Dietary lactoferrin has differential effects on gut microbiota in young versus middle-aged APPswe/PS1dE9 transgenic mice but no effects on cognitive function
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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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.
- 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
- 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].
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Lukiw WJ. Bacteroides fragilis lipopolysaccharide and inflammatory signaling in Alzheimer’s disease. Front Microbiol 2016; 7: 1544. doi: 10.3389/fmicb.2016.01544
- 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
- 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
- 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
- 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
- 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
- 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
- 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
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