Introduction
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by recurrent abdominal pain, bloating, and altered bowel habits. Globally, the prevalence of IBS varies significantly, ranging from 3.3% to 31.6%, with rates as high as 9.6% among Asian populations.1 This variability demonstrates the complex nature of IBS, which is influenced by genetic, environmental, and cultural factors. Based on the Rome IV criteria, IBS is divided into four types: diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), mixed type (IBS-M), and unclassified type (IBS-U).1 Among these, IBS-D is one of the most common forms, significantly affecting patients’ quality of life, reducing work productivity.
In recent years, intestinal barrier dysfunction has garnered extensive attention and is considered to be closely associated with symptoms such as abdominal pain and diarrhea.2 Piche et al3 found that colonic epithelial permeability was significantly increased in patients with IBS and was associated with reduced mRNA expression of the tight junction protein ZO-1.
Genetic predisposition, dietary factors, intestinal structural abnormalities, and gut microbiota dysbiosis may all contribute to the pathogenesis of IBS-D, among which stress-related factors such as stress and anxiety are particularly important. Stress not only induces abnormal secretion of 5-hydroxytryptamine (5-HT), leading to disordered smooth muscle contraction and activation of enteric neurons, thereby triggering abdominal pain in IBS-D,4–6 but also affects intestinal function through the regulation of CRF.7 Currently, therapeutic strategies for IBS-D mainly focus on the downstream effects of 5-HT, such as the use of 5-HT antagonists.8 However, the specific mechanisms by which CRF contributes to IBS-D and the corresponding targeted therapeutic strategies remain largely unclear.
CRF is a neuropeptide predominantly synthesized in the hypothalamus, whose primary physiological function is to regulate stress responses and the endocrine system. By stimulating the pituitary to release adrenocorticotropic hormone (ACTH), it indirectly modulates cortisol secretion from the adrenal cortex, thereby influencing the body’s responses to stress, metabolism, and immune function. Recent studies have emphasized the important role of CRF in the gut-brain axis and its impact on IBS-D.
CRF lies at the intersection of the gut-brain axis and the HPA axis, serving as a key node linking stress to intestinal barrier dysfunction. Studies have shown that CRF is associated with alterations in intestinal epithelial permeability and can induce changes in gastrointestinal motility and watery diarrhea.9,10 It can increase intestinal permeability and impair barrier function in IBS by downregulating tight junction proteins.11 CRF exerts its effects primarily through CRFR1 and CRFR2, and an imbalance in signaling between these two receptors may represent an important mechanism underlying IBS-D.12,13 Overactivation of CRFR1 can lead to downregulation of tight junction proteins, mast cell degranulation, epithelial c ell hypoxia, and cytoskeletal alterations, thereby increasing intestinal permeability.10,14,15 Conversely, CRFR1 antagonists can ameliorate hyperpermeability and motility disorders induced by chronic stress.16,17 In contrast, CRFR2 exerts a protective role by inhibiting CRFR1-mediated enhancement of colonic motility and barrier injury. In rat models of IBS, selective activation of CRFR2 attenuates CRF-induced increases in intestinal permeability.18
CRF-related alterations in the intestinal barrier may be interconnected with other pathological mechanisms of IBS-D. When CRF impairs the mechanical barrier, antigens and bacterial products in the intestinal lumen readily penetrate the mucosa, triggering immune responses and gut microbiota dysbiosis;19 inflammation and microbial dysbiosis, in turn, can further disrupt the barrier through the release of pro-inflammatory cytokines, reduced short-chain fatty acids (SCFAs), epithelial cell injury, and cytoskeletal alterations.20–23 CRF can also directly initiate immune responses and induce gut microbiota imbalance, thereby compromising intestinal barrier function. Under the influence of CRF, the mechanical, immune, and biological barriers can form a mutually reinforcing vicious cycle, and the pathological mechanisms underlying IBS-D are likewise interconnected.
Furthermore, the interactions among CRF, immune cells, and the enteric nervous system form a stress-induced feedback loop influenced by the hypothalamic-pituitary-adrenal (HPA) axis.24 CRF signaling renders sensory nerve endings more susceptible to antigens and inflammatory mediators and enhances the release of neurotransmitters such as acetylcholine, thereby amplifying the transmission of visceral sensory signals and leading to abnormal intestinal motility and visceral hypersensitivity.25,26 The enteric nervous system and immune cells can, in turn, influence CRF release, allowing stress signals to be persistently amplified within the local intestinal environment. Meanwhile, glucocorticoid receptor activity contributes to the maintenance of intestinal epithelial homeostasis, whereas chronic stress exposure may alter the regulation of intercellular junctions between epithelial cells.27 Under chronic stress, impaired negative feedback regulation of the HPA axis leads to sustained CRF release, amplified inflammation, and barrier injury, thereby promoting the persistence of IBS-D symptoms.28 However, the aforementioned mechanisms and effective intervention strategies remain to be further elucidated (Scheme 1). Scheme 1Pathophysiological factors in IBS-D and CRF-mediated mechanisms.
