Maternal obesity and cognitive dysfunction in the offspring: cause-effect role of the GUT MicrobiOMe and early dietary prevention

Early life is fundamental for brain and microbiota development. Gut microbiota influences brain function. Maternal obesity affects maturation of gut microbiota and is an important predictor of cognitive dysfunction in the offspring. Cognitive decline through life is an increasingly invalidating condition, due to population ageing and the high frequency of predisposing factors (obesity, unhealthy diets). We hypothesized that the negative effects of maternal obesity on cognitive function in the offspring are partly mediated by the microbiota and its metabolites, offering the opportunity for non-invasive risk-screening and -reduction by tailored foods and diets, since earliest life stages. We used two existing cohorts of children to provide leads, and preclinical models to prove cause-effect relationships, and develop tailored dietary interventions to counteract the effects of maternal obesity on cognition. GUTMOM involved academic centres, and a private industrial collaborator providing project co-funding. Our results indicate that maternal high-fat diet (HFD) and early-life stress (ELS) were more impactful than maternal body weight on offspring's health in mice; we identified bacteria and fecal metabolites that predicted cognition in children, and showed that fecal transplantation into mice reproduced a correlated phenotype. We also showed that ELS has an important impact on fecal microbiota and metabolites, with gender differences, and that antioxidant treatment during pregnancy is more beneficial for brain BDNF and CD68 expression in female than male mice born to HFD dams. The plan included intensive dissemination and training activities for young scientists, and the study has contributed to the ongoing Knowledge Platform on Diet, Intestinal Microbiomics and Health.


Partner Organization Partner Country
University of Valencia Spain
Radboud UMC Netherlands
Max Planck Gesellschaft (MPG) German
Istituto Superiore di Sanità (ISS) (Collaborator in-kind) Italy
Mead Johnson Nutrition (now RB) (Collaborator in-kind and in cash) Netherlands



Results indicate: 

  • a positive effect of breastfeeding (in girls) or prescholar adherence to a mediterranean diet on selected neurodevelopment domains;
  • maternal BMI effects on microbiota and neurodevelpment in early childhood, but mice and human studies suggest that HFD during pregnancy is more impactful in adulthood than maternal BMI, and
  • a predictive value of meconium bacteria on prescholar neurodevelopment, and 4) of selected fecal metabolites (also related with exclusive breast-feeding), as measured contextual to cognitive function at precholar age;
  • the transfer of prescholar children-donors' phenotype into recipient germ-free mice, via microbiota transplantation;
  • an impact of maternal HFD, ELS and the combination on offspring's body weight, especially in males, and
  • a strong impact of ELS on microbiota, especially in females, and fecal metabolome, especially in males, as well as on the microbiota-metabolome association;
  • efficacy of prenatal (maternal) administration of the antioxidant N-acetyl-cysteine (NAC) to prevent the negative effects of maternal HFD, by buffering adverse changes in brain BDNF and CD68 expression in female mice. 


Title: Two-Week Aflibercept or Erlotinib Administration Does Not Induce Changes in Intestinal Morphology in Male Sprague-Dawley Rats But Aflibercept Affects Serum and Urine Metabolic Profiles
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Title: Human Breast Milk NMR Metabolomic Profile across Specific Geographical Locations and Its Association with the Milk Microbiota.
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Title: A free radical theory of frailty.
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Title: Centenarians Overexpress Pluripotency-Related Genes.
Author: Inglés M*, Mas-Bargues C*, Berna-Erro A*, Matheu A*, Sanchís P*, Avellana JA*, Borrás C*, Viña J*.
Title: Sex Differences in Age-Associated Type 2 Diabetes in Rats—Role of Estrogens and Oxidative Stress.
Author: Díaz A*, López-Grueso R*, Gambini J*, Monleón D*, Mas-Bargues C*, Abdelaziz KM*, Viña J*, Borrás C*.
Title: Relation Between Genetic Factors and Frailty in Older Adults.
