{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:11:24Z","timestamp":1789999884818,"version":"4.0.1"},"reference-count":39,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T00:00:00Z","timestamp":1678147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wyeth Nutrition, China","award":["18.04.INF"],"award-info":[{"award-number":["18.04.INF"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Emerging clinical evidence indicates the potential gastrointestinal (GI) benefits of milk containing only A2 \u03b2-casein, but data from randomized controlled trials is sparse among pediatric populations. We aimed to evaluate the effectiveness of growing-up milk (GUM) containing only A2 \u03b2-casein on GI tolerance in toddlers. Methods: A total of 387 toddlers aged 12\u201336 months were recruited in Beijing, China, and randomized in a 1:1:1 ratio to consume one of two commercially available A2 GUMs (combined in the analysis as A2 GUM) or continue their current feeding regimen of conventional milk for 14 days. The primary outcome was the total Gut Comfort Score (GCS) (range: 10\u201360; higher values indicate greater GI distress) derived from a 10-item (score range: 1\u20136 per item) parent-reported questionnaire, reflecting GI tolerance. Results: The GCS (mean \u00b1 SD) was comparable between the A2 GUM and conventional milk groups on day 7 (14.7 \u00b1 5.0 vs. 15.0 \u00b1 6.1, p = 0.54) and day 14 (14.0 \u00b1 4.5 vs. 14.3 \u00b1 5.5, p = 0.51). Parents reported less constipation in those consuming A2 GUM vs. conventional milk on day 14 (1.3 \u00b1 0.6 vs. 1.4 \u00b1 0.9, p = 0.020). Among 124 participants with minor GI distress at baseline (GCS \u2265 17, top tertile range 17\u201335), GCS was significantly lower in those consuming A2 GUM on day 7 (18.2 \u00b1 5.1 vs. 21.2 \u00b1 6.8, p = 0.004) and day 14 (17.1 \u00b1 5.3 vs. 19.6 \u00b1 6.3, p = 0.026), as were individual GI symptoms (all p &lt; 0.05). In the toddlers without GI issues at baseline (GCS &lt; 17), a low GCS was maintained throughout the study period after switching to A2 GUM (mean values range 10\u201313). Conclusions: Growing-up milk containing only A2 \u03b2-casein were well-tolerated and associated with lower parent-reported constipation scores after two weeks when compared to conventional milks. In healthy toddlers with minor GI distress, A2 GUM improved overall digestive comfort and GI-related symptoms within one week.<\/jats:p>","DOI":"10.3390\/nu15061313","type":"journal-article","created":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T01:58:22Z","timestamp":1678240702000},"page":"1313","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Effectiveness of Growing-Up Milk Containing Only A2 \u03b2-Casein on Digestive Comfort in Toddlers: A Randomized Controlled Trial in China"],"prefix":"10.3390","volume":"15","author":[{"given":"Ying","family":"Meng","sequence":"first","affiliation":[{"name":"National Health Commission Key Laboratory of Reproductive Health\/Institute of Reproductive and Child Health, Peking University Health Science Center, 38 Xueyuan Rd., Beijing 100191, China"},{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, 38 Xueyuan Rd., Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubo","family":"Zhou","sequence":"additional","affiliation":[{"name":"National Health Commission Key Laboratory of Reproductive Health\/Institute of Reproductive and Child Health, Peking University Health Science Center, 38 Xueyuan Rd., Beijing 100191, China"},{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, 38 Xueyuan Rd., Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongtian","family":"Li","sequence":"additional","affiliation":[{"name":"National Health Commission Key Laboratory of Reproductive Health\/Institute of Reproductive and Child Health, Peking University Health Science Center, 38 Xueyuan Rd., Beijing 100191, China"},{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, 38 Xueyuan Rd., Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yipu","family":"Chen","sequence":"additional","affiliation":[{"name":"Nestl\u00e9 Product Technology Center\u2014Nutrition, 1800 Vevey, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grathwohl","family":"Dominik","sequence":"additional","affiliation":[{"name":"Nestl\u00e9 Clinical Research Unit, 1000 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Dong","sequence":"additional","affiliation":[{"name":"Wyeth Nutrition, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youchi","family":"Tang","sequence":"additional","affiliation":[{"name":"Information Management Section, Chaoyang District Maternal and Child Health Hospital, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose M.","family":"Saavedra","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Nutrition, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianmeng","family":"Liu","sequence":"additional","affiliation":[{"name":"National Health Commission Key Laboratory of Reproductive Health\/Institute of Reproductive and Child Health, Peking University Health Science Center, 38 Xueyuan Rd., Beijing 100191, China"},{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, 38 Xueyuan Rd., Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/j.jpeds.2014.11.039","article-title":"Prevalence of functional gastrointestinal disorders in infants and