Novel Strategies to Prevent Total Parenteral Nutrition‐Induced Gut and Liver Inflammation, and Adverse Metabolic Outcomes

Abstract

Total parenteral nutrition (TPN) is a life‐saving therapy administered to millions of patients. However, it is associated with significant adverse effects, namely liver injury, risk of infections, and metabolic derangements. In this review, the underlying causes of TPN‐associated adverse effects, specifically gut atrophy, dysbiosis of the intestinal microbiome, leakage of the epithelial barrier with bacterial invasion, and inflammation are first described. The role of the bile acid receptors farnesoid X receptor and Takeda G protein‐coupled receptor, of pleiotropic hormones, and growth factors is highlighted, and the mechanisms of insulin resistance, namely the lack of insulinotropic and insulinomimetic signaling of gut‐originating incretins as well as the potentially toxicity of phytosterols and pro‐inflammatory fatty acids mainly released from soybean oil‐based lipid emulsions, are discussed. Finally, novel approaches in the design of next generation lipid delivery systems are proposed. Propositions include modifying the physicochemical properties of lipid emulsions, the use of lipid emulsions generated from sustainable oils with favorable ratios of anti‐inflammatory n‐3 to pro‐inflammatory n‐6 fatty acids, beneficial adjuncts to TPN, and concomitant pharmacotherapies to mitigate TPN‐associated adverse effects.

Choice of Lipid Emulsion Determines Inflammation of the Gut‐Liver Axis, Incretin Profile, and Insulin Signaling in a Murine Model of Total Parenteral Nutrition

“…Absence of oral food intake results in bowel atrophy with epithelial barrier dysfunction and inflammation. [ 3 ] In this chain of events, the leakage of endotoxin—generated by an altered intestinal microbiome—into the hepatic circulation, plays a pivotal role. Our study shows that both TPN increased LBP, an acute phase inflammatory protein generated by hepatocytes, which potentiates the cytokine response of hepatic Kupffer cells to endotoxin by facilitating its binding to CD14.…”

“…[ 3 ] In addition, bypassing the digestive track causes complex metabolic maladaptations as a result of diminished insulinotropic signaling by the incretins glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) as well as bile acid signaling. [ 3 ]…”

“…[ 3 ] Changes in insulin sensitivity upon infusion of anti‐inflammatory fish oil‐based lipid emulsions are less pronounced since clearance of n‐3 polyunsaturated fatty acids from the bloodstream is slower due to their relative independence on lipoprotein lipase activity and their distinct tissue‐specific uptake and metabolism. [ 3 ] Moreover, oils rich in EPA and DHA reduce lipid deposition in the liver and other tissues, and even reverse glucose intolerance and insulin resistance. [ 3 ] Our group has recently demonstrated that Omegaven as opposed to Intralipid reverses fatty acid‐induced inhibition of glucose uptake in healthy rat hearts, [ 14 ] while providing additional beneficial metabolic effects to vulnerable diabetic hearts, possibly by enhanced “substrate cycling.” [ 15 ] Recent clinical data also suggest that the use of fish oil‐based lipid emulsions as part of TPN may improve clinical outcomes, specifically in critically ill patients.…”

“…[ 3 ] Moreover, oils rich in EPA and DHA reduce lipid deposition in the liver and other tissues, and even reverse glucose intolerance and insulin resistance. [ 3 ] Our group has recently demonstrated that Omegaven as opposed to Intralipid reverses fatty acid‐induced inhibition of glucose uptake in healthy rat hearts, [ 14 ] while providing additional beneficial metabolic effects to vulnerable diabetic hearts, possibly by enhanced “substrate cycling.” [ 15 ] Recent clinical data also suggest that the use of fish oil‐based lipid emulsions as part of TPN may improve clinical outcomes, specifically in critically ill patients. [ 16–19 ]…”

“…However, metabolic consequences of lipid emulsions with different fatty acid composition have not been studied in adult animals specifically during early TPN devoid of liver injury and deranged bile acid signaling. [ 3 ] Indeed, the use of an murine model of early TPN‐associated maladaptations could provide useful mechanistic insights into the complex events leading to the metabolic derangements and further serve as cost‐efficient experimental TPN model when attempting to optimize the composition of such lipid emulsions. [ 3 ] We hypothesized that the choice of the lipid emulsion in TPN, that is, n‐3 fatty acid‐based Omegaven versus n‐6 fatty acid‐based Intralipid, would determine the degree of inflammation in the gut‐liver axis, the incretin profile, and insulin resistance in the skeletal muscle and liver already at the early stage in TPN.…”