Butyrate Attenuates Lung Inflammation by Negatively Modulating Th9 Cells

Area of Science:

• Immunology
• Allergy and Inflammation
• Microbiome Research

Background:

• Th9 cells drive allergic lung inflammation via IL-9, promoting eosinophil and mast cell recruitment and mucus production.
• FOXP3 transcription factor represses IL-9 production and is induced by microbiota-derived short-chain fatty acids (SCFAs).
• SCFAs like butyrate and propionate possess anti-inflammatory properties but their impact on Th9 cells is unknown.

Purpose of the Study:

• To investigate the hypothesis that SCFAs protect against lung inflammation by negatively modulating Th9 cell differentiation and function.
• To compare the effects of butyrate and propionate on FOXP3 expression, IL-9 production, and Th9 cell differentiation.

Main Methods:

• In vitro assessment of FOXP3 induction and IL-9 repression by butyrate and propionate.
• Evaluation of SCFA effects on in vitro differentiation of T cells expressing IL-13.
• In vivo study using ovalbumin (OVA)-challenged mice treated with butyrate to assess lung inflammation, mucus production, and Th9 cell infiltration.
• Adoptive transfer of Th9 cells and IL-9 treatment in butyrate-treated mice to confirm the role of Th9 cells.

Main Results:

• Butyrate was more effective than propionate in inducing FOXP3 expression and repressing IL-9.
• Propionate inhibited in vitro differentiation of IL-13-expressing T cells.
• Butyrate treatment reduced lung inflammation and mucus production in OVA-challenged mice.
• Butyrate treatment led to a lower frequency of lung-infiltrated Th9 cells and eosinophils.
• Restoration of lung inflammation upon Th9 cell transfer or IL-9 administration in butyrate-treated mice.

Conclusions:

• SCFAs, particularly butyrate, can suppress Th9-mediated immune responses, offering a protective role against allergic lung inflammation.
• The anti-inflammatory effects of butyrate in lung inflammation are significantly mediated by the suppression of Th9 cell activity and IL-9 production.
• Targeting SCFA production or signaling could be a novel therapeutic approach for allergic airway diseases.