Butyrate Attenuates Lung Inflammation by Negatively Modulating Th9 Cells

Abstract

Th9 cells orchestrate allergic lung inflammation by promoting recruitment and activation of eosinophils and mast cells, and by stimulating epithelial mucus production, which is known to be mainly dependent on IL-9. These cells share developmental pathways with induced regulatory T cells that may determine the generation of one over the other subset. In fact, the FOXP3 transcription factor has been shown to bind il9 locus and repress IL-9 production. The microbiota-derived short-chain fatty acids (SCFAs) butyrate and propionate have been described as FOXP3 inducers and are known to have anti-inflammatory properties. While SCFAs attenuate lung inflammation by inducing regulatory T cells and suppressing Th2 responses, their effects on Th9 cells have not been addressed yet. Therefore, we hypothesized that SCFAs would have a protective role in lung inflammation by negatively modulating differentiation and function of Th9 cells. Our results demonstrated that butyrate is more effective than propionate in promoting FOXP3 expression and IL-9 repression. In addition, propionate was found to negatively impact in vitro differentiation of IL-13-expressing T cells. Butyrate treatment attenuated lung inflammation and mucus production in OVA-challenged mice, which presented lower frequency of lung-infiltrated Th9 cells and eosinophils. Both Th9 cell adoptive transfer and IL-9 treatment restored lung inflammation in butyrate-treated OVA-challenged mice, indicating that the anti-inflammatory effects of butyrate may rely on suppressing Th9-mediated immune responses.

Go With Your Gut: The Shaping of T-Cell Response by Gut Microbiota in Allergic Asthma

“…Butyrate-treated mice show lower frequencies of Th9 cells in the lungs, while no difference is observed for Th2 cells (31). Moreover, adoptive transfer of Th9 or IL-9 administration could revert the protective effect of butyrate, indicating that the mechanisms are partially related to this Th subclass (31). Lastly, while the link between obesity and non-allergic bronchial hyperresponsiveness is widely accepted, a high-fat diet has little effect in modulating Tregs responses by an impairment of DCs activation in OVA-induced AAS (33).…”

“…Since Tregs are potent inhibitors of Th9 (32), their capacity to reduce IL-9 expression and Th9 differentiation was assessed. Butyrate-treated mice show lower frequencies of Th9 cells in the lungs, while no difference is observed for Th2 cells (31). Moreover, adoptive transfer of Th9 or IL-9 administration could revert the protective effect of butyrate, indicating that the mechanisms are partially related to this Th subclass (31).…”

“…Other T-cell subsets could be involved in SCFAs-mediated protection against AAS. In newborn mice treated with a commercially available mixture of probiotics, increased levels in butyrate, but not other metabolites, are able to induce the proliferation of Tregs and negatively modulate OVA-induced AAS (31). Since Tregs are potent inhibitors of Th9 (32), their capacity to reduce IL-9 expression and Th9 differentiation was assessed.…”

Th9 cells in allergic diseases: A role for the microbiota?

“…First of all, recent murine studies showed that butyrate, one of the microbiota‐derived SCFAs, suppressed Th9 cell responses in a lung inflammation setting. Specifically, butyrate reduced the frequency of Th9 cells in the lung and subsequently reduced eosinophil infiltration and lung inflammation …”

“…Specifically, butyrate reduced the frequency of Th9 cells in the lung and subsequently reduced eosinophil infiltration and lung inflammation. 56 In addition, antagonizing effects of retinoic acid (RA), a dietary metabolite of vitamin A which is synthesized by mucosal dendritic cells (DCs), were described. 57 RA showed to impact the transcriptome of Th9 cells while not affecting other T helper subtypes to the same extent.…”