Abstract
Background
The gut–skin axis has emerged as a key concept linking cutaneous and gastrointestinal inflammation. Although prior studies have reported an increased risk of irritable bowel syndrome (IBS) among patients with rosacea, the reverse association remains unclear.
Objective
To examine the bidirectional association between rosacea and IBS using a nationwide cohort database, clarifying whether IBS increases the risk of rosacea as well as the reverse relationship.
Methods
We conducted a retrospective cohort study using the Korean National Health Insurance Service-National Sample Cohort (NHIS-NSC), including adults aged ≥20 years from 2002 to 2013. Incident cases of rosacea and IBS were identified using International Classification of Diseases, 10th Revision codes and matched to controls by age, sex, and index year. Cox proportional hazards models were applied to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs), controlling for sociodemographic and clinical covariates.
Results
During follow-up, patients with rosacea showed a higher incidence of IBS than matched controls (56.3 vs. 36.9 per 1,000 person-years), with a significantly increased risk in the fully adjusted Cox model (aHR, 1.30; 95% CI, 1.11–1.52). Conversely, patients with IBS had a higher incidence of rosacea compared with matched controls (0.37 vs. 0.21 per 1,000 person-years), corresponding to an elevated adjusted risk (aHR, 1.61; 95% CI, 1.39–1.87). These bidirectional associations remained consistent across sensitivity and subgroup analyses.
Conclusion
This nationwide study demonstrates a reciprocal relationship between rosacea and IBS, underscoring shared inflammatory and neuroimmune mechanisms underlying the gut–skin axis.
Keywords: Bidirectional association, Cohort Studies, Gastrointestinal Microbiome, Irritable bowel syndrome, Registries, Rosacea
INTRODUCTION
Rosacea is a chronic inflammatory dermatosis characterized by recurrent facial erythema, papulopustular eruptions, and vascular hyperreactivity, underpinned by dysregulation of innate immunity and neurovascular control mechanisms1,2,3,4,5,6. Increasing evidence suggests that rosacea extends beyond the skin, frequently coexisting with systemic disorders including cardiovascular disease, psychiatric illness, and autoimmune or gastrointestinal comorbidities7,8,9,10,11.
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by chronic abdominal discomfort, altered bowel habits, and visceral hypersensitivity12. Both rosacea and IBS share common pathophysiologic mechanisms such as gut microbiota dysbiosis, low-grade systemic inflammation, and epithelial barrier disruption5,13,14,15,16,17. These overlapping processes support the concept of the ‘gut–skin axis,’ a bidirectional communication system involving microbial, immune, and neuroendocrine pathways15,18,19.
Previous studies have mainly focused on the unidirectional association from rosacea to IBS, including our prior multi-institutional case-control study demonstrating an increased risk of IBS in patients with rosacea20. However, whether IBS also predisposes individuals to rosacea remains unclear. Therefore, this study aimed to clarify the reciprocal nature of this relationship by investigating the bidirectional association between rosacea and IBS using a large, population-based cohort.
MATERIALS AND METHODS
Study design and data source
We conducted a retrospective population-based cohort study using the Korean National Health Insurance Service-National Sample Cohort (NHIS-NSC), which contains data of approximately one million individuals representative of the Korean population. The overall study design and analytic framework were similar to those used in our previous investigation of rosacea and IBS20, but the current study expanded this framework to evaluate bidirectional associations.
Study population
Our retrospective study included 746,816 individuals aged 20 years or older from the NHIS-NSC. Those diagnosed with either rosacea or IBS in 2002 were excluded to ensure incident case analysis. We excluded 92 individuals diagnosed with rosacea and 34,391 individuals diagnosed with IBS in 2002. In addition, 2 individuals who had the same diagnosis date for rosacea and IBS within the cohort were excluded. After applying all exclusion criteria, a total of 712,331 participants were included in the final study population (Fig. 1).
Fig. 1. Flowchart of study cohort selection from NHIS-NSC in Korea.
NHIS-NSC: Korean National Health Insurance Service-National Sample Cohort, IBS: irritable bowel syndrome.
Disease ascertainment
Rosacea was identified using International Classification of Diseases, 10th Revision (ICD-10) codes L71.1, L71.8, and L71.9, while IBS was defined using K58. Patients were classified into disease and control groups according to diagnosis status.
Analytical approach
Two complementary analyses were performed: (1) risk of IBS among rosacea patients, and (2) risk of rosacea among IBS patients. For Main Analysis 1, each rosacea patient was matched with up to 4 controls; for Main Analysis 2, each IBS patient was matched with one control, based on age, sex, and index year. Covariates included age, sex, income, region, and comorbidities (hypertension, diabetes, thyroid disorders, autoimmune diseases, depression, and migraine).
Statistical analysis
Kaplan-Meier curves were used to estimate cumulative incidence, and log-rank tests compared survival distributions. Multivariable Cox proportional hazards models calculated adjusted hazard ratio (aHRs) and 95% confidence intervals (CIs), adjusting for sociodemographic and clinical factors. Analyses were performed using SAS 9.4 (SAS Institute, Cary, NC, USA) and IBM SPSS 27.0 (IBM Corp., Armonk, NY, USA), with p<0.05 considered statistically significant.
