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 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.

1.2 Highlights

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, but mice and human studies suggest that HFD during pregnancy is more impactful in adulthood than maternal BMI, and 3) 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; 5) the transfer of prescholar children-donors' phenotype into recipient germ-free mice, via microbiota transplantation; 6) an impact of maternal HFD, ELS and the combination on offspring's body weight, especially in males, and 7) a strong impact of ELS on microbiota, especially in females, and fecal metabolome, especially in males, as well as on the microbiota-metabolome association; 8) 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. 

4. Impact

4.1 List of publications

AuthorsTitleYear, Issue, PPPartners NumberDoiPdf
Forsgård RA, Marrachelli VG*, Lindén J, Frias R, Collado MC*, Korpela R, Monleon D*, Spillmann T, Österlund P.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 Profiles2019 Aug;12(8):1122-1130UV10.1016/j.tranon.2019.04.019. Gold open access
Gómez-Gallego C, Morales JM*, Monleón D*, du Toit E, Kumar H, Linderborg KM, Zhang Y, Yang B, Isolauri E, Salminen S, Collado MC.Human Breast Milk NMR Metabolomic Profile across Specific Geographical Locations and Its Association with the Milk Microbiota.2018 Sep 21;10(10):1355UV10.3390/nu10101355. Gold open access
Viña J*, Borras C*, Gomez-Cabrera MC*.A free radical theory of frailty.2018 Aug 20;124:358-363UV10.1016/j.freeradbiomed.2018.06.028. Green open access
Inglés M*, Mas-Bargues C*, Berna-Erro A*, Matheu A*, Sanchís P*, Avellana JA*, Borrás C*, Viña J*.Centenarians Overexpress Pluripotency-Related Genes.2019 Aug 16;74(9):1391-1395UV10.1093/gerona/gly168
Díaz A*, López-Grueso R*, Gambini J*, Monleón D*, Mas-Bargues C*, Abdelaziz KM*, Viña J*, Borrás C*.Sex Differences in Age-Associated Type 2 Diabetes in Rats—Role of Estrogens and Oxidative Stress.2019 Apr 7;2019:6734836UV10.1155/2019/6734836. Gold open access
Inglés M*, Mas-Bargues C*, Gimeno-Mallench L*, Cruz-Guerrero R, García-García FJ, Gambini J*, Borrás C*, Rodríguez-Mañas L, Viña J*.Relation Between Genetic Factors and Frailty in Older Adults.2019 Nov;20(11):1451-1457UV10.1016/j.jamda.2019.03.011. Green open access
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*.Relevance of Oxygen Concentration in Stem Cell Culture for Regenerative Medicine.2019 Mar 8;20(5):1195UV10.3390/ijms20051195. Gold open access
Pamplona R, Borras C*, Jové M, Pradas I, Ferrer I, Viña J*.Redox lipidomics to better understand brain aging and function.2019 Nov 20;144:310-321UV10.1016/j.freeradbiomed.2019.03.016. Green open access
Häusl AS*, Balsevich G*, Gassen NC*, Schmidt MV*. Focus on FKBP51: A molecular link between stress and metabolic disorders.2019 Nov;29:170-181MPG10.1016/j.molmet.2019.09.003. Gold open access
Balsevich G, Abizaid A, Chen A, Karatsoreos IN, Schmidt MV*. Stress and glucocorticoid modulation of feeding and metabolism.2019 May 15;11:100171MPG10.1016/j.ynstr.2019.100171. Gold open access
Iozzo P*, Guzzardi MA*Imaging of brain glucose uptake by PET in obesity and cognitive dysfunction: life-course perspective.2019;8(11):R169-R183CNR10.1530/EC-19-0348. Review
Sanguinetti E*, Guzzardi MA*, Tripodi M*, Panetta D*, Selma-Royo M, Zega A*, Telleschi M*, Collado MC, Iozzo P*. Microbiota signatures relating to reduced memory and exploratory behaviour in the offspring of overweight mothers in a murine model.2019;9(1):12609CNR10.1038/s41598-019-48090-8. Gold open access
Cirulli F*, Musillo C*, Berry A*. Maternal Obesity as a Risk Factor for Brain Development and Mental Health in the Offspring2020 Nov 1;447:122-135ISS10.1016/j.neuroscience.2020.01.023. Gold open access
