Abstract
Background
Dysregulation of gastrointestinal function has been implicated in the pathogenesis of chronic spontaneous urticaria (CSU). Moreover, persistent wheals and pruritus in CSU are frequently accompanied by sleep disturbances and psychological distress. However, whether sleep quality and psychological factors mediate the association between gastrointestinal symptoms and CSU disease severity remains unclear.
Methods
This study retrospectively analyzed data from 499 CSU patients. Associations between CSU disease activity and gastrointestinal symptoms, sleep quality, and psychological status were assessed. Mediation analyses were conducted to evaluate whether sleep quality and psychological status mediated the relationship between gastrointestinal symptoms and disease activity.
Results
Gastrointestinal symptoms were significantly associated with CSU disease activity. Multivariate analysis identified gastrointestinal symptoms as an independent risk factor for increased CSU disease activity (adjusted OR = 1.85, 95% CI: 1.23–2.78). Among individual gastrointestinal symptoms, diarrhea and abdominal pain showed the strongest correlations. Mediation analyses revealed partial mediation by psychological factors, with sleep disturbance (13.17%), anxiety (17.28%), and stress (21.09%) accounting for significant proportions of the total effect.
Conclusion
Gastrointestinal symptoms are independently associated with increased CSU disease activity. This relationship is partially mediated by sleep disturbances, anxiety, and stress, highlighting the relevance of the gut-brain-skin axis in CSU management.
Keywords: Chronic spontaneous urticaria (CSU), Gastrointestinal symptoms, Mediation analysis, Sleep disorders, Emotional disorders
Introduction
Chronic spontaneous urticaria (CSU) is a debilitating skin disorder characterized by recurrent wheals and/or angioedema lasting for more than 6 weeks.1,2 Its unpredictable course and persistent symptoms place a considerable burden on patients’ daily lives. Beyond physical discomfort caused by itching, burning, and skin edema, CSU significantly impairs sleep quality, reduces work productivity, limits social interactions, and increases emotional distress. Patients often report heightened levels of anxiety, depression, and fatigue.3, 4, 5, 6 The cumulative impact of these symptoms leads to marked reductions in health-related quality of life.
Although CSU is regarded as a mast cell mediated skin disease, accumulating evidence indicates that systemic factors beyond the skin may also play a significant role in its pathogenesis and persistence. Notably, a considerable proportion of CSU patients present with extracutaneous symptoms, particularly involving the gastrointestinal tract. Clinical studies have reported coexisting gastrointestinal disturbances, such as functional dyspepsia and gastroesophageal reflux, in CSU patients.7,8 Moreover, epidemiological and mechanistic investigations have demonstrated associations between CSU and various forms of gastrointestinal dysregulation, including Helicobacter pylori infection, intestinal microbiota imbalance (dysbiosis), and metabolic dysfunction.9, 10, 11 These findings suggest a potential contribution of the gut-skin axis to the clinical heterogeneity and chronicity of CSU.
In addition to gastrointestinal dysregulation, impaired sleep quality and psychological disturbances are frequently observed in patients with CSU, and are believed to contribute to both disease onset and exacerbation.12 Mechanistically, psychosocial stressors may influence CSU through neuroendocrine-immune pathways, and experimental studies have demonstrated that psychological stress can directly activate cutaneous mast cells, thereby aggravating disease activity.13,14 Concurrently, accumulating evidence suggests that gastrointestinal symptoms are associated with an elevated risk of sleep disturbances as well as psychological conditions, including anxiety and depression.15,16 Furthermore, numerous studies have established strong links between psychological disorders (eg, anxiety, depression, stress) and both functional gastrointestinal diseases and chronic inflammatory skin conditions.17,18
Based on these findings, we hypothesized that psychological factors, including sleep disturbance, anxiety, depression, and stress, may mediate the relationship between gastrointestinal symptoms and CSU disease severity. To test this, we systematically assessed CSU disease activity, sleep quality, and psychological status in a cohort of CSU patients. Our results indicate that gastrointestinal symptoms are an independent risk factor for increased CSU severity, and that sleep impairment, anxiety and stress serve as partial mediators in this association.
Methods
Study design and patients
This study was conducted in the dermatology department of the Second Affiliated Hospital of Xi'an Jiaotong University from May 11, 2022 to May 31, 2025. All assessments were performed at the initial visit, before the initiation of any treatment, to capture patients in a treatment-naïve state, minimize potential confounding effects from medications, and ensure strict adherence to the following exclusion criteria: 1.) Diagnosis of inducible urticaria (alone or in combination with CSU); 2.) Presence of other disorders manifesting as urticaria-like lesions; 3.) Patients with a self-reported history of hypertension, diabetes mellitus, malignancy, or other severe autoimmune diseases (such as systemic lupus erythematosus or rheumatoid arthritis); 4.) Documented severe psychiatric disorders requiring ongoing specialized treatment (eg, schizophrenia or bipolar disorder) that might confound the assessment of psychological status using the DASS-21; 5.) Incomplete clinical records lacking key variables required for analysis (eg, UAS7 score for disease activity, standardized assessment of gastrointestinal symptoms, PSQI for sleep quality, or DASS-21 for psychological status); 6.) Age <18 years or pregnancy (to avoid potential confounding factors related to pediatric cases or pregnancy-associated changes). After applying stringent inclusion and exclusion criteria, a total of 499 patients meeting the diagnostic criteria for CSU were included. All patients underwent standardized interviews and physical examinations by qualified dermatologists, and data on demographic characteristics, lifestyle, gastrointestinal comorbidities, CSU clinical symptoms (lesion diameter, presence of dyspnea, presence of angioedema, disease activity classification based on UAS7 scores, family history, comorbidity of allergic rhinitis or asthma, duration of individual wheals and disease duration since initial diagnosis), Dermatology Life Quality Index (DLQI), sleep quality (PSQI scale), and psychological state (standardized anxiety and depression scale) were collected through structured questionnaires and electronic medical record systems. The study protocol was approved by the hospital's ethics committee (approval number: 2024139), and all participants signed informed consent forms.
