TY - JOUR
T1 - Altered gut microbiota and activity in a murine model of autism spectrum disorders
AU - de Theije, Caroline G.M.
AU - Wopereis, Harm
AU - Ramadan, Mohamed
AU - van Eijndthoven, Tiemen
AU - Lambert, Jolanda
AU - Knol, Jan
AU - Garssen, Johan
AU - Kraneveld, Aletta D.
AU - Oozeer, Raish
N1 - Funding Information:
We would like to thank Amra Buco and Rob Slump for their technical support and contribution in the experiments described in this manuscript. This study is part of the Utrecht University ‘Focus en Massa’ program and financially supported by Nutricia Research . H. Wopereis, T. van Eijndthoven, J. Lambert, J. Knol, J. Garssen and R. Oozeer are employees of Nutricia Research and therefore declare potential conflicts of interest. All other authors report no biomedical financial interest or potential conflicts of interest.
PY - 2014/3
Y1 - 2014/3
N2 - Autism spectrum disorder (ASD) is a heterogeneous group of complex neurodevelopmental disorders with evidence of genetic predisposition. Intestinal disturbances are reported in ASD patients and compositional changes in gut microbiota are described. However, the role of microbiota in brain disorders is poorly documented. Here, we used a murine model of ASD to investigate the relation between gut microbiota and autism-like behaviour. Using next generation sequencing technology, microbiota composition was investigated in mice in utero exposed to valproic acid (VPA). Moreover, levels of short chain fatty acids (SCFA) and lactic acid in caecal content were determined. Our data demonstrate a transgenerational impact of in utero VPA exposure on gut microbiota in the offspring. Prenatal VPA exposure affected operational taxonomic units (OTUs) assigned to genera within the main phyla of Bacteroidetes and Firmicutes and the order of Desulfovibrionales, corroborating human ASD studies. In addition, OTUs assigned to genera of Alistipes, Enterorhabdus, Mollicutes and Erysipelotrichalis were especially associated with male VPA-exposed offspring. The microbial differences of VPA in utero-exposed males deviated from those observed in females and was (i) positively associated with increased levels of caecal butyrate as well as ileal neutrophil infiltration and (ii) inversely associated with intestinal levels of serotonin and social behaviour scores. These findings show that autism-like behaviour and its intestinal phenotype is associated with altered microbial colonization and activity in a murine model for ASD, with preponderance in male offspring. These results open new avenues in the scientific trajectory of managing neurodevelopmental disorders by gut microbiome modulation.
AB - Autism spectrum disorder (ASD) is a heterogeneous group of complex neurodevelopmental disorders with evidence of genetic predisposition. Intestinal disturbances are reported in ASD patients and compositional changes in gut microbiota are described. However, the role of microbiota in brain disorders is poorly documented. Here, we used a murine model of ASD to investigate the relation between gut microbiota and autism-like behaviour. Using next generation sequencing technology, microbiota composition was investigated in mice in utero exposed to valproic acid (VPA). Moreover, levels of short chain fatty acids (SCFA) and lactic acid in caecal content were determined. Our data demonstrate a transgenerational impact of in utero VPA exposure on gut microbiota in the offspring. Prenatal VPA exposure affected operational taxonomic units (OTUs) assigned to genera within the main phyla of Bacteroidetes and Firmicutes and the order of Desulfovibrionales, corroborating human ASD studies. In addition, OTUs assigned to genera of Alistipes, Enterorhabdus, Mollicutes and Erysipelotrichalis were especially associated with male VPA-exposed offspring. The microbial differences of VPA in utero-exposed males deviated from those observed in females and was (i) positively associated with increased levels of caecal butyrate as well as ileal neutrophil infiltration and (ii) inversely associated with intestinal levels of serotonin and social behaviour scores. These findings show that autism-like behaviour and its intestinal phenotype is associated with altered microbial colonization and activity in a murine model for ASD, with preponderance in male offspring. These results open new avenues in the scientific trajectory of managing neurodevelopmental disorders by gut microbiome modulation.
KW - Autism spectrum disorders
KW - Butyrate
KW - Gut microbiota
KW - Neurodevelopment
KW - Prenatal
KW - Short chain fatty acids
KW - Valproate
UR - https://www.scopus.com/pages/publications/84896728399
U2 - 10.1016/j.bbi.2013.12.005
DO - 10.1016/j.bbi.2013.12.005
M3 - Article
C2 - 24333160
AN - SCOPUS:84896728399
SN - 0889-1591
VL - 37
SP - 197
EP - 206
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -