Gut dysbiosis and gut-derived inflammation contribute to endothelial dysfunction in Alzheimer's disease: An in-vivo cross-sectional study.

Although recent data support an association between certain bacterial strains and Alzheimer's Disease (AD), it is not clear how these alterations contribute to different aspects of the disease. Increasing evidences also from our group (Cattaneo, AAIC 2020), suggest that endothelial dysfunction, reflected by the upregulation of cell adhesion molecules (CAMs), might have a role in AD pathology development and might be affected by inflammatory mediators. This study aimed at evaluating the gut microbiota (GMB) profile and its association with CAMs and local and systemic inflammation in AD patients.Sixty-six older persons without cognitive performance (HC) and 68 AD patients were recruited and stool and blood samples were collected. Bacterial composition of fecal samples was inferred using 16S sequencing, analyzed with QIIME 2 (Quantitative Insights into Microbial Ecology, https://qiime2.org/). Inflammatory mediators were quantified in the blood using the mesoscale platform (for cytokines) and in the stools using ELISA (for calprotectin), CAMs by FACS.Compared to HC, AD patients showed i) lower abundance of genera known to have anti-inflammatory, neuroprotective or other beneficial effects on the epithelial barrier (as Akkermansia, Roseburia and Fusicatenibacter) as well as higher abundance in pro-inflammatory genera (as Desulfovibrio) (Lefse, p< 0.039); ii) higher levels of the proinflammatory cytokine IL8 (p= 0.044) in the blood and calprotectin in the stools (p= 0.012); iii) higher level of several adhesion molecules (NCAM, PECAM-1, P-, L-, E-Selectin; p< 0.024) in the blood. Low abundance of the beneficial genera as well as high abundance of the proinflammatory genera were associated with elevated levels of fecal calprotectin and blood CAMs (0.19<|rho|<0.30, p<.048). Finally, high calprotectin levels were associated with elevated CAMs expression (0.22<|rho|<0.32, p<.017).These findings confirm our previous results showing that gut dysbiosis was associated with endothelial dysfunction. In addition, we showed that gut derived inflammation, linked to both altered bacteria abundance and CAMs upregulation, might contribute to AD.