Rosmarinic Acid Restores Colonic Mucus Secretion in Colitis Mice by Regulating Gut Microbiota-Derived Metabolites and the Activation of Inflammasomes

Abstract

Maintaining a steady state of mucus barrier is an important potential target for polyphenol to exert its anticolitis activity. This study elucidates the pivotal role of polyphenol rosmaric acid (RA) in regulating the mucus barrier function and alleviating inflammation by identifying its gut microbiota-derived metabolites and evaluating its inhibitory effect on inflammasomes in colitis mice. Results demonstrated that RA treatment promoted the proliferation of goblet cells and restored the level of mucus secretion, especially Muc2. RA reshaped the microbiota of colitis mice, particularly the boost of core probiotics, such as p. Bacteroidaceae, f. Muribaculaceae, g. Muribaculaceae, g. Alistipes, and g. Clostridia_UCG-014. Nontargeted metabonomics and targeted metabonomics confirmed a significant increase in the bile acids and their metabolites (7-sulfocholic acid, stercobilin, chenodeoxycholic acid 3-sulfate, chenodeoxycholic acid sulfate, and ursodeoxycholic acid 3-sulfate), indole metabolites ((R)-2,3-dihydro-3,5-dihydroxy-2-oxo-3-indoleacetic acid, frovatriptan, 3-formyl-6-hydroxyindole, and brassicanal A), and short-chain fatty acids (SCFAs) (acetic acid, butyric acid, isobutyric acid, isovaleric acid, and valeric acid) that contributed to the strengthened mucus barrier function. In addition, being absorbed mainly in the lower digestive tract, RA inhibited the overexpression of inflammasomes (especially NLRP6) that occurred in colitis mice to promote the mucus secretion of goblet cells. These data confirmed that RA, as a promising candidate to enhance gut health, restored colonic mucus secretion in colitis mice by mediating the production of gut microbiota-derived metabolites and the overexpression of inflammasomes. The presented study provides scientific evidence explaining the apparent paradox of low bioavailability and high bioactivity in polyphenols.

Bifidobacterium breve Protects the Intestinal Epithelium and Mitigates Inflammation in Colitis via Regulating the Gut Microbiota–Cholic Acid Pathway

“…The damage to the intestinal mucosal barrier, including mucus and intestinal epithelial cells, contributes to the development and progression of colitis . MUC2, the major component of mucus secreted by goblet cells, is recognized as a contributor to forming the intestinal mucosal barrier. , Previous research has shown that mice with colonic inflammation exhibited MUC2 deficiency and a lack of mucus layer thickness . TJ-proteins contribute to the intestinal barrier function, and their reduced secretion leads to intestinal barrier damage .…”

“…It has been reported that Bifidobacterium and Clostridium in the intestine can produce bile salt hydrolases, which enzymatically deconjugated glycol-conjugated and tauro-conjugated CA and CDCA, converting them into unconjugated bile acids . Bile acids play a role in alleviating inflammation and regulating immunity. − Importantly, they contribute to maintaining gut microbiota homeostasis, preventing bacterial translocation, and enhancing the mucosal barrier. ,, …”

“…28,29 Previous research has shown that mice with colonic inflammation exhibited MUC2 deficiency and a lack of mucus layer thickness. 27 TJ-proteins contribute to the intestinal barrier function, and their reduced secretion leads to intestinal barrier damage. 30 In our study, we observed the significantly downregulated expression of TJ-proteins and MUC2 and a deficiency of the intestinal barrier, which is consistent with previous reports.…”

Effects of dietary traditional Chinese medicine residues on growth performance, intestinal health and gut microbiota compositions in weaned piglets

“…The dietary fiber and active ingredients in the residue may be beneficial for the growth and proliferation of Lactobacillus johnsonii and Weissella jogaeotgali , among others. At the same time, the growth of pathogenic bacteria is inhibited ( Makki et al., 2018 ; Chen et al., 2019 ; Wang et al., 2023 ). Lactobacillus johnsonii and Weissella jogaeotgali are two important probiotics that produce acid, inhibit bacteria and have good adhesion to intestinal epithelial cells.…”

Microbiota-accessible fiber activates short-chain fatty acid and bile acid metabolism to improve intestinal mucus barrier in broiler chickens

“…This effect is mediated via a wide range of small-molecule metabolites, such as short-chain fatty acids (SCFAs) and bile acids, secreted by gut microbes ( 12 ). Recent studies have shown that the production of SCFAs by gut microbes occurs through microbial fermentation of carbohydrates, which act as a source of energy for epithelial cells and provide protection to the intestinal mucus barrier ( 15 , 16 ). In addition, the gut microbiota-derived bile acids serve as natural agonists for farnesoid X receptor and G protein-coupled receptor, and the bile acids chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) play a crucial role in maintaining homeostasis of the intestinal barrier ( 5 , 17 ).…”