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.