What is the link between the gut microbiome and Alzheimer’s disease?

What is the link between the gut microbiome and Alzheimer’s disease?

2560 1920 Maggie Ford, MD

Adding to Brainwork’s existing dossier of articles covering the relationship between neurological conditions and the gastrointestinal tract,1-4 the present article will examine a connection between the gut microbiome and Alzheimer’s disease (AD).

 

Starting with dysbiosis and ending with Alzheimer’s disease

It starts with with an imbalance in the gut microbiome homeostasis, this is called dysbiosis.5,6 The disproportion between “good” anti-inflammatory bacteria and “bad” pro-inflammatory bacteria results in increased permeability of the intestinal brush border causing “leaky gut”.5,6 This allows pro-inflammatory molecules like lipopolysaccharide (LPS) and short-chain fatty acids (SCFAs) that are produced by proinflammatory bacteria to be absorbed into the bloodstream.5,6 As systemic inflammation is triggered by LPS and SCFAs, the blood-brain-barrier permeability is increased, and errant molecules are absorbed into the brain causing neuroinflammation.5,6 These errant molecules also give rise to the deposition of misfolded proteins like amyloid-b, a-synuclein, and prion protein.5,6 The accumulation of these proteins results in synaptic losses, neuronal dysfunction, and ultimately neuronal cell death.5,6 The entire process along the gut-brain axis causing neurodegenerative disease is an immune-mediated response.5,6 In the case of AD, one of the hallmark characteristics is the aggregation of neurotoxic amyloid-b extraneuronally.5,6

 

Are LPS and SCFAs really the missing links?

In 2020, Marizzoni et al. found an association between LPS and SCFA, and brain amyloidosis.7 In a cross-sectional study the authors evaluated 89 people with florbetapir amyloid PET scans to measure brain amyloidosis.7 The cognitive performances of the study participants ranged from normal to having dementia.7 Additionally, blood levels of LPS, SCFAs, and biomarkers for endothelial dysfunction were obtained.7 Their findings support the theory connecting LPS and SCFAs to amyloidosis, as brain amyloid levels were positively associated with blood LPS (P≤0.006) and the SFCAs acetate and valerate (P<0.001).7 Conversely, brain amyloid levels were negatively associated with the SCFA butyrate (P≤0.02) and the anti-inflammatory cytokine interleukin-10 (P≤0.009).7

 

The results of this study suggest that LPS and pro-inflammatory SCFAs are connected to brain amyloidosis, which is one of the key parts of AD.7 Suggesting a potentially protective effect, this study also connected an anti-inflammatory SCFA to decreased brain amyloidosis.7

 

More puzzles left to solve in the gut-brain axis

The findings by Marizzoni et al. are novel and add to the existing literature investigating the presence of a connection between the gut microbiome and AD.5-7 Although this cross-sectional study found positive associations between blood levels of inflammatory molecules and brain amyloidosis,7 further research is needed to determine whether the association is causal. Exploring and discovering the exact pathways and mechanisms of the gut-brain axis could lead to new treatment and prevention approaches for AD.

 


References
  1. Foletti C. Brainwork. 2019.
  2. Stevenson P. Brainwork. 2019.
  3. Holm M. Brainwork. 2018. 
  4. Carter A. Brainwork. 2020. 
  5. González-Sanmiguel J et al. Cells. 2020;9(11):2476
  6. Gubert C et al. Neurobiol Dis. 2020;134:104621
  7. Marizzoni M et al., J Alzheimers Dis. 2020;78(2):683-697

 

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