Microbiota fasting-related changes ameliorate cognitive decline in obesity and boost ex vivo microglial function through the gut-brain axis

BACKGROUND: Obesity-related cognitive decline is linked to gut microbiota dysbiosis, with emerging evidence suggesting that dietary interventions may ameliorate cognitive impairment via gut-brain axis modulation. The role of microglial cells in this process remains underexplored. OBJECTIVE: To investigate how diet-induced changes in gut microbiota influence cognitive function in individuals with obesity and their microglial activity, and to determine the impact of specific dietary interventions. DESIGN: This study included 96 participants with obesity who were randomised into three dietary intervention groups: Mediterranean diet (Med), alternate-day fasting (ADF) and ketogenic diet (Keto). Cognitive performance and microbiota composition were assessed pre-intervention and post-intervention. The effects of microbiota-related changes on microglial function were further evaluated in mice models through faecal transplantation and in vitro model with microbiota exosome treatment. RESULTS: Both the Keto and ADF groups demonstrated significant weight loss, but cognitive performance improved most notably in the ADF group, in association with reduced inflammation. Diet-related microbiota composition was correlated with the cognitive outcomes in the human study. Mice models confirmed that the cognitive benefits of ADF were microbiota-dependent and linked to enhanced microglial phagocytic capacity and reduced inflammation, accompanied by changes in microglia morphology. CONCLUSION: Fasting-induced modifications in gut microbiota contribute to cognitive improvement in individuals with obesity, with microglial cells playing a crucial mediatory role. Among the interventions, ADF most effectively enhanced microglial function and cognitive performance, suggesting its potential as a therapeutic strategy for obesity-related cognitive decline. Further studies are required to fully elucidate the underlying mechanisms. TRIAL REGISTRATION NUMBER: NCT04453150.