Ethics statement
The study was approved by the Institutional Review Board of the Kangwon National University Hospital (KNUH-2024-01-012).
RESULTS
Baseline characteristics
We conducted the study using a final analytic population of 712,331 individuals (Fig. 1). For the analysis examining the risk of IBS among patients with rosacea (Main Analysis 1), 1,625 individuals with rosacea were initially identified. Among them, 540 patients who had been diagnosed with IBS prior to the onset of rosacea were excluded, leaving 1,085 rosacea patients eligible for analysis. To ensure comparability, these patients were matched with controls in a 1:4 ratio based on age, sex, and index year, resulting in a final cohort comprising 1,085 rosacea patients and 4,340 matched controls. For the analysis assessing the risk of rosacea among patients with IBS (Main Analysis 2), 244,389 individuals with IBS were initially identified. After excluding 233 individuals who had been diagnosed with rosacea before the onset of IBS, 244,156 IBS patients remained for analysis. These patients were matched with controls in a 1:1 ratio according to age, sex, and index year, yielding a final cohort of 244,156 IBS patients and 244,156 matched controls. It should be noted that the 244,156 IBS patients represent the cumulative number of incident IBS cases identified throughout the entire observation period from 2002 to 2013, not the point prevalence at any single calendar year. The baseline characteristics of the matched cohorts for both analyses are summarized in Table 1.
Table 1. Characteristics of participants in the bidirectional analysis.
| Variables | Main Analysis 1: Rosacea → IBS | Main Analysis 2: IBS → Rosacea | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Total (n=5,425) | With rosacea (n=1,085) | Without rosacea (n=4,340) | p-value | Total (n=488,312) | With IBS (n=244,156) | Without IBS (n=244,156) | p-value | ||
| Sex | 1.000 | 1.000 | |||||||
| Male | 2,500 (46.1) | 500 (46.1) | 2,000 (46.1) | 219,488 (44.9) | 109,744 (44.9) | 109,744 (44.9) | |||
| Female | 2,925 (53.9) | 585 (53.9) | 2,340 (53.9) | 268,824 (55.1) | 134,412 (55.1) | 134,412 (55.1) | |||
| Age (yr) | 1.000 | 1.000 | |||||||
| 20–29 | 1,035 (19.1) | 207 (19.1) | 828 (19.1) | 101,468 (20.8) | 50,734 (20.8) | 50,734 (20.8) | |||
| 30–39 | 1,485 (27.4) | 297 (27.4) | 1,188 (27.4) | 113,722 (23.3) | 56,861 (23.3) | 56,861 (23.3) | |||
| 40–49 | 1,400 (25.8) | 280 (25.8) | 1,120 (25.8) | 118,408 (24.2) | 59,204 (24.2) | 59,204 (24.2) | |||
| 50–59 | 840 (15.5) | 168 (15.5) | 672 (15.5) | 74,248 (15.2) | 37,124 (15.2) | 37,124 (15.2) | |||
| 60+ | 665 (12.3%) | 133 (12.3) | 532 (12.3) | 80,466 (16.5) | 40,233 (16.5) | 40,233 (16.5) | |||
| Income | <0.001 | <0.001 | |||||||
| High | 1,961 (36.1) | 459 (42.3) | 1,502 (34.6) | 181,337 (37.1) | 96,786 (39.6) | 84,551 (34.6) | |||
| Medium | 2,081 (38.4) | 399 (36.8) | 1,682 (38.8) | 188,381 (38.6) | 92,810 (38.0) | 95,571 (39.1) | |||
| Low | 1,383 (25.5) | 227 (20.9) | 1,156 (26.6) | 118,594 (24.3) | 54,560 (22.3) | 64,034 (26.2) | |||
| Residence | 0.946 | <0.001 | |||||||
| Urban | 2,665 (49.1) | 532 (49.0) | 2,133 (49.1) | 237,238 (48.6) | 116,587 (47.8) | 120,651 (49.4) | |||
| rural | 2,760 (50.9) | 553 (51.0) | 2,207 (50.9) | 251,074 (51.4) | 127,569 (52.2) | 123,505 (50.6) | |||
| CCI score | <0.001 | <0.001 | |||||||
| 0 | 4,160 (76.7) | 775 (71.4) | 3,385 (78.0) | 376,057 (77.0) | 174,199 (71.3) | 201,858 (82.7) | |||
| 1 | 628 (11.6) | 152 (14.0) | 476 (11.0) | 59,207 (12.1) | 36,848 (15.1) | 22,359 (9.2) | |||
| 2 | 446 (8.2) | 106 (9.8) | 340 (7.8) | 35,246 (7.2) | 22,082 (9.0) | 13,164 (5.4) | |||
| More than 3 | 191 (3.5) | 52 (4.8) | 139 (3.2) | 17,802 (3.6) | 11,027 (4.5) | 6,775 (2.8) | |||
| Comorbidities | |||||||||
| Hypertension | 59 (1.1) | 15 (1.4) | 44 (1.0) | 0.295 | 27,478 (5.6) | 15,806 (6.5) | 11,672 (4.8) | <0.001 | |
| DM | 335 (6.2) | 66 (6.1) | 269 (6.2) | 0.888 | 62,472 (12.8) | 33,597 (13.8) | 28,875 (11.8) | <0.001 | |