Assessment of urticaria disease activity
Disease activity in this study was assessed according to the EAACI/GA2LEN/EDF guidelines using the Urticaria Activity Score (UAS) system, specifically the 7-day cumulative UAS7 score. The scoring criteria included the number of wheals per 24 h (0 = no wheals, 1 = fewer than 20, 2 = 20–50, 3 = 50 or more or confluence of wheals) and the intensity of pruritus (0 = no itching, 1 = mild itching that does not affect daily life, 2 = moderate itching that affects daily life but not sleep, 3 = severe itching that significantly interferes with daily activities or sleep). The daily score (0–6) was calculated as the sum of wheal and itch scores, and the total UAS7 score (0–42) represented the sum of daily scores over 7 consecutive days. Disease activity was categorized as follows: 0 points indicating no symptoms, 1–6 points indicating well-controlled disease, 7–15 points as mild, 16–27 points as moderate, and 28–42 points as severe.
Assessment of gastrointestinal symptoms
Gastrointestinal symptoms were assessed based on the core symptom dimensions of the Gastrointestinal Symptom Rating Scale (GSRS). Symptoms were categorized into 3 primary clinical manifestations: abnormal defecation (including diarrhea and constipation), reflux-related symptoms (such as heartburn and acid reflux), and other functional dyspepsia symptoms (including nausea, belching, and abdominal pain). Each symptom category was evaluated using a dichotomous approach, classifying symptoms as either present or absent.
Assessment of sleep quality
Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI),19 which evaluates subjective sleep status over the past month across 7 dimensions: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medications, and daytime dysfunction. Each component was rated on a 4-point scale (0 = not at all, 1 = occasionally, 2 = frequently, 3 = consistently), yielding a total score ranging from 0 to 21. Higher scores indicate poorer sleep quality and more severe sleep disturbances.
Assessment of psychological status
This study employed the Depression Anxiety Stress Scales-21 (DASS-21) to evaluate the psychological status of the participants.20 The DASS-21 comprises 3 subscales, including depression, anxiety, and stress, each containing 7 items rated on a 4-point Likert scale ranging from 0 (did not apply to me at all) to 3 (applied to me very much or most of the time). For scoring, raw scores for each subscale were calculated separately and then multiplied by 2 to yield standardized scores ranging from 0 to 42. These scores reflect the severity of the corresponding negative emotional states.21 The DASS-21 demonstrates good reliability and validity, providing a comprehensive assessment of participants’ negative emotional experiences.
Statistical analysis
All statistical analyses were performed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA) and R version 4.2.0 (R Foundation for Statistical Computing, Vienna, Austria). Continuous variables were presented as mean ± standard deviation (mean ± SD), while categorical variables were summarized as frequencies and percentages [n (%)]. Between-group comparisons were conducted using independent-sample t tests for normally distributed continuous variables and χ2 tests for categorical variables.
To investigate the association between gastrointestinal symptoms and CSU disease severity, a hierarchical analytical approach was employed. First, univariate logistic regression was used to screen potential predictors. Variables with significant associations were then included in a multivariable logistic regression model using an enter method. Adjusted odds ratios (aORs) and their 95% confidence intervals (CIs) were calculated to quantify the strength of association. Additionally, to specifically assess the relationship between the severity of CSU and individual gastrointestinal symptoms, Chi-square tests and univariate logistic regression analyses were performed to calculate the odds ratios (ORs) for each symptom. The group with an OR value of 1 served as the reference group.
Mediation analysis was conducted using the R version 4.5.0 with the mediation package, aiming to examine whether sleep disturbance, stress, depression, and anxiety mediated the relationship between gastrointestinal symptoms and CSU severity. The analysis involved fitting 2 regression models: (1) the mediator model, estimating the effect of gastrointestinal symptoms on the mediator; and (2) the outcome model, estimating the effects of both gastrointestinal symptoms and the mediator on CSU severity. Both models were adjusted for potential confounders, including age, gender, BMI, smoking status, alcohol consumption, marital status, medical history, allergic symptoms, and other baseline variables. We estimated the Average Causal Mediation Effect (ACME) (representing the indirect effect) and the Average Direct Effect (ADE). Statistical significance was defined as a two-sided p-value <0.05. The proportion of the total effect mediated was calculated as: (ACME/Total Effect) × 100%.