The schematic summarizes interacting contributors to IBS-D and distinguishes established symptom-directed approaches from unresolved questions concerning CRF-associated epithelial barrier dysfunction. Connecting arrows indicate causal relationships. Question marks denote mechanisms or therapeutic questions that remain unresolved.
The schematic was assembled by the authors using Figdraw graphic elements.A) Schematic titled, Whats known. Gene and Microorganism point to IBS-D. Intestinal structural abnormalities, Inflammatory factors and Diet point to IBS-D.
B) Schematic with labels, depressed and anxiety, pointing to a brain. From the brain, arrows go to 5-HT and to CRF. 5-HT points to an intestine and to bullet items, Smooth muscle and Neuronal, then to 5-HT antagonist.
CRF points to the intestine and to Epithelial cells, then to Mechanism? and Treatment? and to Currently focused.Two-part schematic linking Gene, Microorganism and stress signals 5-HT and CRF to IBS-D.Abbreviations: CRF, corticotropin-releasing factor; IBS-D, diarrhea-predominant irritable bowel syndrome; 5-HT, 5-hydroxytryptamine.
To summarize, CRF is a key regulator in the stress response, significantly affecting intestinal physiology and contributing to the complex symptoms of IBS-D. This review aims to clarify the mechanisms underlying CRF’s impact on IBS-D, highlight potential therapeutic targets, and ultimately assist in developing future treatment strategies. Understanding how CRF disrupts the intestinal barrier, alters gut motility, and modulates immune responses is crucial to better understand IBS-D pathophysiology.
These findings shed light on the intricate interactions within the gut-brain axis and provide potential therapeutic targets for managing symptoms and improving the quality of life for IBS-D patients. Upcoming sections will examine these pathological mechanisms, signaling pathways, and possible therapeutic interventions targeting CRF and its related pathways, providing fresh perspectives on IBS-D treatment.
Literature Selection
This article is a narrative mechanistic review. Literature was identified using PubMed and Web of Science, with the final search performed on January 2026. Search concepts included corticotropin-releasing factor or hormone, CRF receptors, irritable bowel syndrome, intestinal permeability, tight junctions, neuroimmune signaling, and gut microbiota.
Relevant references from retrieved articles were also examined.
Studies were considered according to their relevance to CRF signaling and intestinal barrier regulation. IBS disease models, IBS-like disease models, other gastrointestinal disease models, and non-intestinal systems were distinguished during interpretation. Evidence from non-IBS systems was included only to provide mechanistic context and was not treated as direct validation in IBS-D.
Overview of the Intestinal Barrier
The intestinal barrier is a complex defense system composed of intestinal epithelial cells, tight junctions, immune cells, gut microbiota, and the mucosal layer, including the mucus barrier.29–31 The intestinal epithelial cells serve as the first line of defense by forming tight junctions (TJs) that regulate gut permeability and prevent harmful substances from entering the bloodstream.32 These TJs, formed by proteins such as Claudins, occludin, and JAMs, provide structural integrity to the epithelial layer.33 The mucus barrier, secreted by goblet cells, enhances protection by trapping pathogens, neutralizing toxins, and maintaining a favorable environment for beneficial bacteria.34 Immune cells in the lamina propria, including T and B lymphocytes, play a crucial role in defending against pathogens and maintaining immune homeostasis.35 Dysregulation of immune cell activity, such as increased secretion of pro-inflammatory cytokines like TNF-α, can lead to intestinal barrier dysfunction.36 The gut microbiota also significantly influences barrier function by competing with pathogenic microbes, modulating immune responses, and producing metabolites such as short-chain fatty acids (SCFAs), which help preserve the integrity of the intestinal barrier.37 Together, these components form a robust system that protects the intestinal environment and supports gut health (Figure 1). Figure 1Comparative analysis of intestinal barrier function in normal and IBS-D conditions. The diagram depicts the epithelial junctional complex, mucus, microbiota, and mucosal immune components.
Increased luminal-product passage and altered junctional protein abundance or localization have been reported in selected IBS-D populations or experimental models and are not universal features of all patients. Horizontal arrows indicate the illustrated comparison between barrier states; the connecting arrow at the epithelial junction represents luminal-product passage. Downward symbols placed next to proteins indicate reduced abundance or expression in the represented studies.
