Intestinal endogenous metabolites affect neuroinflammation in 5×FAD mice by mediating "gut-brain" axis and the intervention with Chinese Medicine

Emerging evidence suggested the association between gut dysbiosis and Alzheimer's disease (AD) progression. However, it remained unclear how the gut microbiome and neuroinflammation in the brain mutually interact or how these interactions affect brain functioning and cognition. Here we hypothesized that "gut-brain" axis mediated by microbial derived metabolites was expected to novel breakthroughs in the fields of AD research and development. Multiple technologies, such as immunofluorescence, 16s rDNA sequencing, mass spectrometry-based metabolomics (LC-QQQ-MS and GC-MS), were used to reveal potential link between gut microbiota and the metabolism and cognition of the host. Microbial depletion induced by the antibiotics mix (ABX) verified that "gut-brain" can transmit information bidirectionally. Short-chain fatty acid-producing (SCFAs-producing) bacteria and amino acid-producing bacteria fluctuated greatly in 5×FAD mice, especially the reduction sharply of the Bifidobacteriaceae and the increase of the Lachnospiraceae family. Concentrations of several Tryptophan-kynurenine intermediates, lactic acid, CD4 cell, and CD8 cells were higher in serum of 5×FAD mice, whilst TCA cycle intermediates and Th1/Th2 were lower. In addition, the levels of iso-butyric acid (IBA) in feces, serum, and brain of 5×FAD mice were increased compared with WT-M mice, especially in serum. And IBA in the brain was positively correlated with Aβ and proinflammatory factors. Together, our finding highlighted that the alternation in gut microbiota affected the effective communication between the "gut-brain" axis in 5×FAD mice by regulating the immune system, carbohydrate, and energy metabolism.