Letter to the Editor: Salidroside in ulcerative colitis - neuroimmune regulatory mechanisms and clinical translation prospects

Abstract

Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease with a complex and incompletely understood pathogenesis. Although current first-line therapies, including 5-aminosalicylic acid, corticosteroids, and immunosuppressants, effectively control acute inflammation, their long-term use is limited by steroid dependence, increased susceptibility to opportunistic infections, drug resistance, and failure to maintain sustained remission. Salidroside, a natural bioactive compound, has recently emerged as a promising therapeutic candidate owing to its anti-inflammatory, antioxidant, neuroprotective, and immunomodulatory properties. We read with great interest the study by Li et al demonstrated that salidroside attenuates intestinal inflammation and promotes intestinal mucosal barrier repair by activating the cyclic adenosine monophosphate (cAMP)-protein kinase A -cAMP response element-binding protein signaling pathway while suppressing the pathological activation of enteric glial cells (EGCs). Building on these findings, this editorial highlights the therapeutic potential of salidroside from the perspective of the enteric neuro-glial-immune regulatory network, emphasizing the pivotal role of EGCs in UC pathogenesis. Furthermore, we discuss how salidroside may alleviate intestinal inflammation by modulating EGC activation, preserving intestinal immune homeostasis, restoring mucosal barrier integrity, and regulating neuro-immune interactions. Finally, we summarize the current challenges and future directions for the clinical translation of salidroside in UC, providing a theoretical basis for the development of EGC-targeted therapeutic strategies and facilitating the future clinical translation of salidroside.

Key Words: Ulcerative colitis; Salidroside; Cyclic adenosine monophosphate pathway; Protein Kinase A pathway; cAMP response element-binding protein pathway; Enteric glial cells; Neuro-glial-immune regulatory network

Core Tip: This article presents a novel perspective based on the “enteric neuro-glial-immune regulatory network” and elucidates the potential mechanisms by which salidroside exerts anti-inflammatory, immunomodulatory, and intestinal mucosal barrier-protective effects through the regulation of enteric glial cells. Furthermore, by discussing the challenges associated with clinical translation and formulation optimization strategies, this article explores the potential application of salidroside as a multi-target therapeutic agent for precision treatment of ulcerative colitis.

TO THE EDITOR

We thoroughly reviewed the recent study by Li et al[1] published in World Journal of Gastroenterology and explored its potential clinical implications. This study revealed the potential mechanism of salidroside in improving ulcerative colitis (UC) from the perspective of the “enteric nervous system-glia-immune” regulatory network. It was found that salidroside could inhibit the abnormal activation of enteric glial cells by activating the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element-binding protein (CREB) signaling pathway, thereby reducing inflammatory responses and promoting intestinal mucosal barrier repair. This finding expands the traditional therapeutic concept of UC centered on immune-inflammatory regulation and provides a new research direction for the intervention of inflammatory bowel disease with natural bioactive compounds.

SALIDROSIDE FOR THE TREATMENT OF ULCERATIVE COLITIS: MECHANISMS OF ACTION AND TRANSLATIONAL PERSPECTIVES

UC is a chronic relapsing inflammatory bowel disease characterized by abdominal pain, diarrhea, rectal bleeding, and mucopurulent bloody stools, all of which markedly impair patients’ quality of life[2]. The global incidence of UC has increased steadily in recent decades, posing a growing public health challenge and imposing substantial socioeconomic and healthcare burdens[3]. Although considerable progress has been made in elucidating its pathogenesis, the precise etiology of UC remains incompletely understood. Current evidence suggests that UC results from complex interactions among genetic susceptibility, environmental factors, gut microbiota dysbiosis, and dysregulated intestinal immune responses[4]. The primary goals of UC treatment are to induce and maintain remission, prevent disease progression and complications, and improve patients’ quality of life. Current therapeutic strategies are tailored according to disease severity and mainly include 5-aminosalicylic acid (5-ASA), glucocorticoids, and immunosuppressive agents[5]. Although these therapies are effective in controlling intestinal inflammation, their long-term clinical use is limited by suboptimal efficacy, adverse effects, and treatment-related complications. Specifically, prolonged 5-ASA therapy may cause gastrointestinal intolerance, nephrotoxicity, and hematological toxicity[6]; glucocorticoids are effective for inducing remission but are unsuitable for long-term maintenance because of steroid dependence, frequent relapse after withdrawal, and serious adverse effects, including osteoporosis, metabolic disorders, and peptic ulcers[7]; and immunosuppressive agents require careful long-term monitoring owing to the risks of hepatotoxicity, nephrotoxicity, bone marrow suppression, and opportunistic infections[8]. Therefore, the limitations of current therapies in achieving sustained efficacy and long-term safety underscore the urgent need for novel therapeutic strategies capable of simultaneously modulating multiple pathogenic pathways, restoring intestinal homeostasis, and providing improved safety profiles.