| Malignancy | 123 (2.3) | 33 (3.0) | 90 (2.1) | 0.055 | 31,584 (6.5) | 17,813 (7.3) | 13,771 (5.6) | <0.001 | |
| Autoimmune disease | 14 (0.3) | 7 (0.6) | 7 (0.2) | 0.005 | 2,486 (0.5) | 1,599 (0.7) | 887 (0.4) | <0.001 | |
| Thyroid disease | 88 (1.6) | 26 (2.4) | 62 (1.4) | 0.024 | 34,448 (7.1) | 22,122 (9.1) | 12,326 (5.0) | <0.001 | |
| Alcoholism | 35 (0.6) | 10 (0.9) | 25 (0.6) | 0.203 | 12,226 (2.5) | 6,984 (2.9) | 5,242 (2.1) | <0.001 | |
| Depression | 63 (1.2) | 18 (1.7) | 45 (1.0) | 0.087 | 27,486 (5.6) | 18,406 (7.5) | 9,080 (3.7) | <0.001 | |
| Migraine | 24 (0.4) | 5 (0.5) | 19 (0.4) | 0.919 | 17,307 (3.5) | 12,238 (5.0) | 5,069 (2.1) | <0.001 | |
| Drug | |||||||||
| Isotretinoin | 35 (0.6) | 28 (2.6) | 7 (0.2) | <0.001 | 3,579 (0.7) | 2,445 (1.0) | 1,134 (0.5) | <0.001 | |
| Doxycycline | 210 (3.9) | 134 (12.4) | 76 (1.8) | <0.001 | 8,588 (1.8) | 5,654 (2.3) | 2,934 (1.2) | <0.001 | |
| Minocycline | 130 (2.4) | 108 (10.0) | 22 (0.5) | <0.001 | 1,253 (0.3) | 830 (0.3) | 423 (0.2) | <0.001 | |
Values are presented as number (%).
IBS: irritable bowel syndrome, CCI: Charlson Comorbidity Index, DM: diabetes mellitus.
In the analysis of the risk of IBS among patients with rosacea (Main Analysis 1), significant differences between groups were observed for income (p<0.001), Charlson Comorbidity Index (CCI) score (p<0.001), autoimmune disease (p=0.005), and thyroid disease (p=0.024). With respect to medication exposure, the use of isotretinoin (p<0.001), doxycycline (p<0.001), and minocycline (p<0.001) was also significantly different between groups. In the analysis of the risk of rosacea among patients with IBS (Main Analysis 2), significant differences were observed for income (p<0.001), residential area (p<0.001), and CCI score (p<0.001). In addition, several comorbidities—including hypertension, diabetes mellitus, malignancy, autoimmune disease, thyroid disease, alcoholism, depression, and migraine—as well as medication use (isotretinoin, doxycycline, and minocycline) differed significantly between groups (p<0.001 for all) (Table 1).
Risk of IBS among patients with rosacea (Main Analysis 1)
During a median follow-up of 6.25 years, the incidence rate of IBS was 56.3 per 1,000 person-years in patients with rosacea and 36.9 per 1,000 person-years in matched controls. A total of 233 IBS events occurred in the rosacea cohort and 652 events in the control group after matching. Kaplan-Meier survival curves demonstrated a significantly higher cumulative incidence of IBS among rosacea patients (log-rank p<0.001) (Fig. 2A). In the fully adjusted Cox model, the risk of developing IBS was significantly increased in the rosacea cohort (aHR, 1.30; 95% CI, 1.11–1.52; p=0.002; Table 2).
Fig. 2. Bidirectional risk and cumulative incidence curves between rosacea and irritable bowel syndrome. Kaplan-Meier curves for (A) cumulative incidence of IBS among rosacea patients (Main Analysis 1) and (B) cumulative incidence of rosacea among IBS patients (Main Analysis 2).
IBS: irritable bowel syndrome.
Table 2. Bidirectional Cox regression analyses of the incidence of IBS and rosacea.
| Model 1 | Model 2 | Model 3 | Model 4 | Model 5 | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | HR | 95% CI | HR | 95% CI | HR | 95% CI | HR | 95% CI | ||
| Rosacea → IBS | |||||||||||
| Overall | 1.53 | 1.31–1.77 | 1.51 | 1.30–1.76 | 1.45 | 1.24–1.68 | 1.44 | 1.23–1.67 | 1.30 | 1.11–1.52 | |
| Male | 1.86 | 1.51–2.31 | 1.83 | 1.47–2.26 | 1.67 | 1.35–2.08 | 1.67 | 1.34–2.07 | 1.52 | 1.21–1.91 | |
| Female | 1.27 | 1.03–1.57 | 1.27 | 1.03–1.58 | 1.24 | 1.00–1.53 | 1.23 | 0.99–1.52 | 1.09 | 0.87–1.37 | |
| IBS → Rosacea | |||||||||||
| Overall | 1.83 | 1.59–2.11 | 1.82 | 1.58–2.10 | 1.78 | 1.54–2.06 | 1.68 | 1.45–1.94 | 1.61 | 1.39–1.87 | |
| Male | 2.36 | 1.86–2.99 | 2.35 | 1.85–3.00 | 2.24 | 1.76–2.86 | 2.15 | 1.68–2.75 | 2.07 | 1.62–2.64 | |
| Female | 1.58 | 1.32–1.89 | 1.57 | 1.31–1.88 | 1.56 | 1.30–1.87 | 1.46 | 1.22–1.75 | 1.41 | 1.17–1.69 | |
Cox regression of IBS incidence in patients diagnosed with rosacea, overall and stratified by sex.
