Microbiota signatures relating to reduced memory and exploratory behaviour in the offspring of overweight mothers in a murine model

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.

Effect of long-term methylene blue treatment on the composition of mouse gut microbiome and its relationship with the cognitive abilities of mice

“…Chronic inflammation is considered an important factor in the cognitive decline [49]. It has been shown repeatedly that the increase in the content of Proteobacteria is associated with certain cognitive deficits [39,50].…”

Imaging of brain glucose uptake by PET in obesity and cognitive dysfunction: life-course perspective

“…According to this, brain insulin resistance can be defined as failure of insulin to suppress brain glucose uptake, which is coherent with the finding of high glucose uptake under human euglycemic insulin clamp conditions. Comparing healthy lean mice of different ages, we observed that the central hypometabolic action of insulin was significant in adult and old mice, but was not present in early post-natal life (69, 92). It is plausible that brain glucose suppressing signals are not yet operative in the first period of life, to ensure sufficient energy provisions during this demanding phase of rapid brain growth.…”

“…Panel A shows that the development of obesity in a genetic rodent model (Zucker rat) is characterized by brain hypermetabolism both in fasting condition (dashed lines) and during oral glucose tolerance test (solid line) (59). Panel B illustrates the effect of exposure to maternal obesity, resulting in a hypermetabolic brain response to isoglycemic insulin stimulation (solid line) in very early life (70), and mild brain hypermetabolism in fasting conditions (dashed lines) (92). Panel C shows the progressive increase of brain glucose uptake in response to food presentation in inhibitory control regions (open circles) and in reward related regions (closed circles) from normal weight women to women with obesity without and with food addiction (62, 64) in adult age.…”

“…It is plausible that brain glucose suppressing signals are not yet operative in the first period of life, to ensure sufficient energy provisions during this demanding phase of rapid brain growth. Interestingly, mice born to high fat fed dams showed brain hypersensitivity to insulin in this early period and brain insulin resistance during (mid-life) adulthood (92), and minipigs born to high fat fed sows showed greater brain-specific insulin receptor density few days post-natally, followed by deficiency in insulin receptors and insulin-dependent glucose transporters (GLUT4) in the cortex and hypothalamus (70). Also the combination of high fat dieting and AD type pathology in mice is characterized by an absent response of brain glucose metabolism to intranasal insulin.…”

Effects of the antibiotic rifaximin on cortical functional connectivity are mediated through insular cortex

“…Strong preclinical evidence testified an effect of the GM on brain functioning and development 10 . Following the pioneering study of Sudo and colleague 11 reporting an alteration of the hypothalamic–pituitary–adrenal (HPA) stress response in germ-free mice, data have accumulated confirming the role of the commensal microbiota in stress responsiveness 12 – 15 , anxiety and depression-like behaviors, and cognitive functions 16 – 19 . However, when studies are translated into humans, understanding the effects of GM on CNS becomes more difficult 20 .…”