Oral lactoferrin influences psychological stress in humans: A single‑dose administration crossover study

Shinjo,Tokiko; Sakuraba,Keishoku; Nakaniida,Atsuko; Ishibashi,Tomoyo; Kobayashi,Miki; Aono,Yuya; Suzuki,Yoshio

doi:10.3892/br.2018.1076

Oral lactoferrin influences psychological stress in humans: A single‑dose administration crossover study

Authors:
- Tokiko Shinjo
- Keishoku Sakuraba
- Atsuko Nakaniida
- Tomoyo Ishibashi
- Miki Kobayashi
- Yuya Aono
- Yoshio Suzuki
View Affiliations

Affiliations: Graduate School of Health and Sports Science, Juntendo University, Chiba 270‑1695, Japan, Faculty of Health and Sports Science, Juntendo University, Chiba 270‑1695, Japan
Published online on: March 12, 2018 https://doi.org/10.3892/br.2018.1076
Pages: 426-432

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Lactoferrin is a secretory protein with various physiological functions. Bovine lactoferrin has been demonstrated to alleviate psychological stresses in rats, but this effect in humans has not yet been assessed. The present study aimed to investigate the changes in psychological stress markers following a calculation task, with either lactoferrin or a placebo orally administered prior to the task. A total of 16 healthy female college students visited Juntendo University, Inzai, Japan following an overnight fast. Subjects were quietly seated for 15 min to stabilize the respiratory rate at 0.25 Hz (one breath every 4 sec). Then, subjects provided saliva, ingested either lactoferrin (800 mg of lactoferrin + soy milk) or a placebo (soy milk), remained seated for another 15 min with respiration rate at 0.25 Hz, and performed a calculation task. The task comprised two sets of 15‑min calculations, with a 5‑min interval between sets. Each calculation set consisted of various multiplications and divisions using pairs of three‑digit numbers. Following the calculation task, saliva was collected again. Heart rate was also monitored to identify the frequency domain of heart‑rate variability. The calculation task resulted in increased activity of salivary amylase, and decreased concentration of chromogranin A for both lactoferrin (P=0.028 and P<0.001, respectively) and placebo (P=0.003 and P<0.001, respectively) treatments. The degrees of changes in these salivary markers were similar between the two treatments. Heart rate variability exhibited an increase in the high‑frequency (HF) component (P=0.022) and a decrease in low‑frequency (LF)/HF and LF/(LF+HF) ratios (both P<0.001) following the calculation task under the placebo condition, demonstrating an upregulation of parasympathetic and a downregulation of sympathetic nervous activities. These changes in parasympathetic (HF) and sympathetic (LF/HF) activities, however, were alleviated by lactoferrin compared with the placebo (P=0.007 and P=0.026, respectively). Collectively these results suggest that oral lactoferrin may mitigate psychological stress in humans.

