It is becoming increasingly evident that many neurological disorders and diseases, including autism spectrum disorder (ASD), Parkinson's disease (PD), Alzheimer's disease (AD), and multiple sclerosis (MS) are multifactorial and are not strictly disorders of the central nervous system (CNS). For example, gastrointestinal symptoms/dysfunction and gut microbiome dysbiosis have been implicated in multiple neurological disorders (Cryan et al., 2019) and specifically in autism (Vellingiri, Aishwarya, Benita Jancy, & Sriram Abhishek, 2022), PD (Dong, Sun, He, & Cheng, 2022; Wallen et al., 2020, Wallen et al., 2022), AD (Giridharan, Barichello De Quevedo, & Petronilho, 2022), and MS (Noto & Miyake, 2022). The number of microorganisms estimated to inhabit the human gastrointestinal tract is upwards of 1014 (Thursby & Juge, 2017). Technological advances in the past decade have made available a number of tools to investigators to interrogate the complexity and function of gut microbiota, including biomarker profiling, metagenomics, metabolomics, large-scale transcriptomics and proteomics (Cryan et al., 2019). The human gut microbiome is primarily composed of bacteria from the phyla Firmicutes, Bacteroidetes, and Actinobacteria (Tap et al., 2009). Under homeostatic conditions, the human gut microbiome is crucial for metabolic function and development of the immune, endocrine, and nervous systems (Foster, 2016). Germ-free mice display a myriad of abnormalities in neurogenesis, myelination, microglia function, neurotransmission and synaptic plasticity, and blood-brain barrier permeability (Cryan et al., 2019).

In humans, approximately 70–80% of immune cells are found in the gut (Kagnoff, 1987) and the gut is directly connected to CNS via the vagal nerve (Fülling, Dinan, & Cryan, 2019), thus the gut microbiome can communicate directly with the CNS. The microbiome-gut-brain axis is a bidirectional pathway connecting the nervous system, immune system, endocrine system, and the gut microbiome (Cryan & Dinan, 2012). Gut microbiome dysbiosis has been linked to several neurological diseases in pre-clinical models of disease. As an example, stroke has been shown to induce gut microbiota dysbiosis in a mouse middle cerebral artery (MCA) occlusion model (Singh et al., 2016). Specifically, species diversity was reduced following stroke and these alterations were particularly noted in the three most abundant phyla Firmicutes, Bacteroidetes, and Actinobacteria (Singh et al., 2016). Thus, it is evident that gut microbiota influences the CNS and vice versa.

In this chapter we discuss the influence of the microbiome on the immune system and the nervous system, particularly in the context of neurological diseases. Gut microbiome influences on central and peripheral immune cells, microbiota-derived neuro-immune mediators, and routes of communication are discussed. We also discuss in broad strokes the likelihood that manipulating the gut-brain axis and gut microbiota could represent opportunities for therapeutic intervention and the challenges the field may face to get to that point.