Gut reactions: How the blood–brain barrier connects the microbiome and the brain

A growing body of evidence indicates that the microbiome interacts with the central nervous system (CNS) and can regulate many of its functions. One mechanism for this interaction is at the level of the blood-brain barriers (BBBs). In this minireview, we examine the several ways the microbiome is known to interact with the CNS barriers. Bacteria can directly release factors into the systemic circulation or can translocate into blood. Once in the blood, the microbiome and its factors can alter peripheral immune cells to promote interactions with the BBB and ultimately with other elements of the neurovascular unit. Bacteria and their factors or cytokines and other immune-active substances released from peripheral sites under the influence of the microbiome can cross the BBB, alter BBB integrity, change BBB transport rates, or induce release of neuroimmune substances from the barrier cells. Metabolic products produced by the microbiome, such as short-chain fatty acids, can cross the BBB to affect brain function. Through these and other mechanisms, microbiome-BBB interactions can influence the course of diseases as illustrated by multiple sclerosis. Impact statement The connection between the gut microbiome and central nervous system (CNS) disease is not fully understood. Host immune systems are influenced by changes to the microbiota and offers new treatment strategies for CNS disease. Preclinical studies provide evidence of changes to the blood-brain barrier when animals are subject to experimental gut infection or when the animals lack a normal gut microbiome. The intestine also contains a barrier, and bacterial factors can translocate to the blood and interact with host immune cells. These metastatic bacterial factors can signal T-cells to become more CNS penetrant, thus providing a novel intervention for treating CNS disease. Studies in humans show the therapeutic effects of T-cell engineering for the treatment of leukemia, so perhaps a similar approach for CNS disease could prove effective. Future research should begin to define the bacterial species that can cause immune cells to differentiate and how these interactions vary amongst CNS disease models.