Propionate catabolism by CD-associated adherent-invasive E. coli counteracts its anti-inflammatory effect

Abstract

Crohn's disease (CD) is a chronic and disabling inflammatory disorder of the gut that is profoundly influenced by intestinal microbiota composition, host genetics and environmental factors. Several groups worldwide have described an imbalance of the gut microbiome composition, called dysbiosis, in CD patients, with an increase in Proteobacteria and Bacteroidetes and a decrease in Firmicutes. A high prevalence of adherent-invasive Escherichia coli (AIEC) pathobionts has been identified in the intestinal mucosa of CD patients. A significant loss in the bacteria that produce short-chain fatty acids (SCFAs) with anti-inflammatory properties, such as propionate, is also a consequence of dysbiosis in CD patients. Here, the AIEC reference strain LF82 was able to degrade propionate in the gut, which was sufficient to counteract the anti-inflammatory effect of propionate both in in vitro models and in mice with DSS-induced colitis. The consumption of propionate by AIEC pathobionts leads to an increase in TNF-α production by macrophages upon infection through the bacterial methyl-citrate pathway. To induce the protective effects of SCFAs on the inflamed gut, we used a G-protein-coupled receptor 43 agonist (GPR43 agonist) that is not metabolizable by intestinal bacteria. Interestingly, this agonist showed anti-inflammatory properties and decreased the severity of colitis in AIEC-infected mice, as assessed by an improvement in the disease activity index (DAI) and a decrease in AIEC pathobiont encroachment. Taken together, these results highlight the effectiveness of GPR43 agonist treatment in the control of gut inflammation and improved our understanding of the ability of AIEC to modulate propionate availability to create an infectious niche to its advantage.

Keywords: Crohn’s disease; GPR43 agonist treatment; adherent-invasive E. coli; methyl-citrate pathway; propionate.

Figure 1.

Inverse correlation between the fecal level of propionate and the number of E. coli in the stool samples and ileal mucosa of Crohn’s disease patients

Figure 2.

The AIEC strain LF82 catabolizes propionate

Figure 3.

The AIEC LF82 strain counteracts the anti-inflammatory effect of propionate in vitro.

Figure 4.

AIEC LF82 decreases the propionate concentration in vivo.

Figure 5.

The AIEC LF82 strain counteracts the anti-inflammatory effect of propionate in mice

Figure 6.

The GPR43 agonist decreases the severity of colitis in AIEC LF82-infected mice

Figure 7.

The GPR43 agonist displays anti-adhesive properties in AIEC LF82-infected mice