Model 1: adjusted age and sex; Model 2: Model 1 + income and residence; Model 3: Model 2 + CCI score; Model 4: Model 3 + comorbidities; Model 5: Model 4 + drugs.
Comorbidities included hypertension, diabetes mellitus, malignancy, autoimmune diseases, thyroid disease, alcoholism, depression, and migraine.
IBS: irritable bowel syndrome, HR: hazard ratio, CI: confidence interval, CCI: Charlson Comorbidity Index.
Risk of rosacea among patients with IBS (Main Analysis 2)
In the reverse analysis, during a median follow-up of 6.24 years, the incidence rate of rosacea was 0.37 per 1,000 person-years among patients with IBS and 0.21 per 1,000 person-years among matched controls. Overall, 540 rosacea events occurred in the IBS cohort and 314 events occurred in the control group after matching. Patients with IBS exhibited a significantly higher cumulative incidence of rosacea compared with controls (log-rank p<0.001) (Fig. 2B). After full adjustment, the risk of rosacea was 1.61 times higher in the IBS group (aHR, 1.61; 95% CI, 1.39–1.87; p<0.001; Table 2).
Sensitivity and subgroup analyses
Sensitivity and subgroup analyses were conducted for both the risk of IBS among patients with rosacea (Main Analysis 1) and the risk of rosacea among patients with IBS (Main Analysis 2). Baseline characteristics stratified by sex are presented in Table 3 (Main Analysis 1) and Table 4 (Main Analysis 2). In the Cox proportional hazards model, male patients with rosacea exhibited a significantly increased risk of developing IBS compared with matched controls (aHR, 1.52; 95% CI, 1.21–1.91; p<0.001). In contrast, female patients with rosacea did not show a statistically significant increase in IBS risk (aHR, 1.09; 95% CI, 0.87–1.37; p=0.452). In Main Analysis 2, sex-stratified subgroup analyses demonstrated that male patients with IBS had a significantly higher risk of developing rosacea (aHR, 2.07; 95% CI, 1.62–2.64; p<0.001). Female patients with IBS also showed a significantly increased risk of rosacea (aHR, 1.41; 95% CI, 1.17–1.69).
Table 3. Sex-specific characteristics related to irritable bowel syndrome.
| Variables | Male | Female | |||||
|---|---|---|---|---|---|---|---|
| With rosacea (n=500) | Without rosacea (n=2,000) | p-value | With rosacea (n=585) | Without rosacea (n=2,340) | p-value | ||
| Age (yr) | 1.000 | 1.000 | |||||
| 20–29 | 89 (17.8) | 356 (17.8) | 118 (20.2) | 472 (20.2) | |||
| 30–39 | 110 (22.0) | 440 (22.0) | 187 (32.0) | 748 (32.0) | |||
| 40–49 | 149 (29.8) | 596 (29.8) | 131 (22.4) | 524 (22.4) | |||
| 50–59 | 90 (18.0) | 360 (18.0) | 78 (13.3) | 312 (13.3) | |||
| 60+ | 62 (12.4) | 248 (12.4) | 71 (12.1) | 284 (12.1) | |||
| Income | 0.022 | <0.001 | |||||
| High | 211 (42.2) | 730 (36.5) | 248 (42.4) | 772 (33.0) | |||
| Medium | 187 (37.4) | 761 (38.1) | 212 (36.2) | 921 (39.4) | |||
| Low | 102 (20.4) | 509 (25.5) | 125 (21.4) | 647 (27.6) | |||
| Residence | 0.390 | 0.482 | |||||
| Urban | 236 (47.2) | 987 (49.4) | 296 (50.6) | 1,146 (49.0) | |||
| Rural | 264 (52.8) | 1,013 (50.7) | 289 (49.4) | 1,194 (51.0) | |||
| CCI score | <0.001 | 0.223 | |||||
| 0 | 347 (69.4) | 1,582 (79.1) | 428 (73.2) | 1,803 (77.1) | |||
| 1 | 62 (12.4) | 183 (9.2) | 90 (15.4) | 293 (12.5) | |||
| 2 | 58 (11.6) | 169 (8.5) | 48 (8.2) | 171 (7.3) | |||
| More than 3 | 33 (6.6) | 66 (3.3) | 19 (3.2) | 73 (3.1) | |||
| Comorbidities | |||||||
| Hypertension | 10 (2.0) | 26 (1.3) | 0.240 | 5 (0.9) | 18 (0.8) | 0.834 | |
| DM | 42 (8.4) | 143 (7.2) | 0.340 | 24 (4.1) | 126 (5.4) | 0.209 | |
| Malignancy | 18 (3.6) | 39 (2.0) | 0.027 | 15 (2.6) | 51 (2.2) | 0.575 | |
| Autoimmune disease | 1 (0.2) | 0 (0.0) | 0.045 | 6 (1.0) | 7 (0.3) | 0.018 | |
| Thyroid disease | 8 (1.6) | 11 (0.6) | 0.016 | 18 (3.1) | 51 (2.2) | 0.201 | |
| Alcoholism | 7 (1.4) | 22 (1.1) | 0.575 | 3 (0.5) | 3 (0.1) | 0.066 | |
| Depression | 4 (0.8) | 13 (0.7) | 0.715 | 14 (2.4) | 32 (1.4) | 0.075 | |
| Migraine | 1 (0.2) | 6 (0.3) | 0.705 | 4 (0.7) | 13 (0.6) | 0.715 | |
| Drugs | |||||||
| Isotretinoin | 10 (2.0) | 3 (0.2) | <0.001 | 18 (3.1) | 4 (0.2) | <0.001 | |
| Doxycycline | 48 (9.6) | 26 (1.3) | <0.001 | 86 (14.7) | 50 (2.1) | <0.001 | |
| Minocycline | 46 (9.2) | 9 (0.5) | <0.001 | 62 (10.6) | 13 (0.6) | <0.001 | |
Values are presented as number (%).
