metabolism; epithelia integrity; inflammation; parenteral nutrition; liver toxicity; gut microbiome; insulin resistance
Lucchinetti Eliana, Lou Phing‐How, Wawrzyniak Paulina, Wawrzyniak Marcin, Scharl Michael, Holtzhauer Gregory A., Krämer Stefanie D., Hersberger Martin, Rogler Gerhard, Zaugg Michael (2020), Novel strategies to prevent total parenteral nutrition‐induced gut and liver inflammation, and adverse metabolic outcomes, in Molecular Nutrition & Food Research
Lucchinetti Eliana, Lou Phing-How, Hersberger Martin, Clanachan Alexander S., Zaugg Michael (2020), Diabetic Rat Hearts Show More Favorable Metabolic Adaptation to Omegaven Containing High Amounts of n3 Fatty Acids Than Intralipid Containing n6 Fatty Acids, in Anesthesia & Analgesia
Lou Phing-How, Lucchinetti Eliana, Hersberger Martin, Clanachan Alexander S., Zaugg Michael (2020), Lipid Emulsion Containing High Amounts of n3 Fatty Acids (Omegaven) as Opposed to n6 Fatty Acids (Intralipid) Preserves Insulin Signaling and Glucose Uptake in Perfused Rat Hearts, in Anesthesia & Analgesia
, 130(1), 37-48.
BACKGROUND: Triglyceride (TG)-based lipid emulsions form an integral part of life-saving total parenteral nutrition (TPN) and are provided to millions of patients (up to 5% of all hospitalized patients) who are unable to orally ingest or digest/absorb the necessary daily amount of food. Although lipid emulsions are essential components of TPN because of their dense supply of calories and provision of essential fatty acids, currently available therapies often cause considerable side-effects (inflammation and immunosuppression, liver toxicity, changes in the gut microbiome with loss of epithelial integrity and increased risk of sepsis, metabolic derangements with insulin resistance, and depression of cardiac function). Lipid emulsions based on fish oil, containing high amounts of w-3 polyunsaturated fatty acids, appear to have less side-effects, but are unsustainable (due to ocean overfishing) and risky (due to accumulation of environmental toxins in the food chain). Hence, there is a clear need for further research in parenteral nutrition to improve drug safety. One area in greatest need for immediate attention in research on parenteral nutrition is (as recently stated by the American Society of Parenteral and Enteral Nutrition, ASPEN) “the development of alternate products or methods of delivery of nutrients that are safe (with reduced toxicity) and effective.” HYPOTHESIS: We hypothesize that by modifying lipid droplet size, composition of fatty acids in triglycerides, and emulsifiers, we will be able to create novel lipid emulsions with reliable physicochemical stability, favorable pharmacokinetics, and superior biological actions with less toxicity compared to conventional lipid emulsions.EXPERIMENTAL APPROACH: Scientific questions will be addressed using complementary experiments and models. Because the mouse is an affordable animal model specifically suitable for screening purposes, and enables the use of genetically engineered animals, mice instrumented for intravenous delivery will be used for all in vivo experiments. Standard procedures will be followed to develop the novel lipid emulsions. Pharmacokinetics will be assessed using radioactive tracers and PET imaging. To assess the impact of the novel emulsions on bowel inflammation, models of induced (by dextran sulfate sodium) and spontaneous (IL-10- and Muc-2-deficient mice) bowel inflammation will be used. Effects of TPN on liver inflammation and on whole body insulin sensitivity will be determined. Effects of lipid emulsions on cardiac function will be assessed by echocardiography and by measuring beat-to-beat intracellular Ca2+ transients in isolated working mouse hearts. Elaborated mass spectrometry including GC-MS, UPLC/MRM-MS, and MALDI MS tissue imaging will be used to determine lipid mediators and intermediates.SIGNIFICANCE: Our integrated research project has the potential to shift paradigms in current TPN practice. Novel lipid emulsions for TPN with favorable anti-inflammatory actions and beneficial whole-body metabolic effects will ultimately reduce complication rates (morbidity and mortality) in patients and help to minimize health care costs associated with TPN. We will investigate the effects of intravenous lipid emulsions on the gut microbiome and intestine epithelial integrity, a novel and uncharted area of research. Furthermore, we will fabricate lipid emulsions from sustainable sources, which will have a high market potential. The development of novel lipid emulsions with reduced systemic toxicity is of greatest scientific relevance to the whole field of medicine beyond disciplinary boundaries, as these emulsions have the potential to be used for drug delivery in other medical applications.