Dietary lactoferrin has differential effects on gut microbiota in young versus middle-aged APPswe/PS1dE9 transgenic mice but no effects on cognitive function

  • Huan-Huan Zhou Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
  • Guiping Wang School of Physical Education, Soochow University, Suzhou, China; and Laboratory Animal Center, Medical College of Soochow University, Suzhou, China
  • Lan Luo Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
  • Wei Ding Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
  • Jia-Ying Xu School of Radiation Medicine and Protection, Soochow University, Suzhou, China
  • Zengli Yu School of Public Health, Zhengzhou University, Zhengzhou, China
  • Li-Qiang Qin Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
  • Zhongxiao Wan Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China; and School of Public Health, Zhengzhou University, Zhengzhou, China
DOI: https://doi.org/10.29219/fnr.v65.5496
Keywords: Alzheimer’s disease; lactoferrin; cognitive function; gut microbiota; amyloid β

Abstract

Background: Existing evidence suggest that lactoferrin might be beneficial for Alzheimer’s disease, while precise mechanisms are not fully elucidated.

Objective: To determine the effects of lactoferrin intervention on cognitive function from APPswe/PS1dE9 (APP/PS1) mice, and potential mechanisms involved.

Design: Both the young and middle-aged male APP/PS1 mice were divided into the control and lactoferrin intervention groups with 16 weeks’ intervention.

Results: Lactoferrin had no effects on cognitive function for both the young and middle-aged mice, and no key markers involved in Aβ, tau pathology, neuro-inflammation and synaptic plasticity were altered after lactoferrin intervention. With regards to gut microbiota profiles, in the young APP/PS1 mice, lactoferrin elevated the α diversity index including ACE and Chao 1, and reduced the relative abundance of the genera Bacteroides and Alistipes and elevated Oscillibacter; in addition, Oscillibacter, Anaerotruncus, EF096579_g, EU454405_g, Mollicutes_RF39, EU474361_g, EU774448_g, and EF096976_g were specifically abundant via linear discriminant analysis with effect size (LEfSe) analysis. In the middle-aged APP/PS1 mice, the relative abundance of the phylum Proteobacteria, as well as the genera Oscillospira, Coprococcus, and Ruminococcus was significantly reduced post lactoferrin; additionally, S24_7, Bacteroidia, Bacteroidetes, and Methylobacterium were specific via LEfSe analysis in the lactoferrin group.

Conclusions: Dietary lactoferrin might be beneficial for gut microbiota homeostasis although it might have no effects on cognition.

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References


  1. Baker EN, Baker HM. A structural framework for understanding the multifunctional character of lactoferrin. Biochimie 2009; 91: 3–10. doi: 10.1016/j.biochi.2008.05.006

  2. Legrand D. Overview of lactoferrin as a natural immune modulator. J Pediatr 2016; 173 (Suppl): S10–5. doi: 10.1016/j.jpeds.2016.02.071

  3. Mulder AM, Connellan PA, Oliver CJ, Morris CA, Stevenson LM. Bovine lactoferrin supplementation supports immune and antioxidant status in healthy human males. Nutr Res 2008; 28: 583–9. doi: 10.1016/j.nutres.2008.05.007

  4. Zhang Y, Lima CF, Rodrigues LR. Anticancer effects of lactoferrIn: underlying mechanisms and future trends in cancer therapy. Nutr Rev 2014; 72: 763–73. doi: 10.1111/nure.12155

  5. Jacobsen LC, Sorensen OE, Cowland JB, Borregaard N, Theilgaard-Monch K. The secretory leukocyte protease inhibitor (SLPI) and the secondary granule protein lactoferrin are synthesized in myelocytes, colocalize in subcellular fractions of neutrophils, and are coreleased by activated neutrophils. J Leukoc Biol 2008; 83: 1155–64. doi: 10.1189/jlb.0706442

  6. Fillebeen C, Descamps L, Dehouck MP, Fenart L, Benaissa M, Spik G, et al. Receptor-mediated transcytosis of lactoferrin through the blood-brain barrier. J Biol Chem 1999; 274: 7011–17. doi: 10.1074/jbc.274.11.7011

  7. Mohamed WA, Salama RM, Schaalan MF. A pilot study on the effect of lactoferrin on Alzheimer’s disease pathological sequelae: impact of the p-Akt/PTEN pathway. Biomed Pharmacother 2019; 111: 714–23. doi: 10.1016/j.biopha.2018.12.118

  8. Guo C, Yang ZH, Zhang S, Chai R, Xue H, Zhang YH, et al. Intranasal lactoferrin enhances alpha-secretase-dependent amyloid precursor protein processing via the ERK1/2-CREB and HIF-1alpha pathways in an Alzheimer’s disease mouse model. Neuropsychopharmacology 2017; 42: 2504–15. doi: 10.1038/npp.2017.8

  9. Wang L, Sato H, Zhao S, Tooyama I. Deposition of lactoferrin in fibrillar-type senile plaques in the brains of transgenic mouse models of Alzheimer’s disease. Neurosci Lett 2010; 481: 164–7. doi: 10.1016/j.neulet.2010.06.079

  10. Kawamata T, Tooyama I, Yamada T, Walker DG, McGeer PL. Lactotransferrin immunocytochemistry in Alzheimer and normal human brain. Am J Pathol 1993; 142: 1574–85.

