MICROCONNECT

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, affecting 1 million people in France. This number is predicted to significantly increase with an aging population. Aging is a major risk of developing AD. AD etiology and pathophysiology remain to date largely unknown, with the implication of Aß peptide as one of the major culprits, but emerging evidence unveiled a potential key role of the microbiota/gut dysbiosis in the pathology. Interestingly, some AD patients manifest gastrointestinal dysfunctions decades before the onset of brain-related symptoms. It is also interesting to note that patients who have shown chronic gastric damage such as constipation are more at risk of developing AD and may show more severe cognitive deficits. On the other hand, altered behavior in patients with AD is accompanied by a gut dysbiosis and, in a large subset of patients, gastrointestinal symptoms. Intestinal dysbiosis is also accompanied by an alteration/reduction in the production of bacterial metabolites such as short chain fatty acids (SCFA). The reduction of these metabolites could promote the production of the Aß peptide. Indeed, the reduction of the SCFA butyrate has been consistently reported in AD patients and animal models. Conversely, increasing butyrate in AD mouse models reduced levels of Aß peptide and rescued memory function. Altered behavior in AD patients is accompanied by gut dysbiosis, which is an alteration of microbial population, and in a large subset of patients, gastro-intestinal symptoms. A possible causal relationship between intestinal dysbiosis, GI symptoms and memory loss in AD has been essentially documented in experimental animal models of AD, but clinical data on humans remains elusive. Our project will directly address the question of a causal relationship between dysbiosis and gut Aß pathology in the one hand, and AD symptoms and digestive comorbidity on the other hand, with the goal to identify the involved bacterial-derived mediators and to decipher their mechanisms of action. The ultimate goal is to ameliorate or prevent gut-brain symptoms through a supplementation of bacterial metabolites that are altered in AD. This project will pave the way for innovative treatment targeting intestinal microbiota or downstream molecular mediators.