Parenteral lipids shape gut bile acid pools and microbiota profiles in the prevention of cholestasis in preterm pigs

Authors: CALL, LEE - Children'S Nutrition Research Center (CNRC); MOLINA, TIFFANY - Baylor College Of Medicine; STOLL, BARBARA - Children'S Nutrition Research Center (CNRC); GUTHRIE, GREGORY - Baylor College Of Medicine; CHACKO, SHAJI - Children'S Nutrition Research Center (CNRC); PLAT, JOGCHUM - Maastricht University; ROBINSON, JASON - Children'S Nutrition Research Center (CNRC); LIN, SEN - Sichuan Agricultural University; VONDEROHE, CAITLIN - Children'S Nutrition Research Center (CNRC); MOHAMMAD, MAHMOUD - Baylor College Of Medicine; KUNICHOFF, DENNIS - Children'S Nutrition Research Center (CNRC); CRUZ, STEPHANIE - Baylor College Of Medicine; LAU, PATRICIO - Baylor College Of Medicine; PREMKUMAR, MURALIDHAR - Baylor College Of Medicine; NIELSEN, JON - Children'S Nutrition Research Center (CNRC); FANG, ZHENGFENG - Children'S Nutrition Research Center (CNRC); OLUTOYE, OLUYINKA - Baylor College Of Medicine; THYMANN, THOMAS - University Of Copenhagen; BRITTON, ROBERT - Metagenome Analytics; SANGLID, PER - University Of Copenhagen; Burrin, Douglas - Doug

Submitted to: Journal of Lipid Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/29/2020
Publication Date: 4/29/2020
Citation: Call, L., Molina, T., Stoll, B., Guthrie, G., Chacko, S., Plat, J., Robinson, J., Lin, S., Vonderohe, C., Mohammad, M., Kunichoff, D., Cruz, S., Lau, P., Premkumar, M., Nielsen, J., Fang, Z., Olutoye, O., Thymann, T., Britton, R., Sanglid, P., Burrin, D.G. 2020. Parenteral lipids shape gut bile acid pools and microbiota profiles in the prevention of cholestasis in preterm pigs. Journal of Lipid Research. https://doi.org/10.1194/jlr.RA120000652.
DOI: https://doi.org/10.1194/jlr.RA120000652

Interpretive Summary: More than half-a-million infants are born prematurely each year in the U.S. and have immature guts that cannot absorb enough food to sustain life. To nourish these babies, doctors use a life-saving therapy called total parenteral nutrition (TPN) in which is a mixture of fluid containing electrolytes, glucose, amino acids, vitamins, minerals and fats that is infused into the bloodstream. In the U.S., the main lipid emulsion approved for use in infants is based on soybean oil, called Intralipid®. Studies in preterm babies and our studies in preterm piglets have shown that long term infusion of soybean emulsions leads to a life-threatening condition known as parenteral nutrition-associated liver disease (PNALD). The current study tested two new lipid emulsions in premature, newborn piglets. One group received the new emulsion containing four different fats, called SMOFlipid (SMOF), and a second group (EXP) got a similar emulsion but with enriched levels of key omega-fatty acids that are important for immune function. We compared these to a control group that received soybean emulsions and a healthy formula group that did not get TPN. The results showed that the SMOF and EXP emulsions prevented PNALD. We also found that these new emulsions maintained the normal flow of bile into the gut and this led to marked changes the gut bacterial population. These findings confirm previous work and show that new generation lipid emulsions prevent liver disease and that the underlying explanation may be related to how it influences the bacteria in the gut.

Technical Abstract: Multi-component lipid emulsions, rather than soy-oil emulsions, prevent cholestasis by an unknown mechanism. Here, we quantified liver function, bile acid pools, and gut microbial and metabolite profiles in premature, parenterally fed pigs given a soy-oil lipid emulsion, Intralipid (IL); a multi component lipid emulsion, SMOFlipid (SMOF); a novel emulsion with a modified fatty-acid composition (EXP); or a control enteral diet (ENT) for 22 days. We assayed serum cholestasis markers; measured total bile acid levels in plasma, liver, and gut contents; and analyzed colonic bacterial 16S rRNA gene sequences and metabolomic profiles. Serum cholestasis markers (i.e. bilirubin, bile acids, and g-glutamyl transferase) were highest in IL-fed pigs and normalized in those given SMOF, EXP, or ENT. Gut bile acid pools were lowest in the IL treatment and were increased in the SMOF and EXP treatments and comparable to ENT. Multiple bile acids, especially their conjugated forms, were higher in the colon contents of SMOF and EXP than in IL pigs. Colonic microbial communities of SMOF and EXP pigs had lower relative abundance of several Gram-positive anaerobes, including Clostridrium XIVa, and higher abundance of Enterobacteriaceae than those of IL and ENT pigs. Differences in lipid and microbial-derived compounds were also observed in colon metabolite profiles. These results indicate that multi-component lipid emulsions prevent cholestasis and restore enterohepatic bile flow in association with gut microbial and metabolomic changes. We conclude that sustained bile flow induced by multi-component lipid emulsions likely exerts a dominant effect in reducing bile acid–sensitive, Gram-positive bacteria.