Author: Inglés M*, Mas-Bargues C*, Gimeno-Mallench L*, Cruz-Guerrero R, García-García FJ, Gambini J*, Borrás C*, Rodríguez-Mañas L, Viña J*.
Title: Relevance of Oxygen Concentration in Stem Cell Culture for Regenerative Medicine.
Author: Mas-Bargues C*, Sanz-Ros J*, Román-Domínguez A*, Inglés M*, Gimeno-Mallench L*, El Alami M*, Viña-Almunia J*, Gambini J*, Viña J*, Borrás C*.
Title: Redox lipidomics to better understand brain aging and function.
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Title: Focus on FKBP51: A molecular link between stress and metabolic disorders.
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Title: Stress and glucocorticoid modulation of feeding and metabolism.
Author: Balsevich G, Abizaid A, Chen A, Karatsoreos IN, Schmidt MV*.
Title: Imaging of brain glucose uptake by PET in obesity and cognitive dysfunction: life-course perspective.
Author: Iozzo P*, Guzzardi MA*
Title: Microbiota signatures relating to reduced memory and exploratory behaviour in the offspring of overweight mothers in a murine model.
Author: Sanguinetti E*, Guzzardi MA*, Tripodi M*, Panetta D*, Selma-Royo M, Zega A*, Telleschi M*, Collado MC, Iozzo P*.
Title: Maternal Obesity as a Risk Factor for Brain Development and Mental Health in the Offspring
Author: Cirulli F*, Musillo C*, Berry A*.
Title: Embedding early experiences into brain function: perspectives from behavioral epigenetics
Author: Cirulli F*
Title: Magnetic resonance microscopy and correlative histopathology of the infarcted heart.
Author: Perez-Terol I*, Rios-Navarro C*, de Dios E*, Morales JM*, Gavara J*, Perez-Sole N*, Diaz A*, Minana G*, Segura-Sabater R*, Bonanad C*, Bayés-Genis A*, Husser O, Monmeneu JV*, Lopez-Lereu MP*, Nunez J*, Chorro FJ*, Ruiz-Sauri A*, Bodi V*, Monleon D*.
Title: Somatic copy number alterations are associated with EGFR amplification and shortened survival in patients with primary glioblastoma.
Author: Muñoz-Hidalgo L*, San-Miguel T*, Megías J*, Monleón D*, Navarro L*, Roldán P*, Cerdá-Nicolás M*, López-Ginés C*.
Title: BCL-xL, a Mitochondrial Protein Involved in Successful Aging: From C. elegans to Human Centenarians.
Author: Borrás C*, Mas-Bargues C*, Román-Domínguez A*, Sanz-Ros J*, Gimeno-Mallench L*, Inglés M*, Gambini J*, Viña J*.
Title: Centenarians: An excellent example of resilience for successful ageing.
Author: Borras C*, Ingles M*, Mas-Bargues C*, Dromant M*, Sanz-Ros J*, Román-Domínguez A*, Gimeno-Mallench L*, Gambini J*, Viña J*.
Title: Extracellular vesicles and redox modulation in aging.
Author: Borras C*, Mas-Bargues C*, Sanz-Ros J*, Román-Domínguez A*, Gimeno-Mallench L*, Inglés M*, Gambini J*, Viña J*.
Title: Exclusive Breastfeeding Predicts Higher Hearing-Language Development in Girls of Preschool Age
Author: Guzzardi MA*, Granziera F*, Sanguinetti E*, Muratori F, Iozzo P*.
Title: High-fat diet during adulthood interacts with prenatal stress, affecting both brain inflammatory and neuroendocrine markers in male rats.
Author: Berry A*, Mazzelli M, Musillo C*, Riva MA, Cattaneo A, Cirulli F*.
Title: Moderate Red Wine Consumption Increases the Expression of Longevity-Associated Genes in Controlled Human Populations and Extends Lifespan in Drosophila melanogaster. Antioxidants (Basel)
Author: Gambini J*, Gimeno-Mallench L*, Olaso-Gonzalez G*, Mastaloudis A, Traber MG, Monleón D*, Borrás C*, Viña J*.
