Akkermansia muciniphila vesicles attenuate smoking-induced cognitive decline via ILA-mediated AhR-dependent microglial reprogramming.

Abstract

Chronic cigarette smoking accelerates age-related cognitive decline, yet the underlying mechanism remains elusive. Here, we elucidate a pathway through which smoking-induced gut dysbiosis contributes to cognitive impairment. This dysbiosis is marked by reductions in the abundances of Akkermansia muciniphila (A. muciniphila) and its metabolite indole-3-lactic acid (ILA), which correlate with cognitive deficits in older adult smokers. Using fecal microbiota transplantation, we demonstrate that the microbiota from smoke-exposed donors recapitulates cognitive impairment and microglial dysfunction in recipient mice. Importantly, these deficits were mitigated by treatment with either A. muciniphila-derived outer membrane vesicles (OMVs) or exogenous ILA, which restore synaptic integrity. Mechanistically, we demonstrate that both OMVs and ILA exert their neuroprotective effects via aryl hydrocarbon receptor (AhR) signaling. This AhR-dependent activation reprograms microglial metabolism toward oxidative phosphorylation, thereby suppressing neuroinflammation and restoring cellular bioenergetics. These findings suggest a mechanism through which smoking influences brain function via specific gut microbial metabolites and highlight the A. muciniphila-ILA-AhR axis as a promising target for preventing cognitive decline.