Claudin, occludin, JAM, and ZO-1 are shown in relation to the actin cytoskeleton. The schematic was assembled by the authors using Figdraw graphic elements.Two-part diagram comparing Normal and IBS-D intestinal barrier, mucus, microbiota, immune response and junctions.Abbreviations: TJs, tight junctions; JAM, junctional adhesion molecule; ZO-1, zonula occludens-1; LPS, lipopolysaccharide; IBS-D, diarrhea-predominant irritable bowel syndrome.
Mechanisms of CRF-Mediated Intestinal Barrier Dysfunction
CRF primarily exerts its effects in IBS by modulating intestinal barrier function through TJs, immune-inflammatory responses, and the gut microbiota. However, the precise mechanisms underlying CRF-induced intestinal barrier impairment in IBS—particularly regarding its regulation of TJ-associated proteins, inflammatory cascades, and microbial composition—remain largely elusive. Current evidence suggests that this pathogenic process may involve the concerted action of multiple signaling cascades, including the glucocorticoid/NR3C1 pathway, cAMP/Epac axis, NF-κB/p38-MAPK signaling, Toll-like receptor (TLR) pathway, MAPK/ERK cascade, and Rho/ROCK/MLC signaling, among others (Figure 2).
Figure 2Mechanisms of CRF-mediated intestinal barrier dysfunction. The central HPA axis is shown separately from peripheral receptor-associated epithelial, immune, and microbiota-related processes. Solid arrows denote targets validated in IBS models (direct evidence); dashed arrows and red text denote relationships or inferences proposed across models (indirect evidence).
Neither line type should be interpreted as proof of the complete pathway in human IBS-D. Upward and downward symbols beside a molecule indicate increased and decreased expression or activity, respectively; P denotes phosphorylation; blunt-ended lines indicate inhibition. The glucocorticoid receptor, MAPK/ERK, Rho/ROCK/MLC, TLR4-associated inflammatory, cAMP/Epac, and PI3K/AKT pathways are depicted with the evidence limits described in CRF Affects the Expression of Tight Junction Proteins–CRF Modulates Gut Microbiota.
The schematic was assembled by the authors using Figdraw graphic elements.Five-part pathway schematic. A) Stress activates the hypothalamic pituitary adrenal axis, leading to corticotropin releasing factor and glucocorticoid. Glucocorticoid binds glucocorticoid receptor nuclear receptor subfamily three group C member one, followed by nuclear translocation and inhibition with reduced tight junction proteins and barrier disruption.
B) Corticotropin releasing factor receptors drive two cascades: Ras to Raf to mitogen activated protein kinase kinase to extracellular signal regulated kinase with phosphorylated extracellular signal regulated kinase and Rho to Rho associated kinase to phosphorylated myosin light chain to filamentous actin; both end with decreased tight junction proteins.Corticotropin releasing factor pathways linking stress to reduced intestinal tight junction proteins and.Abbreviations: ACTH, adrenocorticotropic hormone; AKT, protein kinase B; cAMP, cyclic adenosine monophosphate; CRF, corticotropin-releasing factor; CRFR1/2, CRF receptor types 1/2; Epac, exchange protein directly activated by cAMP; ERK, extracellular signal-regulated kinase; GC, glucocorticoid; HPA, hypothalamic–pituitary–adrenal; IKK, IκB kinase; IL, interleukin; MAPK, mitogen-activated protein kinase; MLC, myosin light chain; MyD88, myeloid differentiation primary response 88; NF-κB, nuclear factor kappa B; NLRP6, NOD-like receptor family pyrin domain-containing 6; NR3C1, the gene encoding the glucocorticoid receptor; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; Rho, Ras homolog family GTPase; ROCK, Rho-associated coiled-coil-containing protein kinase; TLR4, Toll-like receptor 4; TNF-α, tumor necrosis factor alpha; ZO-1, zonula occludens-1.
CRF Affects the Expression of Tight Junction Proteins
Through the GC/NR3C1 Pathway
The pathogenesis of IBS-D is strongly influenced by the gut-brain axis, primarily mediated through hyperactivation of the HPA axis.38 CRF plays a central role in this process by stimulating the release of glucocorticoids from the pituitary and adrenal cortex.39 The glucocorticoid receptor, encoded by the NR3C1 gene, regulates inflammatory responses and intestinal barrier integrity through its interaction with glucocorticoids.28 Upon ligand binding, NR3C1 translocates to the nucleus, where it modulates gene expression.40 Increased HPA axis reactivity, as observed in weaned piglet models, compromises intestinal epithelial integrity and permeability.41
Research by Aranda et al demonstrated that NR3C1 deletion in the intestinal epithelium leads to barrier dysfunction, highlighting the critical role of the GC/NR3C1 pathway in maintaining intestinal barrier function.42 In IBS-D rat models, puerarin was shown to restore the intestinal barrier by inhibiting HPA axis activity and upregulating occludin expression.43 Chronic stress, by elevating CRF levels, downregulates NR3C1, leading to decreased expression of tight junction proteins like claudin-1 and occludin while increasing claudin-2, thus enhancing intestinal permeability.27,44 Therefore, CRF modulates tight junction protein expression through NR3C1, directly influencing intestinal barrier function in IBS-D.
