Translation initiation factor eIF2Bε promotes Wnt-mediated clonogenicity and global translation in intestinal epithelial cells.

Modulation of global mRNA translation, which is essential for intestinal stem cell function, is controlled by Wnt signaling. Loss of tumor supressor APC in stem cells drives adenoma formation through hyperactivion of Wnt signaling and dysregulated translational control. It is unclear whether factors that coordinate global translation in the intestinal epithelium are needed for APC-driven malignant transformation. Here we identified nucleotide exchange factor eIF2Bε as a translation initiation factor involved in Wnt-mediated intestinal epithelial stemness. Using eIF2BεArg191His mice with a homozygous point mutation that leads to dysfunction in the enzymatic activity, we demonstrate that eIF2Bε is involved in small intestinal crypt formation, stemness marker expression, and secreted Paneth cell-derived granule formation. Wnt hyperactivation in ex vivo eIF2BεArg191His organoids, using a GSK3ß inhibitor to mimic Apc driven transformation, shows that eIF2Bε is essential for Wnt-mediated clonogenicity and associated increase of the global translational capacity. Finally, we observe high eIF2Bε expression in human colonic adenoma tissues, exposing eIF2Bε as a potential target of CRC stem cells with aberrant Wnt signaling.

The mycotoxin deoxynivalenol facilitates allergic sensitization to whey in mice.

Intestinal epithelial stress or damage may contribute to allergic sensitization against certain food antigens. Hence, the present study investigated whether impairment of intestinal barrier integrity by the mycotoxin deoxynivalenol (DON) contributes to the development of whey-induced food allergy in a murine model. C3H/HeOuJ mice, orally exposed to DON plus whey once a week for 5 consecutive weeks, showed whey-specific IgG1 and IgE in serum and an acute allergic skin response upon intradermal whey challenge, although early initiating mechanisms of sensitization in the intestine appeared to be different compared with the widely used mucosal adjuvant cholera toxin (CT). Notably, DON exposure modulated tight-junction mRNA and protein levels, and caused an early increase in IL-33, whereas CT exposure affected intestinal γδ T cells. On the other hand, both DON- and CT-sensitized mice induced a time-dependent increase in the soluble IL-33 receptor ST2 (IL-1R1) in serum, and enhanced local innate lymphoid cells type 2 cell numbers. Together, these results demonstrate that DON facilitates allergic sensitization to food proteins and that development of sensitization can be induced by different molecular mechanisms and local immune responses. Our data illustrate the possible contribution of food contaminants in allergic sensitization in humans.

Staging laparoscopy in patients scheduled for pancreaticoduodenectomy minimizes hospitalization in the remaining life time when metastatic carcinoma is found.

OBJECTIVE: To compare the burden of total hospitalization as a ratio of survival of staging laparoscopy versus prophylactic bypass surgery in patients with unresectable periampullary adenocarcinoma. BACKGROUND: Periampullary adenocarcinoma is an aggressive cancer with up to 35% of the patients at surgery found to be unresectable. Palliative prophylactic surgical bypass versus endoscopic stenting has been addressed by randomized controlled trials, but none reported on the burden of hospitalization. METHODS: From a prospective database all patients with periampullary adenocarcinomas with a preoperative patent biliary stent and absent gastric outlet obstruction, but found unresectable during surgery, were analysed. They underwent a staging laparoscopy only versus prophylactic palliative bypass surgery. In-hospital days of the initial admission as well as all consecutive admission days during the remaining life span were compared both in absolute numbers and as relative impact. RESULTS: The inclusion criteria were met by 205 patients. Of these 131 patients underwent a staging laparoscopy detecting metastases in 21 patients. In 184 laparotomies 54 patients underwent prophylactic palliative bypass surgery for unresectable disease. Median total in-hospital-stay in the Laparoscopy Group was 3 days versus 11 days in the Palliative Bypass Group (p = 0.0003). Patients with metastatic disease found during laparoscopy stayed 3.5% of the remaining life time in hospital vs. 10.0% (p = 0.029) in patients with metastatic disease who underwent bypass surgery. CONCLUSIONS: Staging laparoscopy and early discharge in patients with metastatic peri-ampullary carcinoma resulted in reduced hospitalization, both in absolute number of days and as a rate of survival time.

Aryl hydrocarbon receptor activation affects the dendritic cell phenotype and function during allergic sensitization.

Aryl hydrocarbon receptor (AhR) activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses peanut sensitization by affecting T cell subsets. However, effects of AhR activation on dendritic cells (DC) in an allergic setting were not investigated yet. Therefore, we analysed the effects of AhR activation on DC phenotype in vivo, as well as their ex vivo potency to stimulate allergen-specific splenic T cells and to induce CD4+CD25+Foxp3+ regulatory (T(reg)) cells. C3H/HeOuJ mice were treated with TCDD by gavage and subsequently sensitized to peanut extract (PE). After eight days, mice were sacrificed and DC in spleen and mesenteric lymph nodes (MLN) were characterized or cocultured with PE-specific CD4+ T cells. AhR activation almost doubled the absolute number of CD11c+CD103+ DC, while not affecting CD11b+ DC, the absolute number of DC, the expression of the activation makers MHCII, CD86, CD80, CD40, CD54 and CD8 on CD11c+ and the activation status of CD11c+CD103+ DC in the spleen. In the MLN, TCDD decreased the absolute number of DC and CD103+ DC, while not affecting CD11b+ DC and the expression of activation markers on DC. PE-pulsed splenic DC from TCDD-treated mice suppressed IL-5, IL-13 and IFN-γ production by PE-specific T cells, but did not induce CD4+CD25+Foxp3+ T(reg) cells. This suppression of cytokine production was not mediated by the TCDD-induced increase in CD103+ DC in the spleen. Combined, these results indicate that AhR activation suppresses the initiation of food allergic responses by affecting DC and their interaction with effector T cells.