Maternal obesity and cognitive dysfunction in the offspring: cause-effect role of the GUT MicrobiOMe and early dietary prevention
Consortium
| Partner Organization | Partner Country |
|---|---|
| University of Valencia | Spain |
| Radboud UMC | The 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
| Authors | Title | Year, Issue, PP | Partners Number | Doi | |
|---|---|---|---|---|---|
| Project partner: UV | 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 | 10.1016/j.tranon.2019.04.019. Gold open access | |||
| Project partner: UV | Human Breast Milk NMR Metabolomic Profile across Specific Geographical Locations and Its Association with the Milk Microbiota. | 10.3390/nu10101355. Gold open access | |||
| Project partner: UV | A free radical theory of frailty. | 10.1016/j.freeradbiomed.2018.06.028. Green open access | |||
| Project partner: UV | Centenarians Overexpress Pluripotency-Related Genes. | 10.1093/gerona/gly168 | |||
| Project partner: UV | Sex Differences in Age-Associated Type 2 Diabetes in Rats—Role of Estrogens and Oxidative Stress. | 10.1155/2019/6734836. Gold open access | |||
| Project partner: UV | Relation Between Genetic Factors and Frailty in Older Adults. | 10.1016/j.jamda.2019.03.011. Green open access | |||
| Project partner: UV | Relevance of Oxygen Concentration in Stem Cell Culture for Regenerative Medicine. | 10.3390/ijms20051195. Gold open access | |||
| Project partner: UV | Redox lipidomics to better understand brain aging and function. | 10.1016/j.freeradbiomed.2019.03.016. Green open access | |||
| Project partner: MPG | Focus on FKBP51: A molecular link between stress and metabolic disorders. | 10.1016/j.molmet.2019.09.003. Gold open access | |||
| Project partner: MPG | Stress and glucocorticoid modulation of feeding and metabolism. | 10.1016/j.ynstr.2019.100171. Gold open access | |||
| Project partner: CNR | Imaging of brain glucose uptake by PET in obesity and cognitive dysfunction: life-course perspective. | 10.1530/EC-19-0348. Review | |||
| Project partner: CNR | Microbiota 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: ISS | Maternal 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: UV | Magnetic resonance microscopy and correlative histopathology of the infarcted heart. | 10.1038/s41598-019-56436-5. Gold open access | |||
| Project partner: UV | Somatic 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: UV | BCL-xL, a Mitochondrial Protein Involved in Successful Aging: From C. elegans to Human Centenarians. | 10.3390/ijms21020418. Gold open access | |||
| Project partner: UV | Centenarians: An excellent example of resilience for successful ageing. | 10.1016/j.mad.2019.111199 | |||
| Project partner: UV | Extracellular vesicles and redox modulation in aging. | 10.1016/j.freeradbiomed.2019.11.032. Green open access | |||
| Partner CNR | Exclusive Breastfeeding Predicts Higher Hearing-Language Development in Girls of Preschool Age | 12(8):2320 | 1 | 10.3390/nu12082320. Gold open access | |
| Partner: ISS | High-fat diet during adulthood interacts with prenatal stress, affecting both brain inflammatory and neuroendocrine markers in male rats. | 2021 | 10.1111/ejn.15181 | ||
| Partner: UV | Moderate Red Wine Consumption Increases the Expression of Longevity-Associated Genes in Controlled Human Populations and Extends Lifespan in Drosophila melanogaster. Antioxidants (Basel) | 2021 | 10.3390/antiox10020301 | ||
| Partner:UV | The Status of EGFR Modulates the Effect of miRNA-200c on ZEB1 Expression and Cell Migration in Glioblastoma Cells | 2020 | 10.3390/ijms22010368 | ||
| Partner: UV | Importance of stem cell culture conditions for their derived extracellular vesicles therapeutic effect | 2021 | 10.1016/j.freeradbiomed.2021.03.028 | ||
| Partner: UV | Targeting Alzheimer's disease with multimodal polypeptide-based nanoconjugates | 2021 | 10.1126/sciadv.abf9180 | ||
| Partner: UV | Bcl-xL as a Modulator of Senescence and Aging | 2021 | 10.3390/ijms22041527 | ||
| Partner: UV | Methionine transsulfuration pathway is upregulated in long-lived humans | 2021 | 10.1016/j.freeradbiomed.2020.11.026 | ||
| Partner: UV | Garcinoic acid prevents β-amyloid (Aβ) deposition in the mouse brain | 2020 | 10.1074/jbc.RA120.013303 | ||
| Partner: UV | Extracellular Vesicles from Healthy Cells Improves Cell Function and Stemness in Premature Senescent Stem Cells by miR-302b and HIF-1α Activation. Biomolecules | 2020 | 10.3390/biom10060957 | ||
| Partner: UV | Mechanisms of FH Protection Against Neovascular AMD | 2020 | 10.3389/fimmu.2020.00443 | ||
| Partner: UV | CFH exerts anti-oxidant effects on retinal pigment epithelial cells independently from protecting against membrane attack complex | 2019 | 10.1038/s41598-019-50420-9 | ||
| Partner: UV | Exceptional human longevity is associated with a specific plasma phenotype of ether lipids | 2019 | 10.1016/j.redox.2019.101127 |
4.2 Presentation of the project
| Target group | Authors | Means of communication | Hyperlink | |
|---|---|---|---|---|
| Scientists, clinicians, diabetologists, industry | Project partner CNR: “Neuroimaging and neuromodulation in obesity and type 2 diabetes”, Annual Meeting of the American Diabetes Association, Orlando, USA, 2018 | Invited lecture | ||
| General practitioners, specialists | Project partner CNR: “Microbiota, health and obesity”, Medical complications of gut dysbiosis (educational event with credits), Lucca, Italy, 2018 | Plenary 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 2019 | Invited 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 2019 | Invited 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 2019 | Invited 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 CNR | Invited 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 2020 | Lecture. Young Investigators Award in diabetology established by the Italian Society of Diabetology (SID) | ||
| Academic scientists, students | Project partner MPG, University of Darmstadt, Darmstadt (Germany), May 2019 | Invited presentation | ||
| Academic scientists, students | Project partner MPG, University of Ulm, Ulm, Germany, June 2019 | Invited presentation | ||
| Academic scientists, students | Project partner MPG, Neuroscience School of Advanced Studies, Venice, Italy, Sept. 2019 | Invited lecturer | ||
| Academic scientists, students | Project partner MPG, World Association of Stress and Anxiety Disorders (WASAD), Würzburg, Germany, Oct. 2019 | Plenary lecture | ||
| Academic scientists, diabetologists, students | Project 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 2020 | Invited lecture |
4.3 List of submitted patents and other outputs
| Patent licence | Partners involved | Year | International eu or national patent | Comment |
|---|