Through the MAPK/ERK Pathway
The MAPK pathway, including ERK1 and ERK2, regulates cellular processes such as growth, differentiation, and stress responses. Activation of the MAPK/ERK pathway typically occurs via external signals like growth factors or cytokines, triggering a kinase cascade that activates ERK.45 CRF has been shown to induce ERK phosphorylation, a mechanism critical for the expression of pro-opiomelanocortin and the upregulation of TLR4 through the CRF1 receptor.46,47 In the Jeg-3 placental cell line, CRF also induces MAPK subunit phosphorylation, further confirming its role in activating the MAPK/ERK pathway.48
In IBS, miR-219a-5p and miR-338-3p modulate neuronal and MAPK signaling, impacting barrier function and visceral hypersensitivity.49 Traditional Chinese medicine, such as WenTongGanPi Decoction, alleviates IBS-D symptoms by inhibiting the p38/ERK/JNK MAPK pathway, improving intestinal barrier integrity.50 CRF has been shown to enhance neuronal responsiveness to GLP-1 receptor agonists like exendin-4, activating the ERK-MAPK signaling cascade.51 In IBS rat models, CRF expression correlates with ERK activation and ZO-1 expression, indicating its role in regulating tight junction proteins and maintaining intestinal barrier function in IBS-D.52
Through the Rho/ROCK/MLC Pathway
Rho-associated kinase (ROCK), comprising ROCK1 and ROCK2 isoforms,53 regulates key cellular processes such as contraction, migration, and adhesion.54 ROCK is activated by Rho GTPases,53 leading to phosphorylation of substrates like myosin light chain (MLC) and cytoskeletal reorganization. Phosphorylated MLC (pMLC) induces actin-myosin contraction, contributing to changes in cell shape and intestinal permeability by modulating the actin cytoskeleton and tight junction integrity.55 In IBS-D models, abnormal activation of the Rho/ROCK/MLC pathway is linked to reduced expression of tight junction proteins, including occludin, claudin-1, and ZO-1, and alterations in F-actin organization.56
CRF has been shown to regulate Rho GTPases and the ROCK/MLC pathway in both in vitro and in vivo models. In rats, CRF modulates noradrenergic neuronal growth via Rho/ROCK signaling.57 In human myometrial cells, CRFR2 activates the Rho/ROCK/MLC pathway to regulate myometrial contraction.58 In IBD, the ROCK-MLC and ROCK-NF-κB pathways are implicated in intestinal barrier dysfunction.59 Notably, in IBS rat models, CRF and IL-6 levels correlate with tight junction protein expression and the activation of Rho-mediated pathways,60 highlighting CRF’s role in regulating intestinal permeability through the Rho/ROCK/MLC pathway. Jin et al61 recently provided direct evidence for the role of the CRFR1/ROCK2/MLC pathway in a CRF-induced IBS model.
This study demonstrated that CRF activates ROCK2/MLC signaling via CRFR1, leading to downregulation of occludin and claudin-1 expression, disruption of tight junction structure, and increased intestinal permeability in T84 cells and mouse colon, thereby directly validating that the CRFR1/ROCK2/MLC pathway mediates intestinal barrier dysfunction and providing direct evidence for targeting this pathway in the treatment of IBS-D.
CRF-Mediated Inflammatory Regulation
CRF and Inflammation Activation
Immune cells play a central role in amplifying inflammatory responses through the TLR signaling pathway and contribute to the CRF-mediated intestinal inflammatory environment.62 CRF and its receptor CRFR1 are expressed in various immune cell types, including macrophages, dendritic cells, T cells, B cells, and mast cells.63–65 In IBS models, CRFR1 expression is elevated in gut immune cells, indicating a potential link between CRF signaling and immune activation in the gut.66
When activated by CRF, macrophages and dendritic cells stimulate the NF-κB pathway, promoting the release of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, while reducing anti-inflammatory cytokines like IL-4. This enhances antigen presentation and T cell activation, amplifying the immune response.67–70 Inhibition of CRFR1 has been shown to reduce cytokine release and weaken the ability of macrophages and dendritic cells to activate T cells.68,69
Immune cells, such as macrophages, dendritic cells, T cells, and B cells, can autonomously secrete CRF under stress conditions like hypertonicity or hypoxia.63,65,71 This suggests that, in the pathogenesis of IBS-D, the intestinal tissue receives CRF signals not only from the central nervous system but also from immune cells under stress. These immune cells, in turn, amplify immune responses and inflammatory signaling, creating a positive feedback loop that further enhances CRF signaling. This interplay between stress-induced and immune-mediated activation highlights the critical role of immune cells in driving the inflammatory processes that contribute to the progression of IBS-D.
