Cognitive impairment (CI) is a complex condition, and older adults with CI are several times more likely to develop Alzheimer's disease (AD) than their cognitively normal peers. The gut–brain axis plays a crucial role in neurodegeneration, with gut microbiota potentially affecting cognition via autophagy regulation.
Objective
This study aims to elucidate the association between Ruminococcus gnavus and CI in older adults, dissect the autophagy-related mechanisms potentially involved in this association and provide new insights and evidence for the role of R. gnavus in AD-related CI.
Methods
Fecal 16S rRNA profiles from 30 elders with CI and 30 matched controls were compared, then pseudo-germ-free aged mice were monocolonized with R. gnavus. Cognitive performance (Morris water maze), autophagy markers (quantitative PCR, western blot analysis, histology and ELISA) and untargeted metabolomics were evaluated to identify autophagy-related pathways.
Results
R. gnavus was enriched in patients with CI and inversely correlated with Mini-Mental State Examination scores. In aged pseudo-germ-free mice monocolonized with R. gnavus, learning and memory declined and autophagy was suppressed: the mRNA levels of Atg2a, Atg5, Atg7, Atg9a, Atg14, Atg16, Beclin-1, Lc3b and Ulk1 decreased, whereas P62 increased. Consistent protein changes, decreased LC3B and Beclin-1 levels with elevated P62 and immunohistochemistry indicated reduced LC3B-positive plaques in the CA1, CA3 and cortex. Metabolomics revealed disrupted glycerophospholipid metabolism and enriched autophagy-related pathways.
Conclusions
The enrichment of R. gnavus is associated with CI, with autophagy potentially mediating its effects on cognition via the gut–brain axis. Causality remains to be established through longitudinal studies.
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