Treatment of ulcerative colitis via the in situ restoration of local immune and microbial homeostasis by oral administration of Tremella polysaccharide drug-carrying hydrogel

Ulcerative colitis (UC) is a prevalent inflammatory bowel disease, and conventional treatments, such as anti-inflammatory medications and surgery, often prove inadequate due to frequent recurrences and various complications. To alleviate patient suffering, there is an urgent need for a therapeutic system that specifically delivers drugs to the colon for wound healing, inflammation relief, and restoration of microbial homeostasis.

In this paper, we developed a Tremella polysaccharide drug-carrying hydrogel that adheres to the inflamed colonic mucosa, forming an effective artificial barrier and releasing the drug in situ to restore local immune and microbial balance. The hydrogel backbone was synthesized through the chemical cross-linking of Tremella polysaccharide with 1,4-butanediol diglycidyl ether in an alkaline environment. During this process, Soluplus® and TPGS-encapsulated ginsenoside compound K adhered to the hydrogel backbone due to electrostatic attraction.

The enhanced adhesion following cross-linking enables the hydrogel to stably attach to the inflamed colonic mucosa, releasing mixed micelles that improve drug penetration and absorption by inhibiting the cellular efflux protein P-glycoprotein. This mechanism promotes local immune recovery and eliminates harmful intestinal flora, providing significant relief from UC symptoms. This natural polysaccharide-based hydrogel represents a highly effective oral treatment for UC.

Highlights

• Multifunctional nanocomposite hydrogel synthesized from tremella polysaccharide
• Soluplus® and TPGS improved the intestinal cellular uptake of ginsenoside Compound K in hydrogel.
• Hydrogel is used for the prevention and treatment of ulcerative colitis.
• Hydrogel restores local immunity and intestinal flora homeostasis in the intestinal tract.

Introduction

Ulcerative colitis (UC), one of the two primary forms of inflammatory bowel disease (IBD), is a chronic nonspecific condition that is exhibiting a global epidemic [1]. The worldwide burden of IBD continues to rise due to the absence of a short-term cure and the high costs associated with biotherapeutic drugs. Additionally, patients with UC face an elevated risk of developing colorectal cancer compared to the general population. In UC, inflammation is typically restricted to the mucosal surface; however, its precise pathogenesis remains unclear. Research has indicated that defects in the mucus layer, abnormalities in the intestinal epithelium, the inflammatory state of the lamina propria, and dysregulation of the homeostatic balance of local immune responses and intestinal microbiota are critical factors contributing to the pathogenesis of UC [2].

The current treatment for UC includes intravenous corticosteroids, oral anti-inflammatory agents, and colectomy [3]. Conservative treatments often fail to provide sufficient relief for a significant proportion of UC patients and may lead to serious side effects, such as severe diarrhea and systemic immune dysregulation. Additionally, colon resection can result in numerous postoperative complications that may adversely affect the patient’s quality of life and overall physical health status [4].

Oral administration offers several advantages, including simplicity, convenience, avoidance of localized intestinal infections, and higher patient acceptance compared to intravenous and rectal methods. Tremella polysaccharide drug-carrying hydrogels present a promising option for the treatment of UC [5]. The porous network of the hydrogel facilitates drug transport, while the functionally customized, anti-gastric acid, colonic adhesive drug-carrying hydrogel ensures that the medication reaches the colonic ulcer intact. Additionally, it creates an artificial barrier at the ulcer site due to its excellent adherence, preventing exposure of the damaged area to aberrant intestinal microbiota and mitigating the risk of a more severe and detrimental immune response [[6], [7], [8]]. However, due to the harsh gastric environment, there has been limited research on the application of Tremella polysaccharide drug-carrying hydrogels for the treatment of ulcerative colitis.

