Maternal obese-type gut microbiota differentially impact cognition, anxiety and compulsive behavior in male and female offspring in mice.

Annadora J Bruce-Keller,Annadora J Bruce-Keller,R Leigh Townsend,J Michael Salbaum,Richard Carmouche,Claudia Kruger,J Michael Salbaum,Richard Carmouche,Hans-Rudolf Berthoud,Hans-Rudolf Berthoud,Sun-Ok Fernandez-Kim,R Leigh Townsend,Susan Newman,Sun-Ok Fernandez-Kim,Cheryl S Rosenfeld

doi:10.1371/journal.pone.0175577

Annadora J Bruce-Keller, Annadora J Bruce-Keller + Show 13 more

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https://doi.org/10.1371/journal.pone.0175577

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Abstract

Maternal obesity is known to predispose offspring to metabolic and neurodevelopmental abnormalities. While the mechanisms underlying these phenomena are unclear, high fat diets dramatically alter intestinal microbiota, and gut microbiota can impact physiological function. To determine if maternal diet-induced gut dysbiosis can disrupt offspring neurobehavioral function, we transplanted high fat diet- (HFD) or control low fat diet-associated (CD) gut microbiota to conventionally-housed female mice. Recipient mice were then bred and the behavioral phenotype of male and female offspring was tracked. While maternal behavior was unaffected, neonatal offspring from HFD dams vocalized less upon maternal separation than pups from CD dams. Furthermore, weaned male offspring from HFD dams had significant and selective disruptions in exploratory, cognitive, and stereotypical/compulsive behavior compared to male offspring from CD dams; while female offspring from HFD dams had increases in body weight and adiposity. 16S metagenomic analyses confirmed establishment of divergent microbiota in CD and HFD dams, with alterations in diversity and taxonomic distribution throughout pregnancy and lactation. Likewise, significant alterations in gut microbial diversity and distribution were noted in offspring from HFD dams compared to CD dams, and in males compared to females. Regression analyses of behavioral performance against differentially represented taxa suggest that decreased representation of specific members of the Firmicutes phylum predict behavioral decline in male offspring. Collectively, these data establish that high fat diet-induced maternal dysbiosis is sufficient to disrupt behavioral function in murine offspring in a sex-specific manner. Thus these data reinforce the essential link between maternal diet and neurologic programming in offspring and suggest that intestinal dysbiosis could link unhealthy modern diets to the increased prevalence of neurodevelopmental and childhood disorders.

Highlights

A prevailing theory of neurodevelopmental pathogenesis is that environmental factors and genetic predisposition converge to disrupt neural circuits controlling social, emotional, and cognitive behavior [1],[2],[3],[4]
Sample sizes were balanced to 15 mice after weaning, but offspring from only 4 control low fat diet-associated (CD) and 4 high fat diet- (HFD) dams were followed into adulthood as not all litters contained both sexes
While nursing dams spent progressively less time physically in contact with pups as they grew, during the dark cycle, no significant differences in time spent with pups between CD and HFD dams were noted (Fig 2C and 2D)

Summary

Introduction

A prevailing theory of neurodevelopmental pathogenesis is that environmental factors and genetic predisposition converge to disrupt neural circuits controlling social, emotional, and cognitive behavior [1],[2],[3],[4]. The prenatal/perinatal environment plays a critical role in programming offspring’s metabolic and mental health; and an unhealthy maternal diet and/or maternal metabolic disorders (obesity, diabetes, hypertension, and pre-eclampsia) adversely impact offspring physiology and behavioral function [6],[7]. Experimental and clinical studies strongly indicate that disruption to gut microbiota can impair brain function and mental health [11],[17],[18],[19],[20],[21],[22]. With regard to neurodevelopmental disorders, a number of conditions are associated with altered neonatal microbial colonization, which may impact intestinal barrier and immune maturation, the brain-gut axis, and contribute to development of neurologic disease [23],[24]. The aim of the present study was to test the hypothesis that high fat diet-associated maternal microbiota are sufficient to adversely affect neurobehavioral function in offspring. Metagenomic sequencing of microbiota collected from dams and offspring at various times during pregnancy and postnatal development was conducted

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