Research Progress on the Therapeutic Effects of Polyphenolic Compounds in Inflammatory Bowel Disease and Intestinal Fibrosis

Polyphenolic compounds are a class of secondary metabolites produced by plants, collectively referred to as polyhydroxy compounds. Their structures consist of one or more sugar residues linked to hydroxyl groups, and they also contain varying numbers of benzene rings. Based on the number of benzene rings present and the structural elements connecting these rings, polyphenolic compounds can be classified into four categories: phenolic acids (such as gallic acid, ellagic acid, chlorogenic acid, ferulic acid, salvianolic acid, etc.), flavonoids (flavones, flavonols, flavanones, isoflavones, flavanols, anthocyanins, etc.), stilbenes (such as resveratrol, piceatannol, etc.), and lignans (such as phyllanthin, oleuropein, etc.). Polyphenolic compounds are widely found in natural medicinal herbs and exhibit various biological activities, including antioxidant, antibacterial, anti-inflammatory, and anti-fibrotic properties.

Inflammatory bowel disease (IBD) is a chronic intestinal condition primarily categorized into Crohn's disease (CD) and ulcerative colitis (UC). Its onset is primarily associated with damage to the intestinal mucosal barrier and imbalances in immune homeostasis caused by a multitude of factors, including the environment, genetics, and gut microbiota. The pathogenesis of IBD and intestinal fibrosis is complex, and currently available therapeutic drugs, such as mesalazine and dexamethasone, have potential side effects like steroid dependency and severe infections, failing to fundamentally improve patients' symptoms and offering limited preventive and therapeutic effects. Research has indicated that polyphenolic compounds, including flavonoids, catechins, quinones, lignans, and tannins, possess potential therapeutic effects on IBD. Relevant studies have also shown that signaling pathways such as transforming growth factor-β1 (TGF-β1)/Smad, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK) are involved in the development of IBD and intestinal fibrosis.

The Impact of Polyphenolic Compounds on the Development of IBD and Intestinal Fibrosis

1. Curcumin

Curcumin, widely found in various traditional Chinese medicinal materials and foods such as zedoary rhizome and turmeric, is a flavonoid substance with pharmacological effects including anti-tumor, anti-inflammatory, antioxidant, and anti-fibrotic properties. In a study utilizing a rat intestinal epithelial IEC-6 cell fibrosis model induced by 10 ng/mL TGF-β1, different concentrations of curcumin were administered for intervention. The results revealed that 10 μmol/L curcumin significantly inhibited the low expression of epithelial cadherin and the high expression of α-SMA induced by TGF-β1. Furthermore, research has indicated that daily injections of curcumin (15, 30, 60 mg/kg) for 7 consecutive days can downregulate the expression of autophagy-related factors ATG5, beclin-1, and LC-3Ⅱ in the colonic tissues of colitis model mice, while upregulating the expression of B-cell lymphoma/leukemia 2 (Bcl-2). This suggests that curcumin can inhibit cellular autophagy, alleviate intestinal inflammation in colitis model mice, and repair their damaged intestinal mucosa.

2. Baicalin

Baicalin is a flavonoid component extracted from the traditional Chinese medicine Scutellaria baicalensis, which exhibits potent inhibitory effects on tumor cells, inflammation, and viruses. Studies have shown that when baicalin, PI3K/Akt antagonists, and agonists were administered separately to rats with TNBS-induced colitis models, baicalin (100 mg/kg, administered by intragastric infusion for 14 consecutive days) effectively improved TNBS-induced colitis in rats by inhibiting apoptosis of intestinal mucosal epithelial cells, reducing levels of IL-6, TNF-α, and IL-1β in colonic tissues, increasing the content of IL-10, and promoting the expression of tight junction proteins ZO-1 and β-catenin. Additionally, the effect of the PI3K/Akt antagonist was comparable to that of baicalin, suggesting that baicalin's role in alleviating colitis in rats may be achieved through inhibition of the PI3K/Akt signaling pathway. Another study indicated that after continuous intragastric infusion of 150 mg/kg of baicalin extract (with baicalin as the main active ingredient) for 21 days, colonic mass and length, tissue inflammation, and fibrosis were all improved in rats with TNBS-induced intestinal fibrosis models. The expression of collagen I-III, α-SMA, CTGF, TGF-β1, and Smad3 was also inhibited, suggesting that baicalin extract may ameliorate intestinal fibrosis in rats by inhibiting the TGF-β1/Smad signaling pathway.

