NNIW77 - The Importance of Immunonutrition

Editor(s): M. Makrides, J. Ochoa, H. Szajewska. 77

The 77th Nestlé Nutrition Institute Workshop on the importance of immunonutrition held from October 28th – November 1st 2012 in Panama city, presented the latest findings on how nutrient status can modulate immunity and improve health conditions in pediatric patients. Nutrients have tremendous potential to modulate the actions of the immune system, a fact which has significant impact on public health and clinical practice. During the last decade the role of nutrition, beyond providing the calories and the macro and micronutrients for surviving, is well established and clinically proven. The three sessions of this workshop covered major aspects of the interplay between nutrients and the regulation of the immunity and inflammatory process. The first session explored the pharmaceutical value of specific amino acids (arginine and glutamine) and hormones for addressing immune disorders and infant development. The second session revolved around the gut function and immunity, and the right balance of probiotics. The third session explored the role of lipid mediators and how their identities and proportions can tip the balance in favour of health or disease. The chairpersons – Prof. M. Makrides, Prof. J. Ochoa and Prof. H. Szajewska established an excellent scientific workshop program and invited renowned speakers who have further debated and increased the understanding of this important topic through their presentations and participation in discussions. 


Arginine and Asthma

Author(s): C. Morris

Recent studies suggest that alterations of the arginine metabolome and a dysregulation of nitric oxide (NO) homeostasis play a role in the pathogenesis of asthma. L -Arginine, a semi-essential amino acid, is a common substrate for both the arginases and NO synthase (NOS) enzyme families. NO is an important vasodilator of the bronchial circulation, with both bronchodilatory and anti-inflammatory properties, and is synthesized from oxidation of its obligate substrate L -arginine, which is catalyzed by a family of NOS enzymes.Arginase is an essential enzyme in the urea cycle, responsible for the conversion of arginine to ornithine and urea. The NOS and arginase enzymes can be expressed simultaneously under a wide variety of inflammatory conditions, resulting in competition for their common substrate. Although much attention has been directed towards measurements of exhaled NO in asthma, accumulating data show that low bioavailability of L -arginine also contributes to inflammation, hyperresponsiveness and remodeling of the asthmatic airway. Aberrant arginine catabolism represents a novel asthma paradigm that involves excess arginase activity, elevated levels of asymmetric dimethyl arginine, altered intracellular arginine transport, and NOS dysfunction. Addressing the alterations in arginine metabolism may result in new strategies for treatment of asthma.

Arginine Deficiency Caused by Myeloid Cells Importance Identification and Treatment

Author(s): J. Ochoa

Dietary arginine supplementation has been suggested as a means of improving T lymphocyte function and has found its greatest clinical utility in patients undergoing elective surgery. In other illnesses, arginine supplementation is controversial. Breakthroughs in understanding arginine metabolism have led to the identification of myeloid cells that express arginase 1, causing significant depletion of arginine – an essential amino acid for normal T lymphocyte function. Hence, myeloid cells expressing arginase 1 are also known as myeloid-derived suppressor cells. This chapter discusses the hypothesis that argininereplacement therapy may be necessary in arginine deficiency states.

Changes in Arginine Metabolism during Sepsis and Critical Illness in Children

Author(s): C. de Betue, N. Deutz

Arginine is an important amino acid during disease and healing because of functions in the immune system and as precursor of nitric oxide (NO). In critically ill adults and children, plasma arginine and citrulline concentrations are substantially decreased, indicating an argininedeficient state. Arginine availability is reduced because of increased arginine disposal in combination with reduced de novo arginine synthesis. The latter is most likely caused by reduced citrulline availability. As a result, NO synthesis may be impaired, which might compromise microcirculation. These metabolic changes seem to be dependent on the severity of inflammation. Arginine or citrulline supplementation in severe inflammation might thereforebe beneficial. Possibly, the use of protein-energy-enriched formulas may be a first step to improve arginine availability and NO synthesis. In critically ill children, arginine metabolism and supplementation is however a virtually unexplored field. Since pediatric sepsis is a significant health problem, which differs in epidemiology and pathophysiology from sepsis in adults, and because of the scarcity of data in this population, studies focused on pathophysiological mechanisms and possible interventions in arginine metabolism in pediatric critical illness are warranted.