Results
Baseline characteristics of patients
The clinical characteristics of the study population are summarized in Table 1. A total of 499 patients with CSU were included in the analysis. Of these, 196 patients were classified as having asymptomatic to mild disease (UAS7 ≤ 15), while 303 patients were categorized as having moderate to severe disease (UAS7 ≥ 16).
Table 1.
Demographic and clinical findings of the study population.
| Characteristics | Total (N = 499) | Symptom |
P-value | |
|---|---|---|---|---|
| Free-to-mild (UAS7 ≤15) (N = 196) | Moderate-to-severe (UAS7 ≥16) (N = 303) | |||
| Age, y, n(%) | ||||
| <40 years | 338 (67.600%) | 144 (73.500%) | 194 (64.000%) | 0.041 |
| 40–60 years | 137 (27.500%) | 47 (24.000%) | 90 (29.700%) | |
| >60 years | 24 (4.800%) | 5 (2.600%) | 19 (6.300%) | |
| Gender, n(%) | ||||
| Male | 204 (40.900%) | 94 (48.000%) | 110 (36.300%) | 0.010 |
| Female | 295 (59.100%) | 102 (52.000%) | 193 (63.700%) | |
| BMI, n(%) | ||||
| <18.5 | 10 (2.000%) | 4 (2.000%) | 6 (2.000%) | 0.748 |
| 18.5≤BMI<23 | 242 (48.500%) | 102 (52.000%) | 140 (46.200%) | |
| 23≤BMI<25 | 97 (19.400%) | 37 (18.900%) | 60 (19.800%) | |
| 25≤BMI<30 | 115 (23.000%) | 40 (20.400%) | 75 (24.800%) | |
| ≥30 | 35 (7.000%) | 13 (6.600%) | 22 (7.300%) | |
| Duration since initial diagnosis, n(%) | ||||
| <5 years | 246 (49.300%) | 88 (44.900%) | 158 (52.100%) | 0.088 |
| 5–10 years | 161 (32.300%) | 63 (32.100%) | 98 (32.300%) | |
| ≥10 years | 92 (18.400%) | 45 (23.000%) | 47 (15.500%) | |
| With family history, n(%) | ||||
| No | 408 (81.800%) | 168 (85.700%) | 240 (79.200%) | 0.066 |
| Yes | 91 (18.200%) | 28 (30.800%) | 63 (20.800%) | |
| Marital status, n(%) | ||||
| Partnered | 306 (61.300%) | 109 (55.600%) | 197 (65.000%) | 0.035 |
| Single/Other | 193 (38.700%) | 87 (44.400%) | 106 (35.000%) | |
| DLQI, mean (SD) | 14.587 (10.384) | 13.439 (10.167) | 15.330 (10.471) | 0.047 |
| PSQI, mean (SD) | 10.996 (6.025) | 10.082 (6.091) | 11.588 (5.916) | 0.006 |
| Anxiety scores, mean (SD) | 14.435 (7.529) | 12.694 (7.803) | 15.561 (7.136) | <0.001 |
| Depression scores, mean (SD) | 14.178 (8.281) | 12.204 (8.378) | 15.455 (7.975) | <0.001 |
| Stress scores, mean (SD) | 15.261 (7.553) | 13.505 (7.754) | 16.396 (7.208) | <0.001 |
| Combined gastrointestinal discomfort, n(%) | ||||
| Yes | 89 (17.800%) | 20 (10.200%) | 69 (22.800%) | <0.001 |
| No | 410 (82.200%) | 176 (89.800%) | 234 (77.200%) | |
| Lesion diameter, n(%) | ||||
| <5 mm | 191 (38.300%) | 65 (33.200%) | 126 (41.600%) | 0.059 |
| ≥5 mm | 308 (61.700%) | 131 (66.800%) | 177 (58.400%) | |
| Combined angioedema, n(%) | ||||
| Yes | 104 (20.900%) | 26 (13.300%) | 78 (25.700%) | 0.001 |
| No | 395 (79.200%) | 170 (86.700%) | 225 (74.300%) | |
| Combined dyspnea, n(%) | ||||
| Yes | 107 (21.400%) | 28 (14.300%) | 79 (26.100%) | 0.002 |
| No | 392 (78.600%) | 168 (85.700%) | 224 (73.900%) | |
| Combined rhinitis or asthma, n(%) | ||||
| Yes | 99 (19.800%) | 28 (14.300%) | 71 (23.400%) | 0.012 |
| No | 400 (80.200%) | 168 (85.700%) | 232 (76.600%) | |
| Duration of lesions, n(%) | ||||
| <1h | 159 (31.900%) | 57 (29.100%) | 102 (33.700%) | 0.158 |
| 1–6h | 175 (35.100%) | 77 (39.300%) | 98 (32.300%) | |
| 6–12h | 43 (8.600%) | 15 (7.7%) | 28 (9.2%) | |
| 12–24h | 39 (7.800%) | 12 (30.800%) | 27 (8.900%) | |
| 24–48h | 32 (6.400%) | 10 (5.100%) | 22 (7.300%) | |
| 48–72h | 13 (2.600%) | 4 (2.000%) | 9 (3.000%) | |
| >72h | 38 (7.600%) | 21 (10.700%) | 17 (5.600%) | |
| Smoking status, n(%) | ||||
| No | 285 (57.100%) | 121 (61.700%) | 164 (54.100%) | 0.093 |
| Yes | 214 (42.900%) | 75 (38.300%) | 139 (45.900%) | |
| Drinking status, n(%) | ||||
| No | 274 (54.900%) | 117 (59.700%) | 157 (51.800%) | 0.084 |
| Yes | 225 (45.100%) | 79 (40.300%) | 146 (48.200%) | |
Notes: The continuous variables are presented as mean (SD), and the categorical variables are presented as percentages (%).
