Natural Products for Depression: Preclinical Insights into Microbiota–Gut–Brain Axis Modulation and Pharmacological Potential

The microbiota-gut-brain axis (MGBA) is progressively associated with the pathophysiology of depression. This analysis consolidates existing preclinical findings on MGBA mechanisms associated with depression and assesses natural-product therapies through three key metabolite-related pathways: bile acid-responsive signaling via the farnesoid X receptor, G protein-coupled bile acid receptor 1, vitamin D receptor, and pregnane X receptor; metabolites from the kynurenine pathway and their connection to N-methyl-D-aspartate receptor signaling; and microbial indole-aryl hydrocarbon receptor signaling. Bile acid-responsive receptors and signaling pathways are examined as a system connecting microbiota-altered bile acid profiles to receptor-specific impacts on bile acid equilibrium, epithelial barrier integrity, immune modulation, metabolic signaling, and subsequent neuroplasticity-related reactions. These metabolite-associated domains converge with extensive MGBA mechanisms, encompassing short-chain fatty acid signaling, vagal interactions, serotonergic modulation, gamma-aminobutyric acid signaling, hypothalamic-pituitary-adrenal axis function, and barrier-immune pathways. In this analytical framework, natural products from marine and terrestrial sources are evaluated across several mechanistic domains and evidence levels, with direct host-target interactions, microbiota-related alterations, and experimentally validated microbiota-dependent pathways examined independently. This method facilitates a more nuanced evaluation of diverse preclinical results by elucidating the extent of mechanistic backing and translational significance across various fields. Due to the mostly preclinical characteristics of the evidence foundation, clinical application will necessitate authenticated biomarkers, standardized natural product formulations, pharmacokinetic and pharmacodynamic assessments, and regulated human studies.