A comment on « Microglial control of astrocytes in response to microbial metabolites » Rothhammer et al, Nature 2018

Glial cells influence multiple neuronal functions under physiological as well as pathological conditions. For example, microglia constantly survey their local microenvironment and react immediately if they detect any abnormal changes. Furthermore, accumulative evidence indicates that the gut microbiota can modulate neuronal and glial activities, however, their interactions are still poorly understood.

In this Nature paper, the authors dissected the influence of gut metabolites on the orchestration of the glial response in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Multiple sclerosis is a chronic demyelinating and neuro-inflammatory disorder caused by the entry of immune cells into the central nervous system which attack the myelin – a sleeve around the axons of neurons that increase the speed of neurotransmission.

Rothhammer et al. demonstrate that the activation of the aryl hydrocarbon receptor expressed by microglia limits the progression of EAE through the amelioration of motor symptoms, a reduction of demyelination and less recruitment of immune cells into the central nervous system. The activation of this microglial receptor reduces the production of VEGF-B and increases the release of TGFα, two cytokines acting on astrocytes. The microglia-astrocyte VEGF-B/FLT-1 signaling pathway worsens EAE whereas, in contrast, TGF α/ErbB1 signaling ameliorates the disease symptoms. Consequently, the regulation of microglia-derived VEGF-B and TGFα by the activation of the aryl hydrocarbon receptor is beneficial in the EAE context.

Interestingly, the authors found that microbial metabolism of dietary tryptophan produces agonists of the aryl hydrocarbon receptor which reduces CNS inflammation and the pathological activation of both microglia and astrocytes. This finding highlights, for the first time, a direct link between gut metabolites and glia activation in an EAE context.

Finally, Rothhammer et al. had the chance to obtain human brain tissue from multiple sclerosis affected individuals and healthy controls, allowing them to validate their findings from the EAE mouse model. They found a high expression of the aryl hydrocarbon receptor, VEGF-B and TGFα in active lesions in multiple sclerosis samples suggesting their involvement in human pathogenesis.

To conclude, they show that gut metabolites of dietary tryptophan activate a microglial receptor which controls the production of molecular factors (VEGF-B and TGFα) that regulate the astrocytic inflammatory response. This pathway might open up new therapeutic strategies for multiple sclerosis and other disorders to prevent inflammation.

Source: https://www.nature.com/articles/s41586-018-0119-x

Rothhammer, V., Borucki, D.M., Tjon, E.C. et al. Microglial control of astrocytes in response to microbial metabolites. Nature 557, 724–728 (2018). https://doi.org/10.1038/s41586-018-0119-x

Written by Isabelle Arnoux; Edited by Fazi Bekbulat. Featured Image: NGC/Isabelle Arnoux.