Intestinal enteroids recapitulate the effects of short-chain fatty acids on the intestinal epithelium.

Enteroids are cultured primary intestinal epithelial cells that recapitulate epithelial lineage development allowing for a more complex and physiologically relevant model for scientific study. The large presence of intestinal stem cells (ISC) in these enteroids allows for the study of metabolite effects on cellular processes and resulting progeny cells. Short-chain fatty acids (SCFA) such as butyrate (BUT) are bacterial metabolites produced in the gastrointestinal tract that are considered to be beneficial to host cells. Therefore, the objective was to study the effects of SCFAs on biomarkers of ISC activity, differentiation, barrier function and epithelial defense in the intestine using mouse and human enteroid models. Enteroids were treated with two concentrations of acetate (ACET), propionate (PROP), or BUT for 24 h. Enteroids treated with BUT or PROP showed a decrease in proliferation via EdU uptake relative to the controls in both mouse and human models. Gene expression of Lgr5 was shown to decrease with BUT and PROP treatments, but increased with ACET. As a result of BUT and PROP treatments, there was an increase in differentiation markers for enterocyte, Paneth, goblet, and enteroendocrine cells. Gene expression of antimicrobial proteins Reg3β, Reg3γ, and Defb1 were stimulated by BUT and PROP, but not by ACET which had a greater effect on expression of tight junction genes Cldn3 and Ocln in 3D enteroids. Similar results were obtained with human enteroids treated with 10 mM SCFAs and grown in either 3D or Transwell™ model cultures, although tight junctions were influenced by BUT and PROP, but not ACET in monolayer format. Furthermore, BUT and PROP treatments increased transepithelial electrical resistance after 24 h compared to ACET or control. Overall, individual SCFAs are potent stimulators of cellular gene expression, however, PROP and especially BUT show great efficacy for driving cell differentiation and gene expression

Effects of energy restriction during gilt development on milk nutrient profile, milk oligosaccharides, and progeny biomarkers.

An ongoing study at the University of Nebraska-Lincoln (which included 14 batches of gilts; n = 90 gilts/batch) demonstrated that energy restriction during the developmental period of a gilt increases longevity and may also have beneficial effects on progeny health and growth, particularly, parity 1 progeny. Therefore, we hypothesized that energy restriction during gilt development may affect milk nutrient profile, milk oligosaccharides (OS), and postnatal progeny biomarkers. During the development period, batch 14 gilts (n = 128, 8 gilts/pen) were fed 3 dietary treatments including the following: 1) Control diet formulated to NRC (2012) specifications (CTL); 2) Restricted (20% energy restriction via addition of 40% soy hulls; RESTR); and 3) CTL diet plus addition of crystalline amino acids equivalent to the SID Lys:ME of the RESTR diet (CTL+). All diets were fed ad libitum and applied in a 3-phase feeding regimen during gilt development (days 123 to 230 of age). Average daily feed intake was used to estimate daily metabolizable energy intake (Mcal/d) during each phase (Phase 1: 10.13, 6.97, 9.95; Phase 2: 11.25, 8.05, 10.94; and Phase 3: 9.47, 7.95,11.07) for CTL, RESTR, and CTL+, respectively. After 230 d of age, gilts were bred and fed a common diet. Milk samples were collected from batch 14 gilts (n = 7 per treatment) on days 0 and 14 postfarrowing for compositional analysis of N, CP, dry matter (DM), GE, insulin, and OS. Piglet blood samples (n = 6 piglets/gilt) were obtained on days 1 and 15 postfarrowing for quantification of glucagon-like peptide-2 (GLP-2) and insulin. No effects of developmental diet were observed for milk N, CP, DM, or GE; however, N, CP, DM, and insulin were increased (P < 0.05) on day 1 compared with day 14. A total of 61 different milk OS were identified. Milk OS profile was significantly different for neutral and acidic OS (P < 0.05) on day 0, but there were no significant differences on day 14. For piglet GLP-2, a treatment by day interaction was observed (P < 0.009); specifically, on day 1 GLP concentrations were greater (P < 0.001) in CTL+ compared with RESTR (6.73 vs. 1.21 ng/mL). For serum insulin, a treatment by day interaction was observed (P < 0.01); specifically, insulin in RESTR progeny was greater (P < 0.03) than CTL on day 1. In conclusion, nutritional management of the developing gilt may affect milk nutrient composition, milk OS profile, and piglet serum biomarkers

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

RATIONALE: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. OBJECTIVE: To identify additional AAA risk loci using data from all available genome-wide association studies. METHODS AND RESULTS: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. CONCLUSIONS: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease