Role of <i>Ruminococcus gnavus</i> in the elderly with cognitive impairment: A case-control study and an animal experiment

BackgroundCognitive 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.ObjectiveThis study aims to elucidate the association between <i>Ruminococcus gnavus</i> 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 <i>R. gnavus</i> in AD-related CI.MethodsFecal 16S rRNA profiles from 30 elders with CI and 30 matched controls were compared, then pseudo-germ-free aged mice were monocolonized with <i>R. gnavus</i>. 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<i>R. gnavus</i> was enriched in patients with CI and inversely correlated with Mini-Mental State Examination scores. In aged pseudo-germ-free mice monocolonized with <i>R. gnavus</i>, learning and memory declined and autophagy was suppressed: the mRNA levels of <i>Atg2a</i>, <i>Atg5</i>, <i>Atg7</i>, <i>Atg9a</i>, <i>Atg14</i>, <i>Atg16</i>, <i>Beclin-1</i>, <i>Lc3b</i> and <i>Ulk1</i> decreased, whereas <i>P62</i> 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.ConclusionsThe enrichment of <i>R. gnavus</i> 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.