Abbreviations: BMI, body mass index; SD, standard deviation; DLQI, Dermatology Life Quality Index; PSQI, Pittsburgh Sleep Quality Index
The baseline characteristics demonstrated significant differences across symptom severity groups. Overall, the majority of patients were under 40 years of age, accounting for 67.6% of the total population. Age was significantly associated with CSU severity (p = 0.041). Regarding gender distribution, 40.9% of patients were male and 59.1% were female, with females being more likely to have moderate to severe CSU (p = 0.010). Marital status also showed a significant association with disease severity (p = 0.035). Furthermore, moderate to severe CSU was significantly associated with the presence of angioedema (p = 0.001), breathing difficulties (p = 0.002), and allergic comorbidities (p = 0.012). In contrast, no significant differences were observed in BMI (p = 0.748), disease duration (p = 0.088), family history of CSU (p = 0.066), wheal diameter (p = 0.059), wheal duration (p = 0.158), smoking (p = 0.093), or alcohol consumption (p = 0.084).
Notably, patients with moderate to severe CSU exhibited significantly higher levels of anxiety (p < 0.001), depression (p < 0.001), and stress (p < 0.001). They also reported poorer quality of life (p = 0.047) and impaired sleep quality (p = 0.006). In addition, gastrointestinal symptoms such as abdominal discomfort were more prevalent in this group (p < 0.001). These findings underscore the multifaceted burden of CSU, highlighting the interplay between disease severity, psychological distress, sleep disturbance, and gastrointestinal dysregulation.
Gastrointestinal symptoms are related to the severity of urticaria
The results of the univariate analysis (Table 2) showed that gastrointestinal symptoms were significantly correlated with the severity of CSU (p < 0.001). In addition, factors such as age > 60 years, female gender, disease duration ≥10 years, married/cohabiting status, sleep disorders, anxiety, depression, elevated stress levels, and coexisting symptoms of angioedema, dyspnea, and rhinitis/asthma were all significantly associated with the severity of the disease (all p < 0.05). The multivariate logistic regression analysis, after adjusting for all covariates, confirmed that gastrointestinal symptoms still maintained an independent correlation (aOR = 2.375, 95% CI: 1.334–4.230, p = 0.003). At the same time, female gender (aOR = 1.544, 95% CI: 1.030–2.316), coexisting angioedema (aOR = 1.839, 95% CI: 1.086–3.116), dyspnea (aOR = 1.725, 95% CI: 1.018–2.923), and rhinitis/asthma (aOR = 1.883, 95% CI: 1.116–3.178) were identified as independent risk factors for the aggravation of CSU, as shown in Fig. 1.
Table 2.
Univariate analysis of all variables with UAS7.
| Characteristics | OR | Lower 95% CI | Upper 95% CI | P-value |
|---|---|---|---|---|
| Age, y, n(%) | ||||
| <40 years | 1 | – | – | – |
| 40–60 years | 1.421 | 0.940 | 2.149 | 0.095 |
| >60 years | 2.821 | 1.029 | 7.732 | 0.044 |
| Gender, n(%) | ||||
| Male | 1 | – | – | – |
| Female | 1.617 | 1.122 | 2.330 | 0.010 |
| BMI, n(%) | ||||
| <18.5 | 1 | – | – | – |
| 18.5≤BMI<23 | 0.915 | 0.252 | 3.326 | 0.893 |
| 23≤BMI<25 | 1.081 | 0.286 | 4.087 | 0.909 |
| 25≤BMI<30 | 1.250 | 0.333 | 4.689 | 0.741 |
| ≥30 | 1.128 | 0.268 | 4.757 | 0.869 |
| Duration since initial diagnosis, n(%) | ||||
| <5 years | 1 | – | – | – |
| 5–10 years | 0.866 | 0.575 | 1.306 | 0.493 |
| ≥10 years | 0.582 | 0.358 | 0.945 | 0.029 |
| Family history, n(%) | ||||
| No | 1 | – | – | – |
| Yes | 1.575 | 0.968 | 2.563 | 0.067 |
| Marital status, n(%) | ||||
| Partnered | 1.483 | 1.027 | 2.142 | 0.036 |
| Single/Other | 1 | – | – | – |
| PSQI, mean (SD) | 1.043 | 1.012 | 1.075 | 0.007 |
| Anxiety scores, mean (SD) | 1.053 | 1.027 | 1.080 | <0.001 |
| Depression scores, mean (SD) | 1.050 | 1.026 | 1.074 | <0.001 |
| Stress scores, mean (SD) | 1.053 | 1.028 | 1.079 | <0.001 |
| Combined gastrointestinal symptoms, n(%) | ||||
| No | 1 | – | – | – |
| Yes | 2.595 | 1.520 | 4.430 | <0.001 |
| Lesion diameter, n(%) | ||||
| <5 mm | 1 | – | – | – |
| ≥5 mm | 0.697 | 0.479 | 1.014 | 0.059 |
| Combined angioedema, n(%) | ||||
