Scientific Summary. Sn-2 palmitate Oil benefits

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1 Scientific Summary Sn-2 palmitate Oil benefits for Infant Health

3 Contents Executive Summary 01 Introduction 04 INFAT Improves Infant s Comfort 09 Summary 10 References 11

4 Executive Summary 01 Human breast milk provides the optimal nutrition for infants. Designed to provide perfectly balanced nutrition, human breast milk naturally meets the needs of growing infants in the first months of life. In human milk, and in most infant formulas, about 50% of energy is supplied to newborns as fat. More than 98% of this fat is in the form of triglycerides, which contain saturated and unsaturated fatty acids esterified to a glycerol backbone glycerol back bone in certain location called sn-1, sn-2 and sn-3. The special triglycerides structure in human milk, with its specific fatty acids positioning, is one of the keys to its perfection. Palmitic acid (C16:0) is the predominant saturated fatty acid, comprising 17-25% of the fatty acids in human milk. This fatty acid has a preferential positioning in human milk for the sn-2 position (about 70-75%). This is highly conserved across populations, regardless of the mother s nutritional diet and is called sn-2 palmitate. As part of the efforts of developing infant formulas that are close to human milk, sn-2 palmitate from vegetable sources was developed. INFAT is Advanced Lipids sn-2 palmitate fat ingredient, a clinically proven component used in infant formula that mimics the composition, structure and benefits of human milk fat. P O O P P Vegetable oil O Sn-2 Palmitate P Palmitic Acid O Oleic Acid Patented Enzymatic Process

5 02 Newly published clinical and pre-clinical studies of INFAT point to several sn-2 palmitate benefits on infant health and well-being: life. This study strengthen earlier findings on the effect of SN-2 palmitate on bone development published by Kennedy et al Fat absorption: A clinical study on healthy term newborns demonstrated that INFAT affects the fatty acids absorption even on top of prebiotics. INFAT was shown to enhance fatty acids absorption compared to a standard formula 1 and was closer to breastfeeding. Increased Bone Strength: A clinical study on term newborns demonstrated that the bone strength (expressed as speed of sound) was significantly higher in newborns fed for 12 weeks with infant formula containing INFAT, compared to control formula. The bone strength of newborns fed with INFAT formula was similar to that of breastfed newborns 2. Thus, INFAT may have a beneficial role in bone development during early Controlled Intestinal Health: A preclinical study revealed the potential protective role of IN- FAT in a spontaneous colitis mice model, showing that a low sn-2 palmitate diet increased intestinal damage while a high sn-2 palmitate diet limited the damage, though both diets contained the same palmitic acid content 4. This data suggests a crucial role for INFAT in limiting intestinal inflammation. Beneficial Gut Flora: A pilot clinical study on healthy term newborns demonstrated that INFAT may affect the intestinal microbiota composition during the first weeks of life by increasing the Lactobacillus and Bifidobacteria abundance 5. These findings suggest that the lipid structure may play a role in the gut microbiota colonization.

03 IMPROVED COMFORT Less Crying Softer Stools Fat & Calcium Absorption

IMMUNITY Softer Stools: A clinical study demonstrated that the percentage of

8% in the control group (standard vegetable oil) while only 14.

Statistical significance was shown only between the control and the breastfed

The data suggests INFAT may contribute to the comfort of formulafed infants.

the infant crying pattern during the first weeks of life even on top of

6 03 IMPROVED COMFORT Less Crying Softer Stools Fat & Calcium Absorption Healthy Gut Bacteria HEALTHY GROWTH Bone Strength Intestinal Health ENHANCED IMMUNITY Softer Stools: A clinical study demonstrated that the percentage of infants with hard stools were 23.8% in the control group (standard vegetable oil) while only 14.3% in the INFAT and 0% in the breastfed groups. Statistical significance was shown only between the control and the breastfed groups 6. The data suggests INFAT may contribute to the comfort of formulafed infants. Reduced Infant Crying: Two clinical studies demonstrated that INFAT affects the infant crying pattern during the first weeks of life even on top of prebiotics. Comparable to breastfeeding, INFAT was shown to reduce crying duration and frequency, mainly during afternoon and evening hours 6. Therefore, INFAT has a beneficial effect on the well-being of formula-fed infants as well as of their parents.

