Gut-Induced Inflammation during Development May Compromise the Blood-Brain Barrier and Predispose to Autism Spectrum Disorder

Abstract

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.

Keywords: autism spectrum disorder; blood-brain barrier; gastrointestinal problems; gut microbiota; gut-brain axis; immunological mediators; inflammation; neuroinflammation; short chain fatty acids.

Figure 1

Schematic illustration of the gut-brain axis (GBA). Panel (A): Beginning with the microbiota, this diagram illustrates the interactions between the gut and the brain via microbial metabolites, cytokines, neurotransmitters, and hormones. The gut-brain humoral connections which intersect at the blood-brain barrier and the neuronal connections by way of the enteric nervous system and vagus nerve are also illustrated. Through these pathways, dysbiosis and increased barrier permeability may affect neural development, maturation, and function. Panel (B): Structural similarities between the blood-brain barrier (BBB) and the intestinal epithelial barrier. Adapted from [5,6].

Figure 2

Schematic illustration of healthy and disease state blood-brain barrier (BBB) epithelium. (A) A healthy BBB is tightly sealed by the tight junctions of endothelial cells and astrocytes. (B) A disease state BBB has increased translocation of inflammatory mediators, immune cells, and microglial activation, which further increases BBB permeability. Ultimately, this results in neuroinflammation and neuronal cell death. Adapted from [5].