A27 THE IMPACT OF MICROBIAL-DERIVED METABOLITES ON TYPE III INTERFERON SIGNALING IN INTESTINAL EPITHELIAL CELLS

TL;DR

This study explores how gut microbial metabolites affect type III interferon signaling in intestinal cells, revealing some metabolites can reduce its activity.

Contribution

The novel finding is that specific gut microbial-derived metabolites can downregulate type III interferon (IFN-λ) activity in human gut epithelial cells.

Findings

Short-chain fatty acids inhibit IFN-λ3-induced ISG expression in a concentration-dependent manner.

Secretions from one gut microbe inhibited IFN-λ activity, while others had no effect.

Succinate and kynurenine did not alter IFN-λ3-induced ISG expression.

Abstract

Interferons (IFNs) are key cytokines that protect mucosal barriers. There are three types – types I, II and III. Unlike types I and II, which are pro-inflammatory, type III interferons (IFN-λs) are highly expressed in the gut and exert beneficial effects such as mucosal healing and dampening inflammation in mouse colitis models. Gut microbes can directly induce IFN-λ expression and prior studies have shown that microbial-derived metabolites can upregulate IFN-λ activity in the lungs. However, much less is known about the role of gut microbial-derived metabolites in the regulation of IFN-λ activity in the gut.

We hypothesized that specific gut microbial-derived metabolites upregulate IFN-λ activity in human gut epithelial cells.

Caco-2 cells were pre-treated for 2 hours with anaerobic whole microbe secretions (1-10% v/v) and microbial-derived metabolites, including short-chain fatty acids (SCFAs; acetate, butyrate, and propionate), a metabolic intermediate (succinate), and a tryptophan metabolite (kynurenine). Next, cells were treated with or without IFN-λ3 (20-50ng/ml) for 22 hours (n=3 biological repeats). IFN-stimulated genes (ISGs; MX1 and IFIT1) were quantified by RT-qPCR. IFN-λR1 levels were quantified by flow cytometry.

Out of microbe secretions added from four gut microbes thus far, secretions from one pathobiont inhibited IFN-λ activity. All SCFAs tested had a concentration-dependent inhibitory effect on IFN-λ3 induction of ISGs (MX1 and IFIT1; p<0.05). Succinate and kynurenine did not affect ISG induction by IFN-λ3 at any concentration tested. Only specific metabolites affected surface IFN-λR1 levels on Caco-2 cells.

Our findings demonstrate that specific microbial-derived metabolites can regulate intestinal IFN-λ immune responses. Contrary to our hypothesis, some metabolites can downregulate IFN-λ activity. Knowledge from this study provides fundamental knowledge about IFN-λ regulation in the human gut with implications for how to promote optimal IFN-λ activity to promote gut health, such as in inflammatory bowel diseases.

Children’s Hospital Research Institute of Manitoba, University of Manitoba