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

Article type: Research Article

Authors: Marizzoni, Moira^{a; b; 1; *} | Cattaneo, Annamaria^{b; 1} | Mirabelli, Peppino^c | Festari, Cristina^a | Lopizzo, Nicola^{b; d} | Nicolosi, Valentina^a | Mombelli, Elisa^b | Mazzelli, Monica^b | Luongo, Delia^e | Naviglio, Daniele^f | Coppola, Luigi^c | Salvatore, Marco^c | Frisoni, Giovanni B.^g

Affiliations: [a] Laboratory of Neuroimaging and Alzheimer’s Epidemiology, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy | [b] Laboratory of Biological Psychiatry, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy | [c] IRCCS SDN, Naples, Italy | [d] Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy | [e] I.B.B.- CNR Via Mezzocannone, Naples, Italy | [f] Department of Chemical Sciences, University of Naples Federico II, Via Cintia 4, Naples, Italy | [g] Memory Clinic and LANVIE – Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Geneva, Switzerland

Correspondence: [*] Correspondence to: Moira Marizzoni, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. Tel.: +39 030 35 01 362; Fax: +39 030 35 01 592; E-mail: mmarizzoni@gmail.com.

Note: [1] These authors contributed equally to this work.

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 were 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.

Keywords: Brain amyloidosis, inflammation, lipopolysaccharide, microbiota, short chain fatty acids

DOI: 10.3233/JAD-200306

Journal: Journal of Alzheimer's Disease, vol. 78, no. 2, pp. 683-697, 2020