Recently, the gut microbiome has gained considerable interest as one of the major contributors to the pathogenesis of multi-system inflammatory disorders. Several studies have suggested that the gut microbiota plays a role in modulating complex signaling pathways, predominantly via the bidirectional gut-brain-axis (GBA). Subsequent in vivo studies have demonstrated the direct role of altered gut microbes and metabolites in the progression of neurodevelopmental diseases. This review will discuss the most recent advancements in our understanding of the gut microbiome’s clinical significance in regulating blood-brain barrier (BBB) integrity, immunological function, and neurobiological development. In particular, we address the potentially causal role of GBA dysregulation in the pathophysiology of autism spectrum disorder (ASD) through compromising the BBB and immunological abnormalities. A thorough understanding of the complex signaling interactions between gut microbes, metabolites, neural development, immune mediators, and neurobiological functionality will facilitate the development of targeted therapeutic modalities to better understand, prevent, and treat ASD.

The etiology and underlying pathogenetic mechanisms in autism spectrum disorder (ASD) are still largely unknown. In this manuscript, a comprehensive review of the studies which are relevant to ASD and CAPD is conducted and the relationship of ASD and central auditory processing disorders (CAPD) is discussed in the light of recent studies on this subject that may provide new paths in the therapeutical perspective. Many studies confirm that most of the individuals with ASD have some degree of sensory dysfunction related to disorders of processing auditory, visual, vestibular and/or tactile stimuli. Among these, some recent studies addressed CAPD. There is an increasing amount of effort for researches about the link between ASD and CAPD. Most of the studies investigating CAPD in patients with ASD use electrophysiological measurements such as mismatch negativity or P300 event related potentials. Besides these, many publications reported deterioration in speech perception and expression in ASD patients which may also be related with CAPD in this unique group of individuals.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by three core symptoms, specifically impaired social behavior, stereotypic/repetitive behaviors, and sensory/communication deficits. Although the exact pathophysiology of ASD is still unknown, host genetics, oxidative stress, and compromised blood brain barrier (BBB) have been implicated in predisposition to ASD. With regards to genetics, mutations in the genes such as CNTNAP2 have been associated with increased susceptibility of developing ASD. Although some studies observed conflicting results suggesting no association of CNTNAP2 with ASD, other investigations correlated this gene with autism. In addition, CNTNAP2 mediated signaling is generally considered to play a role in neurological disorders due to its critical role in neurodevelopment, neurotransmission, and synaptic plasticity. In this investigation, we studied BBB integrity and oxidative stress in Cntnap2^−/− rats. We observed that the BBB permeability was significantly increased in Cntnap2^−/− rats compared to littermate wild-type (WT) animals as determined by FITC-dextran and Evans blue assay. High levels of thiobarbituric acid reactive substances and lower amounts of reduced glutathione were observed in brain homogenates of Cntnap2^−/− rats, suggesting oxidative stress. Brain sections from Cntnap2^−/− rats showed intense inducible nitric oxide synthase immunostaining, which was undetectable in WT animals. Quantification of nitric oxide in brain homogenates revealed significantly high levels in Cntnap2^−/− rats compared to the control group. As increased permeability of the BBB and oxidative stress have been observed in ASD individuals, our results suggest that Cntnap2^−/− rats have a high construct and face validity and can be explored to develop effective therapeutic modalities.