Regulation of common neurological disorders by gut microbial metabolites

Abstract

The gut is connected to the CNS by immunological mediators, lymphocytes, neurotransmitters, microbes and microbial metabolites. A mounting body of evidence indicates that the microbiome exerts significant effects on immune cells and CNS cells. These effects frequently result in the suppression or exacerbation of inflammatory responses, the latter of which can lead to severe tissue damage, altered synapse formation and disrupted maintenance of the CNS. Herein, we review recent progress in research on the microbial regulation of CNS diseases with a focus on major gut microbial metabolites, such as short-chain fatty acids, tryptophan metabolites, and secondary bile acids. Pathological changes in the CNS are associated with dysbiosis and altered levels of microbial metabolites, which can further exacerbate various neurological disorders. The cellular and molecular mechanisms by which these gut microbial metabolites regulate inflammatory diseases in the CNS are discussed. We highlight the similarities and differences in the impact on four major CNS diseases, i.e., multiple sclerosis, Parkinson's disease, Alzheimer's disease, and autism spectrum disorder, to identify common cellular and molecular networks governing the regulation of cellular constituents and pathogenesis in the CNS by microbial metabolites.

Fig. 1. Microbial metabolites regulate CNS development, integrity, and inflammation.

Microbial metabolites positively and negatively influence CNS development and inflammatory responses. In the best case, beneficial metabolites are produced in symbiosis with a balanced population of diverse microbes in the gut. Together, these microbes produce myriad metabolites that are beneficial for the host. In dysbiosis, the production of harmful metabolites is increased while that of beneficial metabolites is decreased. In general, beneficial metabolites, such as SCFAs and Trp metabolites, reinforce the integrity of the gut barrier and BBB and support the functional maturation of CNS cells such as microglia, oligodendrocytes and astrocytes. Thus, these metabolites support CNS formation, neurological function, and the development of regulatory immune cells for immune tolerance. Moreover, these metabolites suppress harmful immune responses, such as the generation of pathogenic Th17 cells. These functions are mediated in part by various host receptors, such as GPCRs, transcription factors, nuclear ligand receptors (PXR and FXR), and TLRs. Conversely, harmful metabolites weaken the gut barrier and BBB and cause systemic inflammatory responses, neuronal cell death and tissue injury (e.g., demyelination), leading to inflammatory conditions that exacerbate CNS diseases. Not only harmful microbial metabolites but also pathogenic bacterial cells and T cells travel from the gut to the CNS to increase inflammation under pathological conditions.

Fig. 2. The common regulatory network of microbial metabolites, inflammatory diseases and CNS disorders.

The common initiating factors for the four neurological diseases are genetic predisposition and environmental factors, which include diet and lifestyle. Under pathogenic conditions, the intestinal barrier can be breached, and systemic inflammatory responses can occur. These changes can be followed by dysbiosis (i.e., decreased gut microbial diversity leading to decreased levels of beneficial microbes). For example, consumption of a diet high in calories and fat but low in dietary fiber can accelerate pathogenic dysbiosis. As a result, decreased levels of beneficial gut microbial metabolites such as SCFAs, Trp metabolites and phytochemicals are produced, and simultaneously, the production of harmful metabolites such as long-chain fatty acids (LCFAs), certain bile acid metabolites, and toxic microbial metabolites increases, thereby affecting immune and tissue cells in both the intestine and CNS. These changes can decrease immune tolerance, which is important for preventing autoimmune diseases, and exacerbate pathogenic immune responses mediated by inflammatory cells such as Th17 and Th1 cells. These pathogenic inflammatory responses can contribute to tissue damage (demyelination in MS), neuronal cell death (PD and AD), and neuronal synapse development (ASD). Moreover, certain microbial metabolites regulate neurotransmission and, therefore, can directly affect neurological activity.