The gut-brain axis in Alzheimer’s disease: traditional Chinese medicine constituents as modulators of gut-brain homeostasis

Abstract

Alzheimer’s disease (AD) currently lacks curative treatments, and the gut–brain axis plays an important role in regulating neuroinflammation during AD progression. Multiple bioactive components from traditional Chinese medicine (TCM), including polysaccharides, alkaloids, flavonoids and saponins, protect neurons through regulating gut microbiota composition, maintaining intestinal barrier function and modulating short-chain fatty acid (SCFA) metabolism. Different from previous reviews that mainly elaborate correlational relationships, the present paper systematically sorts out a multi-level action network of TCM components along the gut-brain axis. We address an interesting discrepancy in current findings on SCFAs: acetate can inhibit inflammation in microglia under mechanical stretch, yet fails to produce the same effect under LPS exposure. Nevertheless, increased SCFA levels in vivo are able to alleviate microglial dysfunction linked to aging. Such findings indicate that SCFA activities are influenced by stimulus types, compound categories and applied doses, reminding researchers to treat existing conclusions with caution. We also outline six widely existing methodological issues in relevant researches, and propose feasible solutions, including the documentation of absolute SCFA concentrations, experimental verification of causal relationships, and the use of AD pathological stimuli like Aβ and tau. This review may facilitate the shift from correlational analysis to mechanistic exploration, and provide useful references for the development of AD therapies targeting the gut–brain axis with TCM components.