CRF-Mediated Signaling Pathways in Immune Inflammation
Through the TLR Signaling Pathway
The Toll-like receptor (TLR) signaling pathway plays a crucial role in the innate immune system. It is present in intestinal epithelial cells and immune cells, where it detects both microbial and endogenous signals within the gut.72 TLRs initiate immune responses by recognizing pathogen-associated molecular patterns (PAMPs). MYD88 is a pivotal molecule in TLR signaling transduction, capable of initiating a cascade reaction through its TIR domain, thereby regulating downstream signaling pathways.
The activation of TLRs is essential for maintaining intestinal function, mucosal barrier integrity, and regulating gut homeostasis.73
The CRF-TLR4 pro-inflammatory cytokine signaling pathway plays a crucial role in immune modulation and intestinal barrier dysfunction in IBS-D. In models like necrotizing enterocolitis (NEC), increased CRF and CRFR immunoreactivity in the ileum correlate with elevated TLR4 levels, linking CRF signaling to immune activation and gut inflammation.74 Activation of the TLR4/NF-κB pathway promotes oxidative stress and inflammation, impairing the intestinal barrier and triggering systemic responses.75 CRF-induced cytokines, such as TNF-α and IFN-γ, further exacerbate barrier dysfunction.76 TLR4 antagonists, like Eritoran, and IL-1 receptor antagonists, such as anakinra, can block CRF-induced visceral hypersensitivity, highlighting the role of immune modulation in gut dysfunction.18 Excessive TLR activation also affects immune cell differentiation, contributing to IBS-D progression.77,78 Peripheral blood expression levels of CRFR1, CRFR2, TLR2, and TLR4 are elevated in patients with IBS.79 Xi et al80 also demonstrated that the TLR4/NF-κB signaling pathway plays an important role in regulating inflammatory responses and tight junction proteins in IBS-D. Taken together, these findings indicate that CRF modulates immune inflammation and tight junction proteins through the TLR4 pathway, thereby directly affecting intestinal barrier integrity in IBS-D.
CRF regulates inflammation and immune responses via the TLR4 pathway, directly influencing intestinal barrier integrity in IBS-D.
Through the cAMP/Epac Pathway
Cyclic adenosine monophosphate (cAMP) acts as an intracellular second messenger, primarily mediating its effects through protein kinase A (PKA).81 However, cAMP can also activate the exchange protein directly activated by cAMP (Epac), which exists as two isoforms, Epac1 and Epac2, with distinct roles in disease progression.82,83 CRF influences the cAMP/Epac pathway by facilitating the accumulation of intracellular cAMP via CRFR binding, thus modulating CRF signaling.84 Research indicates that CRF reduces the expression of Spexin (SPX) in the hippocampus through this pathway and that downregulation of Epac1 in visceral hypersensitivity models is linked to increased IL-6 and neuronal sensitization mediated by CRF.85,86
Moreover, alterations in Epac levels correlate with changes in tight junction proteins and inflammatory factors. Epac2 activation alleviates colitis symptoms and reduces intestinal permeability.87 In IBS-D, both Epac1 and Epac2 are essential for maintaining intestinal barrier function. Thus, CRF regulates tight junction protein expression and inflammatory responses through the cAMP/Epac pathway, directly impacting intestinal barrier integrity in IBS-D.
Through the p38-MAPK/NF-κB Pathway
CRF plays a significant role in regulating intestinal barrier function in IBS-D by modulating the NF-κB and p38-MAPK pathways. In human HaCaT keratinocytes, CRF downregulates NF-κB dimers (p50/p50 and p50/p65), decreasing IκB-β degradation and κB-driven gene activity.88 In ex vivo hair organ culture models, CRF activates p38 phosphorylation,89 and in zebrafish follicle cells, p38-MAPK activation by CRF is attenuated by the p38 inhibitor SB203580.90 Additionally, CRF induces both NF-κB and MAPK activation in BV2 microglial cells, triggering neuroinflammation.91 These findings suggest that CRF influences intestinal barrier function by modulating tight junction proteins and inflammatory factors via the NF-κB/p38-MAPK pathway.
