Irritable Bowel Syndrome-like Symptoms in Patients With Ulcerative Colitis in Remission as Compared to Irritable Bowel Syndrome: Symptom Severity and Inflammatory Markers

Abstract

Background/Aims

Patients with ulcerative colitis in remission (UC-R) may experience symptoms consistent with irritable bowel syndrome (IBS). This prospective study aims to examine the relative influence of peripheral factors, such as gut mucosal inflammation, and central factors, like psychological conditions, on the severity of IBS symptoms to evaluates (1) the IBS Symptom Severity Score (IBS-SSS), (2) levels of inflammatory markers, and (3) the presence of psychological comorbidities across 3 groups: UC patients with IBS symptoms (UC-IBS), UC-R patients without IBS, and individuals with usual IBS.

Methods

Rome III and IV IBS criteria were used in UC-R patients (Mayo score 0), with symptom severity measured by IBS-SSS. Serum and fecal inflammation markers were compared across UC-R without IBS, UC-IBS, and IBS groups.

Results

Among UC-R patients, 31.3% (26/83) met Rome III and 9.6% (8/83) met Rome IV IBS criteria. IBS-SSS scores were significantly lower in UC-IBS compared to IBS (n = 50; 167.5 [150–200] vs 255 [225–325]; P < 0.001). Fecal calprotectin levels were higher in UC-IBS than in UC-R or IBS (62.6 μg/g [34.1-85.6] vs 50.6 μg/g [27.3-96.6] vs 37.6 μg/g [12.1-62.3], P = 0.057), while other fecal markers (lactoferrin and MMP-9) showed no significant differences between UC-IBS and UC-R. Serum inflammatory marker including tumor necrosis factor-alpha, interleukin-6, interleukin-10, and granulocyte-macrophage colony-stimulating factor, C-reactive protein were similar across groups. Patients with IBS reported significantly higher anxiety, pain, functional impairment, and coping difficulties (all P < 0.001) compared to UC-IBS, with the lowest levels observed in UC-R without IBS.

Conclusions

One-third and one-tenth of UC-R patients met Rome III and IV IBS criteria, respectively. UC-IBS had lower IBS-SSS and higher fecal calprotectin than IBS. Psychological comorbidities were worse in IBS, least in UC-R without IBS, suggesting more peripheral inflammation and less central involvement in UC-IBS.

Introduction

Ulcerative colitis (UC) is a subtype of inflammatory bowel disease (IBD). UC is characterized by inappropriate immune activation in the colonic mucosa, proinflammatory cytokines production, and large intestinal mucosal inflammation.^1-3 Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction characterized by abdominal pain/discomfort, with changed bowel habits. Some evidence suggests that there is low-grade mucosal immune activation in a subset of IBS patients. Psychological stress in IBS patients may also activate intestinal mast cells, which results in the production of histamine, proteases, and chemokines.^4-6 UC and IBS are thought to be 2 distinct, clearly defined, diagonally opposite conditions. Yet, these do have certain commonalities. These include, (1) UC patients in remission may fulfill IBS criteria (UC-IBS),^7-11 (2) some pathophysiological abnormalities such as gut microbiota dysbiosis including small intestinal bacterial overgrowth, abnormal small intestinal permeability, increased mucosal serotonin, and immune activation, well-known in patients with IBS are known in patients with UC in remission (UC-R) as well. However, whereas IBS is a disorder of gut-brain interaction and often has psychological issues, UC is clearly an organic disease with less psychological co-morbidity.

Most earlier studies used Rome II and Rome III criteria to diagnose UC-IBS among UC-R patients.^12-14 The most recent Rome IV criteria have not been commonly used earlier to diagnose IBS among UC-R patients.¹⁵ Furthermore, there is very little information available regarding whether IBS-like symptoms among UC patients are better or worse than IBS patients.

