Maternal obese-type gut microbiota differentially impact cognition, anxiety and compulsive behavior in male and female offspring in mice (original) (raw)
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Scientific Reports
Exposing a male rat to an obesogenic high-fat diet (HFD) influences attractiveness to potential female mates, the subsequent interaction of female mates with infant offspring, and the development of stress-related behavioral and neural responses in offspring. To examine the stomach and fecal microbiome’s potential roles, fecal samples from 44 offspring and stomach samples from offspring and their fathers were collected and bacterial community composition was studied by 16 small subunit ribosomal RNA (16S rRNA) gene sequencing. Paternal diet (control, high-fat), maternal housing conditions (standard or semi-naturalistic housing), and maternal care (quality of nursing and other maternal behaviors) affected the within-subjects alpha-diversity of the offspring stomach and fecal microbiomes. We provide evidence from beta-diversity analyses that paternal diet and maternal behavior induced community-wide shifts to the adult offspring gut microbiome. Additionally, we show that paternal HFD ...
Scientific Reports
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). Microbiotaderived 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. The burden of cognitive dysfunction is increasing due to population aging, and to a growing prevalence of predisposing conditions, such as obesity 1. Mental health disorders (either emotional, behavioural or other) have high lifetime prevalence, with first onset usually in childhood or adolescence 2. Brain and cognitive development prevail in early life, predicting later brain health 3-5. Thus, it may be possible and important to recognize and alleviate early risk determinants. Early life phases are characterized by gut microbiota colonization 6,7. 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. We also observed that brain metabolic responses to acute intranasal
Obese-type Gut Microbiota Induce Neurobehavioral Changes in the Absence of Obesity
Biological Psychiatry, 2015
Background-The prevalence of mental illness, particularly depression and dementia, is increased by obesity. Here we test the hypothesis that obesity-associated changes in gut microbiota are intrinsically able to impair neurocognitive behavior in mice. Methods-Conventionally housed, non-obese, adult male C57BL/6 mice maintained on a normal chow diet were subjected to a microbiome depletion/transplantation paradigm using microbiota isolated from donors (given) on either high-fat (HFD) or control diet (CD). Following recolonization, mice were subjected to comprehensive behavioral and biochemical analyses. Results-The mice given HFD microbiota had significant and selective disruptions in exploratory, cognitive, and stereotypical behavior compared to mice with CD microbiota in the absence of significant differences in body weight. Sequencing-based phylogenetic analysis confirmed the presence of distinct core microbiota between groups, with alterations in αand βdiversity, modulation in taxonomic distribution, and statistically significant alterations to metabolically active taxa. HFD microbiota also disrupted markers of intestinal barrier function, increased circulating endotoxin, and increased lymphocyte expression of Iba1, TLR2, and TLR4. Finally, evaluation of brain homogenates revealed that HFD-shaped microbiota increased neuroinflammation and disrupted cerebrovascular homeostasis.
Journal of Diseases and Medicinal Plants, 2016
Obesity associates with mood and anxiety disorders, cognitive dysfunction, and motor decline, whose major causes are puzzling, since obesogenic mechanisms are complex, including a marked intestinal dysbiosis and a sustained metabolic syndrome encompassing hyperglycemia, hyperinsulinemia, systemic inflammation and oxidative stress in both humans and animal models. We addressed whether the changes occurring in mood, cognitive and motor function in dietinduced pre-obese mice are linked to intestinal dysbiosis and body weight gain. Male and female Swiss mice were made preobese by feeding with a reinforced high-fat diet for 7 weeks, along which body weight and food intake were monitored. Then, holeboard, stress-induced hyperthermia, footprint, and vertical pole tests were performed to assess cognitive and motor functions. Animals were sacrificed and intestinal dysbiosis assessed: (i) by determining fecal pH and gram positive bacteria counts; (ii) by assessing bacterial infiltration to the jejunum using tissue gram stain; and (iii) by assessing jejunal tissue histopathological changes (H&E) and the immunohistochemical expression of the sustained inflammation marker CXCL10. Average increases in body weight were observed in males (37%) and females (49%), as well as increases in fecal pH, gram positive counts, bacterial infiltration and CXCL10 expression, particularly marked in females. For both sexes, HFD-fed animals with more marked changes in indicators of intestinal dysbiosis also gained weight faster and displayed more marked mood, cognitive and motor alterations. These results suggest that intestinal dysbiosis is a major driver of obesity-like cognitive and motor alterations in pre-obese mice.
Maternal Obesity and Gut Microbiota Are Associated With Fetal Brain Development
Obesity in pregnancy induces metabolic syndrome, low-grade inflammation, altered endocrine factors, placental function, and the maternal gut microbiome. All these factors impact fetal growth and development, including brain development. The lipid metabolic transporters of the maternal-fetal-placental unit are dysregulated in obesity. Consequently, the transport of essential long-chain PUFAs for fetal brain development is disturbed. The mother’s gut microbiota is vital in maintaining postnatal energy homeostasis and maternal-fetal immune competence. Obesity during pregnancy changes the gut microbiota, affecting fetal brain development. Obesity and a high-fat diet in pregnancy can induce placental and intrauterine inflammation and thus influence the neurodevelopmental outcomes of the offspring. Several epidemiological studies observed an association between maternal obesity and adverse neurodevelopment. This review discusses the effects of maternal obesity and gut microbiota on fetal ...
