Benedetta Sposito MicrobiotaMi

MicrobiotaMi Comment 25_21  by Benedetta Sposito

Related Journal Article: Interleukin-6 produced by enteric neurons regulates the number and phenotype of microbe-responsive regulatory T cells in the gut

This article was published in the: Immunity. 2021 Mar 9;54(3):499-513.e5. doi: 10.1016/j.immuni.2021.02.002. PMID: 33691135

Gut Microbiota-Neuron-Treg Triangle

It is well known that the microbiota influences the development and skewing of the intestinal immune system. Among the multiplicity of innate and adaptive immune cells that colonize the intestine, regulatory T cells (Tregs) are critical for maintaining tissue homeostasis and tolerance to commensal bacteria. Previous reports have described the ability of specific commensals to induce differentiation of RORγ+ Tregs in the mouse colon. Interestingly, these microbial species also modulate expression of neuropeptides in the colon and have an increased ability to activate neurons suggesting that the enteric nervous system (ENS) might be implicated. The mechanism of such complex interaction between the microbiota, the ENS and Treg differentiation has not been elucidated yet and is the object of this study.

The authors show that indeed enteric neurons have the capacity to inhibit in vitro T reg (iTreg) differentiation and that this process is mediated by a soluble factor. Initially, they test different neuromediators but none of them blocks iTreg induction. They profile the transcriptome of differentiating iTregs co-cultured or not with neurons and find that cytokine signaling pathways are among the most upregulated by neurons. After testing several candidates, they identify IL-6 as the neuron-derived inhibitor of iTreg induction. They also show that neuronal IL-6 can modulate the RORγ+/- Treg ratio.

They then move on to test how colonization of germ-free (GF) mice with either a RORγ+ Treg-inducing commensal (Clostridium ramosum), that they had previously found to have an increased ability to activate neurons, or another commensal (Peptostreptococcus magnus) affects enteric neurons. Colonization with both species but especially with C. ramosum caused a reduction in neuronal density and downregulation of several neurotransmitters at the transcriptional level. Interestingly, microbe-responsive genes were shown to belong to different enteric neuron classes suggesting a broad effect of microbiota colonization on the ENS. A reduction in Il6 was also detected albeit at later time points supporting the hypothesis that microbiota-induced neuronal alterations are impairing Il6 induction. The authors also show that mice deficient in two distinct neuropeptides have increased colonic Tregs and that myenteric neuron supernatants derived from these mice had reduced ability to inhibit iTreg differentiation coupled with lower IL-6 protein levels. Finally, mice lacking expression of Il6 specifically in neurons also repress iTreg differentiation and had increased colonic Tregs and a decrease in RORγ+ Tregs.

Overall, the authors provide evidence that in addition to the direct crosstalk between the microbiota and the host immune system, the microbiota can shape the host immune system indirectly by perturbing the ENS.

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