Picroside III Ameliorates Colitis in Mice: A Study Based on Colon Transcriptome and Fecal 16S Amplicon Profiling.

Picroside III (Pic), an iridoid glycoside derived from Picrorhiza scrophulariiflora, exhibits therapeutic potential in mending damage to the intestinal mucosa. This study aimed to explore Pic's regulatory impact on intestinal inflammation and the gut microbiota in mice with dextran sulfate sodium (DSS)-induced colitis. The findings revealed that pretreatment with Pic mitigated the DSS-induced escalation of the disease activity index (DAI), alleviated intestinal damage, and attenuated intestinal inflammation in mice. RNA-seq analysis, complemented by experimental validation, elucidated that Pic significantly hindered Akt phosphorylation in the colon tissues of colitis-afflicted mice. Furthermore, 16S rRNA sequencing demonstrated that Pic pretreatment effectively rectified microbial dysbiosis in colitis mice by elevating the abundance of Lactobacillus murinus and Lactobacillus gasseri. These observations suggest that Pic's efficacy in colitis treatment stems from its inhibition of intestinal inflammation via the suppression of the PI3K-Akt pathway and modulation of gut microbiota. This study contributes novel scientific insights into the potential application of Pic in the management of inflammatory bowel disease (IBD).

Activation of P2Y1R impedes intestinal mucosa repair during colitis.

Delayed intestinal mucosal healing is one of the pathogenic bases for the recurrence of inflammatory bowel disease (IBD), but how the IBD inflammatory environment impedes intestinal mucosa repair remains unclear. Adenosine diphosphate (ADP) is an endogenous ligand of P2Y1R that is highly produced at sites of inflammation. We herein identify a novel role of ADP to directly facilitate inflammation-induced epithelial permeability, delay wound healing, and disrupt tight junction integrity, and we found that P2Y1R, a receptor preferentially activated by ADP, was significantly upregulated in the colonic mucosa of ulcerative colitis (UC) patients and in colonic epithelial cells of colitis mice. Inhibition of P2Y1R significantly increased the epithelial permeability, decreased the wound healing capacity, and impaired the tight junction integrity in TNF-α-challenged Caco-2 cells. In parallel, the same effects in promoting intestinal mucosa repair were observed in DSS-induced colitis in P2Y1R-/- mice. Mechanistic investigation revealed that P2Y1R inhibition facilitated epithelial AMP-activated protein kinase (AMPK) phosphorylation and gut microbiota homeostasis reconstruction. Taken together, these findings highlight that P2Y1R activation plays an important role in impeding intestinal mucosa repair during colitis, and that P2Y1R is an attractive target for the therapy of IBD.