综述：非编码RNA在肠易激综合征（IBS）内脏高敏感性中的调控作用

《The FASEB Journal》：Regulatory Roles of Noncoding RNAs in Visceral Hypersensitivity in Irritable Bowel Syndrome

本文综述了非编码RNA（ncRNA）在肠易激综合征（IBS）中调控内脏高敏感性和肠道屏障功能的作用，包括miRNA、lncRNA和circRNA的分子机制及作为诊断标志物和治疗靶点的潜力。

　　
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by chronic abdominal pain and altered bowel habits. Recent studies have highlighted the emerging role of noncoding RNAs (ncRNAs) in regulating visceral hypersensitivity, a key pathophysiological mechanism underlying IBS symptoms. This review synthesizes current knowledge on how ncRNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), influence intestinal barrier integrity, ion channel activity, and signaling pathways to contribute to visceral hypersensitivity in IBS.

The paper begins by establishing the clinical context of IBS, emphasizing its prevalence and heterogeneity. It then transitions to the molecular landscape of ncRNAs, detailing their biogenesis and functional mechanisms. The authors systematically categorize the action modes of ncRNAs, including competitive endogenous RNA (ceRNA) sponging, molecular scaffolding, and micropeptide coding. These mechanisms collectively explain how ncRNAs regulate gene expression at transcriptional and post-transcriptional levels, affecting processes such as tight junction assembly, neurotransmitter signaling, and immune responses.

A central focus is the dysregulation of miRNAs in IBS. The review identifies multiple miRNAs, such as miR-29a, miR-16, and miR-155, which are significantly upregulated or downregulated in IBS patients compared to healthy controls. These ncRNAs modulate intestinal permeability by targeting tight junction proteins like claudin-1 and zonula occludens-1 (ZO-1). For instance, miR-29a overexpression in IBS patients correlates with reduced glutamine synthetase (GLUL) expression, impairing intestinal mucosal repair and barrier function. Similarly, miR-16 downregulation in IBS-D patients disrupts TLR4/NF-κB signaling, leading to enhanced intestinal permeability and visceral pain sensitivity. The study also explores the role of miR-155 in amplifying pro-inflammatory pathways through TRAF3 and MLCK, exacerbating visceral hypersensitivity.

Beyond miRNAs, lncRNAs and circRNAs emerge as critical regulators. LncRNA H19 downregulation in IBS-D patients correlates with reduced aquaporin-3 (AQP3) expression, disrupting fluid homeostasis and barrier integrity. Conversely, lncRNA XIST overexpression in animal models enhances visceral hypersensitivity by silencing the serotonin transporter (SERT), altering 5-HT homeostasis. CircRNAs such as circKcnk9 function as miRNA sponges, sequestering miR-124-3p to upregulate EZH2 and STAT3, which respectively mediate neuropathic pain and visceral sensitization through the brain-gut axis. These findings underscore the complexity of ncRNA interactions in IBS pathophysiology.

The clinical implications section discusses the potential use of ncRNAs as biomarkers and therapeutic targets. Elevated miR-29a and miR-155 levels in serum or colon biopsies show promise for early diagnosis and monitoring disease progression. However, the authors caution that most studies rely on animal models and correlative human data, necessitating rigorous validation through causal experimental designs. For therapeutic applications, the stability and specificity of ncRNA-based interventions remain challenges. CircRNAs, for example, exhibit enhanced stability in extracellular fluids, suggesting potential for noninvasive biomarkers, while lncRNAs with coding capacity could be leveraged for targeted peptide delivery.

The review also addresses limitations in current research. While in vitro and in vivo models have successfully linked ncRNA dysregulation to IBS mechanisms, human translation requires addressing variables such as genetic polymorphisms and comorbidities. Most studies lack mechanistic validation through gene rescue experiments, leaving uncertainty about whether observed ncRNA effects are direct or indirect. Additionally, the clinical relevance of identified ncRNAs is constrained by insufficient validation in large-scale trials.

Future directions emphasize the need for multi-omics approaches to comprehensively map ncRNA networks in IBS. The integration of animal models with human clinical data could accelerate the development of ncRNA-specific therapies. For instance, miRNA mimics or antagomirs targeting TRPV1 or SERT pathways have shown promise in preclinical studies, but their clinical translation requires addressing delivery challenges and assessing off-target effects. Similarly, circRNAs with inherent stability could serve as stable biomarkers, while lncRNAs with coding potential might enable novel drug designs combining RNA targeting with peptide therapy.

The paper concludes by highlighting the transformative potential of ncRNA research in IBS management. By elucidating the hierarchical regulatory networks of ncRNAs in visceral hypersensitivity, the study provides a roadmap for future investigations into biomarker development and precision therapies. However, bridging the gap between preclinical findings and clinical applications demands collaborative efforts across molecular biology, pharmacology, and clinical medicine to ensure safe and effective translation of ncRNA-based interventions.