| Yes | 1 | – | – | – |
| No | 2.267 | 1.394 | 3.687 | 0.001 |
| Combined dyspnea, n(%) | ||||
| No | 1 | – | – | – |
| Yes | 2.116 | 1.316 | 3.403 | 0.002 |
| Combined rhinitis or asthma, n(%) | ||||
| No | 1 | – | – | – |
| Yes | 1.836 | 1.136 | 2.968 | 0.013 |
| Duration of lesions, n(%) | ||||
| <1h | 1 | – | – | – |
| 1–6h | 0.711 | 0.458 | 1.105 | 0.130 |
| 7–12h | 1.043 | 0.515 | 2.113 | 0.907 |
| 12–24h | 1.257 | 0.592 | 2.671 | 0.551 |
| 24–48h | 1.229 | 0.544 | 2.777 | 0.619 |
| 48–72h | 1.257 | 0.371 | 4.266 | 0.713 |
| >72h | 0.452 | 0.221 | 0.927 | 0.030 |
| Smoking status, n(%) | ||||
| No | 1 | – | – | – |
| Yes | 1.367 | 0.948 | 1.972 | 0.094 |
| Drinking status, n(%) | ||||
| No | 1 | – | – | – |
| Yes | 0.726 | 0.505 | 1.045 | 0.084 |
Notes: The continuous variables are presented as mean (SD), and the categorical variables are presented as percentages (%).
Abbreviations: BMI, body mass index; SD, standard deviation; DLQI, Dermatology Life Quality Index; PSQI, Pittsburgh Sleep Quality Index
Fig. 1.
Forest plot of multivariate logistic regression analysis identifying factors. Associated with UAS7 scores in patients with chronic spontaneous urticaria (CSU)
Diarrhea and abdominal pain are significantly associated with CSU severity
To further elucidate the relationship between specific gastrointestinal symptoms and the severity of CSU, we performed a detailed analysis of various symptoms (Table 3). The evaluated symptoms included diarrhea, constipation, and other gastrointestinal discomforts such as nausea, abdominal distension, heartburn, reflux, and abdominal pain. The results indicated that diarrhea and abdominal pain were the primary symptoms significantly associated with moderate-to-severe CSU. Specifically, patients presenting with diarrhea exhibited the highest risk of having severe disease (OR = 16.432, p = 0.001). Similarly, abdominal pain was identified as a significant factor associated with increased disease severity (OR = 8.762, p = 0.016). In contrast, no statistically significant associations were observed for the remaining gastrointestinal symptoms, including constipation, heartburn, reflux, abdominal distension, or nausea (all p > 0.05).
Table 3.
Association between specific gastrointestinal symptoms and UAS7.
| UAS7 |
Positive case count | p-value | |
|---|---|---|---|
| Variables | Odds Ratio (OR) | ||
| Diarrhea | 16.432 | 33 | 0.001 |
| Constipation | 1.154 | 38 | 0.782 |
| Other gastrointestinal discomfort | 2.151 | 53 | 0.132 |
| Nausea | 0.350 | 6 | 0.296 |
| Abdominal bloating | 0.378 | 10 | 0.250 |
| Heartburn | 4.138 | 16 | 0.140 |
| Regurgitation | 0.588 | 13 | 0.512 |
| Abdominal pain | 8.762 | 24 | 0.016 |
Notes: OR: Odds Ratio. P-values were calculated using the Chi-square test comparing the prevalence of gastrointestinal symptoms between patients with different UAS7 disease activity levels
Clinical characteristics and high disease burden of CSU patients with gastrointestinal symptoms
We further analyzed the allergic characteristics of patients with gastrointestinal symptoms. Based on clinical manifestations, among the 89 patients with gastrointestinal symptoms, 64.0% (n = 57) presented with wheals larger than 5 mm (Fig. 2a), and 70.8% reported that individual lesions persisted for less than 6 h (Fig. 2b). The majority of patients (77.5%, n = 69) had moderate-to-severe chronic spontaneous urticaria (UAS7 > 16) (Fig. 2c). Systemic symptoms included dyspnea in 38.2% (n = 34) of the patients (Fig. 2d) and angioedema in 29.2% (n = 26) (Fig. 2e). Concurrent rhinitis or asthma was present in 21.3% (n = 19) of the cases (Fig. 2f). Additionally, 59.6% of the cases had a disease duration of 5 years or longer (Fig. 2g), and 23.6% (n = 21) had a positive family history (Fig. 2h).
Fig. 2.
Clinical characteristics and disease burden of CSU patients with gastrointestinal symptoms.
The pie charts illustrate the distribution of clinical features and comorbidities in the subgroup of patients presenting with gastrointestinal symptoms:
(a) lesion diameter.
(b) duration of individual wheals.
(c) disease activity classification based on UAS7 scores.
(d) presence of dyspnea.
(e) presence of angioedema.
