High fat diet is associated with gut microbiota dysbiosis and decreased gut microbial derived metabolites related to metabolic health in young Göttingen Minipigs.

The objectives were 1) to characterize a Göttingen Minipig model of metabolic syndrome regarding its colon microbiota and circulating microbial products, and 2) to assess whether ovariectomized female and castrated male minipigs show similar phenotypes. Twenty-four nine-week-old Göttingen Minipigs were allocated to four groups based on sex and diet: ovariectomized females and castrated males fed either chow or high-fat diet (HFD) for 12 weeks. At study end, body composition and plasma biomarkers were measured, and a mixed meal tolerance test (MMT) and an intravenous glucose tolerance test (IVGTT) were performed. The HFD groups had significantly higher weight gain, fat percentage, fasting plasma insulin and glucagon compared to the chow groups. Homeostatic model assessment of insulin resistance index (HOMA-IR) was increased and glucose effectiveness derived from the IVGTT and Matsuda´s insulin sensitivity index from the MMT were decreased in the HFD groups. The HFD groups displayed dyslipidemia, with significantly increased total-, LDL- and HDL-cholesterol, and decreased HDL/non-HDL cholesterol ratio. The colon microbiota of HFD minipigs clearly differed from the lean controls (GuniFrac distance matrix). The main bacteria families driving this separation were Clostridiaceae, Fibrobacteraceae, Flavobacteriaceae and Porphyromonadaceae. Moreover, the species richness was significantly decreased by HFD. In addition, HFD decreased the circulating level of short chain fatty acids and beneficial microbial metabolites hippuric acid, xanthine and trigonelline, while increasing the level of branched chain amino acids. Six and nine metabolically relevant genes were differentially expressed between chow-fed and HFD-fed animals in liver and omental adipose tissue, respectively. The HFD-fed pigs presented with metabolic syndrome, gut microbial dysbiosis and a marked decrease in healthy gut microbial products and thus displayed marked parallels to human obesity and insulin resistance. HFD-fed Göttingen Minipig therefore represents a relevant animal model for studying host-microbiota interactions. No significant differences between the castrated and ovariectomized minipigs were observed.

Lipid Embolism in Obese Göttingen Minipigs.

Pigs are used as a model of human obesity, both for metabolic characterization and for evaluation of pharmacological interventions. Over a period of 7 years, acute death or clinical signs requiring immediate euthanasia were observed in 12 obese Göttingen minipigs (GMs) included in different pharmacological studies. The GM were fed ad libitum on normal chow-diet and the unscheduled deaths occurred in animals treated with drug candidates as well as in untreated animals. The most prominent clinical signs requiring euthanasia included varying degrees of respiratory distress; and on histopathological examination, thickening of the alveolar septa due to vacuolation was observed throughout the lung in 10 of the 12 animals. Furthermore, vacuolation in glomeruli of the kidney was detected in 9 of the 10 animals. Oil red O staining of cryosections demonstrated that the vacuoles both in lung and kidney contained lipid, and immunohistochemistry with anti-von Willebrand factor and transmission electron microscopy revealed that the lipid was localized in the lumen of blood vessels establishing the occurrence of fatal pulmonary lipid embolism. Additionally, lipogranulomatous inflammation in the abdominal adipose tissue was observed in all the GMs with lipid emboli.