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

Authors: ZELTSER, NICOLE - California Polytechnic State University; MEYER, ISABELL - University Of Bonn; HERNANDEZ, GABRIELLA - California Polytechnic State University; TRAHAN, MATTHEW - California Polytechnic State University; FANTER, ROB - California Polytechnic State University; ABO-ISMAIL, MOHAMMED - California Polytechnic State University; GLANZ, HUNTER - California Polytechnic State University; STRAND, CHRISTINE - California Polytechnic State University; Burrin, Douglas - Doug; LA FRANO, MICHAEL - California Polytechnic State University; MANJARIN, RODRIGO - California Polytechnic State University; MAJ, MAGDALENA - California Polytechnic State University

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/20/2020
Publication Date: 8/28/2020
Citation: Zeltser, N., Meyer, I., Hernandez, G., Trahan, M., Fanter, R., Abo-Ismail, M., Glanz, H., Strand, C., Burrin, D.G., La Frano, M., Manjarin, R., Maj, M. 2020. Neurodegeneration in juvenile Iberian pigs with diet-induced nonalcoholic fatty liver disease. American Journal of Physiology - Endocrinology and Metabolism. 319(3):E592-E606. https://doi.org/10.1152/ajpendo.00120.2020.
DOI: https://doi.org/10.1152/ajpendo.00120.2020

Interpretive Summary: In the U.S., there has been a marked increase in the number of children that develop fatty liver disease, also called nonalcoholic fatty liver disease (NAFLD). This disease is often linked to increased consumption of foods high in fat and sugar. We recently reported results from a study using a unique breed of Iberian pigs that develop NAFLD after only 3 months of age when fed a diet high in fat and sugar. This pig breed provides an exciting new animal model to explore how pediatric NAFLD influences development in children. We were interested in whether there were adverse effects of feeding a diet high in fat and sugar on brain development since studies in adults with NAFLD suggest a deterioration of brain function. The main aim of the current study was to test whether young pigs fed a high fat diet would develop cellular and metabolic signs of poor brain development. Our results showed that pigs fed the high fat-sugar diet for 3 months had fewer brain cells in general, but a greater proportion of brain cells, called astrocytes that respond to stress signals in the brain. We also found that the deterioration of brain function was associated with changes in brain tissue content of a host of metabolites involved in fat metabolism and processing. The study demonstrates that this new pig model of pediatric NAFLD reveals important insights into how high fat diets might lead to deterioration of brain function and development in children.

Technical Abstract: The objective of this study was to investigate whether juvenile Iberian pigs with diet-induced nonalcoholic 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 wk either a control (CON) or high-fructose high-fat (HFF) diet with or without a commercial probiotic mixture. Compared with CON, HFF-fed pigs had a decreased number of neurons and an increase in reactive astrocytes in FC tissue. There was 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-B and phosphorylated Tau did not differ between diets, whereas probiotics increased amyloid-ß 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.