Smoking-induced gut dysbiosis reduces Akkermansia muciniphila and its metabolite indole-3-lactic acid, contributing to cognitive impairment via AhR-dependent microglial reprogramming, and treatment with A. muciniphila-derived outer membrane vesicles or exogenous ILA mitigates these deficits.
Key Findings
Results
Chronic cigarette smoking is associated with reductions in Akkermansia muciniphila abundance and its metabolite indole-3-lactic acid (ILA) that correlate with cognitive deficits in older adult smokers.
Both A. muciniphila abundance and ILA levels were reduced in gut microbiota of older adult smokers compared to non-smokers.
The reductions in A. muciniphila and ILA correlated with measured cognitive deficits in the human cohort.
This finding establishes a link between smoking-induced gut dysbiosis and cognitive impairment.
Results
Fecal microbiota transplantation (FMT) from smoke-exposed donors recapitulates cognitive impairment and microglial dysfunction in recipient mice.
Recipient mice transplanted with microbiota from smoke-exposed donors developed cognitive impairment.
Microglial dysfunction was also observed in FMT recipient mice, mirroring the effects of direct smoke exposure.
This experimental approach demonstrated that the gut microbiota is sufficient to transfer the cognitive phenotype.
Results
Treatment with A. muciniphila-derived outer membrane vesicles (OMVs) mitigated smoking-induced cognitive deficits and restored synaptic integrity.
OMVs derived from A. muciniphila were used as a treatment intervention in smoke-exposed or FMT recipient mice.
OMV treatment restored synaptic integrity that had been disrupted by smoking-induced dysbiosis.
The neuroprotective effects of OMVs were demonstrated to be dependent on aryl hydrocarbon receptor (AhR) signaling.
Results
Exogenous ILA treatment also mitigated smoking-induced cognitive deficits and restored synaptic integrity via AhR signaling.
Administration of exogenous ILA recapitulated the neuroprotective effects seen with OMV treatment.
ILA exerted its effects through AhR-dependent activation, establishing a mechanistic parallel with OMV action.
Restoration of synaptic integrity was observed following ILA treatment.
Results
Both OMVs and ILA exert neuroprotective effects by reprogramming microglial metabolism toward oxidative phosphorylation via AhR signaling.
AhR-dependent activation was identified as the mechanistic pathway through which both OMVs and ILA act on microglia.
This AhR activation reprogrammed microglial metabolism toward oxidative phosphorylation.
The metabolic reprogramming suppressed neuroinflammation and restored cellular bioenergetics in microglia.
Conclusions
The A. muciniphila-ILA-AhR axis is identified as a promising target for preventing smoking-related cognitive decline.
The study highlights the A. muciniphila-ILA-AhR axis as a mechanistic pathway linking gut dysbiosis to brain function.
The findings suggest a mechanism through which smoking influences brain function via specific gut microbial metabolites.
Both OMVs and ILA represent potential therapeutic interventions targeting this axis.