Accordingly, we aim to investigate the frequency of IBS by the Rome III and IV criteria among the patients with UC-R, to study IBS severity using IBS symptom severity score (IBS-SSS) among UC-IBS, and to study the relative role of gut inflammation and psychological factors by Rome III psychosocial alarm questionnaire (PSQ) in patients with UC-IBS as compared to UC-R without IBS and the usual IBS.¹⁶

Materials and Methods

This prospective study recruited adult patients from a tertiary referral center in northern India during a 1.5-year period (June 2021 to December 2022). Inclusion criteria for IBS patients were: (1) age 18 years or older, (2) IBS according to Rome III criteria, and (3) able to provide informed consent. Inclusion criteria for UC patients were: (1) age 18 years or older, (2) UC and its remission diagnosed by standard criteria,¹⁷ and (3) able to provide informed consent. Remission in UC was defined by a total Mayo score ≤ 2 and an endoscopic sub-score of 0 or simple clinical colitis activity index (SCCAI) ≤ 3. Patients not meeting all the criteria were excluded from the study. The study was approved by the Institutional Ethics Committee (No. 2021-42-PhD-119).

Demographic and Clinical Parameters

Demographic data of patients were recorded. Rome III criteria were used to diagnose IBS among patients with UC-R.¹⁵ Subsequently, Rome IV criteria were applied to know how often the Rome III IBS patients fulfilled the Rome IV criteria.¹⁵ IBS-SSS was used for IBS severity assessment among patients with IBS and UC-IBS.¹⁸ It is a set of 5 questions with a maximum score of 100 on each using prompted visual scales, leading to an overall possible score of 500. Scores ranging from 75 to 175, 175 to 300, and > 300 denoted mild, moderate, and severe IBS, respectively.¹⁸

Translated-validated Rome III PSQ was used to study the psychological stress among all the patients.¹⁶ Rome III PSQ is a set of 7 questions to be answered on an ordinal scale. The questions are related to anxiety, depression, suicidal ideas, pain severity, impairment, impaired coping, and abuse.

Laboratory Procedures

Blood and stool samples were collected from UC-R and UC-IBS patients for assessing inflammatory biomarkers. Stool samples were also collected from usual IBS patients to study fecal calprotectin (FC). Blood samples were collected in plain vials and serum was separated after centrifuging blood samples at 4000 revolutions per minute (RPM) for 15 minutes. Ten to 15 mg fecal sample was mixed in 2 mL phosphate-buffered saline (PBS), centrifuged at 10 000 RPM for 15 minutes and the supernatant was collected. Both serum and fecal samples were aliquoted to avoid repeated freeze–thaw cycles and stored at –80°C until analysis.

Enzyme-linked immunosorbent assay (ELISA) for tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin 10 (IL-10), and granulocyte-macrophage colony-stimulating factor (GM-CSF) (in sera) and lactoferrin and matrix metalloproteinase 9 (MMP 9) (in fecal samples) were performed using commercially available ELISA kits (Krishgen Biosystems, Mumbai, India), according to manufacturer’s instructions. FC was also assessed using commercially available ELISA kits (Calprest NG, Eurospital, Via Flavia, Trieste, Italy).

Statistical Methods

The data normality was examined with the appropriate method (Kolmogorov–Smirnov test/Shapiro–Wilk test). Continuous variables were presented as mean ± standard deviation or median and inter-quartile range whereas categorical variables were displayed in frequency (%). For comparison between 2 groups, independent sample t test or Mann Whitney U test was used whereas for more than 2 groups one-way ANOVA test or Kruskal Wallis H test was used. Chi-squared test or Fisher exact test was used to compare the proportions between the groups. A P-value < 0.05 was considered as statistically significant. Statistical analysis was performed using statistical package for social sciences (SPSS) version 23 (SPSS, Inc., Chicago, IL, USA) and R software (R 4.1.3, Vienna, Austria).

Results

Study Population Characteristics

Of 133 patients included in the study, 83 had UC (median age 33 years [27-46]; 48 [58.8%] male) and 50 had IBS (age 35.5 years [28-44]; 36 [72%] males). Of 50 IBS patients by the Rome III criteria, 27 (54%) fulfilled Rome IV criteria. The median BMI of UC patients was 20.9 kg/m² (19.6-22.6) and that of IBS patients was 21.6 kg/m² (20.6-24.9). Out of 83 UC patients, 8 (9.6%) took tobacco, and 10 (12%) took alcohol, and 51 (61.45%) were vegetarian. Among 50 IBS patients, 8 (16%) took tobacco, 8 (16%) took alcohol, and 25 (50%) were vegetarian.

