AbstractBackgroundAlzheimer’s disease (AD) is progressive debilitating public health problem, with no successful preventive and therapeutic strategy. Emerging evidence indicate that the gut microbiome and its metabolites like short chain fatty acids (SCFAs; such as acetate, propionate, butyrate) contribute in AD pathology. SCFAs function as gut microbiome sensors on distinct cell types including neurons through activating G‐couple protein receptors like free fatty acid receptor 2/3 (FFAR2/3). Therefore, targeting this signaling can be a novel strategy to ameliorate AD pathology.MethodUpon screening of >144,000 natural compounds library with human FFAR2 docking patterns, and selected 14 compounds were further studied for FFAR2 signaling agonism by measuring phosph‐ERK1/2, cAMP and calcium levels in SK‐N‐SH cells that express FFAR2. In addition, selected compound (Fenchol) investigated for its beneficial effects on life‐span, Aβ accumulation, neurodegeneration and cognitive functions in Caenorhabditis (C.) elegans and cells.ResultWe demonstrated that FFAR2 expressed in neuronal cells, and its inhibition aggravates Aβ‐induced neuronal cell death. We screened >144,000 natural compound library with human FFAR2 docking patterns, and selected 14 compounds, based on higher binding energy. Further, among them, Fenchol shows highest FFAR2 signaling activation in terms of phospho‐ERK1/2, inhibition in cAMP and increase in intracellular calcium in SK‐N‐SH cells. Interestingly, Fenchol enhanced longevity in wild‐type (N2), and human Aβ42 over‐expressing CL2600 Caenorhabditis (C.) elegans strains. Fenchol also reduced Aβ aggregates, neurodegeneration induced paralysis and cognitive memory (by chemotaxis assay) in C. elegans. In addition, Fenchol induced reduction in Aβ aggregates are linked with significantly increased proteolysis and reduced senescence (β‐galactosidase staining) in C. elegans and neuronal cells.ConclusionOverall, results demonstrate that Fenchol (a microbiome sensor through FFAR2 agonist) ameliorates Aβ aggregation in neuronal cells through activation of proteolysis and reduces senescence which ultimately can ameliorate AD pathology.