Title: The Status of EGFR Modulates the Effect of miRNA-200c on ZEB1 Expression and Cell Migration in Glioblastoma Cells
Author: Muñoz-Hidalgo L*, San-Miguel T*, Megías J*, Serna E*, Calabuig-Fariñas S*, Monleón D*, Gil-Benso R*, Cerdá-Nicolás M*, López-Ginés C*.
Title: Importance of stem cell culture conditions for their derived extracellular vesicles therapeutic effect
Author: Mas-Bargues C*, Borrás C*.
Title: Targeting Alzheimer's disease with multimodal polypeptide-based nanoconjugates
Author: Duro-Castano A*, Borrás C*, Herranz-Pérez V*, Blanco-Gandía MC, Conejos-Sánchez I*, Armiñán A*, Mas-Bargues C*, Inglés M*, Miñarro J*, Rodríguez-Arias M*, García- Verdugo JM*, Viña J*, Vicent MJ.
Title: Bcl-xL as a Modulator of Senescence and Aging
Author: Mas-Bargues C*, Borrás C*, Viña J*.
Title: Methionine transsulfuration pathway is upregulated in long-lived humans
Author: Mota-Martorell N, Jové M, Borrás C*, Berdún R, Obis È, Sol J, Cabré R, Pradas I, Galo-Licona JD, Puig J, Viña J*, Pamplona R.
Title: Garcinoic acid prevents β-amyloid (Aβ) deposition in the mouse brain
Author: Marinelli R, Torquato P, Bartolini D, Mas-Bargues C*, Bellezza G, Gioiello A, Borras C*, De Luca A, Fallarino F, Sebastiani B, Mani S, Sidoni A, Viña J*, Leri M, Bucciantini M, Nardiello P, Casamenti F, Galli F.
Title: Extracellular Vesicles from Healthy Cells Improves Cell Function and Stemness in Premature Senescent Stem Cells by miR-302b and HIF-1α Activation. Biomolecules
Author: Mas-Bargues C*, Sanz-Ros J*, Román-Domínguez A*, Gimeno-Mallench L*, Inglés M*, Viña J*, Borrás C*.
Title: Mechanisms of FH Protection Against Neovascular AMD
Author: Borras C*, Delaunay K, Slaoui Y, Abache T, Jorieux S, Naud MC, Sanharawi ME, Gelize E, Lassiaz P, An N, Kowalczuk L, Ayassami C, Moulin A, Behar-Cohen F, Mascarelli F, Dinet V.
Title: CFH exerts anti-oxidant effects on retinal pigment epithelial cells independently from protecting against membrane attack complex
Author: Borras C*, Canonica J, Jorieux S, Abache T, El Sanharawi M, Klein C, Delaunay K, Jonet L, Salvodelli M, Naud MC, Arsenijevic Y, Shalabi A, Souchaud L, Behar- Cohen F, Dinet V.
Title: Exceptional human longevity is associated with a specific plasma phenotype of ether lipids
Author: Pradas I, Jové M, Huynh K, Puig J, Ingles M*, Borras C*, Viña J*, Meikle PJ, Pamplona R.
Title: Whole-exome sequencing, EGFR amplification and infiltration patterns in human glioblastoma
Author: López-Ginés C*, Muñoz-Hidalgo L*, San-Miguel T*, Megías J*, Triviño JC*, Calabuig S*, Roldán P*, Cerdá-Nicolás M*, Monleón D*.
Title: Lifelong soya consumption in males does not increase lifespan but increases health span under a metabolic stress such as type 2 diabetes mellitus
Author: Borrás C*, Abdelaziz KM*, Díaz A*, Gambini J*, Jové M, López-Grueso R*, Mas-Bargues C*, Monleón D*, Pamplona R, Viña J*.