Cirulli F*Embedding early experiences into brain function: perspectives from behavioral epigenetics2021, Volume 23 in Translational Epigenetics, Pages 157-165ISS10.1016/B978-0-12-819262-7.00009-X
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*.Magnetic resonance microscopy and correlative histopathology of the infarcted heart.2019 Dec 27;9(1):20017UV10.1038/s41598-019-56436-5. Gold open access
Muñoz-Hidalgo L*, San-Miguel T*, Megías J*, Monleón D*, Navarro L*, Roldán P*, Cerdá-Nicolás M*, López-Ginés C*.Somatic copy number alterations are associated with EGFR amplification and shortened survival in patients with primary glioblastoma. 2020 Jan;22(1):10-21UV10.1016/j.neo.2019.09.001. Gold open access
Borrás C*, Mas-Bargues C*, Román-Domínguez A*, Sanz-Ros J*, Gimeno-Mallench L*, Inglés M*, Gambini J*, Viña J*.BCL-xL, a Mitochondrial Protein Involved in Successful Aging: From C. elegans to Human Centenarians.2020 Jan 9;21(2):418UV10.3390/ijms21020418. Gold open access
Borras C*, Ingles M*, Mas-Bargues C*, Dromant M*, Sanz-Ros J*, Román-Domínguez A*, Gimeno-Mallench L*, Gambini J*, Viña J*.Centenarians: An excellent example of resilience for successful ageing.2020 Mar;186:111199UV10.1016/j.mad.2019.111199
Borras C*, Mas-Bargues C*, Sanz-Ros J*, Román-Domínguez A*, Gimeno-Mallench L*, Inglés M*, Gambini J*, Viña J*. Extracellular vesicles and redox modulation in aging. 2020 Mar;149:44-50UV10.1016/j.freeradbiomed.2019.11.032. Green open access
Guzzardi MA*, Granziera F*, Sanguinetti E*, Muratori F, Iozzo P*. Exclusive Breastfeeding Predicts Higher Hearing-Language Development in Girls of Preschool Age12(8):2320CNR10.3390/nu12082320. Gold open access
Berry A*, Mazzelli M, Musillo C*, Riva MA, Cattaneo A, Cirulli F*. High-fat diet during adulthood interacts with prenatal stress, affecting both brain inflammatory and neuroendocrine markers in male rats. 2022 May;55(9-10):2326-2340ISS10.1111/ejn.15181
Gambini J*, Gimeno-Mallench L*, Olaso-Gonzalez G*, Mastaloudis A, Traber MG, Monleón D*, Borrás C*, Viña J*. Moderate Red Wine Consumption Increases the Expression of Longevity-Associated Genes in Controlled Human Populations and Extends Lifespan in Drosophila melanogaster. Antioxidants (Basel)2021 Feb 16;10(2):301UV10.3390/antiox10020301
Muñoz-Hidalgo L*, San-Miguel T*, Megías J*, Serna E*, Calabuig-Fariñas S*, Monleón D*, Gil-Benso R*, Cerdá-Nicolás M*, López-Ginés C*. The Status of EGFR Modulates the Effect of miRNA-200c on ZEB1 Expression and Cell Migration in Glioblastoma Cells2020 Dec 31;22(1):368UV10.3390/ijms22010368
Mas-Bargues C*, Borrás C*. Importance of stem cell culture conditions for their derived extracellular vesicles therapeutic effect2021 May 20;168:16-24UV10.1016/j.freeradbiomed.2021.03.028
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. Targeting Alzheimer's disease with multimodal polypeptide-based nanoconjugates2021 Mar 26;7(13):eabf9180UV10.1126/sciadv.abf9180
Mas-Bargues C*, Borrás C*, Viña J*. Bcl-xL as a Modulator of Senescence and Aging2021 Feb 3;22(4):1527UV10.3390/ijms22041527
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. Methionine transsulfuration pathway is upregulated in long-lived humans2021 Jan;162:38-52UV10.1016/j.freeradbiomed.2020.11.026
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. Garcinoic acid prevents β-amyloid (Aβ) deposition in the mouse brain2020 Aug 14;295(33):11866-11876UV10.1074/jbc.RA120.013303
Mas-Bargues C*, Sanz-Ros J*, Román-Domínguez A*, Gimeno-Mallench L*, Inglés M*, Viña J*, Borrás C*. Extracellular Vesicles from Healthy Cells Improves Cell Function and Stemness in Premature Senescent Stem Cells by miR-302b and HIF-1α Activation. Biomolecules2020 Jun 25;10(6):957UV10.3390/biom10060957
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. Mechanisms of FH Protection Against Neovascular AMD2020 Apr 3;11:443UV10.3389/fimmu.2020.00443