Introduction Human milk provides the optimal nutrition for infants. Designed to provide balanced nutrition, human milk naturally meets the needs of growing infants in the first months after birth.

7 Introduction Human milk provides the optimal nutrition for infants. Designed to provide balanced nutrition, human milk naturally meets the needs of growing infants in the first months after birth. In human milk, and in most infant formulas, approximately 50% of the energy is supplied to newborns as fat, of which more than 98% is in the form of triglycerides 7 ; three fat components called fatty acids, attached together. Triglyceride synthesis occurs in the mammary gland, where the fatty acids are specifically positioned to sn1, sn2 or sn3 positions on the glycerol backbone to yield the structurespecific triglycerides that are found in human milk. Palmitic acid (C16:0) is the predominant saturated fatty acid, comprising 17-25% of the fatty acids in mature human milk, with approximately 70-75% of it esterified to the sn2 position of the triglyceride (sn2 palmitate) 8,9, pointing at the preferential positioning of palmitic acid (16:0) at the sn-2 position. This position differs from other human tissue and plasma lipids, and vegetable oils common in human diets and in the fat blends used in the manufacture of infant formula 10. The significance of this fatty acid and its position is evident from the fact that this positioning is conserved in all women, regardless of their ethnic origin or nutrition, unlike other fatty acids in human milk. The triglycerides with the structure OPO (18:1n-9 16:0 18:1n-9) are the major triglyceride species in human milk and represent an estimated ~12% of total triglyceride species 8. Palmitic acid (16:0) is the major saturated fatty acid mainly esterified at sn-2 position (middle) and Oleic acid (18:1n-9) is the major unsaturated fatty acid mostly esterified at the triglyceride sn-1,3 positions (outer). The development of structured triglycerides enables mimicking both the composition as well as the structure of human milk fat in infant formulas. Structured TG are achieved through an enzymatic process. The resulting product contains 17-25% palmitic acid with above 40% of it located at the sn-2 position. Clinical and pre-clinical studies have provided increasing evidence that this specific positioning of palmitic acid on the triglycerides in human milk has a significant holistic effect on optimal infant development and well-being that is related to the increased absorption of both palmitic acid and calcium, softer stools, increased bone strength, increased beneficial gut flora, controlled intestinal health, and reduced infant crying. All of these contribute to the benefits of infant wellbeing.

8 05 INFAT Enhances Nutrient Absorption Infants require a bio-available source of energy and nutrients to meet the requirements of their rapid growth, development and expanding skeletal mass. Human milk provides the well balanced nutrition satisfying the infants need. For formula-fed infants, the availability of nutrients and energy depends on the composition of the formula. The nutritional environment of infants involves a high fat diet with frequent feedings; therefore, efficient fat absorption is required. In breastfed infants, this is achieved using complex fat globule lipids and TG structures that enable the efficient absorption without requiring a high metabolic effort from the infant. and the fatty acids and calcium absorption. Figure 1 shows the correlation between the level of palmitic acid in the milk or formula triglyceride sn-2 position and infant fatty acid and calcium absorption calculated as a modified Cohen s effect size (f2) 20 using data from published studies. C16 absorption Linear (C16 absorption) Calcium absorption Linear (Calcium absorption) Triglyceride digestion by endogenous lipases leads to hydrolysis of fatty acids from the triacylglyceride sn- 1,3 linkages, releasing two unesterified fatty acids and one sn-2 monoglyceride from each triglyceride 12. The absorption efficiency is influenced by the type of fatty acid and its position on the triglyceride molecule. Palmitic acid is absorbed efficiently from human milk as sn2 monoacylglycerol 13, and it is conserved through digestion and absorption 14. Palmitic acid at sn-2 position of total palmitic acid (%) Clinical studies in term 3, and preterm infants 18, 19 have demonstrated the correlation between the level of palmitic in the sn2 position Figure 1: Modified Cohen s effect size of the effect of palmitic acid position in formula triglycerides on the absorption of palmitic acid and calcium in term and preterm infants based on available publications.