View Figures

View References

1	Arnold RR, Cole MF and McGhee JR: A bactericidal effect for human lactoferrin. Science. 197:263–265. 1977. View Article : Google Scholar : PubMed/NCBI
2	Arnold RR, Brewer M and Gauthier JJ: Bactericidal activity of human lactoferrin: Sensitivity of a variety of microorganisms. Infect Immun. 28:893–898. 1980.PubMed/NCBI
3	Kalmar JR and Arnold RR: Killing of Actinobacillus actinomycetemcomitans by human lactoferrin. Infect Immun. 56:2552–2557. 1988.PubMed/NCBI
4	Yamauchi K, Tomita M, Giehl TJ and Ellison RT III: Antibacterial activity of lactoferrin and a pepsin-derived lactoferrin peptide fragment. Infect Immun. 61:719–728. 1993.PubMed/NCBI
5	Vitetta L, Coulson S, Beck SL, Gramotnev H, Du S and Lewis S: The clinical efficacy of a bovine lactoferrin/whey protein Ig-rich fraction (Lf/IgF) for the common cold: A double blind randomized study. Complement Ther Med. 21:164–171. 2013. View Article : Google Scholar : PubMed/NCBI
6	Ishikado A, Uesaki S, Suido H, Nomura Y, Sumikawa K, Maeda M, Miyauchi M, Takata T and Makino T: Human trial of liposomal lactoferrin supplementation for periodontal disease. Biol Pharm Bull. 33:1758–1762. 2010. View Article : Google Scholar : PubMed/NCBI
7	Kuhara T, Iigo M, Itoh T, Ushida Y, Sekine K, Terada N, Okamura H and Tsuda H: Orally administered lactoferrin exerts an antimetastatic effect and enhances production of IL-18 in the intestinal epithelium. Nutr Cancer. 38:192–199. 2000. View Article : Google Scholar : PubMed/NCBI
8	Koikawa N, Nagaoka I, Yamaguchi M, Hamano H, Yamauchi K and Sawaki K: Preventive effect of lactoferrin intake on anemia in female long distance runners. Biosci Biotechnol Biochem. 72:931–935. 2008. View Article : Google Scholar : PubMed/NCBI
9	Paesano R, Torcia F, Berlutti F, Pacifici E, Ebano V, Moscarini M and Valenti P: Oral administration of lactoferrin increases hemoglobin and total serum iron in pregnant women. Biochem Cell Biol. 84:377–380. 2006. View Article : Google Scholar : PubMed/NCBI
10	Kamemori N, Takeuchi T, Hayashida K and Harada E: Suppressive effects of milk-derived lactoferrin on psychological stress in adult rats. Brain Res. 1029:34–40. 2004. View Article : Google Scholar : PubMed/NCBI
11	Rohleder N, Wolf JM, Maldonado EF and Kirschbaum C: The psychosocial stress-induced increase in salivary alpha-amylase is independent of saliva flow rate. Psychophysiology. 43:645–652. 2006. View Article : Google Scholar : PubMed/NCBI
12	Granger DA, Kivlighan KT, el-Sheikh M, Gordis EB and Stroud LR: Salivary α-amylase in biobehavioral research: Recent developments and applications. Ann N Y Acad Sci. 1098:122–144. 2007. View Article : Google Scholar : PubMed/NCBI
13	Haririan H, Bertl K, Laky M, Rausch WD, Böttcher M, Matejka M, Andrukhov O and Rausch-Fan X: Salivary and serum chromogranin A and α-amylase in periodontal health and disease. J Periodontol. 83:1314–1321. 2012. View Article : Google Scholar : PubMed/NCBI
14	Lee T, Shimizu T, Iijima M, Obinata K, Yamashiro Y and Nagasawa S: Evaluation of psychosomatic stress in children by measuring salivary chromogranin A. Acta Paediatr. 95:935–939. 2006. View Article : Google Scholar : PubMed/NCBI
15	Kanno T, Asada N, Yanase H, Iwanaga T and Yanaihara N: Salivary Secretion of Chromogranin A Control by Autonomic Nervous SystemChromogranins: Functional and Clinical Aspects. Helle KB and Aunis D: Springer US; Boston, MA: pp. 143–151. 2002, View Article : Google Scholar
16	Koibuchi E and Suzuki Y: Exercise upregulates salivary amylase in humans (Review). Exp Ther Med. 7:773–777. 2014. View Article : Google Scholar : PubMed/NCBI
17	Chatterton RT Jr, Vogelsong KM, Lu YC, Ellman AB and Hudgens GA: Salivary alpha-amylase as a measure of endogenous adrenergic activity. Clin Physiol. 16:433–448. 1996. View Article : Google Scholar : PubMed/NCBI
18	Nater UM, La Marca R, Florin L, Moses A, Langhans W, Koller MM and Ehlert U: Stress-induced changes in human salivary alpha-amylase activity - associations with adrenergic activity. Psychoneuroendocrinology. 31:49–58. 2006. View Article : Google Scholar : PubMed/NCBI