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. CFH exerts anti-oxidant effects on retinal pigment epithelial cells independently from protecting against membrane attack complex2019 Sep 25;9(1):13873UV10.1038/s41598-019-50420-9
Pradas I, Jové M, Huynh K, Puig J, Ingles M*, Borras C*, Viña J*, Meikle PJ, Pamplona R. Exceptional human longevity is associated with a specific plasma phenotype of ether lipids2019 Feb;21:101127UV10.1016/j.redox.2019.101127
López-Ginés C*, Muñoz-Hidalgo L*, San-Miguel T*, Megías J*, Triviño JC*, Calabuig S*, Roldán P*, Cerdá-Nicolás M*, Monleón D*. Whole-exome sequencing, EGFR amplification and infiltration patterns in human glioblastoma2021 Nov 15;11(11):5543-5558 eCollection 2021UV
Borrás C*, Abdelaziz KM*, Díaz A*, Gambini J*, Jové M, López-Grueso R*, Mas-Bargues C*, Monleón D*, Pamplona R, Viña J*. Lifelong soya consumption in males does not increase lifespan but increases health span under a metabolic stress such as type 2 diabetes mellitus2021 Dec;200:111596UV10.1016/j.mad.2021.111596
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. Healthy lifestyle, metabolomics and incident type 2 diabetes in a population-based cohort from Spain2022 Jan 27;19(1):8UV10.1186/s12966-021-01219-3
Mas-Bargues C*, Alique M, Barrús-Ortiz MT, Borrás C*, Rodrigues-Díez R. Exploring New Kingdoms: The Role of Extracellular Vesicles in Oxi-Inflamm-Aging Related to Cardiorenal Syndrome2021 Dec 29;11(1):78UV10.3390/antiox11010078
Mirón Mombiela R*, Vucetic J*, Monllor P*, Cárdenas-Herrán JS*, Taltavull de La Paz P, Borrás C*.Diagnostic Performance of Muscle Echo Intensity and Fractal Dimension for the Detection of Frailty Phenotype2021 Nov;43(6):337-352UV10.1177/01617346211029656
Borrás C*, Ferrando M, Inglés M*, Gambini J*, Lopez-Grueso R*, Edo R*, Mas-Bargues C*, Pellicer A*, Viña J*. Estrogen Replacement Therapy Induces Antioxidant and Longevity-Related Genes in Women after Medically Induced Menopause2021 Sep 9;2021:8101615UV10.1155/2021/8101615
Guzzardi MA*, La Rosa F*, Campani D, Cacciato Insilla A, De Sena V*, Panetta D*, Brunetto MR, Bonino F, Collado MC, Iozzo P*. Maturation of the Visceral (Gut-Adipose-Liver) Network in Response to the Weaning Reaction versus Adult Age and Impact of Maternal High-Fat Diet2021 Sep 28;13(10):3438CNR10.3390/nu13103438
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. Identification and Characterization of Human Observational Studies in Nutritional Epidemiology on Gut Microbiomics for Joint Data Analysis2021 Sep 21;13(9):3292CNR10.3390/nu13093292
Granziera F*, Guzzardi MA*, Iozzo P*. Associations between the Mediterranean Diet Pattern and Weight Status and Cognitive Development in Preschool Children2021 Oct 22;13(11):3723CNR10.3390/nu13113723
Guzzardi MA*, Ederveen THA*, Rizzo F, Weisz A, Collado MC, Muratori F, Gross G*, Alkema W*, Iozzo P*. Maternal pre-pregnancy overweight and neonatal gut bacterial colonization are associated with cognitive development and gut microbiota composition in pre-school-age offspring2022 Feb;100:311-320CNR, Radboud UMC, MJN10.1016/j.bbi.2021.12.009
Guzzardi MA*, La Rosa F*, Campani D, Cacciato Insilla A, Nannipieri M, Brunetto MR, Bonino F, Iozzo P*. 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 Mice2022 Feb 28;23(5):2659CNR10.3390/ijms23052659
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*. Liver and White/Brown Fat Dystrophy Associates with Gut Microbiota and Metabolomic Alterations in 3xTg Alzheimer's Disease Mouse Model2022 Mar 22;12(4):278CNR10.3390/metabo12040278
Berry A*, Collacchi B, Masella R, Varì R, Cirulli F*. Curcuma Longa, the "Golden Spice" to Counteract Neuroinflammaging and Cognitive Decline-What Have We Learned and What Needs to Be Done2021 Apr 30;13(5):1519ISS10.3390/nu13051519

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
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

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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