CCI: Charlson Comorbidity Index, DM: diabetes mellitus.
Table 4. Sex-specific characteristics related to rosacea.
| Variables | Male | Female | |||||
|---|---|---|---|---|---|---|---|
| With IBS (n=109,744) | Without IBS (n=109,744) | p-value | With IBS (n=134,412) | Without IBS (n=134,412) | p-value | ||
| Age (yr) | 1.000 | 1.000 | |||||
| 20–29 | 22,292 (20.3) | 22,292 (20.3) | 28,442 (21.2) | 28,442 (21.2) | |||
| 30–39 | 26,682 (24.3) | 26,682 (24.3) | 30,179 (22.5) | 30,179 (22.5) | |||
| 40–49 | 26,996 (24.6) | 26,996 (24.6) | 32,208 (24.0) | 32,208 (24.0) | |||
| 50–59 | 17,192 (15.7) | 17,192 (15.7) | 19,932 (14.8) | 19,932 (14.8) | |||
| 60+ | 16,582 (15.1) | 16,582 (15.1) | 23,651 (17.6) | 23,651 (17.6) | |||
| Income | <0.001 | <0.001 | |||||
| High | 45,721 (41.7) | 36,797 (33.5) | 51,065 (38.0) | 47,754 (35.5) | |||
| Medium | 42,779 (39.0) | 44,804 (40.8) | 50,031 (37.2) | 50,767 (37.8) | |||
| Low | 21,244 (19.4) | 28,143 (25.6) | 33,316 (24.8) | 35,891 (26.7) | |||
| Residence | <0.001 | <0.001 | |||||
| Urban | 52,364 (47.7) | 53,444 (48.7) | 64,223 (47.8) | 67,207 (50.0) | |||
| Rural | 57,380 (52.3) | 56,300 (51.3) | 70,189 (52.2) | 67,205 (50.0) | |||
| CCI score | <0.001 | <0.001 | |||||
| 0 | 79,135 (72.1) | 91,720 (83.6) | 95,064 (70.7) | 110,138 (81.9) | |||
| 1 | 14,420 (13.1) | 8,289 (7.6) | 22,428 (16.7) | 14,070 (10.5) | |||
| 2 | 10,874 (9.9) | 6,202 (5.7) | 11,208 (8.3) | 6,962 (5.2) | |||
| More than 3 | 5,315 (4.8) | 3,533 (3.2) | 5,712 (4.2) | 3,242 (2.4) | |||
| Comorbidities | |||||||
| Hypertension | 6,655 (6.1) | 4,640 (4.2) | <0.001 | 9,151 (6.8) | 7,032 (5.2) | <0.001 | |
| DM | 16,673 (15.2) | 14,349 (13.1) | <0.001 | 16,924 (12.6) | 14,526 (10.8) | <0.001 | |
| Malignancy | 8,627 (7.9) | 6,746 (6.1) | <0.001 | 9,186 (6.8) | 7,025 (5.2) | <0.001 | |
| Autoimmune disease | 437 (0.4) | 174 (0.2) | <0.001 | 1,162 (0.9) | 713 (0.5) | <0.001 | |
| Thyroid disease | 3,834 (3.5) | 1,610 (1.5) | <0.001 | 18,288 (13.6) | 10,716 (8.0) | <0.001 | |
| Alcoholism | 5,918 (5.4) | 4,471 (4.1) | <0.001 | 1,066 (0.8) | 771 (0.6) | <0.001 | |
| Depression | 5,694 (5.2) | 2,716 (2.5) | <0.001 | 12,712 (9.5) | 6,364 (4.7) | <0.001 | |
| Migraine | 2,691 (2.5) | 1,014 (0.9) | <0.001 | 9,547 (7.1) | 4,055 (3.0) | <0.001 | |
| Drugs | |||||||
| Isotretinoin | 1,125 (1.0) | 487 (0.4) | <0.001 | 1,320 (1.0) | 647 (0.5) | <0.001 | |
| Doxycycline | 2,148 (2.0) | 966 (0.9) | <0.001 | 3,506 (2.6) | 1,968 (1.5) | <0.001 | |
| Minocycline | 350 (0.3) | 154 (0.1) | <0.001 | 480 (0.4) | 269 (0.2) | <0.001 | |
Values are presented as number (%).