19	Nakane H, Asami O, Yamada Y, Harada T, Matsui N, Kanno T and Yanaihara N: Salivary chromogranin A as an index of psychosomatic stress response. Biomed Res. 19:401–406. 1998. View Article : Google Scholar
20	Malik M, Bigger J, Camm A, Kleiger R, Malliani A, Moss AJ and Schwartz PJ: Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology: Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Eur Heart J. 17:354–381. 1996. View Article : Google Scholar : PubMed/NCBI
21	Acharya Rajendra U, Joseph Paul K, Kannathal N, Lim CM and Suri JS: Heart rate variability: A review. Med Biol Eng Comput. 44:1031–1051. 2006. View Article : Google Scholar : PubMed/NCBI
22	Bosch JA, Veerman ECI, de Geus EJ and Proctor GB: α-Amylase as a reliable and convenient measure of sympathetic activity: Don't start salivating just yet! Psychoneuroendocrinology. 36:449–453. 2011. View Article : Google Scholar : PubMed/NCBI
23	Morse DR, Schacterle GR, Furst ML, Esposito JV and Zaydenburg M: Stress, relaxation and saliva: Relationship to dental caries and its prevention, with a literature review. Ann Dent. 42:47–54. 1983.PubMed/NCBI
24	Kanno T, Asada N, Yanase H, Iwanaga T and Yanaihara N: Salivary secretion of chromogranin A. Control by autonomic nervous system. Adv Exp Med Biol. 482:143–151. 2000. View Article : Google Scholar : PubMed/NCBI
25	Takeuchi T, Hayashida K, Inagaki H, Kuwahara M, Tsubone H and Harada E: Opioid mediated suppressive effect of milk-derived lactoferrin on distress induced by maternal separation in rat pups. Brain Res. 979:216–224. 2003. View Article : Google Scholar : PubMed/NCBI
26	Zimecki M and Kruzel ML: Milk-derived proteins and peptides of potential therapeutic and nutritive value. J Exp Ther Oncol. 6:89–106. 2007.PubMed/NCBI
27	Mohanty DP, Mohapatra S, Misra S and Sahu PS: Milk derived bioactive peptides and their impact on human health - A review. Saudi J Biol Sci. 23:577–583. 2016. View Article : Google Scholar : PubMed/NCBI
28	Marcone S, Belton O and Fitzgerald DJ: Milk-derived bioactive peptides and their health promoting effects: A potential role in atherosclerosis. Br J Clin Pharmacol. 83:152–162. 2017. View Article : Google Scholar : PubMed/NCBI
29	Kawakami H and Lönnerdal B: Isolation and function of a receptor for human lactoferrin in human fetal intestinal brush-border membranes. Am J Physiol. 261:G841–G846. 1991.PubMed/NCBI
30	Suzuki YA, Shin K and Lönnerdal B: Molecular cloning and functional expression of a human intestinal lactoferrin receptor. Biochemistry. 40:15771–15779. 2001. View Article : Google Scholar : PubMed/NCBI
31	Perez-Burgos A, Wang B, Mao YK, Mistry B, McVey Neufeld KA, Bienenstock J and Kunze W: Psychoactive bacteria Lactobacillus rhamnosus (JB-1) elicits rapid frequency facilitation in vagal afferents. Am J Physiol Gastrointest Liver Physiol. 304:G211–G220. 2013. View Article : Google Scholar : PubMed/NCBI
32	Steinert RE, Feinle-Bisset C, Asarian L, Horowitz M, Beglinger C and Geary N: Ghrelin, CCK, GLP-1, and PYY(3-36): Secretory Controls and Physiological Roles in Eating and Glycemia in Health, Obesity, and After RYGB. Physiol Rev. 97:411–463. 2017. View Article : Google Scholar : PubMed/NCBI
33	Takai N, Yamaguchi M, Aragaki T, Eto K, Uchihashi K and Nishikawa Y: Effect of psychological stress on the salivary cortisol and amylase levels in healthy young adults. Arch Oral Biol. 49:963–968. 2004. View Article : Google Scholar : PubMed/NCBI
34	Nater UM, Rohleder N, Schlotz W, Ehlert U and Kirschbaum C: Determinants of the diurnal course of salivary alpha-amylase. Psychoneuroendocrinology. 32:392–401. 2007. View Article : Google Scholar : PubMed/NCBI
35	Den R, Toda M, Nagasawa S, Kitamura K and Morimoto K: Circadian rhythm of human salivary chromogranin A. Biomed Res. 28:57–60. 2007. View Article : Google Scholar : PubMed/NCBI
36	Grenham S, Clarke G, Cryan JF and Dinan TG: Brain-gut-microbe communication in health and disease. Front Physiol. 2:942011. View Article : Google Scholar : PubMed/NCBI
37	Bengmark S: Gut microbiota, immune development and function. Pharmacol Res. 69:87–113. 2013. View Article : Google Scholar : PubMed/NCBI
38	Forsythe P and Kunze WA: Voices from within: Gut microbes and the CNS. Cell Mol Life Sci. 70:55–69. 2013. View Article : Google Scholar : PubMed/NCBI