Glutamine Supplementation in Neonates Is There a Future

Author(s): J. Neu

Over the past couple of decades, glutamine (GLN) has emerged as important metabolic intermediate, signaling molecule and nutrient that becomes rapidly depleted and therefore critically important during stress. In very low-birthweight (VLBW) infants, a population of patients in whom supplementation of GLN should provide major benefits, GLN is provided in subnutritional quantities because standard parenteral nutrition solutions do not contain GLN and most of these babies do not receive full enteral feedings until several weeks after birth. No evidence of toxicity of GLN supplementation was found in these clinical trials, but the results for efficacy on a limited number of outcomes have been mixed. The use of GLN supplementation in VLBW infants has therefore not become routine. Some authors suggest that further study in this area is no longer warranted. The purpose of this review is to provide an update in the area of GLN supplementation for preterm infants in order to determine whether GLN supplementation is unwarranted and/or additional investigations are needed. Evidence is presented and an argument is made that thoughtful reevaluation of future applications and trials of GLN in premature infants is warranted.

Insulin in Human Milk and the Use of Hormones in Infant Formulas

Author(s): R. Shamir, N. Shehadeh

Human milk contains a substantial number of hormones and growth factors. Studies in animal models show that some of these peptides (e.g. insulin, insulin-like growth factor 1, IGF-1, epidermal growth factors) have an effect on the small intestine after orogastric administration. Recently, two efforts were made to incorporate growth factors into infant formulas. One of these efforts included the incorporation of IGF-1, and the second is an ongoing effort to evaluate the safety and efficacy of incorporating insulin into infant formulas. The rational and current evidence for adding insulin to infant formulas (presence in human milk, effects of orally administrated insulin on gut maturation, intestinal permeability, systemic effects and preliminary encouraging results of supplementing insulin to a preterm infant formula) is detailed in this review. If the addition of insulin to preterm infant formulas indeed results in better growth and accelerated intestinal maturation, future studies will need to address the supplementation of insulin in term infants and assessthe efficacy of such supplementation in enhancing gut maturation and prevention of later noncommunicable diseases such as allergy, autoimmune diseases and obesity.

The MetaHIT Project The Discovery of Enterotypes What We Know and What Is Still Unanswered

Author(s): S. Ehrlich

Diet Gut Enterotypes and Health Is There a Link

Author(s): F. Bushman, J. Lewis, G. Wu

The human gut contains a vast number of microorganisms known collectively as the ‘gut microbiota’. Despite its importance in maintaining the health of the host, growing evidence suggests the gut microbiota may also be an important factor in the pathogenesis of various diseases, a number of which have shown a rapid increase in incidence over the past few decades. Factors including age, genetics, and diet may influence microbiota composition.We used diet inventories and 16S rDNA sequencing to characterize fecal samples from 98 individuals. Fecal communities clustered into previously described enterotypes were distinguished primarily by levels of Bacteroides and Prevotella . Enterotypes were associated with long-term diets, particularly protein and animal fat (Bacteroides) versus simple carbohydrates (Prevotella) . Although the distinction of enterotypes as either discrete clusters or a continuum will require additional investigation, numerous studies have demonstrated the coexclusion of the closely related Prevotella and Bacteroides genera in the gut microbiota in healthy human subjects, where Prevotella appears to be a discriminatory taxon for residence in more agrarian societies. Ultimately, the impact of diet on the human gut microbiota may be an important environmental factor involved in the pathogenesis of disease states that show a rapidly increasing incidence in industrialized nations.

Understanding Immunomodulatory Effects of Probiotics

Author(s): B. Pot, B. Foligne, C. Daniel, C. Grangette

The intestinal microbiota is known to be a driving force in the development and maintenanceof the immune system. While substantial shifts in the microbiota compositionmay influence immune functionality in a longer term, short occasional changes mightalso be sensed. The latter opens considerable perspectives for the use of nutritional interventions,intended to modulate immune functionality in a desired direction. Probioticsare discussed here as a possible way to achieve this goal. It seems that effects are notonly strain specific, but will depend on many environmental factors that make the immunesystem receptive or not to the influences of a given probiotic strain. The interactionsbetween probiotics on the one hand and enterocytes or immune cells on the otherhand, are a complex interplay that is rarely mediated by a single mechanism. Immunomodulationthrough nutrition is therefore a complex phenomenon that needs carefulconsideration, understanding of immune functionality as well as insight into the mechanismsof probiotic activities. Only then can the proper clinical trials with proper readoutsbe set up to prove efficacy of each strain/mixture individually.

