Abstract
Intestinal barrier dysfunction is an important clinical problem in various acute and chronic pathological conditions. Ferulic acid (FA) can attenuate the intestinal epithelial barrier dysfunction, however, the underlying mechanism remains unclear. The present study aimed to uncover the protective effect of FA on intestinal epithelial barrier dysfunction in a Caco-2 cell model of lipopolysaccharide (LPS) stimulation and the underlying mechanism. Caco-2 cells were pretreated with FA and then exposed to LPS stimulation. The barrier function of Caco-2 cells was evaluated by measuring trans-epithelial resistance (TER) and 4-kDa fluorescein isothiocyanate (FITC)-dextran (FD4) flux, and analyzing the tight junction protein expression and structure. The results showed that decreased TER and increased FITC-FD4 flux were observed in Caco-2 cells stimulated with LPS, but these effects were attenuated by FA pretreatment. FA pretreatment inhibited LPS-induced decrease in occludin and ZO-1 mRNA and protein expression. LPS stimulation decreased miR-200c-3p expression, whereas this decrease was inhibited by FA pretreatment. Furthermore, overexpression of miR-200c-3p strengthened the protective effects of FA on LPS-induced Caco-2 cell barrier dysfunction by decreasing epithelial permeability, increasing occludin and ZO-1 protein expression, and maintaining of ZO-1 protein distribution, while suppression of miR-200c-3p reversed the protective effects of FA. LPS treatment increased the expression of PTEN protein and decreased expression of phosphorylated PI3K and AKT proteins. However, pretreatment of FA inhibited expression of PTEN protein and promoted activation of PI3K/AKT signaling pathway in the LPS-treated Caco-2 cells, and this regulatory effect of FA on the PTEN/PI3K/AKT signaling pathway was strengthened or weakened by miR-200c-3p overexpression or suppression, respectively. Our findings suggested that in Caco-2 cells, FA promotes activation of PI3K/AKT pathway by miR-200c-3p-mediated suppression of the negative mediator PTEN, which, in turn, maintains TJ function and thus ameliorates LPS-induced intestinal epithelial barrier dysfunction.
Highlights
The intestinal tract is lined with a single layer of epithelial cells that acts as a selective barrier, allowing absorption of nutrients, electrolytes, and water while preventing the transfer of intestinal pathogens, antigens and toxins from the luminal environment to blood circulation and mesenteric lymph (Odenwald and Turner, 2017)
Our previous studies using the rat IEC-6 cell model demonstrated that Ferulic acid (FA) protects against heat stress-induced intestinal epithelial barrier dysfunction via the PI3K/AKTmediated NF-E2-related factor 2 (Nrf2)/HO-1 signaling pathway (He et al, 2016; He et al, 2018)
Dysfunction of intestinal epithelial barrier leads to increased permeability of intestinal mucosa, subsequent translocation of intestinal pathogenic bacteria or toxins, which in turn aggravates the damage of intestinal barrier integrity, resulting in local intestinal or systemic disease such as inflammatory bowel diseases, multiple organ dysfunction syndromes, and sepsis (Yoseph et al, 2016; Meng et al, 2017)
Summary
The intestinal tract is lined with a single layer of epithelial cells that acts as a selective barrier, allowing absorption of nutrients, electrolytes, and water while preventing the transfer of intestinal pathogens, antigens and toxins from the luminal environment to blood circulation and mesenteric lymph (Odenwald and Turner, 2017). Tight junctions (TJs), located at the apical side of the lateral membranes of intestinal epithelial cells, are the primary factors in determining of paracellular permeability (Buckley and Turner, 2018). Growing investigations indicate that LPS triggers an inflammatory signaling cascade to reduce tight junction protein expression, leading to increased intestinal permeability and disrupting intestinal epithelial barrier function (He et al, 2019; Tunisi et al, 2019). Clinical study demonstrated that circulating blood LPS levels are elevated in Crohn’s disease and sepsis patients, and contribute to the pathogenesis of intestinal and systemic inflammatory response (Guo et al, 2015)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
