Digestion of Human Milk Fat in Healthy Infants
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NUTRITION RESEARCH 83 (2020) 15– 29 Available online at www.sciencedirect.com ScienceDirect www.nrjournal.com Review Article Digestion of human milk fat in healthy infants Xuan He a, b, Shannon M cClorry a, Olle Hernell c, Bo Lönnerdal a, Carolyn M. Slupsky a, b,⁎ a Department of Nutrition, Davis, One Shields Ave, Davis, CA 95616, USA b Department of Food Science and Technology, University of California, Davis, One Shields Ave, Davis, CA 95616, USA c Department of Clinical Sciences, Pediatrics, Umeå University, SE 901 85 Umeå, Sweden ARTICLE INFO ABSTRACT Article history: Lipid digestion is critical for infant development, and yet, the interconnection between lipid Received 17 March 2020 digestion and the microbiota is largely understudied. This review focuses on digestion of the Revised 2 August 2020 human milk fat globule and summarizes the current understanding of the mechanisms Accepted 7 August 2020 underlying this process in infants. We first discuss the partial hydrolysis of milk fat in the stomach, which leads to rearrangement of lipid droplets, creating a lipid-water interface Keywords: necessary for duodenal lipolysis. In the first few months of life, secretion of pancreatic Infant triglyceride lipase, phospholipase A2, and bile salts is immature. The dominant lipases aiding fat Neonate digestion in the newborn small intestine are therefore pancreatic lipase-related protein 2 and Lipid digestion bile salt–stimulated lipase from both the exocrine pancreas and milk. We summarize the Milk fat globule interaction between ionic fatty acids and cations to form insoluble fatty acid soaps and how it is Gut microbiota influenced by various factors, including cation availability, pH, and bile salt concentration, as well as saturation and chain length of fatty acids.Wefurtherarguethattheformationofthe soap complex does not contribute to lipid bioavailability. Next, the possible roles that the gut microbiota plays in lipid digestion and absorption are discussed. Finally, we provide a perspective on how the manufacturing process of infant formula and dairy products may alter the physical properties and structure of lipid droplets, thereby altering the rate of lipolysis. © 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Article Outline 1. Introduction ..........................................................16 2. Partial hydrolysis of MFG in the stomach...........................................16 2.1. Release of MFG from the protein clot .........................................16 2.2. The action of lipase in an oil-in-water emulsion ...................................17 2.3. Factors influencing gastric lipid digestion ......................................19 3. Completion of milk fat digestion in the small intestine ...................................19 Abbreviations: Angptl4, angiopoietin-like protein 4; BSSL, bile salt–stimulated lipase; LCPUFA, long-chain polyunsaturated fatty acid; MFGs, milk fat globules; PLRP2, pancreatic lipase-related protein 2; PTL, pancreatic triglyceride lipase. ⁎ Corresponding author at: Department of Nutrition, University of California, Davis. Tel.: +1 530 752 6804. E-mail address: [email protected] (C.M. Slupsky). https://doi.org/10.1016/j.nutres.2020.08.002 0271-5317/© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). 16 NUTRITION RESEARCH 83 (2020) 15– 29 3.1. Low duodenal bile salts and limited pancreatic triglyceride lipase during early infancy ............. 19 3.2. Major enzymes for duodenal lipolysis ........................................ 20 3.3. Emulsification and digestion in small intestine ................................... 20 4. Formation of calcium–fatty acid soap complexes ...................................... 22 4.1. Factors influencing fatty acid soap formation .................................... 22 4.2. The impact of fatty acid–calcium soap on absorption................................ 22 5. Bidirectional interaction between gut microbiota and infant lipid digestion.......................... 22 6. Perspectives on infant formula and dairy products ..................................... 24 7. Conclusions and future directions .............................................. 24 Acknowledgment .......................................................... 24 References.............................................................. 