GUTMOM

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

Project description

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.

Consortium

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

 

Highlights

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. 

Products

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
Author: Forsgård RA, Marrachelli VG*, Lindén J, Frias R, Collado MC*, Korpela R, Monleon D*, Spillmann T, Österlund P.
Link: https://doi.org/10.1016/j.tranon.2019.04.019
Title: Human Breast Milk NMR Metabolomic Profile across Specific Geographical Locations and Its Association with the Milk Microbiota.
Author: Gómez-Gallego C, Morales JM*, Monleón D*, du Toit E, Kumar H, Linderborg KM, Zhang Y, Yang B, Isolauri E, Salminen S, Collado MC.
Link: https://doi.org/10.3390/nu10101355
Title: A free radical theory of frailty.
Author: Viña J*, Borras C*, Gomez-Cabrera MC*.
Link: https://doi.org/10.1016/j.freeradbiomed.2018.06.028
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*.
Link: https://doi.org/10.1093/gerona/gly168
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*.
Link: https://doi.org/10.1155/2019/6734836
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*.
Link: https://doi.org/10.1016/j.jamda.2019.03.011
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*.
Link: https://doi.org/10.3390/ijms20051195
Title: Redox lipidomics to better understand brain aging and function.
Author: Pamplona R, Borras C*, Jové M, Pradas I, Ferrer I, Viña J*.
Link: https://doi.org/10.1016/j.freeradbiomed.2019.03.016
Title: Focus on FKBP51: A molecular link between stress and metabolic disorders.
Author: Häusl AS*, Balsevich G*, Gassen NC*, Schmidt MV*.
Link: https://doi.org/10.1016/j.molmet.2019.09.003
Title: Stress and glucocorticoid modulation of feeding and metabolism.
Author: Balsevich G, Abizaid A, Chen A, Karatsoreos IN, Schmidt MV*.
Link: https://doi.org/10.1016/j.ynstr.2019.100171
Title: Imaging of brain glucose uptake by PET in obesity and cognitive dysfunction: life-course perspective.
Author: Iozzo P*, Guzzardi MA*
Link: https://doi.org/10.1530/ec-19-0348
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*.
Link: https://doi.org/10.1038/s41598-019-48090-8
Title: Maternal Obesity as a Risk Factor for Brain Development and Mental Health in the Offspring
Author: Cirulli F*, Musillo C*, Berry A*.
Link: https://doi.org/10.1016/j.neuroscience.2020.01.023
Title: Embedding early experiences into brain function: perspectives from behavioral epigenetics
Author: Cirulli F*
Link: https://doi.org/10.1016/B978-0-12-819262-7.00009-X
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*.
Link: https://doi.org/10.1038/s41598-019-56436-5
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*.
Link: https://doi.org/10.1016/j.neo.2019.09.001
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*.
Link: https://doi.org/10.3390/ijms21020418https://doi.org/10.3390/ijms21020418
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*.
Link: https://doi.org/10.1016/j.mad.2019.111199
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*.
Link: https://doi.org/10.1016/j.freeradbiomed.2019.11.032
Title: Exclusive Breastfeeding Predicts Higher Hearing-Language Development in Girls of Preschool Age
Author: Guzzardi MA*, Granziera F*, Sanguinetti E*, Muratori F, Iozzo P*.
Link: https://doi.org/10.3390/nu12082320
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*.
Link: https://doi.org/10.1111/ejn.15181
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*.
Link: https://doi.org/10.3390/antiox10020301
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*.
Link: https://doi.org/10.3390/ijms22010368
Title: Importance of stem cell culture conditions for their derived extracellular vesicles therapeutic effect
Author: Mas-Bargues C*, Borrás C*.
Link: https://doi.org/10.1016/j.freeradbiomed.2021.03.028
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.
Link: https://doi.org/10.1126/sciadv.abf9180
Title: Bcl-xL as a Modulator of Senescence and Aging
Author: Mas-Bargues C*, Borrás C*, Viña J*.
Link: https://doi.org/10.3390/ijms22041527
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.
Link: https://doi.org/10.1016/j.freeradbiomed.2020.11.026
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.
Link: https://doi.org/10.1074/jbc.ra120.013303
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*.
Link: https://doi.org/10.3390/biom10060957
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.
Link: https://doi.org/10.3389/fimmu.2020.00443
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.
Link: https://doi.org/10.1038/s41598-019-50420-9
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.
Link: https://doi.org/10.1016/j.redox.2019.101127
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*.
Link: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8640814/
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*.
Link: https://doi.org/10.1016/j.mad.2021.111596
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.
Link: https://doi.org/10.1186/s12966-021-01219-3
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.
Link: https://doi.org/10.3390/antiox11010078
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*.
Link: https://doi.org/10.1177/01617346211029656
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*.
Link: https://doi.org/10.1155/2021/8101615
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*.
Link: https://doi.org/10.3390/nu13103438
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.
Link: https://doi.org/10.3390/nu13093292
Title: Associations between the Mediterranean Diet Pattern and Weight Status and Cognitive Development in Preschool Children
Author: Granziera F*, Guzzardi MA*, Iozzo P*.
Link: https://doi.org/10.3390/nu13113723
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*.
Link: https://doi.org/10.1016/j.bbi.2021.12.009
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*.
Link: https://doi.org/10.3390/ijms23052659
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*.
Link: https://doi.org/10.3390/metabo12040278
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*.
Link: https://doi.org/10.3390/nu13051519

 

Target group Authors Means of communication Hyperlink Pdf
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    
Scientists, academia, students, industry, clinicians CNR. 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, 28/09/2021 Invited lecture    
Scientists, academia, obesity clinicians, nutritionists CNR. Associations between the Mediterranean Diet Pattern and Weight Status and Cognitive Development in Preschool Children. Congress, Italian Obesity Society, Livorno 28-10-2021 Poster, winner best session poster    
Scientists, industry, academia, students CNR. Non-alcoholic fatty liver: brain and entero-hormones. European Association for the Study of the Liver (EASL), Dublin, scheduled for September 2022 Invited lecture    
Academia, clinicians, students, industry CNR. Obesity and brain. Congress of the Italian Society of Internal Medicine, Rome, scheduled for October 2022 Invited lecture    
Academia, clinicians, students, industry CNR. Imaging of cardiac metabolism. Italian Diabetes Society, Rimini, scheduled for October 2022 Invited lecture    

Features

Project number:
GUTMOM
Duration: 100%
Duration: 100 %
2018
2022
Project lead and secretary:
Patricia Iozzo