Short-Chain Fatty Acids and Lipopolysaccharide as Mediators Between Gut Dysbiosis and Amyloid Pathology in Alzheimer’s Disease

Abstract

Background: Metagenomic data support an association between certain bacterial strains and Alzheimer’s disease (AD), but their functional dynamics remain elusive. Objective: To investigate the association between amyloid pathology, bacterial products such as lipopolysaccharide (LPS) and short chain fatty acids (SCFAs: acetate, valerate, butyrate), inflammatory mediators, and markers of endothelial dysfunction in AD. Methods: Eighty-nine older persons with cognitive performance from normal to dementia underwent florbetapir amyloid PET and blood collection. Brain amyloidosis was measured with standardized uptake value ratio versus cerebellum. Blood levels of LPS was measured by ELISA, SCFAs by mass spectrometry, cytokines by using real-time PCR, and biomarkers of endothelial dysfunction by flow cytometry. We investigated the association between the variables listed above with Spearman’s rank test. Results: Amyloid SUVR uptake was positively associated with blood LPS (rho≥0.32, p≤0.006), acetate and valerate (rho≥0.45, p < 0.001), pro-inflammatory cytokines (rho≥0.25, p≤0.012), and biomarkers of endothelial dysfunction (rho≥0.25, p≤0.042). In contrast, it was negatively correlated with butyrate (rho≤–0.42, p≤0.020) and the anti-inflammatory cytokine IL10 (rho≤–0.26, p≤0.009). Endothelial dysfunction was positively associated with pro-inflammatory cytokines, acetate and valerate (rho≥0.25, p≤0.045) and negatively with butyrate and IL10 levels (rho≤–0.25, p≤0.038). Conclusion: We report a novel association between gut microbiota-related products and systemic inflammation with brain amyloidosis via endothelial dysfunction, suggesting that SCFAs and LPS represent candidate pathophysiologic links between the gut microbiota and AD pathology.

Roles and Mechanisms of Gut Microbiota in Patients With Alzheimer’s Disease

“…They can interfere with various Aβ peptides, thereby potently inhibiting Aβ fibril aggregation in vitro (Ho et al, 2018), possibly reducing the accumulation of neurotoxic oligomers in the brain. Marizzoni et al (2020) reported a novel association between gut microbiota-derived SCFAs and systemic inflammation with brain amyloidosis via endothelial dysfunction in a clinical study. Erny et al (2015) also suggested that SCFAs may help modulate the maturation and function of microglia in the brain.…”

Contribution of Gut Microbiota to Immunological Changes in Alzheimer’s Disease

“…All species within the phylum Bacteroidetes are gram-negative and contain the toxin LPS in their outer membrane ( 15 , 24 , 25 ). Higher circulating levels of LPS were associated with increased Aβ deposition in elderly patients with cognitive complaints ( 62 ). Increased abundance was detected in most genera within Bacteroidetes and most of its species, including B. fragilis ( 60 ), which produces polysaccharide A (PSA) ( 7 ).…”

“…At species level, butyrate-producers like R. hominis , F. prausnitzii, E. rectale and E. hallii were lower abundant in AD patients ( 60 ). Interestingly, butyrate levels in plasma negatively associated with Aβ deposition in cognitively impaired patients ( 62 ).…”

Association of Plasma Hemoglobin A1c with Improvement of Cognitive Functions by Probiotic Bifidobacterium breve Supplementation in Healthy Adults with Mild Cognitive Impairment

“…They are also referred to as friendly or healthy bacteria supplied through foods, beverages, and dietary supplements. One of their reported benefits has been associated with anti-inflammatory effect [ 12 ] and correction of gut microbiota dysbiosis [ 13 ], that is proposed to be a driver of inflammation and recently shown to correlate with amyloid deposition in the brain of living subjects suffering from AD [ 14 ].…”