In animal models, including DSS-induced colitis, chronic stress -induced activation of the NF-κB and p38-MAPK pathways correlates with changes in tight junction proteins such as ZO-1 and Occludin, as well as inflammatory markers like TNF-α and IL-10.50,92 Network pharmacology analyses have further highlighted the involvement of these pathways in IBS pathogenesis.93 The CRF-mediated modulation of these signaling pathways contributes to disrupted intestinal permeability and exacerbates immune inflammatory responses, suggesting that targeting CRF’s effects on NF-κB and MAPK could offer potential therapeutic strategies for IBS-D.
Through the PI3K/Akt Pathway
CRF may play a critical role in IBS-D through the PI3K/AKT signaling pathway. In an IBS-D rat model, Shu-yi-ning-chang decoction reduces serum CRF levels and inhibits mast cell activation by downregulating PI3K activity.94 Chronic restraint stress (CRS) in mice leads to abnormal activation of primordial follicles, elevated CRF levels, and activation of the Kit-PI3K pathway.95 In THP-1 monocytes, CRF activates both the PI3K/AKT and ERK1/2 pathways.96 The PI3K/AKT pathway also impacts tight junction protein expression, which is crucial for maintaining intestinal barrier integrity in IBS-D. In ulcerative colitis animal models, Cimicifuga heracleifolia Kom inhibits the PI3K/AKT/NF-κB pathway, enhancing tight junction protein expression.97 In CaCO2 cells, glutamine upregulates claudin-1 expression through the PI3K/AKT pathway, mitigating IL-13-induced barrier dysfunction.
The PI3K inhibitor LY294002 produces similar effects.98 These findings indicate that CRF influences intestinal barrier function in IBS-D by modulating the PI3K/AKT signaling cascade.
CRF Modulates Gut Microbiota
Research increasingly highlights the pivotal role of CRF in gut microbiota modulation and its impact on intestinal barrier dysfunction. Under stress, elevated CRF levels alter the abundance of microbial taxa, including Muribaculaceae, Ruminococcaceae, Streptococcaceae, and Clostridiaceae.99 Additionally, CRF reduces NLRP6 expression in the gut,100 leading to changes in microbiota composition, which promote intestinal hypersensitivity and inflammation.101 This suggests that CRF/CRFR, as central mediators of stress responses, not only contribute to the pathogenesis of IBS but also play a role in modulating gut microbiota composition.
The mechanisms underlying CRF/CRFR’s regulation of the gut microbiota remain unclear. One study demonstrates that CRF activates the cAMP/Ras/MAPK signaling pathway, causing mitochondrial damage in colonic cells, which alters the gut microbiota composition in IBS-D. Moreover, antagonizing CRFR1 prevents stress-induced dysbiosis.15 The gut microbiota can also influence CRF secretion, modulating stress responses.
For example, germ-free mice exhibit fewer anxiety-like behaviors than SPF mice,102 and transplanting gut microbiota from alcohol-dependent mice into normal mice induces anxiety-like behaviors and CRFR1 elevation following alcohol withdrawal.103 CRF/CRFR dysregulate the gut microbiota by activating MAPK, inhibiting NLRP6, and altering colonic cell metabolism, which disrupts intestinal barrier function and promotes inflammation.51,104 Conversely, the gut microbiota feedbacks to modulate CRF secretion, amplifying stress responses.105,106 These findings emphasize CRF’s critical role in stress-mediated brain-gut axis dysfunction.
Therapeutic Implications and Future Directions
Among patients with IBS-D, approximately 37–62% exhibit intestinal barrier dysfunction.107 Consequently, disturbances in intestinal barrier function are prevalent among these individuals. Over the past decade, the medical community has gained a better understanding of IBS-D; however, research into effective treatment strategies is still ongoing. Therapeutic approaches for IBS-D typically begin with lifestyle interventions, which have been shown to significantly improve symptoms.
Studies indicate that modifications in diet, stress management, and regular exercise can lead to notable symptom relief in approximately 40–50% of IBS-D patients.108,109 Unlike other organic gastrointestinal disorders, pharmacological treatments for IBS-D generally focus on alleviating the primary or most distressing symptoms rather than addressing the underlying pathophysiological factors. As a result, treatment outcomes are often suboptimal, and most interventions do not alter the disease’s natural course in the long term.
Previous research has indicated that while medications aimed at protecting the intestinal barrier show preliminary efficacy in treating IBS-D, the specific mechanisms of action remain unclear. Investigating the potential functions of these medications could enhance our understanding of the pathophysiology of IBS-D and provide a rationale for identifying new therapeutic targets.
