Sulforaphene (LFS-01) is a natural compound derived from traditional herbal medicine. Here, we show that oral administration of LFS-01 is able to dramatically alter the skewed gut microbiota and reverse colitis in model mice associated with an increase of intestinal γδT cells. Through 16S rDNA sequencing, we showed that LFS-01 can selectively suppress enteric pathogens such as Escherichia–Shigella and Helicobacter whereas the protective strains including Lactobacillus and Lachnospiraceae were significantly expanded after LFS-01 treatment. Interestingly, we demonstrated that LFS-01 administration can significantly promote the IL-17+γδT cells in model mice in response to the expanded Lactobacillus. We verified that the intracellular components of Lactobacillus can stimulate the growth of IL-17+γδT cells upon preincubation. The increased IL-17A after LFS-01 treatment in turn recovers the disrupted occludin subcellular location and protects the epithelial barrier in the colon of model mice. Remarkably, LFS-01 does not show apparent toxicity to animals and we demonstrated that LFS-01 also exerts strong protective effects in TNBS-induced colitis rats. Therefore, LFS-01 holds great promise for the treatment of inflammatory bowel disease (IBD) and warrants translation for use in clinical trials. Our work provided a new avenue for the treatment of IBD based on the strategy of harnessing intestinal symbiosis.
Exportin-1
(also named as CRM1) plays a prominent role in autoimmune
disorders and has emerged as a potential therapeutic target for colitis.
Here we report on the rational structure-based discovery of a small-molecule
antagonist of exportin-1, LFS-829, with low-range nanomolar activities.
The co-crystallographic structure, surface plasmon resonance binding
assay, and cell-based phenotypic nuclear export functional assay validated
that exportin-1 is a key target of LFS-829. Moreover, we demonstrated
that the C528S mutation or the knockdown on exportin-1 can abolish
the cellular activities of LFS-829. Strikingly, oral administration
of LFS-829 can significantly reverse the pathological features of
colitis model mice. We revealed that LFS-829 can attenuate dual NF-κB
signaling and the Nrf2 cytoprotection pathway via targeting exportin-1
in colitis mice. Moreover, LFS-829 has a very low risk of cardiotoxicity
and acute toxicity. Therefore, LFS-829 holds great promise for the
treatment of colitis and may warrant translation for use in clinical
trials.
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