Preclinical modeling of metabolic syndrome to study the pleiotropic effects of novel antidiabetic therapy independent of obesity.

Cardiovascular-kidney-metabolic health reflects the interactions between metabolic risk factors, chronic kidney disease, and the cardiovascular system. A growing body of literature suggests that metabolic syndrome (MetS) in individuals of normal weight is associated with a high prevalence of cardiovascular diseases and an increased mortality. The aim of this study was to establish a non-invasive preclinical model of MetS in support of future research focusing on the effects of novel antidiabetic therapies beyond glucose reduction, independent of obesity. Eighteen healthy adult Beagle dogs were fed an isocaloric Western diet (WD) for ten weeks. Biospecimens were collected at baseline (BAS1) and after ten weeks of WD feeding (BAS2) for measurement of blood pressure (BP), serum chemistry, lipoprotein profiling, blood glucose, glucagon, insulin secretion, NT-proBNP, angiotensins, oxidative stress biomarkers, serum, urine, and fecal metabolomics. Differences between BAS1 and BAS2 were analyzed using non-parametric Wilcoxon signed-rank testing. The isocaloric WD model induced significant variations in several markers of MetS, including elevated BP, increased glucose concentrations, and reduced HDL-cholesterol. It also caused an increase in circulating NT-proBNP levels, a decrease in serum bicarbonate, and significant changes in general metabolism, lipids, and biogenic amines. Short-term, isocaloric feeding with a WD in dogs replicated key biological features of MetS while also causing low-grade metabolic acidosis and elevating natriuretic peptides. These findings support the use of the WD canine model for studying the metabolic effects of new antidiabetic therapies independent of obesity.

Dietary benzoic acid and supplemental enzymes alter fiber-fermenting taxa and metabolites in the cecum of weaned pigs.

Inclusion of enzymes and organic acids in pig diets is an important strategy supporting decreased antibiotic usage in pork production. However, limited knowledge exists about how these additives impact intestinal microbes and their metabolites. To examine the effects of benzoic acid and enzymes on gut microbiota and metabolome, 160 pigs were assigned to one of four diets 7 days after weaning: a control diet or the addition of 0.5% benzoic acid, 0.045% dietary enzymes (phytase, ß-glucanase, xylanase, and α-amylase), or both and fed ad libitum for 21 to 22 d. Individual growth performance and group diarrhea incidence data were collected throughout the experimental period. A decrease of 20% in pen-level diarrhea incidence from days 8 to 14 in pigs-fed both benzoic acid and enzymes compared to the control diet (P = 0.047). Cecal digesta samples were collected at the end of the experimental period from 40 piglets (n = 10 per group) and evaluated for differences using 16S rRNA sequencing and two-dimensional gas chromatography and time-of-flight mass spectrometry (GCxGC-TOFMS). Analysis of cecal microbiota diversity revealed that benzoic acid altered microbiota composition (Unweighted Unifrac, P = 0.047, r2 = 0.07) and decreased α-diversity (Shannon, P = 0.041; Faith's Phylogenetic Diversity, P = 0.041). Dietary enzymes increased fiber-fermenting bacterial taxa such as Prevotellaceae. Two-step feature selection identified 17 cecal metabolites that differed among diets, including increased microbial cross-feeding product 1,2-propanediol in pigs-fed benzoic acid-containing diets. In conclusion, dietary benzoic acid and enzymes affected the gut microbiota and metabolome of weaned pigs and may support the health and resolution of postweaning diarrhea.

Feeding weaned pigs diets containing benzoic acid or supplemental enzymes for 21 d after weaning changed the gut microbiota and metabolome. Benzoic acid increased feed intake, weight gain, and the presence of 1,2-propanediol in cecal digesta, which is an important microbial cross-feeding product. Dietary enzymes altered microbiota composition, increasing the presence of fiber-fermenting microbes including Prevotellaceae. Pigs fed a combination of both benzoic acid and enzymes showed improved resolution of postweaning diarrhea. These differences demonstrate the role of these feed additives in the establishment of gut microbes and metabolic pathways for the degradation of complex dietary components in the weaned pig. This study provides new information about alterations in microbial function and community composition using microbiota sequencing and metabolomic analysis.