  11. An L, Sato H, Konishi Y, Walker DG, Beach TG, Rogers J, et al. Expression and localization of lactotransferrin messenger RNA in the cortex of Alzheimer’s disease. Neurosci Lett 2009; 452: 277–80. doi: 10.1016/j.neulet.2009.01.071

  12. International Asd. World Alzheimer Report 2018 [homepage on the Internet]. London: ADI; 2018. Available from: https://www.alz.co.uk/research/world-report-2018 [cited 2 March 2020].

  13. Jiang C, Li G, Huang P, Liu Z, Zhao B. The gut microbiota and Alzheimer’s disease. J Alzheimers Dis 2017; 58: 1–15. doi: 10.3233/JAD-161141

  14. Zhao Y, Dua P, Lukiw WJ. Microbial sources of amyloid and relevance to amyloidogenesis and Alzheimer’s Disease (AD). J Alzheimers Dis Parkinsonism 2015; 5: 177. doi: 10.4172/2161-0460.1000177

  15. Naseer MI, Bibi F, Alqahtani MH, Chaudhary AG, Azhar EI, Kamal MA, et al. Role of gut microbiota in obesity, type 2 diabetes and Alzheimer’s disease. CNS Neurol Disord Drug Targets 2014; 13: 305–11. doi: 10.2174/18715273113126660147

  16. Sherman MP, Sherman J, Arcinue R, Niklas V. Randomized control trial of human recombinant lactoferrIn: a substudy reveals effects on the fecal microbiome of very low birth weight infants. J Pediatr 2016; 173 Suppl: S37–42. doi: 10.1016/j.jpeds.2016.02.074

  17. Hu P, Zhao F, Zhu W, Wang J. Effects of early-life lactoferrin intervention on growth performance, small intestinal function and gut microbiota in suckling piglets. Food Funct 2019; 10: 5361–73. doi: 10.1039/c9fo00676a

  18. Haiwen Z, Rui H, Bingxi Z, Qingfeng G, Jifeng Z, Xuemei W, et al. Oral administration of bovine lactoferrin-derived lactoferricin (Lfcin) B could attenuate enterohemorrhagic Escherichia coli O157:H7 induced intestinal disease through improving intestinal barrier function and microbiota. J Agric Food Chem 2019; 67: 3932–45. doi: 10.1021/acs.jafc.9b00861

  19. Malm T, Koistinaho J, Kanninen K. Utilization of APPswe/PS1dE9 transgenic mice in research of Alzheimer’s disease: focus on gene therapy and cell-based therapy applications. Int J Alzheimers Dis 2011; 2011: 517160. doi: 10.4061/2011/517160

  20. Sun H, Liu M, Sun T, Chen Y, Lan Z, Lian B, et al. Age-related changes in hippocampal AD pathology, actin remodeling proteins and spatial memory behavior of male APP/PS1 mice. Behav Brain Res 2019; 376: 112182. doi: S0166-4328(19)30341-9

  21. Shen L, Liu L, Ji HF. Alzheimer’s disease histological and behavioral manifestations in transgenic mice correlate with specific gut microbiome state. J Alzheimers Dis 2017; 56: 385–90. doi: 10.3233/JAD-160884

  22. Ling CJ, Xu JY, Li YH, Tong X, Yang HH, Yang J, et al. Lactoferrin promotes bile acid metabolism and reduces hepatic cholesterol deposition by inhibiting the farnesoid X receptor (FXR)-mediated enterohepatic axis. Food Funct 2019; 10: 7299–307. doi: 10.1039/c9fo01616c

  23. Ling CJ, Min QQ, Yang JR, Zhang Z, Yang HH, Xu JY, et al. Lactoferrin alleviates the progression of atherosclerosis in ApoE(-/-) mice fed with high-fat/cholesterol diet through cholesterol homeostasis. J Med Food 2019; 22: 1000–08. doi: 10.1089/jmf.2018.4389

  24. Takeuchi T, Matsunaga K, Sugiyama A. Antidepressant-like effect of milk-derived lactoferrin in the repeated forced-swim stress mouse model. J Vet Med Sci 2017; 79: 1803–06. doi: 10.1292/jvms.17-0200

  25. Chen N, Lei T, Xin L, Zhou L, Cheng J, Qin L, et al. Depot-specific effects of treadmill running and rutin on white adipose tissue function in diet-induced obese mice. J Physiol Biochem 2016; 72: 453–67. doi: 10.1007/s13105-016-0493-5

  26. Lv M, Yang S, Cai L, Qin LQ, Li BY, Wan Z. Effects of quercetin intervention on cognition function in APP/PS1 mice was affected by vitamin D status. Mol Nutr Food Res 2018; 62: e1800621. doi: 10.1002/mnfr.201800621

