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

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.

Lactoferrin modulates gut microbiota and Toll-like receptors (TLRs) in mice with dysbiosis induced by antibiotics

“…17 The capacity of bLf to modulate the gut microbiota positively has been previously demonstrated in high-fat diet induced obese mice, 22 dextran sulfate sodium induced colitis model 23 or Alzheimer's disease models. 24 However, its potential to counteract the side effects of antibiotics on the microbiota and the immune system has not yet been fully studied.…”

Neuroprotective Effects of Lactoferrin in Alzheimer’s and Parkinson’s Diseases: A Narrative Review

“…More animal models have also supported the effects of lactoferrin in preventing the three hallmarks of PD, which are motor deficits, substantia nigral dopaminergic neurodegeneration, and striatal dopamine loss, although the precise mechanisms of action were not examined. , However, at least two studies thus far do not affirm the neuroprotective effects of lactoferrin in AD. First, in APP/PSI transgenic mouse model of AD, lactoferrin-supplemented diets (0.8% lactoferrin for 16 weeks) did not improve cognitive symptoms or modulate protein expressions related to amyloid metabolism, tau phosphorylation, and neuroinflammation . The authors speculated that their inconsistent results might be due to differences in study design, such as lactoferrin dosage or the source of lactoferrin .…”

“…130 The authors speculated that their inconsistent results might be due to differences in study design, such as lactoferrin dosage or the source of lactoferrin. 130 However, the administrative route of lactoferrin may also be a source of variation. Most in vivo studies involving AD and PD administered lactoferrin are conducted via intragastric gavage, intranasal instillation, or intraperitoneal injection (Tables 1 and 2).…”

“…Hypothetically, lactoferrin-supplemented diets may be less efficacious due to protein degradation in the digestive system . Indeed, Zhou et al used iron-free lactoferrin, which is known to be more prone to proteolytic degradation than iron-saturated lactoferrin. , Abdelhamid et al, on the other hand, used native lactoferrin that is partially iron-saturated, which may be more efficacious in treating AD (or PD) than iron-free lactoferrin when administered through diets.…”

“…First, in APP/PSI transgenic mouse model of AD, lactoferrin-supplemented diets (0.8% lactoferrin for 16 weeks) did not improve cognitive symptoms or modulate protein expressions related to amyloid metabolism, tau phosphorylation, and neuroinflammation. 130 The authors speculated that their inconsistent results might be due to differences in study design, such as lactoferrin dosage or the source of lactoferrin. 130 However, the administrative route of lactoferrin may also be a source of variation.…”