Irritable Bowel Syndrome-like Symptoms in Ulcerative Colitis and Their Severity

Out of 83 UC patients, 26 (31.3%) and 8 (9.6%) fulfilled Rome III and Rome IV criteria for IBS, respectively. IBS-SSS was lower in UC-IBS patients than in the usual IBS patients (167.5 [150-200] vs 255 [225-325]; P < 0.001) (Fig. 1).

Figure 1.

Comparison between irritable bowel syndrome–symptom severity scores (IBS-SSS) of ulcerative colitis with irritable bowel syndrome (UC-IBS) and usual IBS.

Serum and Fecal Biomarkers

FC levels in UC-IBS were higher than those in UC-R without IBS and usual IBS (62.6 μg/g [34.1-85.6] vs 50.6 μg/g [27.3-96.6] vs 37.6 μg/g [12.1-62.3], P = 0.050) (Fig. 2A). Serum inflammatory markers such as IL-6 (14.9 pg/mL [3.7-38.3] vs 13.4 pg/mL [3.2-36.6]; P = 0.900), TNF-α (15.3 pg/mL [0.0-37.6] vs 23.4 pg/mL [0.0-56.4]; P = 0.200), IL-10 (24.1 pg/mL [16.3-36.1] vs 25.6 [14.41-40.5]; P = 0.700), GM-CSF (13.7 pg/mL [8.03-19.5] vs 12.8 pg/mL [8.9-21.5]; P = 0.600), and CRP (0.37 g/dL [0.09-0.60] vs 0.3 g/dL [0.08-0.54]; P = 0.200), and fecal inflammatory markers such as fecal lactoferrin (0.44 pg/mL [0.29-1.39] vs 0.45 pg/mL [0.29-0.95]; P = 0.900) and fecal MMP 9 (0.4 pg/mL [0.25-1.22] vs 0.48 pg/mL [0.29-1.72]; P = 0.157), were comparable between patients with UC-IBS and UC-R (Fig. 2A-H). There was no difference in serum and fecal inflammatory markers of UC-IBS patients fulfilling and not fulfilling the Rome IV criteria though the former group had higher IBS-SSS values than the later group (215 ± 33 vs 146.7 ± 31; < 0.001). There was no difference in IBS-SSS between UC-IBS patients with normal (< 50 μg/g, n = 10) and abnormal (n = 16) FC levels (169 ± 54 vs 166.9 ± 39.6; P = 0.900).

Figure 2.

Comparison between various inflammatory markers among ulcerative colitis with irritable bowel syndrome (UC-IBS) and ulcerative colitis in remission (UC-R) without IBS. (A) Fecal calprotectin (FC), (B) matrix metalloproteinase 9 (MMP9), (C) fecal lactoferrin (FL), (D) interleukin-6 (IL-6), (E) granulocyte-macrophage colony-stimulating factor (GM-CSF), (F) tumor necrosis factor-alpha (TNF-α), (G) IL-10, (H) C-reactive protein (CRP). *Represents outlier value.

Rome III Psychosocial Alarm Features

The usual IBS patients had greater anxiety (P < 0.001), pain (P < 0.001), impairment (P < 0.001), and lesser impaired coping (P < 0.001) than UC-IBS though UC-R without IBS had these least. The other aspects of the questionnaire like depression, suicidal ideas and abuse were comparable between the 2 groups (Table).

Table.

