The objective of this study was to investigate whether juvenile Iberian pigs with diet-induced non-alcoholic fatty liver disease (NAFLD), cholestasis and gut dysbiosis would develop histological and metabolic markers of neurodegeneration in the frontal cortex (FC), and whether supplementing probiotics would influence the response to the diet. Twenty-eight juvenile Iberian pigs were fed for 10 weeks either a control (CON) or high-fructose high-fat diet (HFF) with or without a commercial probiotic mixture. Compared with CON, HFF-fed pigs had decreased number of neurons and an increase in reactive astrocytes in FC tissue. We found also a decrease in one-carbon metabolites choline and betaine, and a marked accumulation of bile acids, cholesteryl esters, and polyol-pathway intermediates in FC of HFF-fed pigs, which were associated with markers of neurodegeneration and accentuated with the severity of NAFLD. Betaine depletion in FC tissue was negatively correlated with choline-derived phospholipids in colon content, whereas primary conjugated bile acids in FC were associated with cholestasis. Plasma kynurenine-to-tryptophan quotient, as a marker of indoleamine 2,3-dioxygenase activity, and intestinal dysbiosis were also correlated with neuronal loss and astrogliosis. Recognition memory test, and FC levels of amyloid β and phosphorylated Tau did not differ between diets, while probiotics increased amyloid β and memory loss in HFF-fed pigs. In conclusion, our results show evidence of neurodegeneration in FC of juvenile Iberian pigs, and establish a novel pediatric model to investigate the role of gut-liver-brain axis in diet-induced NAFLD.
Genome‐wide association studies (GWAS) are used to identify genetic loci that are associated with a trait of interest in order to decipher underlying biological mechanisms. Metabolite measures in cerebrospinal fluid (CSF), the fluid that surrounds the brain, provides insight into brain function that may be relevant for neurobehavioral traits and neuropsychiatric disorders. We performed a GWAS of 1,000 metabolites in a sample of 600 human subjects, the largest set of CSF data used in a GWAS to date. We applied standard quality control of genetic data including missingness, minor allele frequency cut‐off, and population stratification. Phenotype data were checked for outliers, and non‐normal data were transformed using inverse rank normalization. A linear association, including age and sex as additional covariates, was performed using the PLINK whole genome association analysis toolset. Significant SNP associations were found in 45 metabolites. Analysis via functional mapping and annotation (FUMA) downstream GWAS analysis tool found that many of these SNPs have been associated with other traits by other GWAS. Linked traits include blood metabolite levels and brain related traits such as cognitive performance. Results show that a GWAS can be successfully performed with CSF metabolite data, and indicate a relationship between CSF and blood metabolite levels. Further steps include analysis of other CSF metabolites and the use of dosage genotype data for potentially more detailed results.
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