The Impact of IgA and the Microbiota on CNS Disease

Abstract

Although anatomically distant from the central nervous system (CNS), gut-derived signals can dynamically regulate both peripheral immune cells and CNS-resident glial cells to modulate disease. Recent discoveries of specific microbial taxa and microbial derived metabolites that modulate neuroinflammation and neurodegeneration have provided mechanistic insight into how the gut may modulate the CNS. Furthermore, the participation of the gut in regulation of peripheral and CNS immune activity introduces a potential therapeutic target. This review addresses emerging literature on how the microbiome can affect glia and circulating lymphocytes in preclinical models of human CNS disease. Critically, this review also discusses how the host may in turn influence the microbiome, and how this may impact CNS homeostasis and disease, potentially through the production of IgA.

Keywords: IgA; ageing; gut microbiome; multiple sclerosis; neurodegeneration.

Figure 1

Highlighted evidence for the relationship of microbiota affects in CNS-specific human diseases and animal models. Complex diseases of the CNS are often difficult to query in humans due to scarcity of tissue samples. However, combining evidence from patients, healthy controls (A–C) (–14), as well as animal models (D–F) (–23) can provide some suggestive evidence on how the microbiota may impact disease. Figure made using (BioRender.com).

Figure 2

Putative connection between the gut microbiome and CNS neuroinflammation and neurodegeneration. The gut microbiome is shaped by internal (e.g., genetics and other host factors such as mucosal IgA and age) and external factors (e.g., environmental exposures, infections, diet, etc.). Recent literature has suggested that IgA plays a key role in determining the microbes that reside in the gut, but that IgA levels can also be influenced by colonizing microbiota. The gut microbiome is important for programming of peripheral lymphocytes but can also impact the phenotype and function of CNS resident glial cells (via metabolites such as SCFAs. The activation (or modulation) of lymphocytes and glial cells can lead to neuroinflammation or neurodegenerative disorders in the CNS. Figure made using (BioRender.com).