DTA

Dottorato

GRANZIERA, FEDERICO

etd-07252023-143217

Nutrition and Cognitive Development: The Lasting Role of Early-Life Gut Microbiota and Gut Metabolites

BIO/09

Istituto di Scienze della Vita - PHD IN MEDICINA TRASLAZIONALE

Membro Prof. LIONETTI, VINCENZO

• cognitive development
• early-life nutrition
• faecal microbiota transplant (FMT)
• gut metabolites
• gut microbiota
• in-vivo imaging

29/01/2024;

parziale

Background: Cognitive decline and dementia are public health problems, fostered by population aging and an increasing prevalence of metabolic disorders, including obesity and dysbiosis. They lack a prevention strategy and cure. Evidence indicates that early-life cognition already predicts dementia risk. Therefore, cognitive protection that 1) exploits modifiable factors, 2) accounts for gender and 3) begins early in life could help prevent or delay the onset of dementia. For instance, nutrition is a modifiable factor that provides substrates for brain and gut microbiota development (colonisation and composition). Gut microbiota and gut metabolites (from diet or from intestinal bacteria) are also modifiable factors, influencing brain function, neurodevelopment and the course of neurodegenerative diseases. However, the cause-effect relationship linking gut microbiota or gut metabolites and cognitive development in healthy children remains to be proven. Therefore, the hypothesis of this project was that cognitive development in healthy children is partly driven by the gut microbiota and/or gut metabolites with lasting effects, thus offering opportunities for non-invasive risk screening and risk reduction by specific dietary habits and foods, from earliest life stages. The aims of this project were to evaluate relationships between early life nutrition and cognitive function in preschool children, and prove that gut contents exert an impact on cognitive development, identifying potential dietary leads towards cognitive protection. Methodologies: A cohort of healthy children (Pisa birth cohort, PISAC, originally composed of 90 families, i.e., mothers, fathers, offspring, as recruited during gestation) and germ-free (GF) mice were used. Children were characterized for early feeding (exclusive or non-exclusive breastfeeding from birth to 6 months of age), and for diet in childhood (food frequency questionnaire at 5 years of age). Children’s cognition was assessed in subgroups at different ages (6, 12, 18, 24, 36, 60 months), by Griffith Mental Development Scales-Extended Revised. Parents' age, job and intelligence quotient (IQ, by Raven progressive matrices), and maternal and offspring anthropometric parameters were also measured. These data were used to test relationships between offspring diet or body weight and cognitive development. In order to prove a causal involvement of the gut microbiota-metabolome, faecal microbiota transplants (FMT) from children to GF mice were carried out. Two groups of n=10, 5-year-old children (50% girls/boys), differing in their 5-year practical reasoning (PR) score (high/low) served as FMT donors. Sixty 4/5-week-old GF mice were the FMT recipients (3 sex-matched recipient mice for each donor); in addition, a control group of 12 GF sham mice (no FMT, 50% males/females) was studied. After FMT (by single oral-gastric gavage), mice underwent 6 months monitoring, including repeated cognitive assessments for spatial working or reference memory functions (by Y-maze testing at weeks 1, 4, 15, 22 and 23 post-transplant) and collection of faecal pellets for microbiome and metabolome analyses. Faecal metabolome was measured repeatedly by nuclear magnetic spectroscopy, and microbiota by 16S rRNA amplicon sequencing. After 6 months, FDG-PET/CT (fluorodeoxyglucose positron emission tomography/computed tomography) imaging was performed for the in vivo assessment of brain glucose metabolism. Then, whole brain weight was measured ex vivo, and blood was collected for analysis of circulating biomarkers. Results: In children, exclusive breastfeeding was able to predict higher hearing-language development in 5 years old girls, independent of maternal IQ, age and body mass index (BMI). Importantly, the first 3 months of exclusive breastfeeding seemed sufficient to establish this positive relationship. Dietary habits at the age of 5 revealed that high adherence to a Mediterranean diet (MD) was associated with higher performance scores, whereas BMI (age-gender specific, z-scores) was a negative predictor of PR scores, independent of maternal IQ estimates, parents' socioeconomic status, exclusive/non-exclusive breastfeeding, actual age at cognitive assessment and gender. In turn, BMI was positively predicted by white meat consumption. FMT experiments documented that donors’ and recipient’s cognition were correlated, and the latter differed significantly in adult mice, in coherence with the stratification of donors’ groups, supporting the transfer of donors’ cognitive phenotype into recipient mice, via faecal contents. Brain glucose metabolism was promoted by FMT in males. Circulating markers differed in male recipients of high- vs low-PR boy donors (leptin levels) or between male FMT recipients and sex-matched sham mice (brain-derived neurotrophic factor, monocyte chemoattractant protein-1 and tumour necrosis factor-alpha). Results identified promising faecal taxa and metabolites, differing between mice receiving microbiota from high-PR and low-PR donors and relating to cognitive function and/or brain metabolism in mice. Conclusions: Overall, this research project indicates that the faecal microbiota and/or metabolites have an influence on cognitive development in healthy children, which could support prevention since very early life. The findings offer an opportunity to identify individuals at cognitive risk in a very early stage of life, requiring nutritional attention. Policy relevant nutritional aspects in children include exclusive breastfeeding, especially in the first 3 months of life, high adherence to the MD and low intake of white meat, as predictors of higher cognitive outcomes in children.

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