Against this background, natural bioactive compounds with diverse biological activities and favorable safety profiles have attracted increasing attention as potential therapeutic candidates for UC. Recent studies have demonstrated that various classes of natural compounds, including flavonoids, polyphenols, alkaloids, and glycosides, exhibit multi-target and multi-pathway regulatory properties, exerting intestinal protective effects through the modulation of key pathological processes, such as inflammation, oxidative stress, immune dysregulation, gut microbiota imbalance, and intestinal barrier dysfunction[9]. Several bioactive constituents have been shown to ameliorate experimental colitis by suppressing the aberrant activation of inflammation-associated signaling pathways, including nuclear factor kappa B/NLRP3, restoring Th17/Treg immune balance, and promoting tight junction protein expression, thereby contributing to the maintenance of intestinal homeostasis[10]. Among these natural compounds, salidroside, a major phenolic glycoside isolated from plants of the Rhodiola genus, exhibits diverse pharmacological activities, including anti-inflammatory, antioxidant, neuroprotective, and immunomodulatory effects[11]. Owing to its multi-target regulatory properties, salidroside exerts beneficial effects on multiple pathological processes involved in UC, including inflammatory responses, oxidative stress, and intestinal barrier impairment, and has therefore emerged as a promising natural candidate for UC therapy. Accumulating evidence from preclinical studies has demonstrated that salidroside alleviates experimental colitis, reduces pro-inflammatory cytokine production, restores intestinal mucosal barrier integrity, and enhances tight junction protein expression, providing important evidence supporting its further therapeutic development[12,13]. Moreover, toxicological investigations have indicated that salidroside possesses a favorable safety profile, with no significant hepatotoxicity, nephrotoxicity, embryotoxicity, or teratogenicity observed within experimental dose ranges, further supporting its translational potential[14]. Notably, emerging evidence suggests that the intestinal protective effects of salidroside may also involve regulation of gut microbiota. The gut microbiota not only contributes to the initiation and progression of UC but also represents an important regulatory interface linking the intestinal microenvironment, enteric nervous system, EGCs, and mucosal immune system[15]. Therefore, modulation of the “microbiota-neuro-immune” regulatory network by natural bioactive compounds has recently emerged as a promising direction in intestinal inflammation research. However, the biological effects of salidroside and some Rhodiola-derived constituents may exhibit dose-dependent characteristics. Although salidroside exerts anti-inflammatory, immunomodulatory, and intestinal barrier-protective effects within an appropriate therapeutic range, excessive exposure to certain natural constituents may potentially disrupt intestinal microbial homeostasis, suggesting the possibility of dose-dependent bidirectional regulation[16]. Therefore, further investigations into the therapeutic potential of salidroside should consider dose-response relationships and safety margins to provide a more robust foundation for future clinical translation.

