Gut microbiota manipulation during the prepubertal period shapes behavioral abnormalities in a mouse neurodevelopmental disorder model

Abstract

previous studies demonstrate an association between activation of the maternal immune system during pregnancy and increased risk of neurodevelopmental psychiatric conditions, such as schizophrenia and autism, in the offspring. Relatively recent findings also suggest that the gut microbiota plays an important role in shaping brain development and behavior. Here we show that maternal immune activation (MIA) accomplished by infection with a mouse-adapted influenza virus during pregnancy induced up-regulation of frontal cortex serotonin 5-HT 2A receptor (5-HT 2A R) density in the adult offspring, a phenotype previously observed in postmortem frontal cortex of schizophrenic subjects. 5-HT 2A R agonist-induced head-twitch behavior was also augmented in this preclinical mouse model. Using the novel object recognition (noR) test to evaluate cognitive performance, we demonstrate that MIA induced NOR deficits in adult offspring. Oral antibiotic treatment of prepubertal mice prevented this cognitive impairment, but not increased frontal cortex 5-HT 2A R density or psychedelic-induced head-twitch behavior in adult MIA offspring. Additionally, gut microbiota transplantation from MIA mice produced behavioral deficits in antibiotic-treated mock mice. Adult MIA offspring displayed altered gut microbiota, and relative abundance of specific components of the gut microbiota, including Ruminococcaceae, correlated with frontal cortex 5-HT 2A R density. Together, these findings provide a better understanding of basic mechanisms by which prenatal insults impact offspring brain function, and suggest gut-brain axis manipulation as a potential therapeutic approach for neurodevelopmental psychiatric conditions. Neurodevelopmental psychiatric disorders, including schizophrenia 1 and autism 2 , are severe and usually cause lifelong disability. Epidemiological studies have indicated that environmental insults during pregnancy, particularly infection and severe adverse life events, increase the risk of certain psychiatric disorders in offspring. Thus, it has been reported that maternal infection with agents including viruses (influenza and rubella) 3,4 , bacteria (bronchopneumonia) 5 and protozoa (Toxoplasma gondii) 6 contribute to the etiologies of neuropsychiatric disorders

Role of the Gut Microbiota in the Pathophysiology of Autism Spectrum Disorder: Clinical and Preclinical Evidence

“…As previously mentioned, microbiota alterations were described in all those models. Interestingly, in VPA, BTBR and MIA mice, the 5-HT alterations correlated with some of the observed microbiota changes [53,63,94].…”

“…First, studies on germ-free animals prove that the microbiota is important for maturation of the immune system and helps maintain immune homeostasis [93]. Plus, as previously mentioned, an immune challenge during pregnancy in the MIA model results in a dysbiosis in the offspring along with altered communication, social and repetitive behaviors and cortical defects similar to ASD [48,60,94]. Immune alterations similar to those seen in ASD patients were observed in MIA offspring, such as an increase in IL-6 and IL-17 pro-inflammatory cytokines, and higher proportion of Th17 cells [54,95].…”

“…The authors also observed alterations in 5-HT metabolism in the brain, such as a decrease of 5-HT and increase in 5-HIAA/5-HT ratio in the prefrontal cortex and amygdala. Plus, a recent study found that MIA mice presented increased expression of the 5-HT2A receptor in the frontal cortex [94]. However, it is still unclear if those central alterations are influenced by intestinal 5-HT.…”

“…It is interesting to point out that the effects of the FMT did not appear when it was done at 8 weeks of age, highlighting the existence of a critical time window during which FMT in initially GF mice can impact behavior. In a recent study, Saunders et al (2020) [94] transplanted gut microbiota from adult MIA mice or from control mice into 28-days-old control mice whose microbiota had been depleted by antibiotic treatment. The mice that received MIA microbiota showed impaired performances in the object recognition test compared to mice that received microbiota from controls.…”

Genome, Environment, Microbiome and Metabolome in Autism (GEMMA) Study Design: Biomarkers Identification for Precision Treatment and Primary Prevention of Autism Spectrum Disorders by an Integrated Multi-Omics Systems Biology Approach

“…The fecal samples will be the same as those collected for the in vitro studies described above. In addition to wild type naïve mice, fecal transplantation will be conducted in genetically vulnerable (PCDH-KO), food allergic (CMA), and valproate-treated (VPA) male mice which have been previously demonstrated to show ASD-like behavior [ 40 , 41 , 42 , 43 ]. The natural gut microbiota of these mice will be depleted before transplantation with the human fecal samples.…”