3. Total Flavonoids from Abelmoschus manihot Flowers

Total flavonoids from Abelmoschus manihot flowers, commonly found in the dried corollas of the mallow family plant Abelmoschus manihot, possess potent anti-fibrotic, anti-inflammatory, and anti-infective pharmacological activities. Research has demonstrated that in a rat intestinal epithelial IEC-6 cell fibrosis model induced by TGF-β1, total flavonoids from Abelmoschus manihot flowers at concentrations of 5, 10, and 15 μg/mL inhibited the migration and invasion of model cells in a dose-dependent manner. Furthermore, they increased the expression of epithelial markers such as E-cadherin and ZO-1, while decreasing the levels of mesenchymal markers like vimentin and N-cadherin, thereby reducing the occurrence of epithelial-mesenchymal transition (EMT) and subsequently inhibiting intestinal fibrosis.

4. Isoliquiritigenin

Isoliquiritigenin is a flavonoid compound with prominent biological activity extracted from the roots of the natural plant Glycyrrhizae Radix (licorice). It exhibits significant anti-tumor, anti-inflammatory, and antioxidant stress effects. Studies have shown that after continuous intragastric infusion of 30 mg/kg isoliquiritigenin for 10 days, colitis model mice experienced alleviation of symptoms such as body weight loss, diarrhea, and bloody stool, with a significant reduction in DAI (disease activity index) scores. Furthermore, isoliquiritigenin reduced the expression of IL-6 and TNF-α in the colonic tissues of model mice, inhibited the phosphorylation of ERK1/2 and p38 MAPK, and suppressed the activation of nuclear factor-κB (NF-κB), thereby exerting an anti-colitis effect.

5. Chlorogenic Acid

Chlorogenic acid is a phenolic acid compound extracted from the dried buds or flowers of Lonicera japonica, and it is also commonly found in other traditional Chinese medicinal herbs such as hawthorn and eucommia bark. It possesses various biological activities, including antibacterial, antioxidant, and regulatory effects on glucose and lipid metabolism. Studies have indicated that after intervention with sulfasalazine (100 mg/kg) and chlorogenic acid (30, 60, 120 mg/kg), pathological changes such as colonic mucosal damage and inflammatory cell infiltration were significantly improved in model mice. Additionally, the levels of inflammatory factors (IL-1β, IL-6, and TNF-α) in serum and colonic tissues were markedly reduced, with the effects of high-dose chlorogenic acid being comparable to those of sulfasalazine. Furthermore, other researchers have found that after intervention with 200 mg/kg chlorogenic acid, adverse symptoms in colitis model mice, including body weight loss, colon shortening, and elevated DAI scores, were significantly improved. The phosphorylation of ERK1/2 and JNK1/2, as well as the expression of TNF-α and COX-2, were inhibited in colonic tissues, while the expression of Bcl-2 was upregulated, leading to a reduction in the severity of colitis. These results suggest that chlorogenic acid's ability to reduce colitis inflammation, inhibit cell apoptosis, and alleviate intestinal mucosal damage may be achieved through the MAPK/ERK/JNK signaling pathway.

6. Resveratrol

Resveratrol is a natural polyphenolic compound extracted from the rhizomes of Polygonum cuspidatum, a plant belonging to the Polygonaceae family, and is also the primary active ingredient in the traditional Chinese medicinal herb Polygonum cuspidatum (Hu Zhang). It possesses various biological effects, including antioxidant and anti-inflammatory properties. Studies have shown that radiation can induce intestinal oxidative stress damage, leading to intestinal inflammation. Continuous intragastric administration of resveratrol significantly improved radiation-induced intestinal damage in rats. After intervention, resveratrol notably inhibited the expression levels of PI3K, Akt, and mTOR proteins in rat colonic tissues, decreased malondialdehyde content, and increased glutathione and catalase levels. It also effectively suppressed the overexpression of inflammatory factors TNF-α and IL-1β, thereby exerting an anti-inflammatory effect and alleviating intestinal inflammation. These findings indicate that resveratrol can reduce radiation-induced intestinal inflammation by inhibiting the PI3K/Akt/mTOR signaling pathway, making it a promising adjuvant for radiotherapy.

Polyphenolic compounds, which are ubiquitous in natural medicinal herbs, possess various biological activities such as anti-inflammatory, antioxidant, and anti-fibrotic effects. Their dual roles as both medicine and food have become one of the research hotspots. The medicinal value of polyphenolic compounds is increasingly recognized by scholars, yet clinical studies on their therapeutic effects on inflammatory bowel disease (IBD) and intestinal fibrosis remain scarce. In the future, further research should be conducted to investigate the active polyphenolic components and their pharmacological mechanisms based on their multi-target and multi-pathway characteristics. Gradually, these compounds should be applied in the prevention and treatment of IBD and intestinal fibrosis, with the aim of laying a foundation for the development of safer and more effective new drugs.

Reference:

[1] Li Wanying, Zhao Jian, Chen Haokun, Zeng Zhen, Li Hewei, Song Jiale. Research Progress on the Mechanisms of Polyphenolic Compounds in the Treatment of Inflammatory Bowel Disease and Intestinal Fibrosis [J]. China Pharmacy, 2021, 32(16): 2044-2048.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.