Transforming Growth Factor and Intestinal Inflammation The Role of Nutrition

Author(s): F. Ruemmele, H. Garnier-Lengline

The intestinal mucosa possesses a complex epithelial barrier and a well-organized local immune system, which both efficiently protect this internal-external surface against potential microbial aggressions while guaranteeing tolerance towards harmless bacteria or antigens (oral tolerance). There is good experimental evidence that the intestinal microbiota is a main driver for the development of the mucosal immune system. Any perturbations/ changes of this interaction with the intestinal microbiota or the microbial colonization process may cause health problems with short- and eventually long-termconsequences, such as suspected for allergic or dysimmune disorders. Dendritic cells (DC) play a key role in the initiation of immune responses. Immune responses elicited by intestinal DC differ markedly from those initiated by spleen-derived DC: while intestinal DC induce anti-inflammatory and tolerogenic responses to harmless antigens such as derived from the resident microflora or harmless food allergens, systemic immune activation yields in a strong inflammatory TH1/TH17 reaction to the same antigens. The recent discovery how DC functions are regulated and imprinted by the microenvironment (DC conditioning) will be discussed in this review. High concentrations of retinoic acid or vitamin D metabolites, thymic stromal lymphopoietin and/or transforming growth factor-β(TGF-β) activate signaling programs in DC that yield in priming of regulatory and antiinflammatoryT cell responses. TGF-β is one of the key factors implicated in intestinal immune regulation; it is produced by a large variety of cells in the intestinal mucosa, including intestinal epithelial cells, lymphocytes and monocytes/macrophages/DC. An important anti-inflammatory effect of TGF-β on the immune system is the promotion and generation of FOXP3-positive regulatory T cells in the intestinal compartment.There are first and encouraging data from the treatment of Crohn’s disease, an inflammatory GI condition, that targeted enteral therapy with optimized concentrations of immunoregulatory peptides,such as TGF-β, might of interest for the treatment of inflammatory disorders.

Microbiota Modulation Can Probiotics Prevent Treat Disease in Pediatrics

Author(s): H. Szajewska

A number of metagenomic analyses providing knowledge of the human microbiome have yielded data on the differences between healthy and diseased individuals. Microbiota manipulation, such as through the administration of probiotics, may potentially contribute to improved health outcomes. The objective of this review was to summarize the most recent data on the use of probiotics to treat or prevent diseases in pediatrics. MEDLINE  and The Cochrane Database of Systematic Reviews were searched in September 2012 for randomized controlled trials or their meta-analyses published in the last 3 years. To provideexamples of current research interests, the focus of the search was on well-studied, common pediatric conditions as well as on some chronic diseases for which the benefits of gut microbiota manipulation are only in the early stages.

Membrane Composition and Cellular Responses to Fatty Acid Intakes and Factors Explaining the Variation in Response

Author(s): C. Agostoni, P. Rise, F. Marangoni

The lipid membrane bilayer undergoes continuous changes, and its lipid composition is both adaptive and highly varied, with substantial molecular variety. The balance of dietary fats, namely saturated versus unsaturated, and polyunsaturated fatty acids (PUFA) of the n-6 series versus those of the n-3 series, may change membrane composition thus affecting membrane order, intracellular signaling processes, and gene expression. As a consequence, changes in the production of both lipid and peptide mediators influencing the individual adaptive responses take place. More than that of all the other fatty acids, the n-3 PUFA composition of cell membranes depends on their dietary intake. n-3 PUFA levels in cell membranes are related to both inflammatory and immune diseases, possibly by downregulating the expression of genes involved in their synthesis and maybe the pathogenesis of processes associated with the disease itself. The interindividual variability of DNA sequences involved in the synthesis of long-chain PUFA may explain differences in responses to their dietary contribution in regulating the risk of disease. Lifestyle factors (such as smoking and alcohol consumption) may in turn negatively impact PUFA metabolism. Accordingly, different amounts of dietary PUFA may be necessary to meet the requirements for these nutrients in development and disease prevention on an individual basis.

