Milk, Mucosal Immunity and the Microbiome: Impact on the Neonate Nestlé Nutrition Institute Workshop Series Vol. 94 Milk, Mucosal Immunity and the Microbiome: Impact on the Neonate Editors Pearay L. Ogra Buffalo, NY W. Allan Walker Boston, MA Bo Lönnerdal Davis, CA © 2020 Nestlé Nutrition Institute, Switzerland CH 1814 La Tour-de-Peilz S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Library of Congress Cataloging-in-Publication Data Names: Nestlé Nutrition Workshop (94th : 2019 : Lausanne, Switzerland), author. | Ogra, Pearay L., editor. | Walker, W. Allan, editor. | Lönnerdal, Bo, 1938- editor. | Nestlé Nutrition Institute, issuing body. Title: Milk, mucosal immunity and the microbiome : impact on the neonate / editors, Pearay L. Ogra, W. Allan Walker, Bo Lönnerdal. Other titles: Nestlé Nutrition Institute workshop series ; v. 94. 1664-2147 Description: Basel ; Hartford : Karger ; Switzerland : Nestlé Nutrition Institute, [2020] | Series: Nestlé Nutrition Institute workshop series, 1664-2147 ; vol. 94 | Includes bibliographical references and index. | Summary: “This publication covers the 94th Nestle Nutritional Institute Workshop, which was designed to provide a comprehensive overview on the latest human milk research and its role in modulating mucosal immunity, the microbiome, and its impact on the neonate. This publication should provide scientific support to anyone seeking a deeper understanding of human milk and its immunological properties, and enlarge the knowledge of those who specialize in human milk research”-- Provided by publisher. Identifiers: LCCN 2020007208 (print) | LCCN 2020007209 (ebook) | ISBN 9783318066845 (hardcover ; alk. paper) | ISBN 9783318066852 (ebook) Subjects: MESH: Infant Nutritional Physiological Phenomena | Milk, Human | Breast Feeding | Immunity, Mucosal | Microbiota | Infant, Newborn | Congress Classification: LCC RJ216 (print) | LCC RJ216 (ebook) | NLM W1 NE228D v.94 2020 | DDC 613.2/69--dc23 LC record available at https://lccn.loc.gov/2020007208 LC ebook record available at https://lccn.loc.gov/2020007209 The material contained in this volume was submitted as previously unpublished material, except in the instances in which credit has been given to the source from which some of the illustrative material was derived. Great care has been taken to maintain the accuracy of the information contained in the volume. However, neither Nestlé Nutrition Institute nor S. Karger AG can be held responsible for errors or for any consequences arising from the use of the information contained herein. © 2020 Nestlé Nutrition Institute (Switzerland) and S. Karger AG, Basel (Switzerland). All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or recording, or otherwise, without the written permission of the publisher. Printed on acid-free and non-aging paper (ISO 9706) ISBN 978–3–318–06684–5 e-ISBN 978–3–318–06685–2 ISSN 1664–2147 e-ISSN 1664–2155 Basel · Freiburg · Hartford · Oxford · Bangkok · Dubai · Kuala Lumpur · Melbourne · Mexico City · Moscow · New Delhi · Paris · Shanghai · Tokyo Contents VII Preface X Foreword XII Contributors XV Dedication Immunology of Milk and Lactation 1 The Evolution of Lactation in Mammalian Species Oftedal, O.T. (USA) 11 Immunology of Human Milk and Lactation: Historical Overview Ogra, P.L. (USA) 27 The Mammary Gland as an Integral Component of the Common Mucosal Immune System Mestecky, J. (USA/Czech Republic) 38 Immunomodulatory Components of Human Colostrum and Milk Tlaskalová-Hogenová, H.; Kverka, M.; Hrdý, J. (Czech Republic) 48 Breastfeeding, a Personalized Medicine with Influence on Short- and Long-Term Immune Health Verhasselt, V. (Australia) 59 Summary on Immunology of Milk and Lactation Ogra, P.L. (USA) Microbiology of Milk and Lactation: Influence on Gut Colonization 65 Milk Microbiome and Neonatal Colonization: Overview Rautava, S. (Finland) 75 Human Milk Microbiota: Origin and Potential Uses Fernández, L.; Rodríguez, J.M. (Spain) 86 Beyond the Bacterial Microbiome: Virome of Human Milk and Effects on the Developing Infant Mohandas, S.; Pannaraj, P.S. (USA) V 94 Gut Microbiota, Host Gene Expression, and Cell Traffic via Milk Neu, J. (USA) 103 Breast Milk and Microbiota in the Premature Gut: A Method of Preventing Necrotizing Enterocolitis Walker, W.A.; Meng, D. (USA) 113 Summary on Microbiota of Milk and Lactation: Influence on Gut Colonization Walker, W.A. (USA) Protective Factors in Human Milk 115 Human Milk Oligosaccharides: Structure and Functions Bode, L. (USA) 124 Oligosaccharides and Viral Infection: Human Milk Oligosaccharides versus Algal Fucan-Type Polysaccharides Hanisch, F.