Curr Opin Immunol. 2025 Dec 11;98:102708. doi: 10.1016/j.coi.2025.102708. Online ahead of print.

ABSTRACT

The microbiota-gut-brain axis (MGBA) has been recognized as an important communication network between the gut and the brain. This network operates through immune, neural, and endocrine pathways, wherein microbiota-derived metabolites act as essential messengers regulating MGBA. Among gut metabolites, indole and its derivatives derived from tryptophan by gut microbiota are emerging as critical factors along the MGBA. By activating the aryl hydrocarbon receptor (AhR), these metabolites help modulate neuroimmune responses by regulating microglial activation, astrocyte reactivity, and the integrity of the blood-brain barrier (BBB), thereby exerting impacts on neuroinflammation, nerve regeneration, and BBB function. Although animal studies are promising, turning these findings into clinical translation is still difficult due to the conditional effects of AhR signaling, the reliable biomarkers, and the challenges in gut metabolite delivery. This review aims to summarize recent advances in understanding the indole-brain connection, critically evaluate current therapeutic strategies, and highlight the need for more targeted therapies.

PMID:41385980 | DOI:10.1016/j.coi.2025.102708