06 The results show that progressively increasing ratio of palmitic acid at the sn-2 position of the formula triglyceride leads to a dose-dependent increase in palmitic acid and calcium absorption

9 06 The results show that progressively increasing ratio of palmitic acid at the sn-2 position of the formula triglyceride leads to a dose-dependent increase in palmitic acid and calcium absorption (r=0.95 and r=0.78 for palmitic acid and calcium, respectively). The reduction in fecal calcium and saponified palmitic acid (calcium soaps) is accompanied by a decrease in the incidence of hard stools 3, 17, 21, 22. INFAT was recently shown to enhance fat absorption and reduce calcium soaps formation in infant formulas containing prebiotics (GOS) 1. In a multicenter clinical study on Chinese term infants, consumption of infant formula with INFAT resulted in better nutrient absorption, specifically fat absorption. Comparable with breastfeeding, the formula with INFAT reduced fat excretion, primarily in form of saponified fat or insoluble calcium soaps (Figure 2) 1. Soaped palmitic acid excreted (gr) Control INFAT BF Figure 2: Stool fatty acids in 24 hr stool collection at 6 weeks postnatal. The significance was calculated for the two groups by the Mann Whitney test. Different letters indicate statistical significance (p<0.05) between groups.

10 07 INFAT Supports Healthy Bone Development The absorption of nutritional factors, such as minerals, fats, carbohydrates, and proteins, is significantly important for normal infant growth and development and may contribute to early bone mineral accretion 23. Kennedy et al., showed in a randomized, controlled, double-blind study higher body bone mass in infants after 12 weeks of feeding with sn2 palmitate formula 3 by using dual-energy X-ray absorptiometry (DEXA) to assess bone mineralization. Litmanovitz et al., showed in a randomized, controlled, doubleblind study, that bone speed of sound (SOS) of healthy term newborns fed for the first 12 weeks of life with sn2 palmitate infant formula was significantly higher than that of newborns fed with regular formula and comparable to that of breastfed newborns 2 (figure 3). INFAT Promotes Development of Beneficial Intestinal Flora The human gut is the natural habitat for a large and dynamic microorganisms community 24. The colonization begins immediately after birth and is influenced by the mode of delivery, the infant s diet, hygiene levels and medications 25. The intestinal microflora is an essential organ that is involved in numerous important functions for the human host, including protection against pathogens and provision of enhanced metabolic capabilities. INFAT was shown to increase numbers of Lactobacilli and Bifidobacteria in the stool of healthy term infants fed for 6 weeks postnatal compared to a control infant formula 5 (Figure 4). The infants in the INFAT group exhibited also a notable increase in the counts of beneficial bacteria at week six from birth compared to start of feeding. Bone speed of sound (m/sec) Lactobacilli counts (CFU/gr x1e+09) Study groups: Control INFAT BF Control INFAT BF Baseline 6 weeks Figure 3: Ultrasound Speed of Sound (SOS) of the tibia of term infants 3 months of age after 12 weeks of feeding. Figure 4: The effect of the type of feeding on the lactobacillus counts at baseline and 6 postnatal weeks.

08 INFAT Controls Intestinal Inflammation Damage An animal knock out model for intestinal inflammation (Muc2 deficient mice), which is a well-described model of enterocolitis, was used to address the

Muc2 deficient mice (Muc2 -/- ) lack mucin2, which is a major component of the mucus layer that provides a barrier for the intestinal epithelial cells from the intraluminal contents 26, and forms a

11 08 INFAT Controls Intestinal Inflammation Damage An animal knock out model for intestinal inflammation (Muc2 deficient mice), which is a well-described model of enterocolitis, was used to address the possible role of INFAT on intestinal inflammation. Muc2 deficient mice (Muc2 -/- ) lack mucin2, which is a major component of the mucus layer that provides a barrier for the intestinal epithelial cells from the intraluminal contents 26, and forms a physical barrier protecting the underlying epithelium against luminal substances and microbes The deficiency of mucins in the Muc2 -/- mice affects the protective capacities of the mucus layer 30, and as a consequence, bacteria are in direct contact with the intestinal epithelial cells 31. This leads to the development of spontaneous colitis in Muc2 -/- mice In this study mice fed diet with INFAT demonstrated a lower extent of intestinal inflammatory damage compared with mice fed the control diet 4 (Figure 5). Figure 5: Morphology of the distal colon of Muc2-/- mice fed AIN93G, control diet (low sn2 palmitate), or sn2 palmitate (INFAT). Distal colonic sections of mice fed with the different diets were stained with hematoxylin and eosin. Shown are representative sections for each diet group.

