{
  "abstract": "Abstract 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.",
  "authors": [
    {
      "affiliations": [
        "Department of Endocrinology and Nutrition, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina–IBIMA Plataforma Bionand, Málaga, Spain",
        "Center for Biomedical Network Research in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain",
        "Department of Endocrinology and Nutrition, Hospital Universitario Virgen de la Victoria–IBIMA Plataforma Bionand, Málaga, Spain"
      ],
      "name": "Virginia Mela"
    },
    {
      "affiliations": [
        "Department of Endocrinology and Nutrition, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina–IBIMA Plataforma Bionand, Málaga, Spain",
        "Center for Biomedical Network Research in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain",
        "Department of Endocrinology and Nutrition, Hospital Universitario Virgen de la Victoria–IBIMA Plataforma Bionand, Málaga, Spain"
      ],
      "name": "Violeta Heras"
    },
    {
      "affiliations": [
        "Department of Endocrinology and Nutrition, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina–IBIMA Plataforma Bionand, Málaga, Spain",
        "Department of Biological Models, Vilnius University, Vilnius, Lithuania"
      ],
      "name": "Monika Iesmantaite"
    },
    {
      "affiliations": [
        "Biomedical Magnetic Resonance Laboratory-BMRL, Fundación Pública Andaluza Progreso y Salud (FPS), Seville, Spain",
        "Biomedical Magnetic Resonance Laboratory-BMRL, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina–IBIMA Plataforma Bionand, Málaga, Spain",
        "Biomedical Research Networking Center in Bioengineering, Biomaterials & Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, Madrid, Spain"
      ],
      "name": "María Luisa García-Martín"
    },
    {
      "affiliations": [
        "Departament of Molecular Biology and Biochemistry, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain",
        "Molecular Basis of Biological systems (SIBIUMA), Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina–IBIMA Plataforma Bionand, Málaga, Spain",
        "Center for Biomedical Network Research in Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain"
      ],
      "name": "Manuel Bernal"
    },
    {
      "affiliations": [
        "Departament of Molecular Biology and Biochemistry, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain",
        "Molecular Basis of Biological systems (SIBIUMA), Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina–IBIMA Plataforma Bionand, Málaga, Spain"
      ],
      "name": "Joel D Posligua-García"
    },
    {
      "affiliations": [
        "Department of Endocrinology and Nutrition, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina–IBIMA Plataforma Bionand, Málaga, Spain",
        "Center for Biomedical Network Research in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain",
        "Department of Endocrinology and Nutrition, Hospital Universitario Virgen de la Victoria–IBIMA Plataforma Bionand, Málaga, Spain",
        "Department of Medicine and Dermatology, Facultad de Medicina, Universidad de Málaga, Málaga, Spain"
      ],
      "name": "Alba Subiri-Verdugo"
    },
    {
      "affiliations": [
        "Department of Endocrinology and Nutrition, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina–IBIMA Plataforma Bionand, Málaga, Spain",
        "Center for Biomedical Network Research in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain",
        "Department of Endocrinology and Nutrition, Hospital Universitario Virgen de la Victoria–IBIMA Plataforma Bionand, Málaga, Spain",
        "Department of Medicine and Dermatology, Facultad de Medicina, Universidad de Málaga, Málaga, Spain"
      ],
      "name": "José Ignacio Martínez-Montoro"
    },
    {
      "affiliations": [
        "Department of Endocrinology and Nutrition, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina–IBIMA Plataforma Bionand, Málaga, Spain",
        "Center for Biomedical Network Research in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain",
        "Department of Endocrinology and Nutrition, Hospital Universitario Virgen de la Victoria–IBIMA Plataforma Bionand, Málaga, Spain",
        "Department of Medicine and Dermatology, Facultad de Medicina, Universidad de Málaga, Málaga, Spain"
      ],
      "name": "Ana María Gómez-Pérez"
    },
    {
      "affiliations": [
        "Department of Endocrinology and Nutrition, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina–IBIMA Plataforma Bionand, Málaga, Spain",
        "Center for Biomedical Network Research in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain",
        "Department of Endocrinology and Nutrition, Hospital Universitario Virgen de la Victoria–IBIMA Plataforma Bionand, Málaga, Spain",
        "Department of Medicine and Dermatology, Facultad de Medicina, Universidad de Málaga, Málaga, Spain"
      ],
      "name": "Borja Bandera"
    },
    {
      "affiliations": [
        "Department of Endocrinology and Nutrition, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina–IBIMA Plataforma Bionand, Málaga, Spain",
        "Center for Biomedical Network Research in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain",
        "Department of Endocrinology and Nutrition, Hospital Universitario Virgen de la Victoria–IBIMA Plataforma Bionand, Málaga, Spain"
      ],
      "name": "Isabel Moreno-Indias"
    },
    {
      "affiliations": [
        "Department of Endocrinology and Nutrition, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina–IBIMA Plataforma Bionand, Málaga, Spain",
        "Center for Biomedical Network Research in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain",
        "Department of Endocrinology and Nutrition, Hospital Universitario Virgen de la Victoria–IBIMA Plataforma Bionand, Málaga, Spain",
        "Department of Medicine and Dermatology, Facultad de Medicina, Universidad de Málaga, Málaga, Spain"
      ],
      "name": "Francisco J Tinahones"
    }
  ],
  "title": "Microbiota fasting-related changes ameliorate cognitive decline in obesity and boost ex vivo microglial function through the gut-brain axis",
  "uid": "98de73aa-934e-5478-a25b-17fa8a52e057"
}