IBS: irritable bowel syndrome, CCI: Charlson Comorbidity Index, DM: diabetes mellitus.
The bidirectional associations persisted across multiple sensitivity models, including those adjusted for medication exposures (e.g., isotretinoin, doxycycline, minocycline) (Table 2). No significant interaction effects were observed between comorbidity burden and disease association. Cumulative incidence curves confirmed the temporal sequence of disease development, supporting a reciprocal relationship between rosacea and IBS (Fig. 2).
DISCUSSION
This nationwide, population-based cohort study provides epidemiological evidence that rosacea and IBS are bidirectionally associated, reinforcing the concept of systemic inflammatory interplay between the gut and the skin. While our previous work demonstrated that rosacea increases the risk of IBS20, the present study expands this understanding by confirming that IBS also predisposes individuals to rosacea, supporting shared inflammatory and neuroimmune mechanisms15,18,20,21.
The gut–skin axis represents a complex network of bidirectional interactions between intestinal microbiota, immune responses, and neurovascular regulation22,23,24. Disruption of gut microbial diversity can increase intestinal permeability and trigger systemic inflammation, which in turn may alter cutaneous immune and vascular homeostasis25,26. Dysbiosis of the gut flora and low-grade inflammatory signaling have been observed in both rosacea and IBS27,28, supporting the hypothesis of a shared inflammatory substrate. Likewise, chronic skin inflammation and neurovascular activation in rosacea may influence intestinal physiology through circulating cytokines, stress-related hormonal pathways, and autonomic regulation, completing a feedback loop that links both organs within the same inflammatory spectrum29,30,31.
Microbial factors may play a pivotal role in this connection. Studies have reported higher frequencies of Helicobacter pylori infection, Demodex colonization, and small intestinal bacterial overgrowth (SIBO) in rosacea32. Similarly, altered gut microbiota composition has been described in IBS, contributing to mucosal immune activation and visceral hypersensitivity33. Notably, prior studies have reported improvement of rosacea following SIBO eradication, suggesting a potential causal link between microbial dysbiosis and cutaneous inflammation24,32.
Neuroimmune and neurovascular mechanisms may also contribute to the bidirectional association. Both rosacea and IBS exhibit heightened sensitivity to stress and abnormal autonomic responses, mediated by neuropeptides such as substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide30,31. Based on prior literature, these mediators may amplify vasodilation, pain perception, and immune activation, suggesting a shared neurogenic pathway that could link gut and skin symptoms. Chronic stress, in particular, may exacerbate both conditions by activating hypothalamic pituitary adrenal and sympathetic pathways, perpetuating inflammation and vascular instability31,32.
Recognition of this 2-way relationship has important clinical implications12. Physicians managing either condition should be aware of the potential coexistence of the other, promoting interdisciplinary collaboration between dermatologists and gastroenterologists. Comprehensive care strategies including microbiome-targeted therapy, dietary modulation34, and stress management may help break the inflammatory feedback cycle between the gut and skin24,25. These insights also highlight the need for mechanistic studies exploring the microbiome–immune–neural interface through longitudinal and interventional designs.
Furthermore, the potential influence of therapeutic interventions on the gut–skin axis warrants consideration. In our analysis, the risk estimates were slightly attenuated after adjusting for rosacea-specific medications, suggesting that these treatments may partially mediate the observed association. Long-term use of systemic tetracyclines (e.g., doxycycline, minocycline) is known to induce gut microbiota dysbiosis, a well-established pathophysiologic factor in IBS35,36. Conversely, pharmacological modulation of the gut can influence cutaneous outcomes; for instance, SIBO eradication with rifaximin has been reported to significantly improve rosacea lesions32. Thus, a comprehensive understanding of the link between rosacea and IBS requires consideration of pharmacological interactions alongside intrinsic disease pathophysiology.
The strengths of our study lie in the large, nationally representative cohort, bidirectional design, and adjustment for comorbidities and drug exposures. Nonetheless, limitations should be acknowledged: diagnoses were based on administrative codes without disease severity data; lifestyle factors such as diet, stress, or microbiome profiles were unavailable; and causality cannot be fully inferred. Furthermore, patients with rosacea or IBS may have more frequent healthcare utilization, which could increase the likelihood of receiving a diagnosis of the other condition, potentially inflating the observed associations; this surveillance bias cannot be fully excluded in this study. Additionally, the exclusion of participants diagnosed with either condition in 2002 (calendar-year washout) may have introduced selection bias. Because this criterion is based on calendar-year boundaries rather than a clinically defined lag period, patients diagnosed near year-end may have been disproportionately excluded compared to those diagnosed at other times of the year. Although rhinophyma (L71.1) was included as part of the rosacea definition in accordance with ICD-10 classification, its distinct pathophysiology—characterized by sebaceous gland hyperplasia and fibrosis—may differ mechanistically from other rosacea subtypes in relation to the gut–skin axis. Additionally, IBS subtypes were not analyzed separately, which may limit subgroup-level interpretability. However, the consistency of the associations across analyses is consistent with systemic interconnections between gastrointestinal and cutaneous inflammation.
