area, the intestine undergoes a compensatory adaptive response. The observation that adaptation is inhibited in vitamin A-deficient rats following submassive intestinal resection suggested that vitamin A is required for this response and raised the possibility that exogenous vitamin A could augment adaptation. Therefore, to directly assess whether chronically administered retinoic acid could stimulate gut adaptation in a model of short bowel syndrome and to address the mechanisms of any such effects, Sprague-Dawley rats were implanted with controlled release retinoic acid or control pellets and then subjected to mid-small bowel or sham resections.

Local glutathione redox status does not regulate ileal mucosal growth after massive small bowel resection in rats.

Glutathione (GSH) concentration affects cell proliferation and apoptosis in intestinal and other cell lines in vitro. However, in vivo data on gut mucosal GSH redox status and cell turnover are limited. We investigated the effect of altered GSH redox status on the ileal mucosa in a rat model of short bowel syndrome following massive small bowel resection (SBR).

Stimulation of colonic mucosal growth associated with oxidized redox status in rats.

Limited data in animal models suggest that colonic mucosa undergoes adaptive growth following massive small bowel resection (SBR). In vitro data suggest that intestinal cell growth is regulated by reactive oxygen species and redox couples [e.g.

Epimorphin(-/-) mice have increased intestinal growth, decreased susceptibility to dextran sodium sulfate colitis, and impaired spermatogenesis.

Dynamic and reciprocal epithelial-mesenchymal interactions are critical for the normal morphogenesis and maintenance of epithelia. Epimorphin has been identified as a unique molecule expressed by mesenchymal cells and myofibroblasts and has putative morphogenetic effects in multiple epithelial tissues, including intestine, skin, mammary gland, lung, gallbladder, and liver. To define the in vivo role of epimorphin, we created epimorphin-null mice by targeted inactivation of the epimorphin gene.

Increased apoptosis and accelerated epithelial migration following inhibition of hedgehog signaling in adaptive small bowel postresection.

The intestinal epithelium undergoes a marked adaptive response following loss of functional small bowel surface area characterized by increased crypt cell proliferation and increased enterocyte migration from crypt to villus tip, resulting in villus hyperplasia and enhanced nutrient absorption. Hedgehog (Hh) signaling plays a critical role in regulating epithelial-mesenchymal interactions during morphogenesis of the embryonic intestine. Our previous studies showed that blocking Hh signaling in neonatal mice results in increased small intestinal epithelial crypt cell proliferation and altered enterocyte fat absorption and morphology.

Targeted intestinal overexpression of the immediate early gene tis7 in transgenic mice increases triglyceride absorption and adiposity.

Following loss of functional small bowel surface area due to surgical resection, the remnant gut undergoes an adaptive response characterized by increased crypt cell proliferation and enhanced villus height and crypt depth, resulting in augmented intestinal nutrient absorptive capacity. Previous studies showed that expression of the immediate early gene tis7 is markedly up-regulated in intestinal enterocytes during the adaptive response. To study its role in the enterocyte, transgenic mice were generated that specifically overexpress TIS7 in the gut.

Inhibition of Hedgehog signaling protects adult mice from diet-induced weight gain.

Hedgehog (Hh) signaling plays an important role in embryonic development of many tissues, including the gastrointestinal tract. Sonic Hh-and Indian Hh-deficient mice die before or soon after birth, precluding further study of this signaling pathway in the mature intestine. Maternal transfer of inactivating monoclonal antibodies to Hh proteins (anti-Hh moAb) during late stages of embryogenesis or to early postnatal mice produced intestinal villous abnormalities, progressive runting, and severe malabsorption of dietary fat.

Bax is required for resection-induced changes in apoptosis, proliferation, and members of the extrinsic cell death pathways.

Background And Aims: To define better the homeostatic mechanisms contributing to small intestinal adaptation following partial resection, the relative contributions of apoptosis, cell proliferation, and enterocyte migration and the comparative roles of the intrinsic (mitochondrial) and extrinsic (death receptor-mediated) apoptotic pathways were assessed.

Methods: After 50% jejunoileal resections or transections, adaptation was analyzed in duodenal-jejunal and ileal segments from C57BL/6 Bax(+/+) (16, 48, and 168 hours postoperative) and Bax(-/-) mice (168 hours).

Results: Basal apoptotic rates were equivalent in all mice.