The Brain-Gut-Microbiome System: Pathways and Implications for Autism Spectrum Disorder

Abstract

Gastrointestinal dysfunction is one of the most prevalent physiological symptoms of autism spectrum disorder (ASD). A growing body of largely preclinical research suggests that dysbiotic gut microbiota may modulate brain function and social behavior, yet little is known about the mechanisms that underlie these relationships and how they may influence the pathogenesis or severity of ASD. While various genetic and environmental risk factors have been implicated in ASD, this review aims to provide an overview of studies elucidating the mechanisms by which gut microbiota, associated metabolites, and the brain interact to influence behavior and ASD development, in at least a subgroup of individuals with gastrointestinal problems. Specifically, we review the brain-gut-microbiome system and discuss findings from current animal and human studies as they relate to social-behavioral and neurological impairments in ASD, microbiota-targeted therapies (i.e., probiotics, fecal microbiota transplantation) in ASD, and how microbiota may influence the brain at molecular, structural, and functional levels, with a particular interest in social and emotion-related brain networks. A deeper understanding of microbiome-brain-behavior interactions has the potential to inform new therapies aimed at modulating this system and alleviating both behavioral and physiological symptomatology in individuals with ASD.

Keywords: autism spectrum disorder; brain-gut-microbiome system; gut-brain axis; microbiome; probiotics; tryptophan pathway.

Figure 1

Bidirectional interactions within the Brain-Gut-Microbiome (BGM) System taken from Mayer et al. [6]. The BGM system comprises a complicated network with multiple feedback loops that allow signaling between microbiota and the brain and gut connectomes. The microbiome can modulate sensory processing, social behavior, affect, and the two arms of the stress response, in addition to abdominal pain, directly via various neuroactive and inflammatory signaling molecules, or indirectly via the vagus nerve. In turn, the brain can modulate gut microbial composition and function directly by the release of neuroactive compounds into the gut lumen acting on receptors of certain gut microbes, or via the regulation of intestinal motility and secretion activities, indirectly affecting the composition and functions of the gut microbiome. Both prenatal and postnatal perturbations to the BGM system, including but not limited to diet, infection, inflammation, and psychosocial stress, can influence the stability of these neural, neuroendocrine and immunoregulatory communication channels to create fundamental changes in brain structure and function. ANS = autonomic nervous system; HPA = hypothalamic-pituitary-adrenal; SMC = smooth muscle cells; ICC = interstitial cells of Cajal; ECC = enterochromaffin cells; SCFAs = short-chain fatty acids; FMT = fecal microbial transplant. Copyright © 2021, American Society for Clinical Investigation. The request has been put in and we are waiting for documentation.

Figure 2

Figure modified from Mayer [9] depicting diversity and abundance of gut microbes across the lifespan of a human. Early and late periods of low diversity coincide with vulnerability to neurodevelopmental disorders and neurodegenerative disorders, respectively. IBS = Irritable Bowel Syndrome.

Figure 3

The observed relationship between probiotic use and amelioration of ASD-like symptoms in MIA offspring. Figure taken from Hsiao et al. [49] Graphical Abstract. Cell 2013 155, 1451–1463 DOI: (https://doi.org/10.1016/j.cell.2013.11.024) Copyright © 2021 Elsevier Inc.

Figure 4

Simplified illustration of the tryptophan pathway in the GI tract and potential impacts on behavior, CNS, and GI dysfunction. BBB = blood brain barrier; TPH = tryptophan hydroxylase; IDO = indolamine 2,3-dioxygenase; TDO = tryptophan 2,3-dioxygenase; TnaA = tryptophanase; 5-HTP = 5-hydroxytryptophan; 5-HT = 5-hydroxytryptamine, or serotonin; ACh = acetylcholine; NMDA = N-methyl-D-aspartate; CNS = central nervous system; GI = gastrointestinal; arrow thickness represents strength of pathway.