Comparison of Rome III Psychosocial Alarm Features Between Ulcerative Colitis With Irritable Bowel Syndrome and Ulcerative Colitis in Remission

Psychosocial alarm features	UC (n = 57)	UC-IBS (n = 26)	IBS (n = 50)	P-value
Anxiety				< 0.001
Not at all	17 (29.8%)	5 (19.2%)	7 (14%)
Occasionally	39 (68.4%)	14 (53.8%)	16 (32%)
A lot of the time	1 (1.8%)	5 (19.2%)	22 (44%)
Most of the time	0 (0.0%)	2 (7.7%)	5 (10%)
Depression				0.163
Not at all	15 (26.3%)	4 (15.4%)	12 (24%)
Occasionally	34 (59.6%)	16 (61.5%)	21(42%)
A lot of the time	5 (8.8%)	3 (11.5%)	13 (26%)
Most of the time	3 (5.3%)	3 (11.5%)	4 (8%)
Suicidal ideas				0.720
Not at all	55 (96.5%)	24 (92.3%)	47 (94%)
Occasionally	2 (3.5%)	2 (7.7%)	2 (4%)
Often	0 (0.0%)	0 (0.0%)	1 (2%)
Pain severity				< 0.001
None	35 (61.4%)	7 (26.9%)	8 (16%)
Mild	13 (22.8%)	7 (26.9%)	10 (20%)
Moderate	9 (15.8%)	11 (42.3%)	21 (42%)
Severe	0 (0.0%)	1 (3.8%)	9 (18%)
Very severe	0 (0.0%)	0 (0.0%)	2 (4%)
Impairment				< 0.001
Not at all	37 (64.9%)	7 (26.9%)	12 (24%)
A little bit	14 (24.6%)	11 (42.3%)	16 (32%)
Moderately	3 (5.3%)	6 (23.1%)	9 (18%)
Quite a bit	3 (5.3%)	2 (7.7%)	11 (22%)
Extremely	0 (0.0%)	0 (0.0%)	2 (4%)
Impaired coping				< 0.001
Never	40 (70.2%)	8 (30.8%)	23 (46%)
Sometimes	17 (29.8%)	18 (69.2%)	15 (30%)
Always	0 (0.0%)	0 (0.0%)	12 (24%)
Abuse				0.498
No	48 (84.2%)	23 (88.5%)	39 (78%)
Yes	9 (15.8%)	3 (11.5%)	11 (22%)

UC, ulcerative colitis; IBS, irritable bowel syndrome.

Discussion

The current study showed that (1) one-third UC-R patients had IBS by Rome III criteria and one-tenth had IBS by Rome IV criteria; (2) UC patients in remission with IBS had lower IBS-SSS as compared to usual IBS; (3) FC was higher in UC-IBS than usual IBS and UC-R without IBS; (4) the inflammatory serum and fecal biomarkers were comparable between UC-IBS and UC-R; and (5) IBS patients had significantly more anxiety, pain and impairment, along with lesser impaired coping than UC-IBS patients.

Some IBD patients in clinical remission have lately been observed to exhibit IBS-like symptoms. It is difficult to determine whether these symptoms indicate “true IBS” or whether these are marker of subclinical IBD activity. Some data on the frequency of IBS-like symptoms in UC patients in remission are available in the literature. According to the most recent meta-analysis by Fairbrass et al,¹⁹ 28.7% of patients with UC in remission experienced IBS-like symptoms. With an odds ratio of nearly 5 when compared to controls, the pooled prevalence of IBS-like symptoms among IBD patients in remission was 32.5% (95% CI, 27.4-37.9).¹⁹ In another meta-analysis of 13 studies published in 2012, 36% of UC patients in remission reported having IBS symptoms.¹⁰ The IBS symptoms in UC are associated with high levels of anxiety and depression.^10,19,20

Compared to the IBD patients, those with IBS experienced more severe lower GI symptoms, such as abdominal pain, discomfort and bloating.²¹ These findings were supported by another study that found abdominal distention, discomfort, and bowel habit dissatisfaction were more prevalent in IBS than in IBD.²² However, these analyses had limitations in that they generalized symptoms in IBS and IBD patients, without taking into account the disease activity or the degree of inflammation at the time of assessment. In our study, we used SCCAI to assess the disease activity of UC patients and confirmed if they were in remission (SCCAI < 3). We also used IBS-SSS to calculate the IBS severity in UC-IBS as well as IBS patients. This is the first such study that compared the IBS symptom severity between the 2 groups. We found that the severity is higher in IBS patients than in UC-IBS. This can be linked to the fact that IBS patients have been reported to have increased visceral sensitivity.^23,24 It has been shown that IBS patients exhibit hypervigilance, an increased focus on unpleasant stimuli, or an increased propensity to describe experiences as troublesome.²⁵