(f) comorbidity of allergic rhinitis or asthma.
(g) disease duration since initial diagnosis.
(h) family history
Increased risk of sleep and emotional disorders in patients with chronic spontaneous urticaria presenting with gastrointestinal symptoms or elevated disease activity
To further explore the potential mediating role of sleep and emotional disturbances, we analyzed their distribution among patients with gastrointestinal symptoms and those with more severe chronic spontaneous urticaria (CSU) (Fig. 3, Fig. 4). Patients in the severe CSU group exhibited significantly higher Pittsburgh Sleep Quality Index (PSQI) scores compared to those with less severe symptoms (11.59 ± 5.92 vs. 10.08 ± 6.09, p = 0.007; Fig. 3A). Similarly, patients with gastrointestinal symptoms demonstrated significantly higher PSQI scores than those without gastrointestinal symptoms (12.80 ± 6.24 vs. 10.60 ± 5.91, p = 0.003; Fig. 4A).
Fig. 3.
Elevated sleep and emotional disorder scores in CSU patients with gastrointestinal symptoms.
Sleep and emotional disturbance scores were compared between patients with chronic spontaneous urticaria (CSU) with and without gastrointestinal (GI) symptoms.
(a) Sleep disturbance scores.
(b) Anxiety scores.
(c) Stress scores.
(d) Depression scores.
∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001
Fig. 4.
Increased sleep disturbances and psychological burden in CSU patients with higher disease activity.
Sleep and psychological burden scores were compared among CSU patients stratified by disease severity levels.
(a) Sleep disturbance scores.
(b) Anxiety scores.
(c) Stress scores.
(d) Depression scores.
∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001
Regarding emotional disturbances, anxiety scores were significantly elevated in patients with higher UAS7 (15.56 ± 7.14 vs. 12.69 ± 7.80, p < 0.001; Fig. 3B) and in those with gastrointestinal symptoms (17.46 ± 6.01 vs. 13.78 ± 7.67, p < 0.001; Fig. 4B). Stress scores were also significantly higher in both the severe CSU group (16.40 ± 7.21 vs. 13.51 ± 7.75, p < 0.001; Fig. 3C) and the gastrointestinal symptom group (18.48 ± 6.04 vs. 14.56 ± 7.67, p < 0.001; Fig. 4C). Likewise, depression scores were elevated in patients with severe CSU (15.46 ± 7.98 vs. 12.20 ± 8.38, p < 0.001; Fig. 3D) and those with gastrointestinal symptoms (15.82 ± 6.58 vs. 13.82 ± 8.57, p = 0.015; Fig. 4D).
Psychological factors and sleep disturbances mediate the association between gastrointestinal symptoms and CSU severity
Mediation analysis demonstrated a significant mediating role of psychological factors and sleep disturbances in the association between gastrointestinal symptoms and the severity of CSU. Specifically, sleep disturbances accounted for 13.17% of the total effect (p = 0.016; Fig. 5A), anxiety symptoms for 17.28% (p = 0.012; Fig. 5B), perceived stress for 21.09% (p = 0.040; Fig. 5C), and depressive symptoms for 9.87% (p = 0.002; Fig. 5D) in mediating the association between gastrointestinal symptoms and CSU severity.
Fig. 5.
Psychological factors mediate the relationship between gastrointestinal symptoms and UAS7 scores in CSU patients.
Mediation analyses were conducted to evaluate the mediating effects of psychological factors on the association between gastrointestinal symptoms and UAS7 scores.
(a) Mediation effect of sleep disturbances.
(b) Mediation effect of anxiety.
(c) Mediation effect of stress.
(d) Mediation effect of depression
Discussion
CSU affects a large number of patients and is characterized by recurrent wheals and pruritus, which are commonly accompanied by impaired sleep quality and gastrointestinal dysfunction. Through clinical data analysis, we demonstrated that gastrointestinal symptoms in patients with CSU are significantly associated with increased disease severity. Furthermore, mediation analysis revealed that sleep disturbances and psychological factors partially mediate this association.
