Brain inflammatory cascade controlled by gut-derived molecules

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Figure 1 | Long-distance regulation of immune cells in the brain. Gut bacteria process the dietary component tryptophan to produce metabolite molecules that enter the central nervous system (CNS). In the brain, these metabolites act as ligands for the aryl hydrocarbon receptor (AHR) — a transcription factor expressed in cells called microglia and astrocytes that mediate responses to inflammation in the CNS. Rothhammer et al.2 report that, when activated in microglia, AHR binds to the genes that encode the proteins VEGF-B and TGF-α, inhibiting the expression of the former and promoting that of the latter. Any VEGF-B released from microglia enhances the responsiveness of astrocytes to CNS inflammation. By contrast, TGF-α dampens astrocyte responsiveness.

So, the activity of microglia and astrocytes is modulated by AHR during brain inflammation in autoimmune disease. But which signals might modulate microglial AHR? In addition to environmental toxins, AHR is bound by a broad range of molecules, including dietary derivatives8. In particular, food plants such as broccoli and other members of the cabbage family contain components that bind AHR either directly or after being processed into metabolite molecules, such as derivatives of tryptophan (Trp), by gut microbes9. Rothhammer et al. fed their mice diets either depleted or enriched in Trp. Trp depletion exacerbated EAE in wild-type mice, whereas enrichment ameliorated the effects of the disease. By contrast, neither diet had any effect on the progress of EAE in AHR-deficient animals, as might have been predicted — in these animals, Trp cannot bind to AHR to dampen immune responses.

To determine whether their work is likely to have implications for humans, the authors verified basic elements of their analyses in tissue samples from people with MS, in which an autoimmune attack drives glial inflammation, destruction of nerve processes and their insulating myelin sheaths, and ultimately scar formation10. The group found that AHR, TGF-α and VEGF-B were expressed in microglia-like cells in MS tissues. Levels of the proteins were higher in newly inflamed regions than in old scar tissue or unaffected surrounding tissue. This suggests (but does not prove) that TGF-α and VEGF-B have a role in the formation of MS scar tissue.

Rothhammer and colleagues’ work sheds light on the complex regulation of inflammatory reactivity in the CNS and adds another facet to our understanding of the gut–brain connection. Robust regulation of inflammatory responsiveness is essential for proper CNS function. Deficient regulation, with unrestrained inflammatory episodes, leads to sickness, irreversible cell loss and scar formation11, whereas compromised inflammatory reactivity can result in tumour formation and opportunistic infection12. The authors’ findings are therefore likely to have implications beyond MS.

The interactions between the gut, microglia and astrocytes outlined by Rothhammer et al. are not the only mechanisms that safeguard inflammatory responses in the brain13. It will be of interest to examine how other regulators of the CNS immune microenvironment modulate the newly identified signalling pathway. These factors include the cells associated with the cerebral blood vessels, as well as active neurons. Indeed, pharmacological silencing of neurons leads to the activation of neighbouring microglia14.

That the behaviour of microglia can be controlled remotely by intestinal products is intriguing, although not without precedent. A flurry of observations previously linked the CNS to the gut and its microbial contents. Neuronal pathways, hormones, microbial molecules and metabolites are all involved in signalling between these regions15. Specifically, short-chain fatty acids produced by gut bacteria can modulate microglia cells16, and tryptophan metabolites act directly on astrocytes6. Nonetheless, the current findings broaden our understanding of the gut–brain connection. The authors speculate that this pathway might support the repair of injured neural cells.

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