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

HDHL INTIMIC cofunded call “Interrelation of the Intestinal Microbiome, Diet and Health” (IM 2017)
Maternal obesity and cognitive dysfunction in the offspring: cause-effect role of the GUT MicrobiOMe and early dietary prevention
Patricia Iozzo
Consiglio Nazionale delle Ricerche (CNR)


Partner Organization Partner Country
University of ValenciaSpain
Radboud UMCThe Netherlands
Max Planck Gesellschaft (MPG)Germany
Istituto Superiore di Sanità (ISS) (Collaborator in-kind)Italy
Mead Johnson Nutrition (now RB) (Collaborator in-kind and in cash)The Netherlands

1. Overall project description

1.1 Summary

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 hypothesize 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 use two existing cohorts of children to identify the gut bacteria and metabolites that are related to maternal obesity and offspring’s cognitive development in early, pre-scholar and scholar age. We use preclinical models to investigate cause-effect mechanisms, and develop tailored dietary interventions to counteract the effects of maternal obesity on the gut microbiota, improving offspring’s cognition. GUTMOM involves 6 academic centres, and a private industrial collaborator providing project co-funding. The plan includes dissemination and training activities for young scientists. Data management will follow the FAIR principles, and the study will contribute to the ongoing Knowledge Platform on Diet, Intestinal Microbiomics and Health.

1.2 Highlights

Current results indicate: 1) a positive effect of breastfeeding (in girls) or prescholar adherence to a mediterranean diet on selected neurodevelopment domains; 2) maternal BMI effects on microbiota and neurodevelpment in early childhood, and 3) a predictive value of meconium bacteria on prescholar neurodevelopment; 4) the transfer of children-donors' behaviour and phenotype into recipient germ-free mice (correlations) via microbiota transplantation; 5) an impact of maternal HFD, ELS and the combination on offspring's body weight, especially in males, and 6) a strong impact of ELS on microbiota, especially in females; 6) a moderate to strong impact of sex, gestational age, and smoking status on the metabolome of children; 7) efficacy of prenatal (maternal) administration of the antioxidant N-acetyl-cysteine (NAC) to prevent the negative effects of maternal obesity and to buffer adverse changes in the cognitive/emotional phenotype. 

4. Impact

4.1 List of publications

AuthorsTitleYear, Issue, PPPartners NumberDoiPdf
Project partner: UVTwo-Week Aflibercept or Erlotinib Administration Does Not Induce Changes in Intestinal Morphology in Male Sprague-Dawley Rats But Aflibercept Affects Serum and Urine Metabolic Profiles10.1016/j.tranon.2019.04.019. Gold open access
Project partner: UVHuman Breast Milk NMR Metabolomic Profile across Specific Geographical Locations and Its Association with the Milk Microbiota.10.3390/nu10101355. Gold open access
Project partner: UVA free radical theory of frailty.10.1016/j.freeradbiomed.2018.06.028. Green open access
Project partner: UVCentenarians Overexpress Pluripotency-Related Genes.10.1093/gerona/gly168
Project partner: UVSex Differences in Age-Associated Type 2 Diabetes in Rats—Role of Estrogens and Oxidative Stress.10.1155/2019/6734836. Gold open access
Project partner: UVRelation Between Genetic Factors and Frailty in Older Adults.10.1016/j.jamda.2019.03.011. Green open access
Project partner: UVRelevance of Oxygen Concentration in Stem Cell Culture for Regenerative Medicine.10.3390/ijms20051195. Gold open access
Project partner: UVRedox lipidomics to better understand brain aging and function.10.1016/j.freeradbiomed.2019.03.016. Green open access
Project partner: MPGFocus on FKBP51: A molecular link between stress and metabolic disorders.10.1016/j.molmet.2019.09.003. Gold open access
Project partner: MPGStress and glucocorticoid modulation of feeding and metabolism.10.1016/j.ynstr.2019.100171. Gold open access
Project partner: CNRImaging of brain glucose uptake by PET in obesity and cognitive dysfunction: life-course perspective.10.1530/EC-19-0348. Review
Project partner: CNRMicrobiota signatures relating to reduced memory and exploratory behaviour in the offspring of overweight mothers in a murine model.10.1038/s41598-019-48090-8. Gold open access
Project partner: ISSMaternal Obesity as a Risk Factor for Brain Development and Mental Health in the Offspring.10.1016/j.neuroscience.2020.01.023. Gold open access
Project partner: UVMagnetic resonance microscopy and correlative histopathology of the infarcted heart.10.1038/s41598-019-56436-5. Gold open access
Project partner: UVSomatic copy number alterations are associated with EGFR amplification and shortened survival in patients with primary glioblastoma. 10.1016/j.neo.2019.09.001. Gold open access
Project partner: UVBCL-xL, a Mitochondrial Protein Involved in Successful Aging: From C. elegans to Human Centenarians.10.3390/ijms21020418. Gold open access
Project partner: UVCentenarians: An excellent example of resilience for successful ageing.10.1016/j.mad.2019.111199
Project partner: UVExtracellular vesicles and redox modulation in aging. 10.1016/j.freeradbiomed.2019.11.032. Green open access
Partner CNRExclusive Breastfeeding Predicts Higher Hearing-Language Development in Girls of Preschool Age12(8):2320110.3390/nu12082320. Gold open access
Partner: ISSHigh-fat diet during adulthood interacts with prenatal stress, affecting both brain inflammatory and neuroendocrine markers in male rats. 202110.1111/ejn.15181
Partner: UVModerate Red Wine Consumption Increases the Expression of Longevity-Associated Genes in Controlled Human Populations and Extends Lifespan in Drosophila melanogaster. Antioxidants (Basel)202110.3390/antiox10020301
Partner:UVThe Status of EGFR Modulates the Effect of miRNA-200c on ZEB1 Expression and Cell Migration in Glioblastoma Cells202010.3390/ijms22010368
Partner: UVImportance of stem cell culture conditions for their derived extracellular vesicles therapeutic effect202110.1016/j.freeradbiomed.2021.03.028
Partner: UVTargeting Alzheimer's disease with multimodal polypeptide-based nanoconjugates202110.1126/sciadv.abf9180
Partner: UVBcl-xL as a Modulator of Senescence and Aging202110.3390/ijms22041527
Partner: UVMethionine transsulfuration pathway is upregulated in long-lived humans202110.1016/j.freeradbiomed.2020.11.026
Partner: UVGarcinoic acid prevents β-amyloid (Aβ) deposition in the mouse brain202010.1074/jbc.RA120.013303
Partner: UVExtracellular Vesicles from Healthy Cells Improves Cell Function and Stemness in Premature Senescent Stem Cells by miR-302b and HIF-1α Activation. Biomolecules202010.3390/biom10060957
Partner: UVMechanisms of FH Protection Against Neovascular AMD202010.3389/fimmu.2020.00443
Partner: UVCFH exerts anti-oxidant effects on retinal pigment epithelial cells independently from protecting against membrane attack complex201910.1038/s41598-019-50420-9
Partner: UVExceptional human longevity is associated with a specific plasma phenotype of ether lipids201910.1016/j.redox.2019.101127

4.2 Presentation of the project

Target groupAuthorsMeans of communicationHyperlinkPdf
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

4.3 List of submitted patents and other outputs

Patent licencePartners involvedYearInternational eu or national patentCommentPdf

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This project has received funding from the European Union’s
H2020 Research and Innovation Programme under grant agreement n.696300

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