12 INFAT improves infant s comfort 09 One of the major concerns of parents is their baby s comfort and wellbeing. Various parameters may indicate comfort to the newborn infants. Those parameters include stool characteristics, such as consistency, frequency and volume, as well as crying duration and frequency during the day. The reduction in calcium and fatty acid absorption is accompanied by increased calcium soaps and, consequently, hard stools 21. Infants receiving the high sn2 formula had softer stools and fewer hard stools compared to the control regular vegetable oil formula group 3, 6, 35. A double blind clinical study revealed that feeding term infants an infant formula with INFAT for 12 weeks from birth reduced the number of infants with hard stools (Figure 6), the number of crying infants, and their crying duration during the day and night, and especially in the afternoon and evening hours compared to a control formula (Figure 7). Lately, this was shown also on top of prebiotics (data not shown). Infants with hard stools (%) Total Daily Crying Duration (min) Control INFAT BF Control INFAT BF Figure 6: The percent of infants with hard stools at age of 12 weeks. Hard stools were evaluated by using parents questionnaires based on 3 consecutive days. Figure 7: Total daily crying duration at 12 weeks postnatal. Crying was evaluated by calculating the mean crying duration per day based on parents reports of crying periods of more than 5 minutes.

Summary Human breast milk is the optimal nutrition for infants, by providing a perfectly balanced nutrition meeting the naturally needs of growing infants in the first months of life.

13 Summary Human breast milk is the optimal nutrition for infants, by providing a perfectly balanced nutrition meeting the naturally needs of growing infants in the first months of life. In human milk, and in most infant formulas, about 50% of energy is supplied to newborns as fat. More than 98% of this fat is in the form of triglycerides, which contain saturated and unsaturated fatty acids esterified to a glycerol backbone. The special triglycerides structure in human milk, with its specific fatty acids positioning, is one of the keys to its perfection. Palmitic acid (C16:0) is the predominant saturated fatty acid, comprising 17-25% of the fatty acids in human milk. Surprisingly, 70-75% of the palmitic fatty acids are esterified to the sn-2 position of the triglyceride (sn-2 palmitate). This preferential positioning is highly conserved across populations, regardless of the mother s nutritional diet. INFAT is Advanced Lipids sn-2 palmitate fat ingredient, a clinically proven component used in infant formula that mimics the composition, structure and benefits of human milk fat. Studies over the last two to three decades have provided increasing evidence that this specific positioning of palmitic acid on triglycerides in human milk has a significant holistic effect on optimal infant development and well-being. It was shown to contribute to the increased absorption of both palmitic acid and calcium, softer stools, increased bone strength, increased beneficial gut flora, controlled intestinal health, and reduced infant crying.

