Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders

Abstract

SUMMARY Although autism spectrum disorder (ASD) is defined by core behavioral impairments, gastrointestinal (GI) symptoms are commonly reported. Subsets of ASD individuals display dysbiosis of the gut microbiota, and some exhibit increased intestinal permeability. Here we demonstrate GI barrier defects and microbiota alterations in a mouse model displaying features of ASD, maternal immune activation (MIA). Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition and ameliorates ASD-related defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naïve mice with a metabolite that is increased by MIA and restored by B. fragilis causes behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in ASD and identify a potential probiotic therapy for GI and behavioral symptoms of autism.

Maternal immune activation alters brain microRNA expression in mouse offspring

“…Although ASD is a neurodevelopmental disorder, there are several comorbidities, such as gastrointestinal distress and immune dysregulation, observed in patients with ASD 43. Moreover, a gut‐microbiome‐brain connection was found to contribute to ASD pathogenesis,16 further suggesting that ASD is a systemic disorder caused by both genetic and environmental factors. In this regard, peripheral blood samples have been used to identify pathophysiology and biomarker of ASD.…”

“…To generate the MIA model, pregnant C57BL6 mice were given intraperitoneal injections of 20 mg/kg of poly(I:C) (P9582, Sigma‐Aldrich, St. Louis, MO) on embryonic day 12.5 (E12.5), according to methods previously described 14, 16. Poly(I:C) lyophilized powder was reconstituted in nuclease‐free distilled water (10 mg/mL) to yield Poly(I:C) in an isotonic buffer solution, according to the manufacturer's instructions.…”

“…Startle response of tested mice was recorded by a piezoelectric sensor within the chamber. This experiment was conducted as previously described 16. A five‐min habituation period, with background noise of 65 dB, was provided 1 day before, and immediately prior to, the PPI testing.…”

Trimethylamine‐N‐oxide promotes brain aging and cognitive impairment in mice

“…Increasing evidence has shown that the action of microbial metabolites can be a link between external factors and central nervous system function and behaviour (Cryan & Dinan, 2012; Hsiao et al., 2013). However, the exact mechanisms underlying how microbial metabolites regulate brain function have not been fully elucidated.…”

Biome engineering‐2020

“…Numerous ‘axes’ were defined that link the gut with the lung, the skin and the brain and the gut microbiota is frequently considered as an important transducer of effects. Disturbances in the gut microbiota were, for example, reported to affect via a ‘gut–brain axis’ blood glucose homeostasis (De Vadder et al ., 2014) and even behavioural conditions like autism (Hsiao et al ., 2013). …”