Gut Microbiota Depletion from Early Adolescence in Mice: Implications for Brain and Behaviour
Brain, Behavior, and Immunity, 2015
Background: There is growing appreciation for the importance of bacteria in shaping brain development and behaviour. Adolescence and early adulthood are crucial developmental periods during which exposure to harmful environmental factors can have a permanent impact on brain function. Such environmental factors include perturbations of the gut bacteria that may affect gut-brain communication, altering the trajectory of brain development, and increasing vulnerability to psychiatric disorders. Here we assess the effects of gut bacterial depletion from weaning onwards on adult cognitive, social and emotional behaviours and markers of gut-brain axis dysfunction in mice. Methods: Mice were treated with a combination of antibiotics from weaning onwards and effects on behaviours and potential gut-brain axis neuromodulators (tryptophan, monoamines, and neuropeptides) and BDNF expression were assessed in adulthood. Results: Antibiotic-treatment depleted and restructured gut microbiota composition of caecal contents and decreased spleen weights in adulthood. Depletion of the gut microbiota from weaning onwards reduced anxiety, induced cognitive deficits, altered dynamics of the tryptophan metabolic pathway, and significantly reduced BDNF, oxytocin and vasopressin expression in the adult brain. Conclusions: Microbiota depletion from weaning onwards by means of chronic treatment with antibiotics in mice impacts on anxiety and cognitive behaviours as well as key neuromodulators of gut-brain communication in a manner that is similar to that reported in germ-free mice. This model may represent a more amenable alternative for germ-free mice in the assessment of microbiota modulation of behaviour. Finally, these data suggest that despite the presence of a normal gut microbiome in early postnatal life, reduced abundance and diversity of the gut microbiota from weaning influences adult behaviours and key neuromodulators of the microbiota-gut-brain axis suggesting that dysregulation of this axis in the post-weaning period may contribute to the pathogenesis of disorders associated with altered anxiety and cognition.
Microbiota and host determinants of behavioural phenotype in maternally separated mice
Nature communications, 2015
Early-life stress is a determinant of vulnerability to a variety of disorders that include dysfunction of the brain and gut. Here we exploit a model of early-life stress, maternal separation (MS) in mice, to investigate the role of the intestinal microbiota in the development of impaired gut function and altered behaviour later in life. Using germ-free and specific pathogen-free mice, we demonstrate that MS alters the hypothalamic-pituitary-adrenal axis and colonic cholinergic neural regulation in a microbiota-independent fashion. However, microbiota is required for the induction of anxiety-like behaviour and behavioural despair. Colonization of adult germ-free MS and control mice with the same microbiota produces distinct microbial profiles, which are associated with altered behaviour in MS, but not in control mice. These results indicate that MS-induced changes in host physiology lead to intestinal dysbiosis, which is a critical determinant of the abnormal behaviour that character...
Child and Adolescent Psychiatry and Mental Health
Background and aim Maternal overweight and breastfeeding seem to have a significant impact on the gut microbiota colonization process, which co-occurs simultaneously with brain development and the establishment of the “microbiota-gut-brain axis”, which potentially may affect behavior later in life. This study aimed to examine the influence of maternal overweight, obesity and/or gestational diabetes on the offspring behavior at 3.5 years of age and its association with the gut microbiota already established at 18 months of life. Methods 156 children born to overweight (OV, n = 45), obese (OB, n = 40) and normoweight (NW, n = 71) pregnant women participating in the PREOBE study were included in the current analysis. Stool samples were collected at 18 months of life and gut microbiome was obtained by 16S rRNA gene sequencing. Behavioral problems were evaluated at 3.5 years by using the Child Behavior Checklist (CBCL). ANOVA, Chi-Square Test, ANCOVA, Spearman’s correlation, logistic reg...
Normal gut microbiota modulates brain development and behavior
Proceedings of the National Academy of Sciences, 2011
Microbial colonization of mammals is an evolution-driven process that modulate host physiology, many of which are associated with immunity and nutrient intake. Here, we report that colonization by gut microbiota impacts mammalian brain development and subsequent adult behavior. Using measures of motor activity and anxiety-like behavior, we demonstrate that germ free (GF) mice display increased motor activity and reduced anxiety, compared with specific pathogen free (SPF) mice with a normal gut microbiota. This behavioral phenotype is associated with altered expression of genes known to be involved in second messenger pathways and synaptic long-term potentiation in brain regions implicated in motor control and anxiety-like behavior. GF mice exposed to gut microbiota early in life display similar characteristics as SPF mice, including reduced expression of PSD-95 and synaptophysin in the striatum. Hence, our results suggest that the microbial colonization process initiates signaling m...