Fecal Supernatant from Adult with Autism Spectrum Disorder Alters Digestive Functions, Intestinal Epithelial Barrier, and Enteric Nervous System

Abstract

Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders defined by impaired social interactions and communication with repetitive behaviors, activities, or interests. Gastrointestinal (GI) disturbances and gut microbiota dysbiosis are frequently associated with ASD in childhood. However, it is not known whether microbiota dysbiosis in ASD patients also occurs in adulthood. Further, the consequences of altered gut microbiota on digestive functions and the enteric nervous system (ENS) remain unexplored. Therefore, we studied, in mice, the ability offecal supernatant (FS) from adult ASD patients to induce GI dysfunctions and ENS remodeling. First, the analyses of the fecal microbiota composition in adult ASD patients indicated a reduced α-diversity and increased abundance of three bacterial 16S rRNA gene amplicon sequence variants compared to healthy controls (HC). The transfer of FS from ASD patients (FS–ASD) to mice decreased colonic barrier permeability by 29% and 58% compared to FS–HC for paracellular and transcellular permeability, respectively. These effects are associated with the reduced expression of the tight junction proteins JAM-A, ZO-2, cingulin, and proinflammatory cytokines TNFα and IL1β. In addition, the expression of glial and neuronal molecules was reduced by FS–ASD as compared to FS-HC in particular for those involved in neuronal connectivity (βIII-tubulin and synapsin decreased by 31% and 67%, respectively). Our data suggest that changes in microbiota composition in ASD may contribute to GI alterations, and in part, via ENS remodeling.

Gastrointestinal symptoms have a minor impact on autism spectrum disorder and associations with gut microbiota and short-chain fatty acids

“…A recent investigation of fecal SCFA in constipated ASD children indicated a two-fold increase in VA concentrations associated with Acidobacteria in children with ASD compared to TD children (Hua et al, 2020). However, SCFA was not different in adults with ASD (Gonzales et al, 2021), and De Angelis et al reported that total short-and medium-chain fatty acids were significantly higher in TD individuals than in ASD individuals (De Angelis et al, 2013). Individuals with Rett syndrome (the leading monogenic cause of ASD) had less bacterial gut microbiota richness and diversity than TD individuals and displayed high levels of SCFAs, especially isovalerate and isobutyrate propionate.…”

A host-microbial metabolite interaction gut-on-a-chip model of the adult human intestine demonstrates beneficial effects upon inulin treatment of gut microbiome

“…Still, by using cell lines and supernatants of single probiotic strains, these in vitro models have a rather limited representation of the complex situation in vivo with respect to both the gut tissue and the microbiome. Both aspects were grasped in their full complexity in a recent study by Gonzales et al , where they showed impaired intestinal digestive and barrier function upon transferring fecal supernatant of human Autism Spectrum Disorder patients into mice [ 72 ] . Although mouse models are frequently employed in biomedical research and allow for studying host-microbe interactions in a controlled setting, using a mouse model for human gut microbiota research has often limited translatability [ 73 ] .…”

Gut microbiota and autism spectrum disorders: a bidirectional Mendelian randomization study

“…Changes in early-life gut microbiota can impact host neuroimmunoregulation ( Morais et al., 2021 ). It is now understood that ASD patients typically exhibit a dysregulated intestinal epithelial barrier ( Gonzales et al., 2021 ). Similarly, an observational study found that SCFAs produced by gut microbiota metabolism could modulate the production of interleukin-2 (IL-2), and autistic patients exhibited an abnormally high level of IL-2, consistent with our GO analysis results ( Vinolo et al., 2011 ; Cao et al., 2021 ).…”