14 11 References 1. Bar-Yoseph, F., et al., SN2 Palmitate Reduces Fatty Acid Excretion in Chinese Formula-fed Infants: A Double-Blind Randomized Clinical Trial. J Pediatr Gastroenterol Nutr, Litmanovitz, I., et al., High Beta-palmitate formula and bone strength in term infants: a randomized, doubleblind, controlled trial. Calcif Tissue Int, (1): p Kennedy, K., et al., Double-blind, randomized trial of a synthetic triacylglycerol in formula-fed term infants: effects on stool biochemistry, stool characteristics, and bone mineralization. Am J Clin Nutr, (5): p Lu, P., et al., High beta-palmitate fat controls the intestinal inflammatory response and limits intestinal damage in mucin Muc2 deficient mice. PLoS One, (6): p. e Yaron, S., et al., Effect of high beta-palmitate content in infant formula on the intestinal microbiota of term infants. J Pediatr Gastroenterol Nutr, (4): p Litmanovitz, I., et al., Reduced crying in term infants fed high beta-palmitate formula: a double-blind randomized clinical trial. BMC Pediatr, (1): p Giovannini, M., E. Riva, and C. Agostoni, Fatty acids in pediatric nutrition. Pediatr Clin North Am, (4): p Breckenridge, W.C., L. Marai, and A. Kuksis, Triglyceride structure of human milk fat. Can J Biochem, (8): p Jensen, R.G., Lipids in human milk. LIPIDS, (12): p Jensen, R.G., Comments on the extraction of fat from human milk for analysis of contaminants. Chemosphere, (9): p ; author reply Jensen, R.G., M.M. Hagerty, and K.E. McMahon, Lipids of human milk and infant formulas: a review. Am J Clin Nutr, (6): p Mu, H. and C.E. Hoy, The digestion of dietary triacylglycerols. Prog Lipid Res, (2): p Innis, S.M., R. Dyer, and C.M. Nelson, Evidence that palmitic acid is absorbed as sn-2 monoacylglycerol from human milk by breast-fed infants. Lipids, (8): p Nelson, C.M. and S.M. Innis, Plasma lipoprotein fatty acids are altered by the positional distribution of fatty acids in infant formula triacylglycerols and human milk. Am J Clin Nutr, (1): p Carnielli, V.P., et al., Structural position and amount of palmitic acid in infant formulas: effects on fat, fatty acid, and mineral balance. J Pediatr Gastroenterol Nutr, (5): p Lopez-Lopez, A., et al., The influence of dietary palmitic acid triacylglyceride position on the fatty acid, calcium and magnesium contents of at term newborn faeces. Early Hum Dev, Suppl: p. S Yao, M., et al., Effects of Term Infant Formulas Containing High sn-2 Palmitate with and Without Oligofructose on Stool Composition, Stool Characteristics, and Bifidogenicity: A Randomized, Double-Blind, Controlled Trial. J Pediatr Gastroenterol Nutr, 2014.

15 Carnielli, V.P., et al., Feeding premature newborn infants palmitic acid in amounts and stereoisomeric position similar to that of human milk: effects on fat and mineral balance. Am J Clin Nutr, (5): p Lucas, A., et al., Randomised controlled trial of a synthetic triglyceride milk formula for preterm infants. Arch Dis Child Fetal Neonatal Ed, (3): p. F Cohen, J., Statistical power analysis for the behavioral sciences.. second ed. 1988: Hillsdale, NJ: Lawrence Earlbaum Associates.Chappell JE, Clandinin MT, Kearney-Volpe C, Reichman B, Swyer PW. 21. Quinlan, P.T., et al., The relationship between stool hardness and stool composition in breast- and formulafed infants. J Pediatr Gastroenterol Nutr, (1): p Sidnell, A. and E. Greenstreet, Infant nutrition review of lipid innovation in infant formula. Nutrition Bulletin. 36(3): p Specker, B., Nutrition influences bone development from infancy through toddler years. J Nutr, (3): p. 691S-695S. 24. Guarner, F. and J.R. Malagelada, Gut flora in health and disease. Lancet, (9356): p Niers, L., et al., Nutritional support for the infant s immune system. Nutr Rev, (8 Pt 1): p Velcich, A., et al., Organization and regulatory aspects of the human intestinal mucin gene (MUC2) locus. J Biol Chem, (12): p Hecht, G., Innate mechanisms of epithelial host defense: spotlight on intestine. Am J Physiol, (3 Pt 1): p. C Dharmani, P., et al., Role of intestinal mucins in innate host defense mechanisms against pathogens. J Innate Immun, (2): p Hollingsworth, M.A. and B.J. Swanson, Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer, (1): p Johansson, M.E., et al., Composition and functional role of the mucus layers in the intestine. Cell Mol Life Sci, (22): p Johansson, M.E., et al., The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci U S A, (39): p Velcich, A., et al., Colorectal cancer in mice genetically deficient in the mucin Muc2. Science, (5560): p Van der Sluis, M., et al., Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology, (1): p Lu, P., et al., Colonic gene expression patterns of mucin muc2 knockout mice reveal various phases in colitis development. Inflamm Bowel Dis, Yao, M., et al., Effects of Term Infant Formulas Containing High sn-2 Palmitate With and Without Oligofructose on Stool Composition, Stool Characteristics, and Bifidogenicity. J Pediatr Gastroenterol Nutr, (4): p

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