{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T20:37:05Z","timestamp":1790023025127,"version":"4.0.1"},"reference-count":57,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,6,27]],"date-time":"2021-06-27T00:00:00Z","timestamp":1624752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>People experiencing sleep problems may benefit from nutrients supporting serotonin metabolism and stress reduction. We studied the effect of a dairy-based product (DP) containing protein, galacto-oligosaccharides, vitamins and minerals, on sleep quality, stress, and gut-microbiota. In a cross-over RCT (three weeks intervention; three weeks washout), adults (n = 70; 30\u201350 y) with sleep disturbances (Pittsburgh Sleep Quality Index (PSQI) \u2265 9) consumed products 1 h before bed-time. Sleep quality (PSQI) was measured weekly, stress at base- and end-line (Depression Anxiety Stress Scale and saliva cortisol). Fecal samples were collected in the 1st intervention period only. Compared to placebo (skimmed milk), PSQI was only lower at day 14 in the 2nd intervention period in intention-to-treat (ITT) (p = 0.017; n = 69) and per-protocol (PP) (p = 0.038; n = 64) analyses. Post-hoc analysis (modified-PP: n=47, with baseline PSQI \u2265 9, and endline day 14), however, showed a decrease in PSQI (\u22121.60 \u00b1 2.53; p = 0.034). Early morning saliva cortisol decreased versus placebo (p = 0.045). Relative abundance of Bifidobacterium increased (p = 0.02). Redundancy analysis showed an inverse relationship between baseline microbiota composition and baseline PSQI (p = 0.046). Thus, although DP did not improve sleep quality in ITT and PP populations, it did in the modPP. DP reduced salivary cortisol and stimulated Bifidobacterium, which possibly is important for sleep improvement.<\/jats:p>","DOI":"10.3390\/nu13072204","type":"journal-article","created":{"date-parts":[[2021,6,27]],"date-time":"2021-06-27T23:57:22Z","timestamp":1624838242000},"page":"2204","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["The Effect of A Whey-Protein and Galacto-Oligosaccharides Based Product on Parameters of Sleep Quality, Stress, and Gut Microbiota in Apparently Healthy Adults with Moderate Sleep Disturbances: A Randomized Controlled Cross-Over Study"],"prefix":"10.3390","volume":"13","author":[{"given":"Anne","family":"Schaafsma","sequence":"first","affiliation":[{"name":"FrieslandCampina, 3818 LE Amersfoort, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard","family":"Mallee","sequence":"additional","affiliation":[{"name":"FrieslandCampina, 3818 LE Amersfoort, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maartje","family":"van den Belt","sequence":"additional","affiliation":[{"name":"NIZO, Nutrition & Health, 6710 BA Ede, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Floris","sequence":"additional","affiliation":[{"name":"NIZO, Nutrition & Health, 6710 BA Ede, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guus","family":"Kortman","sequence":"additional","affiliation":[{"name":"NIZO, Nutrition & Health, 6710 BA Ede, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jouke","family":"Veldman","sequence":"additional","affiliation":[{"name":"FrieslandCampina, 3818 LE Amersfoort, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daan","family":"van den Ende","sequence":"additional","affiliation":[{"name":"Philips Research, 5656 AE Eindhoven, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alwine","family":"Kardinaal","sequence":"additional","affiliation":[{"name":"NIZO, Nutrition & Health, 6710 BA Ede, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Chattu, V., Manzar, M., Kumary, S., Burman, D., Spence, D., and Pandi-Perumal, S. (2018). The Global Problem of Insufficient Sleep and Its Serious Public Health Implications. Healthcare, 7.","DOI":"10.3390\/healthcare7010001"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1111\/psyg.12319","article-title":"Sleep disorders in the elderly: A growing challenge","volume":"18","author":"Gulia","year":"2018","journal-title":"Psychogeriatrics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.tins.2016.05.002","article-title":"Sleep: A novel mechanistic pathway, biomarker, and treatment target in the pathology of Alzheimers\u2019s disease?","volume":"39","author":"Mander","year":"2016","journal-title":"Trends Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jbio.201900102","article-title":"The inner clock\u2014Blue light sets the human rhythm","volume":"12","author":"Wahl","year":"2019","journal-title":"J. Biophotonics"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Watson, E.J., Coates, A.M., Kohler, M., and Banks, S. (2016). Caffeine consumption and sleep quality in Australian adults. Nutrients, 8.","DOI":"10.3390\/nu8080479"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.lfs.2017.02.008","article-title":"Association between light at night, melatonin secretion, sleep deprivation, and the internal clock: Health impacts and mechanisms of circadian disruption","volume":"173","author":"Touitou","year":"2017","journal-title":"Life Sci."