-G. (Germany); Aydogan, C. (Switzerland) 133 Milk Fat Globule Membranes: Effects on Microbiome, Metabolome, and Infections in Infants and Children Hernell, O. (Sweden); Lönnerdal, B. (USA); Timby, N. (Sweden) 141 Clinical Trials of Lactoferrin in the Newborn: Effects on Infection and the Gut Microbiome Embleton, N.D.; Berrington, J.E. (UK) 152 Effects of Milk Osteopontin on Intestine, Neurodevelopment, and Immunity Jiang, R.; Lönnerdal, B. (USA) 158 Effects of Milk Secretory Immunoglobulin A on the Commensal Microbiota Dunne-Castagna, V.P.; Mills, D.A.; Lönnerdal, B. (USA) 169 Summary on Protective Factors in Human Milk Lönnerdal, B. (USA) 172 Subject Index For more information on related publications, please consult the NNI website: www.nestlenutrition-institute.org VI Contents Published online: April 8, 2020 Ogra PL, Walker WA, Lönnerdal B (eds): Milk, Mucosal Immunity and the Microbiome: Impact on the Neonate. Nestlé Nutr Inst Workshop Ser. Basel, Karger, 2020, vol 94, pp VII–IX (DOI:10.1159/000505372) Preface Lactation and the process of breastfeeding has been integral to the survival and long-term well-being of neonates and infants of most mammalian species. Mothers’ milk has been considered as a complete source of nutrition for the suck- ling infant from times immemorial, often with many magical healing powers. It is only in the past 2 centuries that significant scientific information has become available about the evolution of the mammary glands and the development of lactation and its impact on the suckling mammalian neonate. Since the observa- tions of Paul Ehrlich over 120 years ago, it is now clear that mammalian breast- feeding is associated with significant reduction in infant mortality, protection against enteric, respiratory, and other mucosal and systemic infections, and pro- tection against the development of allergic disorders. Recent observations have demonstrated that breastfeeding has a profound impact on the development and function of the neonatal immune system, mucosal microbiological homeostasis, and long-term protection against autoimmune and other inflammatory disease states and malignancy. The nutritional and immunobiological benefits attributed to breastfeeding are related to the diverse spectrum of specific cellular and soluble products present in the early colostrum and milk. It is now clear that the immu- nologic activity in the products of lactation represents the effector functional el- ements of the common mucosal immune system. The discovery of the secretory IgA (SIgA) immunoglobulin isotype in the milk, followed by the identification of antibacterial, antiviral, and antiparasitic activity in the milk associated with SIgA and demonstration of important elements of cellular immunity in the milk rep- resent crucial milestones in the understanding of lactation as the single most im- portant element of neonatal health in most mammalian species. The 94th Nestlé Nutrition Institute workshop is dedicated to Prof. Lars A. Hanson, who was the first investigator to identify SIgA in the colostrum and milk. He has been one of the most devoted scholars to the study of mam- malian lactation and breastfeeding, and has also been instrumental in a global effort to foster breastfeeding in the developing world and for undernourished infants. He is rightfully considered as the “father of modern breastfeeding.” This workshop was designed to develop a comprehensive perspective about available information on the evolution of lactation in most mammalian species, and to examine in some detail the origin, composition, and functional charac- teristics of different nutritional and immunologic components in mammalian milk and other lactation products. Specifically, the workshop focused on the following areas: (1) the evolution of mammalian lactation and breast feeding; (2) immunologic aspects of cellular and soluble products in milk; (3) the micro- bial composition of human milk and its effects on the development of the mu- cosal microbiome in the suckling infant, and (4) the role of oligosaccharides, antimicrobial peptides, and other important soluble compounds in the products of lactation, especially in the human milk. The evolution of mammary glands and lactation has been the subject of deep interest and considerable speculation since Darwin. More recently, it has been pos- sible to compare the evolutionary development of mammary glands across diverse taxa. The workshop began with a comprehensive discussion of the genetic origins and functions of different components of lactation across the evolutionary tree. The keynote addressed by Olav T. Oftedal introduced the prevailing concepts about the evolution of mammary glands and different constituents in the products of lac- tation. It was suggested