CRF-mediated intestinal barrier dysfunction is a significant contributor to the symptoms of IBS-D. Consequently, interventions aimed at addressing CRF-mediated intestinal barrier dysfunction have emerged as a focal point in IBS-D research, representing a promising therapeutic approach. Various medications have been identified that can restore intestinal barrier function and alleviate symptoms of IBS-D by modulating CRF levels.
In maternal separation rat models, metformin has been shown to mitigate intestinal barrier damage by reducing CRF levels, inhibiting ERK activation, and decreasing the expression of tight junction proteins and inflammatory mediators.52 Additionally, research has indicated that Eritoran (a TLR4 antagonist) and anakinra (an interleukin-1 receptor antagonist) can block visceral hypersensitivity and increased intestinal permeability induced by CRF, thus offering new insights into targeted therapies for IBS-D.18 However, despite the demonstrated efficacy of metformin, Eritoran, and anakinra in preclinical models, clinical trials for IBS-D treatment have not yet been initiated. Furthermore, several potential therapeutic strategies based on the signaling pathways of CRF-mediated intestinal barrier dysfunction, including inhibitors targeting GC/NR3C1 and compounds directed against the NF-kB/p38-MAPK pathway, have exhibited therapeutic promise (Table 1). Table 1Comprehensive Treatment Strategies for IBS-D: Mechanisms and ApproachesTreatment CategoriesTreatment ApproachesMechanismModel SystemReferencesPharmacological therapyMetforminAlleviates intestinal barrier injury by reducing CRF levels, inhibiting ERK activation, and decreasing the expression of tight junction proteins and inflammatory mediators in a maternal separation rat model.Rodent model[52]BenzodiazepinesReduce the activity of hypothalamic CRH neurons, thereby modulating stress responses associated with IBS-D.Human RCTRodent modelCell culture[110]Selective serotonin reuptake inhibitors (SSRIs)Inhibit CeA-CRH release, increase glucocorticoid receptor density in the hippocampus and hypothalamus, and promote negative feedback regulation of the HPA axis.Human RCTRodent model[110]Tricyclic antidepressantsAntidepressant drugs regulate human CRH gene promoter activity in Neuro-2A and AtT-20 cells, thereby modulating CRH gene expression and potentially influencing HPA axis activity.Cell culture[111]The phosphodiesterase type-5 inhibitor tadalafilTadalafil may have an antidepressant like effect by targeting glucocorticoid receptors and reducing intestinal permeability.Rodent model[112]Alternative therapiesCatalpolThe antidepressant effects of catalpol include inhibition of HPA axis and dual regulation of NF-κB.Rodent model[113]Shu-yi-ning-chang decoctionDownregulates key proteins in the Nr4a3/PI3K pathway, affecting inflammation-related mast cell activation and reducing serum CRF levels.Rodent model[94]PuerarinInhibits CRF expression associated with HPA axis activity.
Additionally, upregulates p-ERK expression to enhance proliferation of colonic epithelial cells and repairs the colonic mucus barrier by increasing occludin expression, thereby improving gut function.Rodent model[43]Ganoderma lucidum extractPhosphorylation of MAPK signaling pathway in CRF-related stress response by targeting CRH.Cell culture[114]PaeoniflorinDirectly targets CRFR1, inhibits the CRFR1/ROCK2/MLC signaling pathway, restores tight junction integrity (upregulates occludin and claudin-1), reduces intestinal permeability, enhances goblet cell mucus secretion, and alleviates anxiety-like behaviors and visceral hypersensitivity in CRF-induced IBS.Rodent modelCell culture[61]Monoclonal antibody therapyJTC-017Acts as a specific CRF-R1 antagonist, reducing the release of norepinephrine in the hippocampus, visceral perception, CRF release, and anxiety following acute colorectal distention in rats.Rodent model[115]Alpha-helical CRH (alphahCRH)Functions as a non-selective CRH receptor antagonist, blocking CRH-mediated effects.Human RCTRodent model[116]AntalarminServes as a CRHR1 antagonist, exhibiting antidepressant effects in LPS-induced depressive mice, with CRHR1/nectin3 signaling potentially playing a key role in this process.Rodent model[117]EritoranA TLR4 antagonist that, along with anakinra, can block CRF-induced visceral hypersensitivity and increased intestinal permeability.Rodent model[18]AnakinraAn IL-1 receptor antagonist that specifically blocks CRF-induced visceral hypersensitivity and increased intestinal permeability.Rodent model[18]NGD98-2/NGD9002Prevents CRF-induced colonic secretomotor stimulation following intracerebroventricular injection, reduces acute defecation induced by water avoidance stress, and blocks visceral sensitization caused by repeated colorectal distension.Rodent model[118]Annexin A1Annexin A1-dependent inhibition of adrenocorticotrophin release involves the enhancement of actin polymerization to prevent exocytosis via formyl peptide receptor and Rho kinase signaling pathways.Cell culture[119]Nutritional Supplementation TherapiesVitamin D3Regulates serum CRF and IL-6 levels, thereby improving symptoms in patients with IBS-D.Human RCT[120]Lacticaseibacillus rhamnosus