  27. Quast C, Pruesse E, Yilmaz P, Gerken J, Schweer T, Yarza P, et al. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res 2013; 41: D590–6. doi: 10.1093/nar/gks1219

  28. Lozupone C, Lladser ME, Knights D, Stombaugh J, Knight R. UniFrac: an effective distance metric for microbial community comparison. ISME J 2011; 5: 169–72. doi: 10.1038/ismej.2010.133

  29. Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, et al. Metagenomic biomarker discovery and explanation. Genome Biol 2011; 12: R60. doi: 10.1186/gb-2011-12-6-r60

  30. Carro E, Bartolome F, Bermejo-Pareja F, Villarejo-Galende A, Molina JA, Ortiz P, et al. Early diagnosis of mild cognitive impairment and Alzheimer’s disease based on salivary lactoferrin. Alzheimers Dement (Amst) 2017; 8: 131–8. doi: 10.1016/j.dadm.2017.04.002

  31. Abdelhamid M, Jung CG, Zhou C, Abdullah M, Nakano M, Wakabayashi H, et al. Dietary lactoferrin supplementation prevents memory impairment and reduces amyloid-beta generation in J20 mice. J Alzheimers Dis 2020; 74: 245–59. doi: 10.3233/JAD-191181

  32. Liu H, Wu H, Zhu N, Xu Z, Wang Y, Qu Y, et al. Lactoferrin protects against iron dysregulation, oxidative stress, and apoptosis in MPTP-induced Parkinson’s disease in mice. J Neurochem 2019; 152: 397–415. doi: 10.1111/jnc.14857

  33. Kim BS, Song MY, Kim H. The anti-obesity effect of Ephedra sinica through modulation of gut microbiota in obese Korean women. J Ethnopharmacol 2014; 152: 532–9. doi: 10.1016/j.jep.2014.01.038

  34. de Faria Ghetti F, Oliveira DG, de Oliveira JM, de Castro Ferreira L, Cesar DE, Moreira APB. Influence of gut microbiota on the development and progression of nonalcoholic steatohepatitis. Eur J Nutr 2018; 57: 861–76. doi: 10.1007/s00394-017-1524-x

  35. Lukiw WJ. Bacteroides fragilis lipopolysaccharide and inflammatory signaling in Alzheimer’s disease. Front Microbiol 2016; 7: 1544. doi: 10.3389/fmicb.2016.01544

  36. Guo WL, Pan YY, Li L, Li TT, Liu B, Lv XC. Ethanol extract of Ganoderma lucidum ameliorates lipid metabolic disorders and modulates the gut microbiota composition in high-fat diet fed rats. Food Funct 2018; 9: 3419–31. doi: 10.1039/c8fo00836a

  37. Ma H, Zhang B, Hu Y, Wang J, Liu J, Qin R, et al. Correlation analysis of intestinal redox state with the gut microbiota reveals the positive intervention of tea polyphenols on hyperlipidemia in high fat diet fed mice. J Agric Food Chem 2019; 67: 7325–35. doi: 10.1021/acs.jafc.9b02211

  38. Shin N-R, Whon TW, Bae J-W. Proteobacteria: microbial signature of dysbiosis in gut microbiota. Trends Biotechnol 2015; 33: 496–503. doi: 10.1016/j.tibtech.2015.06.011

  39. Konikoff T, Gophna U. Oscillospira: a central, enigmatic component of the human gut microbiota. Trends Microbiol 2016; 24: 523–24. doi:S0966-842X(16)00052-4

  40. Mancabelli L, Milani C, Lugli GA, Turroni F, Mangifesta M, Viappiani A, et al. Unveiling the gut microbiota composition and functionality associated with constipation through metagenomic analyses. Sci Rep 2017; 7: 9879. doi: 10.1038/s41598-017-10663-w

  41. Rajilic-Stojanovic M, Jonkers DM, Salonen A, Hanevik K, Raes J, Jalanka J, et al. Intestinal microbiota and diet in IBS: causes, consequences, or epiphenomena? Am J Gastroenterol 2015; 110: 278–87. doi: 10.1038/ajg.2014.427

  42. Zhuang ZQ, Shen LL, Li WW, Fu X, Zeng F, Gui L, et al. Gut microbiota is altered in patients with Alzheimer’s disease. J Alzheimers Dis 2018; 63: 1337–46. doi: 10.3233/JAD-180176

Published
2021-10-18
How to Cite
Zhou H.-H., Wang G., Luo L., Ding W., Xu J.-Y., Yu Z., Qin L.-Q., & Wan Z. (2021). Dietary lactoferrin has differential effects on gut microbiota in young versus middle-aged APPswe/PS1dE9 transgenic mice but no effects on cognitive function. Food & Nutrition Research, 65. https://doi.org/10.29219/fnr.v65.5496
Issue
Vol 65 (2021)
Section
Original Articles
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