Dysregulated FXR-FGF19 signaling and choline metabolism are associated with gut dysbiosis and hyperplasia in a novel pig model of pediatric NASH

Feb 1, 2020American journal of physiology. Gastrointestinal and liver physiology

Disrupted bile acid and choline processing linked to gut imbalance and tissue overgrowth in a new pig model of childhood fatty liver disease

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Abstract

Juvenile Iberian pigs fed a high fructose, high fat diet for 10 weeks developed nonalcoholic steatohepatitis (NASH) without obesity or insulin resistance.

NASH was associated with cholestasis and impaired signaling of the Farnesoid-X receptor (FXR) and fibroblast growth factor 19 (FGF19).
Choline depletion in the liver correlated with reduced lipoprotein and cholesterol levels in serum, alongside increased choline-containing phospholipids in colon contents.
Gut dysbiosis and hyperplasia worsened with the severity of NASH and were linked to higher levels of choline metabolites and secondary bile acids in the colon.
Probiotic supplementation in the high fructose, high fat diet worsened NASH, inhibited liver cell cleaning processes, and reduced gut microbial diversity.
Dysregulated bile acid homeostasis may contribute to liver injury and choline depletion, affecting lipoprotein synthesis and promoting further liver damage.

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To investigate the role of bile acids (BAs) in the pathogenesis of diet-induced nonalcoholic steatohepatitis (NASH), we fed a "Western-style diet" [high fructose, high fat (HFF)] enriched with fructose, cholesterol, and saturated fat for 10 wk to juvenile Iberian pigs. We also supplemented probiotics with in vitro BA deconjugating activity to evaluate their potential therapeutic effect in NASH. Liver lipid and function, cytokines, and hormones were analyzed using commercially available kits. Metabolites, BAs, and fatty acids were measured by liquid chromatography-mass spectrometry. Histology and gene and protein expression analyses were performed using standard protocols. HFF-fed pigs developed NASH, cholestasis, and impaired enterohepatic Farnesoid-X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling in the absence of obesity and insulin resistance. Choline depletion in HFF livers was associated with decreased lipoprotein and cholesterol in serum and an increase of choline-containing phospholipids in colon contents and trimethylamine--oxide in the liver. Additionally, gut dysbiosis and hyperplasia increased with the severity of NASH, and were correlated with increased colonic levels of choline metabolites and secondary BAs. Supplementation of probiotics in the HFF diet enhanced NASH, inhibited hepatic autophagy, increased excretion of taurine and choline, and decreased gut microbial diversity. In conclusion, dysregulation of BA homeostasis was associated with injury and choline depletion in the liver, as well as increased biliary secretion, gut metabolism and excretion of choline-based phospholipids. Choline depletion limited lipoprotein synthesis, resulting in hepatic steatosis, whereas secondary BAs and choline-containing phospholipids in colon may have promoted dysbiosis, hyperplasia, and trimethylamine synthesis, causing further damage to the liver.Impaired Farnesoid-X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling and cholestasis has been described in nonalcoholic fatty liver disease (NAFLD) patients. However, therapeutic interventions with FXR agonists have produced contradictory results. In a swine model of pediatric nonalcoholic steatohepatitis (NASH), we show that the uncoupling of intestinal FXR-FGF19 signaling and a decrease in FGF19 levels are associated with a choline-deficient phenotype of NASH and increased choline excretion in the gut, with the subsequent dysbiosis, colonic hyperplasia, and accumulation of trimethylamine--oxide in the liver. N N NEW & NOTEWORTHY

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Dysregulated FXR-FGF19 signaling and choline metabolism are associated with gut dysbiosis and hyperplasia in a novel pig model of pediatric NASH

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