Title: Healthy lifestyle, metabolomics and incident type 2 diabetes in a population-based cohort from Spain
Author: Delgado-Velandia M, Gonzalez-Marrachelli V*, Domingo-Relloso A*, Galvez-Fernandez M, Grau-Perez M*, Olmedo P*, Galan I, Rodriguez-Artalejo F, Amigo N, Briongos-Figuero L, Redon J*, Martin-Escudero JC, Monleon-Salvado D*, Tellez-Plaza M*, Sotos-Prieto M.
Title: Exploring New Kingdoms: The Role of Extracellular Vesicles in Oxi-Inflamm-Aging Related to Cardiorenal Syndrome
Author: Mas-Bargues C*, Alique M, Barrús-Ortiz MT, Borrás C*, Rodrigues-Díez R.
Title: Diagnostic Performance of Muscle Echo Intensity and Fractal Dimension for the Detection of Frailty Phenotype
Author: Mirón Mombiela R*, Vucetic J*, Monllor P*, Cárdenas-Herrán JS*, Taltavull de La Paz P, Borrás C*.
Title: Estrogen Replacement Therapy Induces Antioxidant and Longevity-Related Genes in Women after Medically Induced Menopause
Author: Borrás C*, Ferrando M, Inglés M*, Gambini J*, Lopez-Grueso R*, Edo R*, Mas-Bargues C*, Pellicer A*, Viña J*.
Title: Maturation of the Visceral (Gut-Adipose-Liver) Network in Response to the Weaning Reaction versus Adult Age and Impact of Maternal High-Fat Diet
Author: Guzzardi MA*, La Rosa F*, Campani D, Cacciato Insilla A, De Sena V*, Panetta D*, Brunetto MR, Bonino F, Collado MC, Iozzo P*.
Title: Identification and Characterization of Human Observational Studies in Nutritional Epidemiology on Gut Microbiomics for Joint Data Analysis
Author: Pinart M, Nimptsch K, Forslund SK, Schlicht K, Gueimonde M, Brigidi P, Turroni S, Ahrens W, Hebestreit A, Wolters M, Dötsch A, Nöthlings U, Oluwagbemigun K, Cuadrat RRC, Schulze MB, Standl M, Schloter M, De Angelis M, Iozzo P*, Guzzardi MA*, Vlaemynck G, Penders J, Jonkers DMAE, Stemmer M, Chiesa G, Cavalieri D, De Filippo C, Ercolini D, De Filippis F, Ribet D, Achamrah N, Tavolacci MP, Déchelotte P, Bouwman J, Laudes M, Pischon T.
Title: Associations between the Mediterranean Diet Pattern and Weight Status and Cognitive Development in Preschool Children
Author: Granziera F*, Guzzardi MA*, Iozzo P*.
Title: Maternal pre-pregnancy overweight and neonatal gut bacterial colonization are associated with cognitive development and gut microbiota composition in pre-school-age offspring
Author: Guzzardi MA*, Ederveen THA*, Rizzo F, Weisz A, Collado MC, Muratori F, Gross G*, Alkema W*, Iozzo P*.
Title: Evidence of a Gastro-Duodenal Effect on Adipose Tissue and Brain Metabolism, Potentially Mediated by Gut-Liver Inflammation: A Study with Positron Emission Tomography and Oral 18FDG in Mice
Author: Guzzardi MA*, La Rosa F*, Campani D, Cacciato Insilla A, Nannipieri M, Brunetto MR, Bonino F, Iozzo P*.
Title: Liver and White/Brown Fat Dystrophy Associates with Gut Microbiota and Metabolomic Alterations in 3xTg Alzheimer's Disease Mouse Model
Author: Guzzardi MA*, La Rosa F*, Campani D, Collado MC, Monleon D, Cacciato Insilla A, Tripodi M, Zega A*, Dattilo A, Brunetto MR, Maffei M, Bonino F, Iozzo P*.
Title: Curcuma Longa, the "Golden Spice" to Counteract Neuroinflammaging and Cognitive Decline-What Have We Learned and What Needs to Be Done
Author: Berry A*, Collacchi B, Masella R, Varì R, Cirulli F*.