},{"key":"ref_7","unstructured":"Kandel, E.R., Schwartz, J.H., and Jessell, T.M. (2000). Sleep and dreaming. Principles of Neuroscience, McGraw-Hill."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1002\/cne.20770","article-title":"Homeostatic, circadian, and emotional regulation of sleep","volume":"493","author":"Saper","year":"2005","journal-title":"J. Comp. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.yfrne.2007.08.001","article-title":"Orexin neuronal circuitry: Role in the regulation of sleep and wakefulness","volume":"29","author":"Ohno","year":"2008","journal-title":"Front. Neuroendocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1093\/nutrit\/nuy004","article-title":"Applications for a-lactalbumin in human nutrition","volume":"76","author":"Layman","year":"2018","journal-title":"Nutr. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.neuropharm.2016.07.002","article-title":"Kynurenine pathway metabolism and the microbiota-gut-brain axis","volume":"112","author":"Kennedy","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"26","DOI":"10.2174\/1874620900902010026","article-title":"Effects of a bovine alpha S1-casein tryptic hydrolysate (CTH) on sleep disorder in Japanese general population","volume":"2","author":"Messaoudi","year":"2009","journal-title":"Open Sleep J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1016\/j.peptides.2005.10.001","article-title":"A tryptic hydrolysate from bovine milk \u03b1S1-casein improves sleep in rats subjected to chronic mild stress","volume":"27","author":"Guesdon","year":"2006","journal-title":"Peptides"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1177\/1098612X16669399","article-title":"Therapeutic effects of an alpha-casozepine and L-tryptophan supplemented diet on fear and anxiety in the cat","volume":"19","author":"Landsberg","year":"2017","journal-title":"J. Feline Med. Surg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8302","DOI":"10.1038\/s41598-021-87865-w","article-title":"Anxiolytic effects of a galacto-oligosaccharides prebiotic in healthy females (18\u201325 years) with corresponding changes in gut bacterial composition","volume":"11","author":"Johnstone","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.bbr.2016.07.013","article-title":"A tryptic hydrolysate from bovine milk \u03b1s1-casein enhances pentobarbital-induced sleep in mice via the GABAA receptor","volume":"313","author":"Kim","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kim, H.J., Kim, J., Lee, S., Kim, B., Kwon, E., Lee, J.E., Chun, M.Y., Lee, C.Y., Boulier, A., and Oh, S. (2019). A double-blind, randomized, placebo-controlled crossover clinical study of the effects of alpha-s1 casein hydrolysate on sleep disturbance. Nutrients, 11.","DOI":"10.3390\/nu11071466"},{"key":"ref_18","unstructured":"Pennisi, E. (2020). Meet the \u2018psychobiome\u2019: The gut bacteria that may alter how you think, feel, and act. Science, 200."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.brainres.2018.03.015","article-title":"Neurotransmitter modulation by the gut microbiota","volume":"1693","author":"Strandwitz","year":"2018","journal-title":"Brain Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/s41564-018-0307-3","article-title":"GABA modulating bacteria of the human gut microbiota","volume":"4","author":"Strandwitz","year":"2019","journal-title":"Nat. Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ynstr.2017.03.001","article-title":"Stress & the gut-brain axis: Regulation by the microbiome","volume":"7","author":"Foster","year":"2017","journal-title":"Neurobiol. Stress"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3848","DOI":"10.1038\/s41598-020-60679-y","article-title":"Dietary prebiotics alter novel microbial dependent fecal metabolites that improve sleep","volume":"10","author":"Thompson","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12263-018-0605-7","article-title":"Optimal vitamin D spurs serotonin: 1,25-dihydroxyvitamin D represses serotonin reuptake transport (SERT) and degradation (MAO-A) gene expression in cultured rat serotonergic neuronal cell lines","volume":"13","author":"Sabir","year":"2018","journal-title":"Genes Nutr."