Diet Modifies Colonic Microbiota and CD4+ T-Cell Repertoire to Induce Flares of Colitis in Mice With Myeloid-Cell Expression of Interleukin 23.

BACKGROUND & AIMS: Several studies have shown that signaling via the interleukin 23 (IL23) receptor is required for development of colitis. We studied the roles of IL23, dietary factors, alterations to the microbiota, and T cells in the development and progression of colitis in mice. METHODS: All mice were maintained on laboratory diet 5053, unless otherwise noted. We generated mice that express IL23 in CX3CR1-positive myeloid cells (R23FR mice) upon cyclic administration of tamoxifen dissolved in diet 2019. Diets 2019 and 5053 have minor differences in the overall composition of protein, fat, fiber, minerals, and vitamins. CX3CR1CreER mice (FR mice) were used as controls. Some mice were given antibiotics, and others were raised in a germ-free environment. Intestinal tissues were collected and analyzed by histology and flow cytometry. Feces were collected and analyzed by 16S rDNA sequencing. Feces from C57/Bl6, R23FR, or FR mice were fed to FR and R23FR germ-free mice in microbiota transplant experiments. We also performed studies with R23FR/Rag-/-, R23FR/Mu-/-, and R23FR/Tcrd-/- mice. R23FR mice were given injections of antibodies against CD4 or CD8 to deplete T cells. Mesenteric lymph nodes and large intestine CD4+ cells from R23FR or FR mice in remission from colitis were transferred into Rag-/- mice. CD4+ cells were isolated from donor R23FR mice and recipient Rag-/- mice, and T-cell receptor sequences were determined. RESULTS: Expression of IL23 led to development of a relapsing-remitting colitis that was dependent on the microbiota and CD4+ T cells. The relapses were caused by switching from the conventional diet used in our facility (diet 5053) to the diet 2019 and were not dependent on tamoxifen after the first cycle. The switch in the diet modified the microbiota but did not alter levels of IL23 in intestinal tissues compared with mice that remained on the conventional diet. Mesenteric lymph nodes and large intestine CD4+ cells from R23FR mice in remission, but not from FR mice, induced colitis after transfer into Rag-/- mice, but only when these mice were placed on the diet 2019. The CD4+ T-cell receptor repertoire of Rag-/- mice with colitis (fed the 2019 diet) was less diverse than that from donor mice and Rag-/- mice without colitis (fed the 5053 diet) because of expansion of dominant T-cell clones. CONCLUSIONS: We developed mice that express IL23 in CX3CR1-positive myeloid cells (R23FR mice) and found that they are more susceptible to diet-induced colitis than mice that do not express IL23. The R23FR mice have a population of CD4+ T cells that becomes activated in response to dietary changes and alterations to the intestinal microbiota. The results indicate that alterations in the diet, intestinal microbiota, and IL23 signaling can contribute to pathogenesis of inflammatory bowel disease.

IL-23 activates innate lymphoid cells to promote neonatal intestinal pathology.

Interleukin-23 (IL-23) responsive group 3 innate lymphoid cells (ILC3s) have been implicated in immune homeostasis and pathogenesis in the adult, but little is known about their roles in the newborn. Here we show that IL-23 promotes conversion of embryonic intestinal Lin(-)IL-23R(+)Thy1(+) cells into IL-22-producing Thy1(+)Sca-1(hi) ILC3s in vitro. Gut-specific expression of IL-23 also activated and expanded Thy1(+)Sca-1(hi) ILC3s, which produced IL-22, IL-17, interferon gamma (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) and were distinct from canonical CD4(+) lymphoid tissue inducer (LTi) cells. These ILC3s accumulated under the epithelium in intercellular adhesion molecule (ICAM)-1-positive cell aggregates together with neutrophils that disrupted the epithelium, leading to the formation of discrete intestinal erosions, bleeding, and neonatal death. Genetic and antibody depletion of ILC3s rescued the mice from neonatal death. Antibiotic treatment of pregnant mothers and offspring prolonged survival of IL-23 transgenic mice, suggesting a role for the commensal flora on ILC3-induced pathogenesis. Our results reveal a novel role for the IL-23-ILC3s axis in the pathogenesis of neonatal intestinal inflammation.

Mucinous cystadenocarcinoma of the testis: a case report.

We present a rare case of unilateral intratesticular cystadenocarcinoma with mucinous differentiation in a 71-year-old male patient. The orchiectomy specimen revealed a 3.5-cm well to moderately differentiated cystic neoplasm with elongated fine papillary structures lined by columnar epithelium with alternating goblet and ciliated cells completely replacing the testicular parenchyma. Immunohistochemical studies showed positivity for cytokeratin 20, carcinoembryonic antigen, and mucin 2, and negativity for cytokeratin 7, mucin 5AC, vimentin, thyroid transcription factor 1, Wilms' tumor 1, and cancer antigen 125. The current case shows a focal cyst-lining component with benign appearance. Imaging studies and colonoscopy showed no evidence of other suspicious lesions. This tumor resembles morphologically to an intestinal-type ovarian surface epithelial tumor.