Communication & Dissemination Activities

Target groupAuthorsMeans of communication
Scientists, clinicians, diabetologists, industryProject partner CNR: “Neuroimaging and neuromodulation in obesity and type 2 diabetes”, Annual Meeting of the American Diabetes Association, Orlando, USA, 2018Invited lecture
General practitioners, specialistsProject partner CNR: “Microbiota, health and obesity”, Medical complications of gut dysbiosis (educational event with credits), Lucca, Italy, 2018Plenary lecture
PhD students, young post-doc investigators, academic scientists (approximately 30 attendants)Project partner CNR: “Insulin sensitivity by PET imaging”, Turku Lifespan seminars, Turku, Finland, 29th April 2019Invited seminar
Academic scientists (approximately 50 attendants)Project partner CNR: “Brain metabolism in Obesity, diabetes, cognitive dysfunction. Genetic models & translational approach”, Neuroendocrinology and Brain Imaging meeting (satellite symposium of the Human Brain Mapping project), Rome, 8-9 June 2019Invited lecture
Academic scientists (approximately 300 attendants)Project partner CNR: “Cognitive decline: new evidence” as part of MULTIDISCIPLINARY AND MULTIDIMENSIONAL PANORAMA DIABETES FORUM, Italian Society of Diabetology (SID), Riccione, 8-12 March 2019Invited lecture
Academic, scientist, policy makers, journalists, industry, schools (approximately 300 attendants)Project partner CNR: “Obesity: early onset and long-term complications”, IFC50, Pisa 4 April 2019. Event created in order to celebrate 50 years of the Institute of Clinical Physiology of CNRInvited lecture
Academic, scientist (approximately 50 attendants)Project partner CNR: “Organ metabolism in the obesity pathogenesis and its complications”, in the context of the XII edition of Parma Diabetes, Parma, 23-24 January 2020Lecture. Young Investigators Award in diabetology established by the Italian Society of Diabetology (SID)
Academic scientists, studentsProject partner MPG, University of Darmstadt, Darmstadt (Germany), May 2019Invited presentation
Academic scientists, studentsProject partner MPG, University of Ulm, Ulm, Germany, June 2019Invited presentation
Academic scientists, studentsProject partner MPG, Neuroscience School of Advanced Studies, Venice, Italy, Sept. 2019Invited lecturer
Academic scientists, studentsProject partner MPG, World Association of Stress and Anxiety Disorders (WASAD), Würzburg, Germany, Oct. 2019Plenary lecture
Academic scientists, diabetologists, studentsProject Partner CNR: “Intestino e SNC” (Gut and CNS), session “Diabetes: a central nervous system disease”, Incontri Pisani di Endocrinologia e metabolismo (IPEM) - attualità in ambito diabetologico, remote conference with ECM, 13-14 november 2020Invited lecture
Scientists, academia, students, industry, cliniciansCNR. Investigation of metabolism by PET-CT, Symposium of the Study Group DiabImage, Annual Congress of the European Association for the Study of Diabetes, Virtual EASD Meeting, 28/09/2021Invited lecture
Scientists, academia, obesity clinicians, nutritionistsCNR. Associations between the Mediterranean Diet Pattern and Weight Status and Cognitive Development in Preschool Children. Congress, Italian Obesity Society, Livorno 28-10-2021Poster, winner best session poster
Scientists, industry, academia, studentsCNR. Non-alcoholic fatty liver: brain and entero-hormones. European Association for the Study of the Liver (EASL), Dublin, scheduled for September 2022Invited lecture
Academia, clinicians, students, industryCNR. Obesity and brain. Congress of the Italian Society of Internal Medicine, Rome, scheduled for October 2022Invited lecture
Academia, clinicians, students, industryCNR. Imaging of cardiac metabolism. Italian Diabetes Society, Rimini, scheduled for October 2022Invited lecture


Project number:
Duration: 100%
Duration: 100 %
Project lead and secretary:
Patricia Iozzo