Ginsenoside CK is a naturally occurring active compound found in the Chinese herb ginseng. It exhibits a range of beneficial effects, including antitumor, anti-inflammatory, immunomodulatory, hypoglycemic, anti-aging, and neuromodulatory properties. Additionally, it can inhibit inflammatory responses and regulate intestinal flora, thereby alleviating ulcerative colitis by suppressing NF-kB activation [[9], [10], [11], [12], [13], [14]]. However, CK has very poor water solubility, being almost insoluble in water, and exhibits low bioavailability, which limits its use. Polymeric micelles have high potential as nanomedicines to control the distribution and function of in vivo loaded bioactive agents and effectively overcome biological barriers [15,16]. Natural polysaccharide-based hydrogels have attracted much attention due to their excellent immunomodulatory ability and desirable structural strength, and a great deal of research is being conducted on natural polysaccharides, such as pectin, chitosan, cellulose, and inulin, as hydrogel carriers for IBD drugs [17]. Tremella polysaccharide is the main active substance in Tremella, and its molecular structure is based on mannose as the main chain and glucuronic acid, xylose, and fucose (with a small amount of glucose) as the branched structure [[18], [19], [20]]. As a kind of indigestible dietary fiber, tremella polysaccharide possesses certain anti-inflammatory, immunomodulatory, and regulating intestinal microbial homeostasis effects [[21], [22], [23], [24]]. Compared to other natural polysaccharides, Tremella polysaccharide has received little attention, but also has great potential, due to their excellent anti-gastric acidity and high-water retention properties when used satisfactorily as drug carriers in the oral treatment of ulcerative colitis. Uncross-linked tremella polysaccharide solution has poor adherence at the intestinal tract, whereas the formation of hydrogels by crosslinking with BDDE can enhance its mechanical properties and is expected to enhance its intestinal adherence [25].

For the treatment of ulcerative colitis (UC), we propose the development of a Tremella polysaccharide drug-carrying hydrogel that exhibits properties of anti-gastric acidity and intestinal adhesion. This hydrogel can be administered orally, allowing it to traverse the stomach and release the drug in the colon, thereby alleviating UC symptoms (see Scheme 1). The hydrogel was synthesized through a two-step process using precursors known for their favorable biosafety profiles, including Tremella polysaccharide, ginsenoside CK, Soluplus®, and TPGS. Specifically, mixed micelles of Soluplus® and TPGS loaded with CK (CK-S/T) were first synthesized via thin-film hydration, followed by the formation of the hydrogel skeleton through the chemical cross-linking of Tremella polysaccharide with BDDE. During this process, the CK-S/T (8.57 ± 0.77 mV) spontaneously attached to the hydrogel skeleton (−16.9 ± 0.30 mV) due to the mutual attraction of heterogeneous charges. Each precursor used has its own advantages and disadvantages in the treatment of UC; notably, the organic combination of these components in the construction of Tremella polysaccharide drug-carrying hydrogels mitigates their disadvantages while enhancing their benefits. The uncross-linked Tremella polysaccharide solution exhibited poor adhesion to the intestinal lining, whereas BDDE cross-linking improved its intestinal adhesion and mechanical properties. This enhancement allows the hydrogel to effectively block further intestinal invasion by foreign antigens and harmful bacterial flora, while promoting the regeneration of intestinal epithelial cells. The mixed micelles of Soluplus® and TPGS (CK-S/T) loaded with ginsenoside CK increase the water solubility of CK and inhibit the exocytosis of the drug efflux protein P-glycoprotein (P-gp), facilitating effective penetration of the intestinal epithelial barrier and reaching the lamina propria to restore local immune homeostasis in the intestinal tract, thereby alleviating colon inflammation. This study demonstrates that the Tremella polysaccharide drug-carrying hydrogel can significantly reduce disease severity in a mouse model of colitis without significant side effects, providing a novel and effective method for the oral treatment of UC.

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Materials

Tremella polysaccharide (Mw < 1000 kDa), D-α-Tocopherol polyethylene glycol succinate (TPGS), 1,4-Butanediol diglycidyl ether (BDDE), Coumarin 6 and 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide (DiR) were purchased from Aladdin Industrial Co., Ltd. (Shanghai, China). Soluplus® was from BASF (Ludwigshafen, Germany). Ginsenoside compound K (CK) (purity ≥99 %) was obtained from Puruifa Technology Development Co., Ltd. (Chengdu, Sichuan, China).

Xue Wang, Zhuo Zhang, Huan Lei, Chenhui Zhu, Rongzhan Fu, Xiaoxuan Ma, Zhiguang Duan, Daidi Fan, Treatment of ulcerative colitis via the in situ restoration of local immune and microbial homeostasis by oral administration of Tremella polysaccharide drug-carrying hydrogel, International Journal of Biological Macromolecules, Volume 285, 2025, 138223, ISSN 0141-8130, https://doi.org/10.1016/j.ijbiomac.2024.138223.

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