In conclusion, this is the first nationwide analysis to demonstrate a reciprocal relationship between rosacea and IBS. The findings provide epidemiologic support for the gut–skin axis hypothesis and suggest shared microbial, inflammatory, and neuroimmune pathways underlying both disorders.
Footnotes
FUNDING SOURCE: This research was supported by the Research Grant from Institute of Medical Sciences, Kangwon National University 2024 (No. KNUH_2024-02-04) and supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2025-24535069). This study was also supported by the 2025 Kangwon National University Hospital Grant (No. KNUH_2025-01-01).
CONFLICTS OF INTEREST: The authors have nothing to disclose.
DATA SHARING STATEMENT: The data used in this study are available from the National Health Insurance Service-National Sample Cohort (NHIS-NSC), but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are, however, available from the authors upon reasonable request and with permission of NHIS.
References
- 1.Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013;69:S15–S26. doi: 10.1016/j.jaad.2013.04.045. [DOI] [PubMed] [Google Scholar]
- 2.Woo YR, Lim JH, Cho DH, Park HJ. Rosacea: molecular mechanisms and management of a chronic cutaneous inflammatory condition. Int J Mol Sci. 2016;17:1562. doi: 10.3390/ijms17091562. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Buhl T, Sulk M, Nowak P, Buddenkotte J, McDonald I, Aubert J, et al. Molecular and morphological characterization of inflammatory infiltrate in rosacea reveals activation of Th1/Th17 pathways. J Invest Dermatol. 2015;135:2198–2208. doi: 10.1038/jid.2015.141. [DOI] [PubMed] [Google Scholar]
- 4.Addor FAS. Skin barrier in rosacea. An Bras Dermatol. 2016;91:59–63. doi: 10.1590/abd1806-4841.20163541. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Tan J, Almeida LM, Bewley A, Cribier B, Dlova NC, Gallo R, et al. Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel. Br J Dermatol. 2017;176:431–438. doi: 10.1111/bjd.15122. [DOI] [PubMed] [Google Scholar]
- 6.Schaller M, Almeida LMC, Bewley A, Cribier B, Del Rosso J, Dlova NC, et al. Recommendations for rosacea diagnosis, classification and management: update from the global ROSacea COnsensus 2019 panel. Br J Dermatol. 2020;182:1269–1276. doi: 10.1111/bjd.18420. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Gomaa AHA, Yaar M, Eyada MM, Bhawan J. Lymphangiogenesis and angiogenesis in non-phymatous rosacea. J Cutan Pathol. 2007;34:748–753. doi: 10.1111/j.1600-0560.2006.00695.x. [DOI] [PubMed] [Google Scholar]
- 8.Choi D, Choi S, Choi S, Park SM, Yoon HS. Association of rosacea with cardiovascular disease: a retrospective cohort study. J Am Heart Assoc. 2021;10:e020671. doi: 10.1161/JAHA.120.020671. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Martínez-García E, Arias-Santiago S, Herrera-Acosta E, Affleck A, Herrera-Ceballos E, Buendía-Eisman A. Quality of life of cohabitants of people living with acne. Acta Derm Venereol. 2020;100:adv00290. doi: 10.2340/00015555-3636. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Woo YR, Kim HS, Lee SH, Ju HJ, Bae JM, Cho SH, et al. Systemic comorbidities in Korean patients with rosacea: results from a multi-institutional case-control study. J Clin Med. 2020;9:3336. doi: 10.3390/jcm9103336. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Egeberg A, Weinstock LB, Thyssen EP, Gislason GH, Thyssen JP. Rosacea and gastrointestinal disorders: a population-based cohort study. Br J Dermatol. 2017;176:100–106. doi: 10.1111/bjd.14930. [DOI] [PubMed] [Google Scholar]
- 12.Mayer EA, Ryu HJ, Bhatt RR. The neurobiology of irritable bowel syndrome. Mol Psychiatry. 2023;28:1451–1465. doi: 10.1038/s41380-023-01972-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Chun EJ, Jo YW, Min JH, Kwon JW, Lee KU, Kim SS, et al. A nationwide population-based study on the association between rosacea and psychiatric disorders: new findings of behavioral disorders. Korean J Dermatol. 2023;61:170–178. [Google Scholar]
- 14.Geng RSQ, Bourkas AN, Mufti A, Sibbald RG. Rosacea: pathogenesis and therapeutic correlates. J Cutan Med Surg. 2024;28:178–189. doi: 10.1177/12034754241229365. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.van Zuuren EJ. Rosacea. N Engl J Med. 2017;377:1754–1764. doi: 10.1056/NEJMcp1506630. [DOI] [PubMed] [Google Scholar]
- 16.Gallo RL, Granstein RD, Kang S, Mannis M, Steinhoff M, Tan J, et al. Standard classification and pathophysiology of rosacea: the 2017 update by the National Rosacea Society Expert Committee. J Am Acad Dermatol. 2018;78:148–155. doi: 10.1016/j.jaad.2017.08.037. [DOI] [PubMed] [Google Scholar]
- 17.Holmes AD, Spoendlin J, Chien AL, Baldwin H, Chang ALS. Evidence-based update on rosacea comorbidities and their common physiologic pathways. J Am Acad Dermatol. 2018;78:156–166. doi: 10.1016/j.jaad.2017.07.055. [DOI] [PubMed] [Google Scholar]