TF318L. rhamnosus TF318 leads to decreased levels of corticotropin and corticotropin releasing factor in the hippocampus, and this change may involve cyclic adenosine phosphate (cAMP)/cAMP response element binding (CREB)/BDNF signaling pathways.Rodent model[121]Neuromodulatory therapiesNeuropeptide SInteracts with multiple neurotransmitters, including glutamate, norepinephrine, serotonin, CRF, and γ-aminobutyric acid (GABA), influencing stress responses and gut motility.Human RCTRodent modelCell culture[122]Injection into the Central Amygdala (CeA)Suppresses activation of the CRH promoter when histone deacetylase inhibitors are injected into the CeA, thereby preventing stress-induced visceral hypersensitivity.Rodent model[123]Non-pharmacological therapiesElectroacupunctureAlleviates IBS mechanisms induced by water avoidance stress, potentially involving the regulation of gut microbiota dysbiosis and suppression of CRF expression.Rodent model[106]
It is worth noting that some of the mechanistic evidence cited in this review was derived from related gastrointestinal disease models or stress models rather than studies directly addressing IBS-D. Although such models can reproduce certain pathological features of IBS-D to some extent, their pathological mechanisms, intestinal microenvironment, and immune status are not entirely equivalent to those of IBS-D. Moreover, the available mechanistic evidence is predominantly derived from basic experimental studies rather than clinical studies, and thus retains certain limitations regarding species differences, model constraints, and experimental conditions.
Therefore, future studies should incorporate basic experimental models directly targeting IBS-D and further conduct clinical studies to validate the relevant mechanisms under conditions that more closely approximate the authentic pathological state in humans.
Real-world pharmacovigilance studies suggest that the safety of gastrointestinal therapeutic agents such as mesalazine still warrants attention.124 An et al found that alosetron and tegaserod were significantly associated with risk signals for ischemic colitis, with some risks not yet adequately warned in drug labels.125 Meanwhile, clinical studies on mucosal protective agents have shown that improving intestinal barrier function helps alleviate abdominal pain and improve stool characteristics in patients with IBS-D.126 Jin et al61 further demonstrated that paeoniflorin can improve tight junction integrity and intestinal permeability in CRF-induced IBS models by inhibiting the CRFR1/ROCK2/MLC signaling pathway. These findings suggest that targeting CRF-mediated intestinal barrier dysfunction holds potential therapeutic value. Future studies should further clarify the relevant signaling pathways and, by integrating clinical research with real-world evidence, systematically evaluate the efficacy and safety of targeted interventions to provide a basis for clinical translation.
In subsequent clinical research, it is also necessary to incorporate more recent clinical evidence on gastrointestinal diseases and pharmacological interventions, with attention to the real-world efficacy and safety of such interventions, so as to more comprehensively assess the benefits and risks of barrier-targeted therapy and provide a foundation for its transition from experimental research to clinical practice.
Conclusion
IBS-D has emerged as one of the most prevalent functional gastrointestinal disorders. Clinically, most patients with IBS-D experience recurrent symptoms that significantly impact their quality of life and demand considerable medical resources, rendering it a persistent clinical challenge and a focal point of research in the field of gastroenterology. The pathogenesis and mechanisms underlying IBS-D are complex, involving both environmental and psychological factors.
An increasing number of studies have confirmed the association between IBS-D and CRF-mediated intestinal barrier dysfunction. This dysfunction holds promise for the development of innovative therapeutic strategies for the condition. Barrier-targeted therapy has attracted considerable attention.
However, the current evidence is largely derived from cell and animal models, and its clinical translation still requires further validation. Future research should more clearly define priority directions: first, to advance CRF-related intervention strategies into the clinical validation stage and evaluate their actual effects on the intestinal barrier and clinical symptoms in rigorously designed clinical trials; second, to strengthen the connection between basic research and human studies and verify the applicability of signaling pathways and intervention targets identified in animal and cell models to humans; third, to further identify more specific therapeutic targets and clarify the roles of different CRF receptor subtypes and related molecular pathway targets in the pathological process of IBS-D. In summary, systematically elucidating the signaling pathways involved in CRF-mediated intestinal barrier dysfunction and strengthening clinical validation and safety assessment will lay a solid foundation for addressing IBS-D and advancing new drug development.