Sex-related alterations of gut microbiota composition in the BTBR mouse model of autism spectrum disorder

Abstract

Alterations of microbiota-gut-brain axis have been invoked in the pathogenesis of autism spectrum disorders (ASD). Mouse models could represent an excellent tool to understand how gut dysbiosis and related alterations may contribute to autistic phenotype. In this study we paralleled gut microbiota (GM) profiles, behavioral characteristics, intestinal integrity and immunological features of colon tissues in BTBR T + tf/J (BTBR) inbred mice, a well established animal model of ASD. Sex differences, up to date poorly investigated in animal models, were specifically addressed. Results showed that BTBR mice of both sexes presented a marked intestinal dysbiosis, alterations of behavior, gut permeability and immunological state with respect to prosocial C57BL/6j (C57) strain. Noticeably, sex-related differences were clearly detected. We identified Bacteroides, Parabacteroides, Sutterella, Dehalobacterium and Oscillospira genera as key drivers of sex-specific gut microbiota profiles associated with selected pathological traits. Taken together, our findings indicate that alteration of GM in BTBR mice shows relevant sex-associated differences and supports the use of BTBR mouse model to dissect autism associated microbiota-gut-brain axis alteration.

Prenatal stress disrupts social behavior, cortical neurobiology and commensal microbes in adult male offspring

“…In addition, we found that this early life exposure affects cortical 5HT metabolism, elevated markers of neuroinflammation, and oxytocin, as well as corticosterone levels in response to social interaction. This constellation of changes reflects neurobiological changes seen in individuals with ASD [9,31,42,43,50–52]. Our findings suggest that the roots of the psychopathology of this disorder may lie in utero, and be connected to aberrant establishment of the Gut-brain-axis.…”

“…We previously have demonstrated a significant reduction in Bacteriodes in males exposed to restraint stress and a social defeat stressor, and significantly increased circulating levels of IL-6 and CCL2 [18] [Bailey et al, unpublished observation]. Of note, a recent study has linked Bacteroides and Parabacteroides , along with a number of other microbes, to contributing to sex-specific changes in behavior in a mouse model of autism [50]. In addition, treatment with Bacteroides fragilis was able to ameliorate the behavioral and inflammatory abnormalities in the maternal immune activation (MIA) model of autism [10].…”

Sex Differences in Autism Spectrum Disorder: a Review

“…On the other hand, some groups have found immune-related phenotypes in females only. For example, the BTBR mouse model of ASD exhibited female-specific increases in self-grooming behavior, and levels of IL-6 and CD11c [131]. At 6 weeks, wildtype mice prenatally treated with Poly I:C had decreased DNA methylation globally, particularly in females, and decreased methylation at the promoter region of MeCP2, a gene associated with ND [132].…”

A systematic review of gut‐immune‐brain mechanisms in Autism Spectrum Disorder

“…Gene sequencing analyses by Foley, MacFabe, Kavaliers, and Ossenkopp (2015) revealed that infants with ASD have a higher abundance of bacterial genera Faecalibacterium, and lower levels of Blautia, in fecal and blood samples. Recently, a study by Coretti et al (2017) on mice models have elucidated markedly unique microbial and immune profiles in male and female autistic mice, suggesting the possible role of the microbiota in influencing sex-specific susceptibility to autism.…”