Related Experiment Video
Updated: May 12, 2025

Murine Fecal Isolation and Microbiota Transplantation
Published on: May 26, 2023
Microbiota fasting-related changes ameliorate cognitive decline in obesity and boost ex vivo microglial function
Virginia Mela1,2,3, Violeta Heras4,2,3, Monika Iesmantaite4,5
1Department of Endocrinology and Nutrition, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma Bionand, Málaga, Spain virginiamelarivas@gmail.com.
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.
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