toddlers","volume":"166","author":"Hyman","year":"2015","journal-title":"J. Pediatr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6547","DOI":"10.3748\/wjg.v22.i28.6547","article-title":"Epidemiology of functional gastrointestinal disorders in infants and toddlers: A systematic review","volume":"22","author":"Matijasevich","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1097\/MPG.0000000000000949","article-title":"Prevalence and Health Outcomes of Functional Gastrointestinal Symptoms in Infants From Birth to 12 Months of Age","volume":"61","author":"Vandenplas","year":"2015","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_4","first-page":"611","article-title":"Survey on common gastrointestinal problems among infants aged 1~12 months in fifteen cities in China","volume":"26","author":"Shuo","year":"2018","journal-title":"Chin. J. Child Health Care"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1053\/j.gastro.2016.02.016","article-title":"Childhood Functional Gastrointestinal Disorders: Neonate\/Toddler","volume":"150","author":"Benninga","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"248","DOI":"10.3748\/wjg.14.248","article-title":"Prevalence and dietetic management of mild gastrointestinal disorders in milk-fed infants","volume":"14","year":"2008","journal-title":"World J. Gastroenterol."},{"key":"ref_7","first-page":"917","article-title":"Epidemiology of mild gastrointestinal disorders among infants and young children in Shanghai area","volume":"47","author":"Liu","year":"2009","journal-title":"Zhonghua Er Ke Za Zhi"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1093\/jn\/121.3.277","article-title":"The importance of alpha-lactalbumin in infant nutrition","volume":"121","author":"Heine","year":"1991","journal-title":"J. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Fernandez-Rico, S., Mondragon, A.D.C., Lopez-Santamarina, A., Cardelle-Cobas, A., Regal, P., Lamas, A., Ibarra, I.S., Cepeda, A., and Miranda, J.M. (2022). A2 Milk: New Perspectives for Food Technology and Human Health. Foods, 11.","DOI":"10.3390\/foods11162387"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1038\/pr.2015.10","article-title":"Bioactive peptides released from in vitro digestion of human milk with or without pasteurization","volume":"77","author":"Wada","year":"2015","journal-title":"Pediatr. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"739","DOI":"10.3945\/an.116.013953","article-title":"Systematic Review of the Gastrointestinal Effects of A1 Compared with A2 beta-Casein","volume":"8","author":"Dwyer","year":"2017","journal-title":"Adv. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1093\/nutrit\/nuy063","article-title":"Milk A1 beta-casein and health-related outcomes in humans: A systematic review","volume":"77","author":"Lohner","year":"2019","journal-title":"Nutr. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ramakrishnan, M., Eaton, T.K., Sermet, O.M., and Savaiano, D.A. (2020). Milk Containing A2 beta-Casein ONLY, as a Single Meal, Causes Fewer Symptoms of Lactose Intolerance than Milk Containing A1 and A2 beta-Caseins in Subjects with Lactose Maldigestion and Intolerance: A Randomized, Double-Blind, Crossover Trial. Nutrients, 12.","DOI":"10.3390\/nu12123855"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s12937-016-0164-y","article-title":"Effects of milk containing only A2 beta casein versus milk containing both A1 and A2 beta casein proteins on gastrointestinal physiology, symptoms of discomfort, and cognitive behavior of people with self-reported intolerance to traditional cows\u2019 milk","volume":"15","author":"Jianqin","year":"2016","journal-title":"Nutr. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s12937-017-0275-0","article-title":"Effects of cow\u2019s milk beta-casein variants on symptoms of milk intolerance in Chinese adults: A multicentre, randomised controlled study","volume":"16","author":"He","year":"2017","journal-title":"Nutr. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1093\/ajcn\/nqz279","article-title":"Comparison of the impact of bovine milk beta-casein variants on digestive comfort in females self-reporting dairy intolerance: A randomized controlled trial","volume":"111","author":"Milan","year":"2020","journal-title":"Am. J. Clin Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"253","DOI":"10.3390\/nu5010253","article-title":"Does milk cause constipation? A crossover dietary trial","volume":"5","author":"Crowley","year":"2013","journal-title":"Nutrients"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1097\/MPG.0000000000002437","article-title":"Effects of Conventional Milk Versus Milk Containing Only A2 beta-Casein on Digestion in Chinese Children: A Randomized Study","volume":"69","author":"Sheng","year":"2019","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1097\/00005176-198807000-00015","article-title":"The bowel habit of milk-fed infants","volume":"7","author":"Weaver","year":"1988","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.infbeh.2006.01.004","article-title":"Measurement of fine-grained aspects of toddler temperament: The early childhood behavior questionnaire","volume":"29","author":"Putnam","year":"2006","journal-title":"Infant Behav. Dev."},{"key":"ref_21","unstructured":"WHO (2008). The WHO Child Growth Standards, WHO."