Docosahexaenoic Acid and Its Derivative Neuroprotectin D1 Display Neuroprotective Properties in the Retina, Brain and Central Nervous System

Author(s): N. Bazan

The significance of the selective enrichment in omega-3 essential fatty acids (docosahexaenoyl – DHA – chains of membrane phospholipids, 22C and 6 double bonds) in the nervous system (e.g. synaptic membranes and dendrites) has remained, until recently, incompletely understood. While studying mechanisms of neuronal survival, we contributed to the discovery of a docosanoid synthesized by 15-lipoxygenase-1 from DHA, which we dubbed neuroprotectin D1 (NPD1; 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15E,19Z hexaenoic acid). NPD1 is a docosanoid because it is derived from a 22C precursor (DHA), unlike eicosanoids, which are derived from the 20C arachidonic acid family of essentialfatty acids not enriched in the nervous system. We found that NPD1 is promptly made in response to oxidative stress, seizures and brain ischemia-reperfusion. NPD1 is neuroprotective in experimental brain damage, retinal pigment epithelial cells, and in human brain cells. Thus, NPD1 acts as a protective sentinel, one of the very first defenses activated when cell homeostasis is threatened by neurodegenerations. NPD1 also has been shown to have a specificity and potency that provides beneficial bioactivity during initiation and early progression of neuronal and retinal degenerations, epilepsy and stroke. In short, NPD1 regulation promotes homeostatic regulation of neural circuitry integrity.

Branched-Chain Fatty Acids in the Neonatal Gut and Estimated Dietary Intake in Infancy and Adulthood

Author(s): R. Ran-Ressler, R. Glahn, S. Bae, J. Brenna

Branched-chain fatty acids (BCFA) are primarily saturated fatty acids (FA) with a methyl branch, usually near the terminal methyl group. BCFA are abundant in bacteria, skin, and vernix caseosa but have seldom been studied with respect to human nutrition. They are constituents of the term newborn infant gut lumen, being swallowed as vernix particulate components of amniotic fluid in the last trimester of normal pregnancy. We recently showed that BCFA protect against necrotizing enterocolitis (NEC) in the rat pup model.Dietary BCFA at levels similar to those found in human vernix reduced NEC incidence by more than 50%, increased the abundance of BCFA-containing bacteria, and increased the expression of ileal anti-inflammatory IL-10. The few published reports of BCFA in human milk enable an estimate that breastfed infants consume 19 mg BCFA per 100 ml milk. Dietary BCFA consumption from milk fat and other ruminant products, the main sources of dietary BCFA, is more than 400 mg BCFA per day in adult Americans. This estimate exceeds by severalfold the average dietary intake of bioactive FA, such as docosahexaenoic acid. BCFA are bioactive, abundant but neglected components of the human food supply.

Clinical Overview of Effects of Dietary Long-Chain Polyunsaturated Fatty Acids during the Perinatal Period

Author(s): S. Carlson

The current report provides a brief background introducing 30 years of research on longchain polyunsaturated fatty acids (LC-PUFA) and infant development, but focuses mainly on challenges for future studies. Infants fed formulas containing only vegetable fats were found to have lower docosahexaenoic acid (DHA, 22: 6n-3) and arachidonic acid (20: 4n-6) status than infants fed human milk. Studies soon focused on efforts to improve LC-PUFA status and evaluate functions suggested by early primate studies of DHA deficiency. Despite evidence for the importance of these fatty acids for development, particularly DHA, several recent meta-analyses conclude dietary supplementation does not enhance development.Future studies should employ (1) more finely grained measures of brain development as opposed to global measures, and (2) tests that evaluate development later in childhood when children are able to be tested on more complex behaviors (if found effective these would also be evidence of early brain programming). (3) Studies are needed to understand the cause of high variability in transfer of DHA to the fetus. (4) Finally, the role of single-nucleotide polymorphisms of the fatty acid desaturase genes 1 and 2 of mother and infant needs study to determine how they affect requirements for these fatty acids by the fetus/infant.

Dietary n-3 LC-PUFA during the Perinatal Period as a Strategy to Minimize Childhood Allergic Disease

Author(s): M. Makrides

There has been growing interest in the role of n-3 long-chain polyunsaturated fatty acids (LC-PUFA) in the modulation of the immune response during early childhood and whether this may translate to a reduction in childhood allergic disease. Several randomized controlled trials of n-3 LC-PUFA supplementation have been reported, largely involving children who are at high hereditary risk of developing allergies. These studies relatively consistently indicate that supplementation during pregnancy results in fewer children with atopic eczema in early childhood. On the other hand, supplementation studies confined exclusively to the postnatal period have demonstrated mixed results with one trial showing no effect and the other suggesting a transient effect on symptoms of respiratory disease. In summary, supplementation with n-3 LC-PUFA during the perinatal period and before allergic response is established may be a useful strategy to prevent early childhood allergic disease in children at high hereditary risk. Further work is needed to establish the optimal period of supplementation and whether longer term benefits exist.