A study refuted the idea that hidden inflammation is the cause of IBS-like symptoms in IBD.²⁶ When IBD is properly treated, remission is successfully attainable. Remission of the disease is not only indicated by the absence of symptoms and reduced disease activity but also by endoscopic and laboratory data. Many physicians utilize FC levels as a marker of gut mucosal inflammation. Calprotectin is a calcium and zinc-binding protein that is mostly secreted by neutrophils. FC levels strongly correlate with the degree of intestinal inflammation and can indicate mucosal repair. Therefore, FC has been used to consider the diagnosis IBD, track the progression of the condition, monitor treatment, and also to differentiate IBD from IBS. Our study showed that the level of calprotectin is higher in UC-IBS than in UC-R and IBS, though not significant. In a research conducted by Keohane et al,²⁷ 38.6% of individuals with UC in remission exhibited IBS-like symptoms (diagnosed using Rome II criteria) and had significantly high FC levels. In another study by Jonefjäll et al,²⁸ in which remission was defined by endoscopic findings and an FC level (≤ 200 μg/g), only 18.2% of patients reported these symptoms. However, recent studies using Rome III criteria contradicted this idea.^29,30 They found no link between FC levels and the presence of IBS-like symptoms. No statistically significant difference was seen between FC levels of UC patients in clinical remission with and without IBS symptoms.^29,30 Even though the physicians found no signs of active inflammation, it could be more challenging to rule out lingering micro-inflammation in the mucosa of patients who are in remission. The presence of inflammatory biomarkers during relapse may cause epithelial barrier deficiencies and increased colonic paracellular permeability, which are identical in IBS patients.

The studies on relative roles of colonic inflammation and central factors in pathogenesis of UC-IBS as compared to usual IBS are scarce. Hence, we compared various inflammatory biomarkers between UC-IBS and UC-R. Lack of significant difference in most of these biomarkers between the 2 groups may suggest that these symptoms are not entirely related to peripheral gut inflammation. However, the study has a few limitations such as relatively small sample size in general and for subgroup comparison for patients with UC-IBS fulfilling and not fulfilling Rome IV criteria in particular.

There is significant evidence in the literature demonstrating the association of depression and anxiety to both IBD and IBS. It is well established that IBS is influenced by psychological variables, whereas IBD is an autoimmune inflammatory disease with psychological issues resulting from chronic illness.^31,32 Studies have revealed that IBD patients with severe disease have a greater likelihood of experiencing anxiety and/or depression.^33,34 Additional research was required to look at psychological risk factors in the IBD-IBS group and that is what we have done in our study.

In our study, 4 out of the 7 variables (anxiety, pain severity, impairment, and impaired coping) of Rome III PSQ were more frequently present in IBS patients than in UC-IBS and least in UC-R. In comparison to UC-R patients, UC-IBS patients were shown to have significantly higher levels of anxiety, pain, and impairment as well as less impaired coping. IBS symptoms were more common in those who reported pain. Abdominal pain is a major IBS symptom. IBS-like symptoms reduce the patient’s quality of life.¹² Another study found that UC patients with symptoms resembling IBS appeared to have significantly lower health-related QOL.¹³ Researchers have proposed a mechanism for the emergence of IBS-like symptoms following GI disease that may involve both psychological and biological elements.³⁵

In conclusion, one-third of UC-R patients have IBS by Rome III criteria. However, the symptom severity of UC-IBS patients was less than usual IBS patients. FC was higher in UC-IBS than in usual IBS. Inflammatory biomarkers were comparable between UC-IBS and UC-R. The results of our study suggest greater trend towards peripheral inflammatory and lesser central mechanisms for UC-IBS than usual IBS.