From a mechanistic perspective, the pathogenesis of UC extends beyond dysregulated immune inflammation and involves complex interactions among the enteric nervous system, the mucosal immune system, and the intestinal epithelial barrier. Enteric glial cells serve as a central regulatory hub within this enteric neuro-glial-immune network, coordinating neural signaling, immune responses, and mucosal barrier integrity[17]. Under physiological conditions, EGCs secrete glial cell line-derived neurotrophic factor (GDNF), which enhances the expression of tight junction proteins, including occludin and zonula occludens-1, thereby maintaining intestinal epithelial barrier function and mucosal homeostasis[18]. During UC progression, however, EGCs undergo pathological activation, characterized by increased glial fibrillary acidic protein expression and excessive secretion of pro-inflammatory mediators, including interleukin-1β, interleukin-6, and tumor necrosis factor-α. These mediators promote immune cell recruitment and activation, amplify neuroimmune inflammation, and disrupt epithelial barrier integrity, thereby perpetuating intestinal inflammation[19]. Li et al[1] demonstrated that salidroside alleviates experimental UC by activating the the cAMP/PKA/CREB pathway signaling pathway, thereby suppressing pathological EGC activation, reducing pro-inflammatory cytokine production, enhancing GDNF expression, and restoring intestinal mucosal barrier function. Mechanistically, activation of upstream G protein-coupled receptors increases intracellular cAMP levels, leading to PKA activation and CREB phosphorylation, which subsequently regulates the transcription of genes involved in inflammation and cellular homeostasis[20]. These findings suggest that salidroside restores intestinal homeostasis by targeting the cAMP/PKA/CREB signaling in EGCs, thereby re-establishing the enteric neuro-glial-immune regulatory network rather than merely suppressing inflammation. In contrast, current therapies for UC, including 5-ASA, glucocorticoids, and immunosuppressive agents, primarily exert therapeutic effects by inhibiting inflammatory signaling pathways, suppressing pro-inflammatory cytokine production, and modulating immune cell activity[21,22]. Although these treatments effectively control intestinal inflammation, they have limited capacity to correct enteric nervous system dysfunction or restore neuroimmune homeostasis and mucosal barrier integrity. Consequently, achieving durable mucosal healing and sustained clinical remission remains challenging for a substantial proportion of patients, highlighting the therapeutic potential of EGC-targeted strategies represented by salidroside.

Although salidroside has demonstrated promising anti-inflammatory and intestinal mucosal protective effects in experimental models of UC, its clinical translation remains challenging (Figure 1). A major limitation is its suboptimal oral bioavailability and insufficient colon-targeting efficiency, which may result in inadequate drug exposure at inflamed intestinal sites and consequently compromise therapeutic efficacy[23]. To overcome these limitations, considerable progress has been made in colon-targeted drug delivery systems, including pH-responsive formulations, polysaccharide-based sustained-release carriers, lipid nanoparticles, and hydrogel-based delivery platforms. These approaches enhance local drug retention, improve colon-specific delivery, and have shown considerable promise for improving the therapeutic efficacy of natural bioactive compounds in inflammatory bowel disease[24,25]. In addition, current evidence is largely derived from cellular and animal studies, whereas the clinical efficacy, safety, and pharmacokinetic characteristics of salidroside remain to be systematically evaluated. Future investigations should focus on optimizing colon-targeted delivery systems, performing comprehensive pharmacokinetic/pharmacodynamic studies to characterize drug exposure and establish optimal dosing strategies, and validating therapeutic efficacy and safety through well-designed randomized clinical trials. Furthermore, emerging technologies, including single-cell RNA sequencing, spatial transcriptomics, and intestinal organoid models, provide powerful platforms for dissecting the cellular and molecular mechanisms underlying UC pathogenesis[26,27]. Integrating these technologies with studies of salidroside will facilitate a deeper understanding of how it modulates the enteric neuro-glial-immune regulatory network and accelerate the development of precision therapeutic strategies and its clinical translation for UC.

Figure 1 Schematic summary of salidroside: Anti-ulcerative colitis mechanisms, translational barriers, and pharmacokinetic-based colon-targeted delivery strategies. UC: Ulcerative colitis; GFAP: Glial fibrillary acidic protein; S100B: S100 calciumbinding protein B; IL-1β: Interleukin-1β; TNF-α: Tumor necrosis factor α; IL-6: Interleukin-6.

CONCLUSION

Based on the “enteric nervous system-glia-immune” regulatory network, this article summarizes the potential mechanisms by which salidroside regulates enteric glial cell activation, restores intestinal immune homeostasis, and promotes mucosal barrier repair. Targeting EGCs may provide a novel neuroimmune regulatory strategy for UC treatment beyond traditional anti-inflammatory approaches. Furthermore, addressing the challenges of low bioavailability and limited clinical evidence through colon-targeted delivery systems and advanced research technologies may facilitate the clinical translation of salidroside.