Defects in the expression of colonic host defense factors associate with barrier dysfunction induced by a high-fat/high-cholesterol diet.

The effect of Western diets in the gastrointestinal system is largely mediated by their ability to promote alterations in the immunity and physiology of the intestinal epithelium, and to affect the composition of the commensal microbiota. To investigate the response of the colonic epithelium to high-fat/high-cholesterol diets (HFHCDs), we evaluated the synthesis of host defense factors involved in the maintenance of the colonic homeostasis. C57BL/6 mice were fed an HFHCD for 3 weeks and their colons were evaluated for histopathology, gene expression, and microbiota composition. In addition, intestinal permeability and susceptibility to Citrobacter rodentium were also studied. HFHCD caused colonic hyperplasia, loss of goblet cells, thinning of the mucus layer, moderate changes in the composition of the intestinal microbiota, and an increase in intestinal permeability. Gene expression analyses revealed significant drops in the transcript levels of Muc1, Muc2, Agr2, Atoh1, Spdef, Ang4, Camp, Tff3, Dmbt1, Fcgbp, Saa3, and Retnlb. The goblet cell granules of HFHCD-fed mice were devoid of Relmß and Tff3, indicating defective production of those two factors critical for intestinal epithelial defense and homeostasis. In correspondence with these defects, colonic bacteria were in close contact with, and invading the epithelium. Fecal shedding of C. rodentium showed an increased bacterial burden in HFHCD-fed animals accompanied by increased epithelial damage. Collectively, our results show that HFHCD perturbs the synthesis of colonic host defense factors, which associate with alterations in the commensal microbiota, the integrity of the intestinal barrier, and the host's susceptibility to enteric infections.

IL-15Rα-Independent IL-15 Signaling in Non-NK Cell-Derived IFNγ Driven Control of Listeria monocytogenes.

Interleukin-15, produced by hematopoietic and parenchymal cells, maintains immune cell homeostasis and facilitates activation of lymphoid and myeloid cell subsets. IL-15 interacts with the ligand-binding receptor chain IL-15Rα during biosynthesis, and the IL-15:IL-15Rα complex is trans-presented to responder cells that express the IL-2/15Rßγc complex to initiate signaling. IL-15-deficient and IL-15Rα-deficient mice display similar alterations in immune cell subsets. Thus, the trimeric IL-15Rαßγc complex is considered the functional IL-15 receptor. However, studies on the pathogenic role of IL-15 in inflammatory and autoimmune diseases indicate that IL-15 can signal independently of IL-15Rα via the IL-15Rßγc dimer. Here, we compared the ability of mice lacking IL-15 (no signaling) or IL-15Rα (partial/distinct signaling) to control Listeria monocytogenes infection. We show that IL-15-deficient mice succumb to infection whereas IL-15Rα-deficient mice clear the pathogen as efficiently as wildtype mice. IL-15-deficient macrophages did not show any defect in bacterial uptake or iNOS expression in vitro. In vivo, IL-15 deficiency impaired the accumulation of inflammatory monocytes in infected spleens without affecting chemokine and pro-inflammatory cytokine production. The inability of IL-15-deficient mice to clear L. monocytogenes results from impaired early IFNγ production, which was not affected in IL-15Rα-deficient mice. Administration of IFNγ partially enabled IL-15-deficient mice to control the infection. Bone marrow chimeras revealed that IL-15 needed for early bacterial control can originate from both hematopoietic and non-hematopoietic cells. Overall, our findings indicate that IL-15-dependent IL-15Rα-independent signaling via the IL-15Rßγc dimeric complex is necessary and sufficient for the induction of IFNγ from sources other than NK/NKT cells to control bacterial pathogens.

Effects of in utero exposure to D-004, a lipid extract from Roystonea regia fruits, in the male rat: a comparison with finasteride.

D-004 is a lipid extract obtained from Cuban royal palm fruits, consisting of a mixture of free fatty acids, that prevents prostate hyperplasia induced with testosterone in rodents. This study investigated the possible alterations due to D-004 of androgen-dependent development after exposure in utero and compared them with those due to finasteride. Rats were randomized into five experimental groups: a control group, three groups treated with D-004 at 500, 750, or 1,000 mg/kg/day, respectively, and a group treated with finasteride (10 mg/kg/day). Male rats were treated 10 weeks before and during mating. Female rats were treated for 15 days prior mating, during mating, during pregnancy, and until lactation (day 21) except for those treated with finasteride, which were only administered the drug on gestational days 12-21. All male offspring were monitored individually until necropsy after postnatal day 90. The results of the present study indicate that D-004 induced no alterations in androgen-dependent development after the exposure in utero. Also, the current study demonstrated a permanent reduction in anogenital distance and retention of nipples in adult male rats exposed to finasteride during late gestation. Significant alterations induced by exposure to finasteride were mainly in tissues dependent on dihydrotestosterone during development.

Oral subchronic toxicity of a lipid extract from Roystonea regia fruits in mice.

D-004 is a lipid extract of royal palm (Rosytonea regia) fruits that prevents prostate hyperplasia induced with testosterone in rodents. Previous studies have shown no D-004-related toxicity in rats, but no study in mice had been reported. D-004 (500, 1000, and 2000 mg/kg) was evaluated in a subchronic (eight weeks) study in NMRI mice. No evidences of treatment-related toxicity were detected. Thus, body-weight gain, clinical observations, food consumption, blood biochemical, hematology, organ-weight ratios, and histopathological findings were similar in control and treated groups. This study supports that D-004 orally administered up to 2000 mg/kg did not induce treatment-related toxicity.