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2333794X17750271","DOI":"10.1177\/2333794X17750271","article-title":"Infant Feeding Regimens and Gastrointestinal Tolerance: A Multicenter, Prospective, Observational Cohort Study in China","volume":"5","author":"Mao","year":"2018","journal-title":"Glob. Pediatr. Health"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/1475-2891-13-105","article-title":"Stool fatty acid soaps, stool consistency and gastrointestinal tolerance in term infants fed infant formulas containing high sn-2 palmitate with or without oligofructose: A double-blind, randomized clinical trial","volume":"13","author":"Nowacki","year":"2014","journal-title":"Nutr. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1097\/MPG.0000000000000443","article-title":"Effects of term infant formulas containing high sn-2 palmitate with and without oligofructose on stool composition, stool characteristics, and bifidogenicity","volume":"59","author":"Yao","year":"2014","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_25","first-page":"431","article-title":"A community-based study of the prevalence of constipation in young children and the role of dietary fibre","volume":"11","author":"Ip","year":"2005","journal-title":"Hong Kong Med. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1097\/MPG.0b013e3181de0651","article-title":"Families\u2019 perspectives on the effect of constipation and fecal incontinence on quality of life","volume":"51","author":"Kaugars","year":"2010","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1111\/j.1440-1754.2007.01212.x","article-title":"Increased prevalence of constipation in pre-school children is attributable to under-consumption of plant foods: A community-based study","volume":"44","author":"Lee","year":"2008","journal-title":"J. Paediatr. Child Health"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Wang, C., Shang, L., Zhang, Y., Tian, J., Wang, B., Yang, X., Sun, L., Du, C., Jiang, X., and Xu, Y. (2013). Impact of functional constipation on health-related quality of life in preschool children and their families in Xi\u2019an, China. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0077273"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1097\/01.mpg.0000167500.34236.6a","article-title":"Chronic childhood constipation is associated with impaired quality of life: A case-controlled study","volume":"41","author":"Youssef","year":"2005","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1542\/peds.2005-1773","article-title":"The Avon Longitudinal Study of Parents and Children Study Team Psychological differences between children with and without soiling problems","volume":"117","author":"Joinson","year":"2006","journal-title":"Pediatrics"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Fu, X., Lovell, A.L., Braakhuis, A.J., Mithen, R.F., and Wall, C.R. (2021). Type of Milk Feeding and Introduction to Complementary Foods in Relation to Infant Sleep: A Systematic Review. Nutrients, 13.","DOI":"10.3390\/nu13114105"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1056\/NEJM199810153391602","article-title":"Intolerance of cow\u2019s milk and chronic constipation in children","volume":"339","author":"Iacono","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1038\/ejcn.2014.127","article-title":"Comparative effects of A1 versus A2 beta-casein on gastrointestinal measures: A blinded randomised cross-over pilot study","volume":"68","author":"Ho","year":"2014","journal-title":"Eur. J. Clin Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/s00787-018-1162-8","article-title":"Psychosocial risks for constipation and soiling in primary school children","volume":"28","author":"Joinson","year":"2019","journal-title":"Eur. Child Adolesc. Psychiatry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1053\/j.gastro.2005.11.057","article-title":"Psychosocial aspects of the functional gastrointestinal disorders","volume":"130","author":"Levy","year":"2006","journal-title":"Gastroenterology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.comppsych.2018.09.008","article-title":"Temperament and character in patients with acute abdominal pain","volume":"87","author":"Lexne","year":"2018","journal-title":"Compr. Psychiatry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s11136-009-9583-y","article-title":"Functional abdominal complaints in pre-school children: Parental reports of health-related quality of life","volume":"19","author":"Oostenbrink","year":"2010","journal-title":"Qual. Life Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"720","DOI":"10.3109\/09637486.2014.898260","article-title":"Dietary A1 beta-casein affects gastrointestinal transit time, dipeptidyl peptidase-4 activity, and inflammatory status relative to A2 beta-casein in Wistar rats","volume":"65","author":"Barnett","year":"2014","journal-title":"Int. J. Food Sci. Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"30289","DOI":"10.3402\/fnr.v60.30289","article-title":"Food groups consumed by infants and toddlers in urban areas of China","volume":"60","author":"Yu","year":"2016","journal-title":"Food Nutr. Res."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/6\/1313\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:49:55Z","timestamp":1760122195000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/6\/1313"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,7]]},"references-count":39,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["nu15061313"],"URL":"https:\/\/doi.org\/10.3390\/nu15061313","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,7]]}}}