Fecal let-7b and miR-21 directly modulate the intestinal microbiota, driving chronic inflammation

Abstract

Inflammatory bowel diseases (IBD) etiology is multifactorial. Luminal microRNAs (miRNAs) have been suspected to play a role in the promotion of chronic inflammation, but the extent to which fecal miRNAs are interacting with the intestinal ecosystem in a way that contribute to diseases, including IBD, remains unknown. Here, fecal let-7b and miR-21 were found elevated, associated with inflammation, and correlating with multiple bacteria in IBD patients and IL-10^-/- mice, model of spontaneous colitis. Using an in vitro microbiota modeling system, we revealed that these two miRNAs can directly modify the composition and function of complex human microbiota, increasing their proinflammatory potential. In vivo investigations revealed that luminal increase of let-7b drastically alters the intestinal microbiota and enhances macrophages' associated proinflammatory cytokines (TNF, IL-6, and IL-1β). Such proinflammatory effects are resilient and dependent on the bacterial presence. Moreover, we identified that besides impairing the intestinal barrier function, miR-21 increases myeloperoxidase and antimicrobial peptides secretion, causing intestinal dysbiosis. More importantly, in vivo inhibition of let-7b and miR-21 with anti-miRNAs significantly improved the intestinal mucosal barrier function and promoted a healthier host-microbiota interaction in the intestinal lining, which altogether conferred protection against colitis. In summary, we provide evidence of the functional significance of fecal miRNAs in host-microbiota communication, highlighting their therapeutic potential in intestinal inflammation and dysbiosis-related conditions, such as IBD.

Keywords: Anti-miR-21; anti-let-7b; colitis; dysbiosis; gastrointestinal microbiome; host-microbiota interaction; intestinal permeability; let-7b; miR-21; microRNA.

Figure 1.

Let-7b and miR-21 are inflammation-associated miRNAs in mice and IBD patients.

Figure 2.

Let-7b and miR-21 directly affect human microbiota composition.

Figure 3.

Administration of exogenous miRNAs induced colonic inflammation, but only miR-21 treatment impaired the intestinal barrier function.

Figure 4.

The treatment with miR-21 and let-7b alters the microbiota in vivo.

Figure 5.

The administration of exogenous miRNAs modified the mucus composition and promoted the production of antibacterial factors.

Figure 6.

Let-7b-induced inflammation was associated with long-term microbiota alterations and prevented by antibiotics.

Figure 7.

The powerful therapeutic anti-inflammatory potential by inhibiting endogenous miR-21 and let-7b.

Figure 8.

Graphical summary of our key findings.