- 18.Gether L, Overgaard LK, Egeberg A, Thyssen JP. Incidence and prevalence of rosacea: a systematic review and meta-analysis. Br J Dermatol. 2018;179:282–289. doi: 10.1111/bjd.16481. [DOI] [PubMed] [Google Scholar]
- 19.Baldwin HE, Harper J, Baradaran S, Patel V. Erythema of rosacea affects health-related quality of life: results of a survey conducted in collaboration with the National Rosacea Society. Dermatol Ther (Heidelb) 2019;9:725–734. doi: 10.1007/s13555-019-00322-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Jo YW, Min JH, Kwon JW, Her Y. Rosacea and its potential role in the development of irritable bowel syndrome: insights from the Korean National Health Insurance Service-National Sample Cohort. J Korean Med Sci. 2025;40:e97. doi: 10.3346/jkms.2025.40.e97. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Haber R, El Gemayel M. Comorbidities in rosacea: a systematic review and update. J Am Acad Dermatol. 2018;78:786–792.e8. doi: 10.1016/j.jaad.2017.09.016. [DOI] [PubMed] [Google Scholar]
- 22.Gallo RL, Granstein RD, Kang S, Mannis M, Steinhoff M, Tan J, et al. Rosacea comorbidities and future research: the 2017 update by the National Rosacea Society Expert Committee. J Am Acad Dermatol. 2018;78:167–170. doi: 10.1016/j.jaad.2017.06.150. [DOI] [PubMed] [Google Scholar]
- 23.O’Neill CA, Monteleone G, McLaughlin JT, Paus R. The gut-skin axis in health and disease: a paradigm with therapeutic implications. BioEssays. 2016;38:1167–1176. doi: 10.1002/bies.201600008. [DOI] [PubMed] [Google Scholar]
- 24.Salem I, Ramser A, Isham N, Ghannoum MA. The gut microbiome as a major regulator of the gut–skin axis. Front Microbiol. 2018;9:1459. doi: 10.3389/fmicb.2018.01459. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Wang FY, Chi CC. Rosacea, germs, and bowels: a review on gastrointestinal comorbidities and gut–skin axis of rosacea. Adv Ther. 2021;38:1415–1424. doi: 10.1007/s12325-021-01624-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Forbes JD, Van Domselaar G, Bernstein CN. The gut microbiota in immune-mediated inflammatory diseases. Front Microbiol. 2016;7:1081. doi: 10.3389/fmicb.2016.01081. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Mahmud MR, Akter S, Tamanna SK, Mazumder L, Esti IZ, Banerjee S, et al. Impact of gut microbiome on skin health: gut-skin axis observed through the lenses of therapeutics and skin diseases. Gut Microbes. 2022;14:2096995. doi: 10.1080/19490976.2022.2096995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Wang FY, Chi CC. Association of rosacea with inflammatory bowel disease: A MOOSE-compliant meta-analysis. Medicine (Baltimore) 2019;98:e16448. doi: 10.1097/MD.0000000000016448. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Pessôa R, Clissa PB, Sanabani SS. The interaction between the host genome, epigenome, and the gut–skin axis microbiome in atopic dermatitis. Int J Mol Sci. 2023;24:14322. doi: 10.3390/ijms241814322. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Schwab VD, Sulk M, Seeliger S, Nowak P, Aubert J, Mess C, et al. Neurovascular and neuroimmune aspects in the pathophysiology of rosacea. J Investig Dermatol Symp Proc. 2011;15:53–62. doi: 10.1038/jidsymp.2011.6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Aubdool AA, Brain SD. Neurovascular aspects of skin neurogenic inflammation. J Investig Dermatol Symp Proc. 2011;15:33–39. doi: 10.1038/jidsymp.2011.8. [DOI] [PubMed] [Google Scholar]
- 32.Parodi A, Paolino S, Greco A, Drago F, Mansi C, Rebora A, et al. Small intestinal bacterial overgrowth in rosacea: clinical effectiveness of its eradication. Clin Gastroenterol Hepatol. 2008;6:759–764. doi: 10.1016/j.cgh.2008.02.054. [DOI] [PubMed] [Google Scholar]
- 33.Feng B, La JH, Schwartz ES, Gebhart GF. Irritable bowel syndrome: methods, mechanisms, and pathophysiology. Neural and neuro-immune mechanisms of visceral hypersensitivity in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2012;302:G1085–G1098. doi: 10.1152/ajpgi.00542.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Weiss E, Katta R. Diet and rosacea: the role of dietary change in the management of rosacea. Dermatol Pract Concept. 2017;7:31–37. doi: 10.5826/dpc.0704a08. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Ramirez J, Guarner F, Bustos Fernandez L, Maruy A, Sdepanian VL, Cohen H. Antibiotics as major disruptors of gut microbiota. Front Cell Infect Microbiol. 2020;10:572912. doi: 10.3389/fcimb.2020.572912. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Simrén M, Barbara G, Flint HJ, Spiegel BM, Spiller RC, Vanner S, et al. Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut. 2013;62:159–176. doi: 10.1136/gutjnl-2012-302167. [DOI] [PMC free article] [PubMed] [Google Scholar]