The high prevalence of CSU frequently prompts patient inquiries in both clinical settings and online platforms.22 One of the most common questions concerns whether CSU is associated with other contributing factors. Accumulating evidence indicates that the pathogenesis of CSU involves multiple interacting factors. Among them, gastrointestinal infections (including Helicobacter pylori and Ascaris infection) as important triggers have been widely recognized. Epidemiological data show that approximately 33.3% of CSU patients have non-skin-related symptoms (NSRS), and comorbidities such as gastrointestinal diseases are considered triggering factors for CSU.23 Notably, clinical observations have found that patients with chronic diarrhea have a significantly higher risk of developing CSU than those without diarrhea,24 and changes in the intestinal microbiota are associated with chronic urticaria. This phenomenon suggests that the intestinal microenvironment may participate in the pathological process of chronic urticaria by regulating the immune response mechanism.25,26
A large amount of research data has confirmed that intestinal microbiota disorders are significantly associated with skin diseases. Among them, the evidence for atopic dermatitis (AD) is one of the most sufficient.27 From the perspective of pathophysiological mechanisms, the intestinal microbiome can maintain intestinal homeostasis and plays a key role in ensuring the integrity of the intestinal wall, and regulates the balance of the immune system.28 The homeostatic function depends on the short-chain fatty acids (SCFA) produced and released by the Firmicutes phylum. SCFA can produce antibacterial peptides that protect intestinal epithelial cells,29 and can enhance intestinal barrier function, thereby preventing it from being damaged by pathogenic bacteria and LPS and other harmful substances entering the bloodstream.30,31 Notably, LPS, as a component of the cell wall of Gram-negative bacteria, can simultaneously promote IgE-mediated degranulation of mast cells through the Toll-like receptor 4 (TLR4) signaling pathway,32 and stimulate the release of inflammatory mediators such as TNFα and IL6.33
Although the pathogenesis of CSU has focused on IgE-mediated pathways, other factors have also been implicated,34,35 including alterations in the intestinal microbiota, characterized by a significant reduction in bacterial diversity, which has been identified as a risk factor for allergic diseases.9 Moreover, through the analysis of the serum metabolome of CSU patients, it was found that the levels of short-chain fatty acids (SCFA) with inhibitory effects on mast cell activation were significantly decreased.9 More importantly, further research has found that changes in key bacterial groups, especially the beneficial bacteria that produce SCFA (such as Homo Rosburii), have decreased, while the number of opportunistic pathogens (such as Klebsiella pneumoniae) has increased, and there is a significant correlation with the enhanced inflammatory response of skin mast cells mediated by IgE in the body.10 These important findings provide more conclusive evidence for elucidating the association between the intestinal microbiota and CSU.
This study further revealed that gastrointestinal symptoms may indirectly aggravate the condition of urticaria by inducing sleep disorders and emotional problems, and the mediation effect analysis showed that the mediating proportions of sleep disorders, anxiety, and stress were 13.17%, 17.28%, and 21.09%, respectively. This finding is consistent with the results of previous studies, which have confirmed that gastrointestinal symptoms may affect the sleep quality and motion of patients. Firstly, the Gallup survey showed that approximately 63% of patients with nocturnal gastroesophageal reflux disease (GERD) had significant sleep disorders.36 Secondly, Ranjbaran et al used the Pittsburgh Sleep Quality Index (PSQI) to confirm that patients with inflammatory bowel disease commonly had sleep problems such as prolonged sleep latency, increased daytime fatigue, and increased use of sleeping pills.37 Moreover, patients with irritable bowel syndrome (IBS) often present with not only gastrointestinal symptoms but also mental symptoms such as depression (manifested as fatigue, sleep disorders, and loss of appetite) and anxiety (manifested as tension, worry, and panic attacks).38 These research results collectively support the pathophysiological mechanism that gastrointestinal symptoms may exacerbate skin lesions by affecting sleep and emotion.
Research evidence indicates that sleep disorders may aggravate the progression of CSU through multiple mechanisms. Firstly, sleep disorders cause a disruption in the circadian rhythm of cortisol secretion, resulting in elevated levels of inflammatory cytokines and decreased levels of cortisol 39, 40, 41. Additionally, sleep deprivation eliminates the circadian rhythm of CD4 (+)CD25(+) regulatory T cells (Treg), which are crucial for maintaining peripheral tolerance and preventing autoimmunity.42 Moreover, studies have found that circulating Treg cells are significantly reduced in patients with chronic urticaria.43 In conclusion, sleep disorders may trigger CSU by increasing CRH secretion and activating inflammation through the HPA axis and circadian rhythm.
In addition, psychological stress (such as anxiety, stress, etc.) is not only an important trigger for CSU but also a key factor contributing to the worsening of the condition. Chronic long-term stress can activate various inflammatory mediators, including interleukin-6 (IL-6), interleukin-1 (IL-1), and interferon-γ, and stimulate the activation of the hypothalamic-pituitary-adrenal axis (CRH-ACTH-cortisol axis).44 Moreover, chronic stress seems to be associated with increased density of dermal nerve fibers, mast cells, nerve growth factor, and calcitonin gene-related peptide (CGRP).45 This interaction not only aggravates clinical symptoms but may also promote the persistence of chronic urticaria.46
In summary, this study not only reveals the positive correlation between gastrointestinal symptoms and the severity of CSU, but also suggests through mediation effect analysis the potential mechanisms by which sleep disorders and psychological factors are involved in the occurrence and development of the disease. These findings provide new clinical evidence for elucidating the possible pathogenesis of CSU and offer theoretical basis for developing comprehensive treatment plans targeting gastrointestinal symptoms, sleep disorders, and psychological factors, which is of great value for improving the clinical management of CSU.
These findings have important clinical implications for the management of patients with chronic spontaneous urticaria (CSU).Clinically, we recommend that initial evaluation of CSU patients routinely include brief screening for GIT symptoms (via targeted questionnaires) and psychological distress (using the validated Depression Anxiety Stress Scales-21 [DASS-21]). Early detection of these factors could guide personalized management, including timely referral to gastroenterology or mental health services and consideration of adjunctive interventions targeting gut-brain influences.
Longitudinal follow-up should incorporate periodic reassessment of both UAS7 scores and these associated symptoms. Changes in GIT or psychological/sleep parameters may parallel disease activity, informing decisions on treatment escalation, de-escalation, or integration of non-pharmacological strategies alongside standard therapies. This multidimensional approach has the potential to improve symptom control, quality of life, and overall outcomes in CSU.
