Neurodegeneration in juvenile Iberian pigs with diet-induced nonalcoholic fatty liver disease

Abstract

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.

Multi-omics analysis reveals the impact of microbiota on host metabolism in hepatic steatosis

“…The plasma level of quinolinate, a precursor for nicotinamide adenine dinucleotide (NAD + ) synthesis, was significantly downregulated only in subjects with moderate steatosis vs no steatosis (Figure 4C). It has been reported that downregulation of quinolinate is associated with NAFLD in animals (Zeltser et al , 2020), and the altered NAD + metabolism is associated with NAFLD in humans (Mardinoglu et al ., 2017).…”

Cognitive Dysfunction in Non-Alcoholic Fatty Liver Disease—Current Knowledge, Mechanisms and Perspectives

“…Concordantly, in a small study, Filipovic et al showed that reduced brain volume in patients with NAFLD was associated with poor cognitive performance [35]. In a juvenile minipig model of diet-induced NAFLD, neurodegeneration was demonstrated as neuronal loss and astrogliosis in the frontal cortex, compared with control pigs [127].…”

High-Fructose, High-Fat Diet Alters Muscle Composition and Fuel Utilization in a Juvenile Iberian Pig Model of Non-Alcoholic Fatty Liver Disease

“…Approval for all experimental procedures was obtained from the Institutional Animal Care and Use Committee of California State University (#1611) before experiments began, and all procedures were in compliance with the National Research Council Guide for the Care and Use of Laboratory Animals. Two previous publications characterized the Iberian pig NAFLD phenotype in terms of liver and gut histology, biochemistry, blood, and metabolomics [21] and documented impairment of neurogenesis in the cerebral frontal cortex [22].…”

“…In addition, 43% of CON and 17% of HFF-fed pigs developed steatosis without inflammation and/or cellular ballooning, and 57% of the CON group had no lesions in the liver. Further, HFF-fed pigs presented gut dysbiosis and hyperplasia that were positively correlated with the severity of the hepatic injury, as well as metabolic changes in liver, plasma, and colon digesta consistent with choline depletion and dysregulation of one-carbon metabolism [21,22]. Compared to CON, HFF-fed pigs had decreased cholesterol (p ≤ 0.01), and high and low-density lipoproteins (p ≤ 0.05), whereas triglycerides, non-esterified fatty acids, leptin, and pro-inflammatory cytokines TNF-α, IL-1α, and TNF-β did not differ across groups.…”

“…Several studies suggest that diet-based insulin resistance and inflammation may be the cause of concurrent skeletal muscle weakness and liver dyslipidemia, although there is limited evidence supporting this relationship [6,7,20]. To explore whether NAFLD precedes or accompanies a dysregulation of skeletal muscle composition and metabolism, we utilize a previously developed and characterized pediatric pig model of NAFLD induced by a high-fructose, high-fat (HFF) diet [21,22]. Juvenile Iberian pigs fed an HFF diet for 10 weeks developed steatosis, hepatocellular injury, and dysregulation of enterohepatic bile acid signaling similar to that observed in human children with NAFLD.…”