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Impact of miR-21 on the intestinal mucus barrier and subsequent inflammation
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Date
2026-01-26
Authors
Stiegeler, Sarah
Journal Title
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Publisher
University College Cork
Published Version
Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that play crucial roles in various biological processes. They are best known for fine-tuning protein synthesis at the translational level. Most often, miRNAs are studied in the context of human diseases, where their dysregulation is linked to disease pathology, such as in Inflammatory Bowel Disease (IBD). IBD is a recurrent, multifactorial inflammatory condition. In the twentieth century, IBD was mainly regarded as a disease of industrialised countries. Today, the incidence of IBD is rising globally, with increasing cases in newly industrialised nations. Here, we focus on the regulatory role of miR-21 in the intestinal barrier and how pathological upregulation of miR-21 may contribute to IBD. Previously, our lab demonstrated that loss of miR-21 offers protection against DSS-induced colitis and influences the intestinal microbiota. To build on these findings, we sought to examine the underlying molecular mechanism. We investigated gene expression associated with the intestinal mucin barrier and performed bulk RNA sequencing and shotgun metagenomics following a DSS challenge. For the first time, we show that miR-21 deficiency confers sex-specific protection, with female KO mice exhibiting greater resistance to chemically induced colitis. Interestingly, female HET mice showed even more protection than KO mice. This phenotype appears to be partly due to an enhanced mucus barrier, including increased production of mucus components such as muc2. RNA sequencing further revealed a reduced pro-inflammatory and strong regenerative profile in mice (heterozygote) deficient for miR-21, suggesting reduced DSS-mediated epithelial damage or enhanced wound healing. Furthermore, KO mice exhibited reduced inflammation-mediated disruption of the intestinal microbiota, with females showing remarkable resilience in microbial composition.
Additionally, we introduced C. rodentium-induced colitis, enabling us to examine immune-mediated epithelial dysfunction. Once again, we demonstrated protection from pathogen-induced colitis in KO; however, this protection was strongly linked to the breeding scheme. While littermate-bred KO mice exhibited significant protection with increased IL-22-mediated strengthening of the intestinal barrier in females, non-littermate KO mice lacked the genotype-related effect on the intestinal barrier. This work highlights the modulatory role of miR-21 on the intestinal mucus barrier and the microbiota. Furthermore, we began to decipher the impact of miR-21 on unspecific (DSS) and specific (pathogen) epithelial insults, discovering a potentially strong maternal or developmental influence of miR-21. In addition, our findings in female HET mice suggest that controlled miR-21 expression is preferable to complete loss in females, which might be relevant when developing novel therapeutics against IBD and other chronic inflammatory conditions with dysregulated miR-21.
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Keywords
miRNA-21 , Inflammatory Bowel Disease (IBD) , Intestinal barrier , Mucus
Citation
Stiegeler, S. M. 2026. Impact of miR-21 on the intestinal mucus barrier and subsequent inflammation. PhD Thesis, University College Cork.