Several limitations of the present study should be acknowledged. Firstly, as a single-center retrospective study, the sample may not fully represent the broader population of patients with chronic spontaneous urticaria (CSU), despite the application of strict inclusion and exclusion criteria. This may limit the generalizability (external validity) of our findings. Secondly, the cross-sectional and retrospective design precludes definitive conclusions regarding causality and temporal sequence. Although mediation analysis revealed significant associations, the relationships among gastrointestinal symptoms, psychological/sleep disturbances, and CSU severity are likely bidirectional, with each domain potentially influencing the others. Systematic treatment intervention trials—such as those targeting gastrointestinal symptoms or psychological/sleep disturbances and monitoring subsequent changes in CSU severity—would be particularly valuable to clarify causal pathways and directionality. Thirdly, reliance on self-reported medical history for certain exclusion criteria (eg, hypertension, diabetes, thyroid disease, malignancy, and severe autoimmune diseases) introduces the possibility of recall bias, underreporting, or inaccurate reporting, which may have resulted in the inadvertent inclusion of patients with undiagnosed or unreported conditions. Additionally, we did not systematically screen for other potential underlying systemic diseases (beyond excluding known severe organic psychiatric disorders) or perform quantitative assessments of nutritional status or dietary intake (eg, via validated dietary questionnaires, food diaries, or nutritional biomarkers). Given that dietary factors (such as pseudoallergens or histamine-rich foods) and unmeasured/undiagnosed systemic diseases can influence both gastrointestinal symptoms and CSU activity, these omissions represent important potential confounding factors. Finally, future multicenter studies are needed to validate these findings in diverse populations, and mechanistic investigations are warranted to elucidate the underlying molecular and physiological mechanisms.
Overall, this study demonstrates that CSU is significantly associated with gastrointestinal symptoms, sleep disturbances, and psychological stress. Mediation analysis further identified sleep disturbances, anxiety, and perceived stress as significant mediators in the relationship between gastrointestinal symptoms and CSU severity. These findings offer new insights into the clinical evaluation and management of CSU by highlighting the interconnected roles of the nervous system, gut environment, and cutaneous manifestations in disease pathogenesis.
Abbreviations
ACTH, Adrenocorticotropic Hormone; AD, Atopic Dermatitis; aOR, adjusted Odds Ratio; BMI, Body Mass Index; CI, Confidence Interval; CGRP, Calcitonin Gene-Related Peptide; CRH, Corticotropin-Releasing Hormone; CSU, Chronic Spontaneous Urticaria; DASS-21, Depression Anxiety Stress Scales-21; DLQI, Dermatology Life Quality Index; EAACI, European Academy of Allergy and Clinical Immunology; EDF, European Dermatology Forum; GA2LEN, Global Allergy and Asthma European Network; GERD, Gastroesophageal Reflux Disease; GSRS, Gastrointestinal Symptom Rating Scale; HPA, Hypothalamic-Pituitary-Adrenal; IgE, Immunoglobulin E; IBS, Irritable Bowel Syndrome; IL-1, Interleukin-1; IL-6, Interleukin-6; LPS, Lipopolysaccharide; NSRS, Non-Skin Related Symptoms; OR, Odds Ratio; PSQI, Pittsburgh Sleep Quality Index; SCFA, Short-Chain Fatty Acids; SD, Standard Deviation; TLR4, Toll-like Receptor 4; TNFα, Tumor Necrosis Factor-alpha; Treg, Regulatory T cells; UAS, Urticaria Activity Score.
Informed consent statement
All participants (or subjects) in this study provided written informed consent prior to the commencement of the research, clearly acknowledging their understanding of the study's purpose, procedures, potential risks, and rights.
Author contributions
Conceptualization, Z.W.; investigation, HS.L., YX.M., XX.L., LY.Z., CZ.Q., ZY.G., WH.Z.; data curation, Z.W.; writing—original draft preparation, Z.W., HS.L.; writing—review and editing, Z.W., WH.Z.; visualization, Z.W., YX.M.; supervision, Z.W.; project administration, Z.W., WH.Z.; funding acquisition,W.Z. All authors have read and agreed to the published version of the manuscript.
Ethics approval
The study protocol was approved by the hospital's ethics committee (approval number: 2024139), and all participants signed informed consent forms.
Declaration of generative AI and AI-assisted technologies in the writing process
During the preparation of this work the author(s) used ChatGPT in order to improve language.
Funding
This work was funded by the National Natural Science Foundation of China (NSFC) (82201966) and Natural Science Basic Research Program of Shaanxi (2023-JC-QN-0924) to Zhao Wang.
Declaration of competing interest
All authors declare that there are no financial, commercial, or personal conflicts of interest that could influence the results or interpretation of this study. The research did not receive funding from any organization or entity that might pose a conflict of interest, and no authors have non-financial relationships that could affect the objectivity of the research.
Footnotes
Full list of author information is available at the end of the article
Contributor Information
Weihui Zeng, Email: zengwh88@126.com.
Zhao Wang, Email: wang.zhao@xjtu.edu.cn.
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