Abstract
An elevated number of women of reproductive age are overweight, predisposing their offspring to metabolic and neuropsychiatric disorders. Gut microbiota is influenced by maternal factors, and has been implicated in the pathogenesis of neurodegenerative diseases. Our aim was to explore the effects of maternal high-fat feeding on the relationship linking gut microbiota and cognitive development in the offspring. Murine offspring born to dams undergoing normal diet (NDm) and high-fat diet (HFDm) were studied at 1 or 6 months of age to assess cognitive function by Y-maze test, cerebral glucose metabolism and insulin sensitivity by Positron Emission Tomography, brain density by Computed Tomography, microbiota profile (colon, caecum) and inferred metabolic pathways (KEGG analysis) by 16S ribosomal RNA sequencing. From 3 weeks post-weaning, mice born to HFDm developed hyperphagia and overweight, showing reduction in memory and exploratory behaviour, and brain insulin resistance in adulthood. We identified a panel of bacteria characterizing offspring born to HFD dams from early life, and correlating with dysfunction in memory and exploratory behaviour in adults (including Proteobacteria phylum, Parabacteroides and unclassified Rikenellaceae genera). Microbiota-derived metabolic pathways involved in fatty acid, essential aminoacid and vitamin processing, sulphur metabolism, glutaminergic activation and Alzheimer’s disease were differently present in the HFDm and NDm offspring groups. Our results document tight relationships between gut dysbiosis and memory and behavioural impairment in relation to maternal HFD. Persistent bacterial signatures induced by maternal HFD during infancy can influence cognition during adulthood, opening the possibility of microbiota-targeted strategies to contrast cognitive decline.
Highlights
The burden of cognitive dysfunction is increasing due to population aging, and to a growing prevalence of predisposing conditions, such as obesity[1]
We hypothesized that brain function and gut microbiota are influenced by maternal gestational high-fat diet (HFD), and that the gut microbiota might explain the dual dysregulation in eating behaviour and memory and exploratory behaviour in the offspring of HFD dams
At 6 months, HFD mothers (HFDm) offspring showed elevated leptin and resistin, www.nature.com/scientificreports and lower insulin and monocyte chemoattractant protein-1 (MCP-1) levels compared to age-matched controls (Fig. 1D,E)
Summary
The burden of cognitive dysfunction is increasing due to population aging, and to a growing prevalence of predisposing conditions, such as obesity[1]. Gut bacteria regulate body metabolism, eating behaviour, adiposity and systemic inflammation[8,9], and have been recently associated with cognitive disorders in adult humans[10] and rodents[11,12]. In an adult mouse model of cognitive pathology, we have identified specific microbiota signatures, and additive effects of high-fat feeding[13], correlating with cognitive dysfunction and brain glucose metabolism. Few studies have examined the effects of maternal obesity or HFD on the offspring’s gut microbiota. Our aim was to examine, in a murine model, the effects of maternal HFD on memory and exploratory behaviour, cerebral metabolism, gut microbiota, and their relationship at weaning and adult age, accounting for eating behaviour, body weight, and inflammatory profiles. Since the microbiota has different composition in the adult caecum and colon[13], we examined both intestinal tracts
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