Ulcerative colitis (UC) is a chronic inflammatory bowel disease that significantly impacts quality of life and increases the risk of colorectal cancer. While treatments exist, many patients suffer from adverse effects or develop resistance to current therapies.
A new study published in the journal iMetaMed identifies a promising dual-action therapeutic strategy using Everolimus (Eve), a selective mTORC1 inhibitor traditionally used in oncology and transplant medicine.
The research team investigated the potential of Everolimus in treating UC using experimental models. The study demonstrates that Everolimus alleviates colitis symptoms—including weight loss, tissue injury, and inflammation—through two distinct but complementary mechanisms: suppressing specific inflammatory signaling and reshaping the gut ecosystem.
Blocking the inflammatory trigger
The researchers found that the expression of a protein called CLEC4E is significantly elevated in colitis. CLEC4E, primarily found on macrophages (immune cells), acts as a trigger for the NF-κB signaling pathway, which drives the release of pro-inflammatory cytokines. The study reveals that Everolimus effectively inhibits the CLEC4E/Syk/NF-κB signaling axis. By blocking this pathway, the drug reduces the production of inflammatory molecules and prevents the nuclear translocation of p65, a critical step in the inflammatory response.
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To validate this mechanism, the team used a CLEC4E agonist. When the CLEC4E pathway was artificially reactivated, the protective benefits of Everolimus were abolished, confirming that this receptor is a key target for the drug’s anti-inflammatory efficacy.
Remodeling the gut microbiota and metabolites
Beyond its direct effect on immune cells, Everolimus was found to significantly alter the composition of the gut microbiota. In UC, the gut microbiome is often dysbiotic, characterized by a loss of diversity and beneficial bacteria. Treatment with Everolimus restored microbial diversity and specifically enriched beneficial species such as Bacteroides acidifaciens.
Metabolomic analysis revealed that this shift in microbiota led to increased levels of propionic acid, a short-chain fatty acid known for its gut-protective properties. The study demonstrated that propionic acid mimics the effects of Everolimus by suppressing inflammation and strengthening the intestinal epithelial barrier.
Transferable protection
The researchers utilized Fecal Microbiota Transplantation (FMT) to prove the causal role of the microbiome. Transferring gut microbiota from Everolimus-treated donors to recipient subjects conferred protection against colitis, improving barrier integrity and reducing inflammation. Conversely, depleting the gut microbiota with antibiotics eliminated the therapeutic efficacy of Everolimus, highlighting that the drug relies partly on the microbiome to function.
This study provides comprehensive evidence that Everolimus protects against ulcerative colitis via a dual mechanism: inhibiting CLEC4E-driven inflammation and remodeling the gut microbiota-metabolite axis. These findings highlight the drug’s therapeutic promise and suggest that targeting upstream regulators of inflammation while simultaneously restoring metabolic homeostasis could be a vital strategy for clinical translation in UC management.
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