},{"key":"ref_24","first-page":"357","article-title":"Potassium affects actigraph-identified sleep","volume":"14","author":"Drennan","year":"1991","journal-title":"Sleep"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"249","DOI":"10.3122\/jabfm.2015.02.140176","article-title":"Magnesium Intake and Depression in Adults","volume":"28","author":"Tarleton","year":"2015","journal-title":"J. Am. Board Fam. Med."},{"key":"ref_26","first-page":"S311","article-title":"Role of magnesium in the treatment of depression","volume":"32","author":"Tarleton","year":"2017","journal-title":"PLoS ONE"},{"key":"ref_27","first-page":"107","article-title":"Is systemic treatment of osteoporosis and mandibular resorption possible?","volume":"87","author":"Driessens","year":"1990","journal-title":"Acta Stomatol. Belg."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1038\/nrn1671","article-title":"The neurobiology of zinc in health and disease","volume":"6","author":"Frederickson","year":"2005","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/S0006-2952(99)00135-5","article-title":"Mechanisms of inhibitory effects of zinc and cadmium ions on agonist binding to adenosine A1 receptors in rat brain","volume":"58","author":"Rosati","year":"1999","journal-title":"Biochem. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1046\/j.1471-4159.1997.68051990.x","article-title":"Zinc allosterically modulates antagonist binding to cloned D1 and D2 dopamine receptors","volume":"68","author":"Schetz","year":"1997","journal-title":"J. Neurochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1111\/j.1476-5381.1995.tb13335.x","article-title":"An electrophysiological investigation of the properties of a murine recombinant 5-HT3 receptor stably expressed in HEK 293 cells","volume":"114","author":"Gill","year":"1995","journal-title":"Br. J. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/0165-1781(89)90047-4","article-title":"The Pittsburgh Sleep Quality Index: A new instrument for psychiatric practice and research","volume":"18","author":"Buysse","year":"1989","journal-title":"Psychiatry Res."},{"key":"ref_33","first-page":"35","article-title":"De DASS: Een vragenlijst voor het meten van depressie, angst en stress","volume":"34","author":"Marquenie","year":"2001","journal-title":"Gedragstherapie"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1136\/gutjnl-2017-314418","article-title":"Prebiotic galacto-oligosaccharides mitigate the adverse effects of iron fortification on the gut microbiome: A randomised controlled study in Kenyan infants","volume":"66","author":"Paganini","year":"2017","journal-title":"Gut"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nmeth.f.303","article-title":"QIIME allows analysis of high-throughput community sequencing data","volume":"7","author":"Caporaso","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.1093\/bioinformatics\/btr381","article-title":"UCHIME improves sensitivity and speed of chimera detection","volume":"27","author":"Edgar","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1093\/nar\/gkn879","article-title":"The Ribosomal Database Project: Improved alignments and new tools for rRNA analysis","volume":"37","author":"Cole","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_38","first-page":"276","article-title":"Vom richtigen Umgang mit dem Crossover-Design in klinischen Studien: Teil 18 der Serie zur Bewertung wissenschaftlicher Publikationen","volume":"109","author":"Wellek","year":"2012","journal-title":"Dtsch. Arztebl. Int."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Twisk, J.W.R. (2016). Inleiding in de Toegepaste Statistiek, Bohn Staflei van Loghum. [3rd ed.].","DOI":"10.1007\/978-90-368-1534-5"},{"key":"ref_40","unstructured":"Ter Braak, C., and \u0160milauer, P. (2012). Canoco Reference Manual and User\u2019s Guide: Software for Ordination (Version 5.0), Microcomputer Power."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/0005-7967(94)00075-U","article-title":"The structure of negative emotional states: Comparison of the Depression Anxiety Stress Scales (DASS) with the Beck Depression and Axiety Inventories","volume":"33","author":"Lovibond","year":"1995","journal-title":"Behav. Res. