**12.6 Lipid formulations (soy vs fish oil lipid emulsions); enhancing brain growth, normalizing PNALD**

For decades, intravenous soybean oil-based lipid formulations have been used extensively in PN patients in the United States. However, the use of soybean oilbased lipid emulsion may not be optimal for the safety and benefit of PN patients. While this is a great source of essential fatty acids, soybean oil based lipid contains a higher amount of proinflammatory ω-6 PUFA including oleic acid, linoleic acid (18:2), and phytosterols [168]. A high amount of linoleic acid in ω-6 fatty acid has inflammatory properties [169]. Plant based phytosterols inhibit bile flow, increase triglyceride storage, increase hepatic cholestasis, and increase neurological disorders [170, 171]. Phytosterols are thought to be toxic to hepatocytes, but if they are taken enterally, they are absorbed by GI tract.

Over the years, PN with a fish oil-based lipid emulsion or a mixture of fish, soybean, and olive oil derived lipid emulsions have been preferred. Recent literature supports the idea of considering the use of fish oil based lipids solely, or a mixture of fish, olive and soybean oil based lipid emulsions as an alternative as significant improvements have been observed using fish oil based composition. This especially applies to preterm babies with immature brains and pediatric patients with PNALD. Fish oil or mixed oil lipid emulsions have increased antioxidant properties because the triglycerides formed from each lipid emulsion differ based on the fatty acid content, such as long vs. short chain fatty acid chains (LCFAs vs. SCFAs) and unsaturated vs. saturated. Different length FAs have different biological properties and clinical outcomes. Fish oil based lipid emulsions contain a high concentration of anti-inflammatory ω-3 unsaturated fatty acids with small amounts of linoleic acid and higher amounts of Omegaven, docosahexaenoic acid (DHA) and eicosapentaenoic (EPA). These have been shown reduce oxidative stress and inflammation by blocking proinflammatory cytokines to prevent or reverse PNALD with cholestasis in neonates as well as in the setting of intestinal failure [172–174]. DHA and EPA are the major metabolites of ω-3 fatty acids highly enriched in fish oil. DHA plays an important role in reducing inflammation by suppressing inflammatory markers [110]. Additionally, DHA present in Omegaven modulates the liver X-receptor involved in bile regulation [175, 176]. Further, DHA and arachidonic acid present in fish-oil or mixed lipid modulate neuronal development and brain maturation in piglets and preterm infants [132, 133, 177]. Alternatively, olive oil-based lipid emulsions have been proven as another alternative because they have a low amount of ω-6 fatty acid which reduces oxidative stress with no major changes in liver enzymes [178].

## **13. Future directions in PN research**

Although PN is highly effective in pediatric and adult patients, the pathophysiology of its association with PNALD and neurological disorders and the underlying mechanisms are not well understood and are of high priority in the clinical setting. Over the years, most of the research has emphasized understanding the maturation

of the GI tract in PN patients. There are no specific safer therapies yet established for the prevention or treatment of multifactorial PNALD or brain abnormalities in PN patients. There are challenges to overcome in terms of the characterization and standardization of PN supplements for optimal nutrition to promote normal brain development trajectories and normal liver function. PN is essential but detrimental in preterm babies and infant patients on long term feeding, and they are at high risk for liver and brain abnormalities. Optimal nutrition with minimal side effects is highly important in early neonates for their developing brain and normal liver function. Several key questions need to be addressed including (1) the revision of PN components, (2) the characterization of current PN components, (3) the use of ω-3 fatty acid enriched fish-oil based lipid or mixed oil based lipid rather than soyabean oil based lipid, 4) the inclusion of essential short chain FA (SCFAs) and essential amino acids, and 5) the effects of specific dietary solutions in the rapidly developing brain in early life.

There is a need to consider cyclic PN (cPN) rather than continuous PN for long term in infants. Studies in neonates suggest that patients on cyclic (cPN) have delayed liver dysfunction compared to continuous PN [179]. Another study from Costadel Sol Hospital in Spain shows that patients ≥18 years had delayed hepatic abnormalities on cPN for 12–15 days compared to patients on continuous PN. The cPN patients showed significant reduction in hepatic enzymes such as Bilirubin, AST, ALT and GGT with no change in ALP [180]. However, the limitations of this study were the exclusion of patients having early liver abnormalities and sample size [180]. Future studies involving cPN instead of continuous PN administration will help in addressing early hepatic and brain related issues.

There is also the possibility for improvement of the route of PN, including partial enteral nutrition (EN) that may reduce the risk of developing PNALD. Given the limitations of current therapies, more research is needed for the optimization of current nutritional components and advancement in PN associated with neurological disorders and PNALD. The next key question in the field is to identify the driving factors and associated cellular and molecular mechanisms that modulate neurodevelopmental outcomes in the rapidly developing brain of preterm neonates and infants.

Another key factor to consider is how to maintain bacterial diversity (*Bacteriodities* vs. *Firmicuties*) and prevent unwanted bacterial overgrowth. Additionally, we need to focus on understanding the molecular mechanisms driving gut-brain maturation in pediatric patients on PN. In summary, there are several challenges remaining in clinical trials to optimize efficacy and safety of PN for patients.

## **14. Conclusions**

The work that has been done in animal models to both characterize the molecular effects of PN on the body and to optimize PN additives has influenced the development of safer PN for patients. PN is essential and life-saving, so it is important that GI, immune, hepatic, and nervous system complications be minimized. Researchers have described the changes in intestinal cellularity, mucous composition, microbial population, innate immune function, enterohepatic circulation, and brain development induced by PN. Even though many patients requiring PN are critically ill and often malnourished making them predisposed to infection and underlying metabolic complications, a vast body of work demonstrates that route of feeding can dramatically alter the gut immune system, gut microbiome, metabolic handling, and organ function, which may contribute to

*Parenteral Nutrition Modeling and Research Advances DOI: http://dx.doi.org/10.5772/intechopen.101692*

the pathophysiology observed in PN settings. The elegant work demonstrating the mechanisms by through mucosal immune cell signaling is altered under PN show that these alterations are targetable. Several additives have been explored that show promise in restoring normal function in the absence of enteric stimulation. For example, immune-enhancing metabolites like glutamine are helpful in patients with hypermetabolism. A major area of investigation has been using exogenous ENS neuropeptides to stimulate normal GALT function. Elsewhere, bile acid agonists and the use of fish oil lipid emulsions have been shown to support normal gutliver feedback and reduce the incidence of PNALD in PN patients. Explorations of administering microbial metabolites, such as bile acid analogues, SCFAs, and polyamines are promising areas of research that can be further deliniated using translational models of PN feeding in the laboratory setting.
