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

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-N-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.NEW & NOTEWORTHY 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-N-oxide in the liver.

Effect of piglet separation from dam at birth on colostrum uptake.

The objective of this study was to determine whether birth order influences piglet survival because of reduced uptake of maternal antibodies by the piglets born later in large litters. Forty-five litters were serially allocated to one of 2 study groups. The crèche group consisted of 18 litters for which the 205 piglets were removed to a warm box to prevent suckling until 4 h after delivery of the first pig, and the control group of 27 litters for which 306 piglets were allowed to suckle from birth. The protein content of piglet blood and sow colostrum was determined with Brix refractometers. Parity, farrowing duration, liveborn litter size, litter size at 12 d, and piglet weight at birth and at 24 h and 12 d of age did not differ between the 2 treatment groups (P > 0.1). There were also no significant differences (P > 0.1) at any time point in weight or in the mean percent protein in plasma between the first 3 and the last 3 piglets born to an individual sow. However, the mean percent protein in plasma was significantly higher in the control group than in the crèche group at both 24 h (P ≤ 0.05) and day 12 (P ≤ 0.01) postpartum. The lack of differences in plasma protein levels between the first and last pigs born along with the lower percent plasma protein in the piglets that were prevented from suckling immediately after birth militate against the use of this technique as a way to equalize the opportunity for adequate transfer of maternal antibodies.

L'objectif de la présente étude était de déterminer si l'ordre de naissance influence la survie des porcelets à cause de la réduction d'ingestion d'anticorps maternels par les porcelets nés plus tard dans les portées nombreuses. Quarante-cinq portées ont été réparties de manière successive à l'un des deux groupes d'étude. Le groupe crèche était constitué de 18 portées pour lesquelles les 205 porcelets ont été maintenus dans une boîte chauffée pour empêcher la tétée jusqu'à 4 h après la naissance du premier porcelet, et le groupe témoin de 27 portées pour lesquelles les 306 porcelets ont pu téter dès la naissance. Le contenu en protéine du sang des porcelets et du colostrum de la truie a été déterminé avec un réfractomètre Brix. La parité, la durée de la mise-bas, le nombre de porcelets nés vivants, la taille de la portée à 12 j, et le poids des porcelets à la naissance et à 24 h et 12 j d'âge n'étaient pas différents entre les deux groupes de traitement (P > 0,1). Il n'y avait également pas de différence significative (P > 0,1) à aucun des temps mesurés pour le poids ou le pourcentage moyen de protéines dans le plasma entre les trois premiers et les trois derniers porcelets nés à une truie individuelle. Toutefois, le pourcentage moyen en protéine dans le plasma était significativement plus élevé dans le groupe témoin que dans le groupe crèche à 24 h (P ≤ 0,05) et au jour 12 (P ≤ 0,01) post-partum. Le manque de différence dans les quantités de protéines plasmatiques entre le premier et le dernier né avec également le pourcentage de protéine plasmatique plus faible chez les porcelets qui ont été empêché de boire immédiatement après la naissance milite contre l'utilisation de cette technique comme moyen d'égaliser l'opportunité pour un transfert adéquat d'anticorps maternels.(Traduit par Docteur Serge Messier).