Autonomic Nervous System Neuroanatomical Alterations Could Provoke and Maintain Gastrointestinal Dysbiosis in Autism Spectrum Disorder (ASD): A Novel Microbiome-Host Interaction Mechanistic Hypothesis

Abstract

Dysbiosis secondary to environmental factors, including dietary patterns, antibiotics use, pollution exposure, and other lifestyle factors, has been associated to many non-infective chronic inflammatory diseases. Autism spectrum disorder (ASD) is related to maternal inflammation, although there is no conclusive evidence that affected individuals suffer from systemic low-grade inflammation as in many psychological and psychiatric diseases. However, neuro-inflammation and neuro-immune abnormalities are observed within ASD-affected individuals. Rebalancing human gut microbiota to treat disease has been widely investigated with inconclusive and contradictory findings. These observations strongly suggest that the forms of dysbiosis encountered in ASD-affected individuals could also originate from autonomic nervous system (ANS) functioning abnormalities, a common neuro-anatomical alteration underlying ASD. According to this hypothesis, overactivation of the sympathetic branch of the ANS, due to the fact of an ASD-specific parasympathetic activity deficit, induces deregulation of the gut-brain axis, attenuating intestinal immune and osmotic homeostasis. This sets-up a dysbiotic state, that gives rise to immune and osmotic dysregulation, maintaining dysbiosis in a vicious cycle. Here, we explore the mechanisms whereby ANS imbalances could lead to alterations in intestinal microbiome-host interactions that may contribute to the severity of ASD by maintaining the brain-gut axis pathways in a dysregulated state.

Keywords: autism spectrum disorder (ASD); autonomic nervous system (ANS); brain–gut axis (BGA); dysbiosis; gastrointestinal (GI) tract; microbiome; neurodevelopment.

Figure 1

The ENS is connected to the CNS via the sympathetic and parasympathetic pathways, forming the brain–gut axis (BGA) [95]. Four levels for the control of the BGA are shown: activation of the ENS, including afferent and efferent intrinsic intestinal nerves (afferent nerves send signals from the periphery to the brain; efferent nerves from the brain to the periphery); and extrinsic innervations, whether sympathetic (splanchnic) or parasympathetic (vagus nerve) influences the generation of dIgA and/or the pIgR-mediated trancytosis. NTs, neurotransmitters; NPs, neuropeptides; GCs, glucocorticoids. Epithelial cell types: blue, enterochromaffin cells; green, neuroendocrine cells; red, Paneth cells; yellow, enterocytes.

Figure 2

Bidirectional interactions within the gut microbiota/brain axis [126]. A network of specialized target/transducer cells in the gut wall functions as an interface between the microbiota and the host lumen. In response to external and bodily demands, the brain modulates these specialized cells within this network via the branches of the ANS (sympathetic and parasympathetic/vagal efferents) and the HPA axis. Such modulation can be transient, such as in response to transient perturbations, or long lasting such as in response to chronically altered brain output. The microbiota are in constant bidirectional communication with this interface via multiple microbial signaling pathways, and this communication is modulated in response to perturbations of the microbiota or the brain. The integrated output of the gut microbial–brain interface is transmitted back to the brain via multiple afferent signaling pathways including the endocrine (metabolites, cytokines, and microbial signaling molecules) and neurocrine (vagal and spinal afferents). While acute alterations in this interoceptive feedback can result in transient functional brain changes (GI infections), chronic alterations are associated with neuroplastic brain changes. Potential therapies aim to normalize altered microbiota signaling to the ENS and central nervous system. ECC, enterochromaffin cells; FMT, fecal microbial transplant; ICC, interstitial cell of Cajal; SCFA, short-chain fatty acid; SMC, smooth muscle cell.