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Lovibond, S.H., and Lovibond, P.F. (1995). Psychology Foundation of Australia. Manual for the Depression Anxiety Stress Scales, School of Psychology, University of New South Wales.","DOI":"10.1037\/t01004-000"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Scholey, A., Benson, S., Gibbs, A., Perry, N., Sarris, J., and Murray, G. (2017). Exploring the effect of lactiumTM and zizyphus complex on sleep quality: A double-blind, randomized placebo-controlled trial. Nutrients, 9.","DOI":"10.3390\/nu9020154"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.smrv.2016.12.004","article-title":"Acupressure effect on sleep quality: A systematic review and meta-analysis","volume":"37","author":"Wait","year":"2018","journal-title":"Sleep Med. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Hidese, S., Ogawa, S., Ota, M., Ishida, I., Yasukawa, Z., Ozeki, M., and Kunugi, H. (2019). Effects of L-Theanine administration on stress-related symptoms and cognitive functions in healthy adults: A randomized controlled trial. Nutrients, 11.","DOI":"10.3390\/nu11102362"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1111\/j.1365-2982.2011.01796.x","article-title":"The anxiolytic effect of Bifidobacterium longum NCC3001","volume":"23","author":"Bercik","year":"2011","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_47","first-page":"19","article-title":"Sleep improving effects of enriched milk, a randomised double-blind trial in adult women with insomnia","volume":"6","author":"Kiers","year":"2007","journal-title":"Nutrafoods"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1079\/BJN20051492","article-title":"The effects of a diet enriched with \u03b1-lactalbumin on mood and cortisol response in unmedicated recovered depressed subjects and controls","volume":"94","author":"Merens","year":"2005","journal-title":"Br. J. Nutr."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.bbr.2015.02.044","article-title":"Bifidobacteria modulate cognitive processes in an anxious mouse strain","volume":"287","author":"Savignac","year":"2015","journal-title":"Behav. Brain Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"283","DOI":"10.3920\/BM2019.0105","article-title":"Revealing new leads for the impact of galacto-oligosaccharides on gut commensals and gut health benefits through text mining","volume":"11","author":"Sijbers","year":"2020","journal-title":"Benef. Microbes"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1080\/1028415X.2018.1493808","article-title":"A review of dietary and microbial connections to depression, anxiety, and stress","volume":"23","author":"Taylor","year":"2020","journal-title":"Nutr. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1111\/nmo.12427","article-title":"Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB\/c mice","volume":"26","author":"Savignac","year":"2014","journal-title":"Gastroenterol. Motil."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/j.chom.2018.05.003","article-title":"Gut Microbiota regulation of tryptophan metabolism in health and disease","volume":"23","author":"Agus","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1007\/s00213-014-3810-0","article-title":"Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers","volume":"232","author":"Schmidt","year":"2015","journal-title":"Psychopharmacology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1111\/j.1365-2036.2008.03911.x","article-title":"Clinical trial: The effects of a trans-galactooligosaccharide prebiotic on faecal microbiota and symptoms in irritable bowel syndrome Study population","volume":"29","author":"Silk","year":"2009","journal-title":"Alim. Pharmacol. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Gonnissen, H.K.J., Mazuy, C., Rutters, F., Martens, E.A.P., Adam, T.C., and Westerterp-Plantenga, M.S. (2013). Sleep architecture when sleeping at an unusual circadian time and associations with insulin sensitivity. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0072877"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1210\/jc.2002-021057","article-title":"Melatonin in patients with reduced REM sleep duration: Two randomized controlled trials","volume":"89","author":"Kunz","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/7\/2204\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:25:08Z","timestamp":1760163908000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/7\/2204"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,27]]},"references-count":57,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["nu13072204"],"URL":"https:\/\/doi.org\/10.3390\/nu13072204","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,27]]}}}