24 1. Introduction and pH during the suckling period and (b) describe lipid digestion in detail, emphasizing a few critical enzymes. The Infants are not “small adults.” An infant's physiology un- progressive maturation of the infant digestive system also dergoes several dynamic changes due to the rapid alteration influences the gut microbiota and its actions. We discuss in cellular structure and functional maturation of organs. current views of how the gut microbiota influences lipid During infancy, the brain accounts for a large fraction of digestion and absorption and, finally, provide a perspective energy expenditure [1], much of which is used for brain cell on other dairy products. proliferation, neurogenesis, and myelination [2]. An ever- increasing body of evidence indicates that early life is a unique developmental window that is characterized by 2. Partial hydrolysis of MFG in the stomach considerable plasticity, which can be altered by environmen- tal stresses and diet. Nutrition during this critical period of 2.1. Release of MFG from the protein clot development is of utmost importance, as it may have profound and long-lasting effects on intelligence [3,4] and It has been shown in freshly expressed bovine milk that small the risk of developing chronic diseases [5,6] later in life. casein micelles (average diameter <50 nm) adhere to the MFG Human milk is the preferred form of feeding to support membrane with lipids, as well as other proteins and glyco- optimal growth and development of healthy infants. Milk can proteins, through relatively weak hydrophobic and electro- be characterized as an emulsion of milk fat globules (MFGs) in static interactions [16]. As milk reaches the stomach, the pH an aqueous liquid. The core of these MFGs is predominantly drops and the surface of casein becomes less charged, thereby in the form of triacylglycerols that provide approximately half enhancing hydrophobic interactions between the MFG and of the energy content of milk [7,8]. Beyond energy, milk fat casein [17]. As the ratio of protein to fat in milk increases, the supplies essential nutrients such as n-3 and n-6 long-chain diameter of the casein micelle adsorbed on the surface of the polyunsaturated fatty acids (LCPUFAs), phospholipids, and MFG membrane also increases [16]. cholesterol, which are important for the development of Fig. 1 highlights major differences between infant and brain and cognitive functions during the first year of life [9-11]. adult lipid digestion that will be discussed throughout the The amount of fat in human milk is highly variable, as it following sections. As casein micelles are proteolyzed in the fluctuates throughout the day and with nursing frequency, and stomach by gastric pepsin (the concentrations and efficiency is further influenced by several maternal factors, including of which are relatively low at birth, increasing over time body mass index, age, diet, parity number, and smoking status but still below the adult level [18]), MFGs become entrapped [12-14]. Typical human milk consists of 39% monounsaturated in a “protein clot,” with whey proteins remaining in the serum fatty acid, 35% saturated fatty acid, and 18% LCPUFA [15]. phase (Fig. 2). Over time, gastric pepsin activity gradually Palmitic acid (16:0), oleic acid (18:0 n-9), and linoleic acid (18:2 n-6) reduces the size of protein clot. It has been demonstrated in are the most dominant fatty acids in human milk and remain vitro using bovine milk that addition of protease stable over time [15]. The energetic demands of the developing reduces the particle radius of the κ-casein–coated MFG brain and digestive system, as well as the immaturity of exocrine complex by 10-20 nm at pH 5.5 and 6.0 [17]. MFG membrane pancreatic function during infancy, highlight the importance of components, such as polar lipids and proteins, are essential the complex physical and biochemical processes of milk fat to the physical stability of the MFG, and MFG structural digestion in infancy. stability is pH dependent. As the pH drops below 5.5, the MFG The study of milk fat digestion in infants has received membrane structure visualized becomes less stable and tends considerable attention over the years. Although by no means to favor aggregation and coalescence of lipid particles [19]. complete, there is a growing body of information on lipid Furthermore, protease hydrolyzes transmembrane proteins digestion in the stomach and small intestine during infancy. on the MFG membrane, which further alters the MFG In this review, we (a) summarize the current state of structure and enhances aggregation and coalescence of fat knowledge of the action of lipases in an oil-in-water emulsion globules within the protein matrix. Both in vitro [20-22] and in and their interaction with proteases, stabilizers, emulsifiers, vivo [23] studies of human and bovine MFG have shown NUTRITION RESEARCH 83 (2020) 15– 29 17 Fig. 1 – Summary of major differences in lipid digestion of infants relative