Patients with Chronic Constipation Experience Psychological Stress as Measured By the POMS2 Test and Salivary Stress Markers

Introduction

Constipation is a condition in which a sufficient amount of feces is not comfortably excreted from the body because of infrequent or difficult passage [1]. The Japanese Society of Gastroenterology defines it as a condition in which no defecation for three days or more is observed, or when there is a feeling of an incomplete bowel movement, even if the defection is performed every day.

According to the 2016 Comprehensive Survey of Living Conditions conducted by the Japanese Ministry of Health, Labor and Welfare, the prevalence of constipation in Japan is reported to be 2%-5%, and it tends to be higher in women (4.6%) than in men (2.5%) and to increase with age in both men and women [2]. The prevalence in Western countries is approximately 15% (2%-28%), and as in Japan, women are more likely to complain of constipation than men and the prevalence increases with age in both men and women [3].

Constipation can be acute or chronic, but what is generally referred to as “constipation” is chronic constipation, which includes functional constipation, drug-induced constipation, organic constipation, and symptomatic constipation. The most common type of constipation is functional constipation, including flaccid constipation, spasmodic constipation, and rectal constipation [4]. However, constipation causes a variety of symptoms, such as abdominal pain, abdomen enlarged feeling (or abdominal distension), nausea, loss of appetite, and malnutrition, resulting in a significantly decrease in the quality of life and labor productivity [1].

Psychologically, patients with chronic constipation have been reported to have a higher prevalence of depression, anxiety, somatization symptoms (or hypochondriasis), and neuropathy (neurological disorders), such as Parkinson’s disease and multiple sclerosis [5, 6]. In addition, patients with chronic constipation have been reported to have a higher complication rate for ischemic heart diseases, such as myocardial infarction and angina, leading to increased mortality [7]. The findings described above suggest that patients with constipation routinely experience more mental and physical stress than patients without constipation. In fact, patients with functional bowel disease, including constipation, have been reported to experience psychological distress [5]. Psychological stress was also reported to be strongly associated with the development of constipation in children [8] and adolescents [9]. In Korean male college students, life stress was reported to be strongly associated with functional constipation [10]. Thus, a positive correlation has been shown between psychological stress and constipation, and stress load is considered to be one of the causes and exacerbations of constipation. Therefore, understanding the stress status in patients with constipation may be useful in the treatment and prevention of constipation.

These psychological stresses have been evaluated by subjective psychological tests using various questionnaires. Psychological tests include the Manifest Anxiety Scale (MAS), Self-Rating Depressive Scale (SDS), the Minnesota Multiphasic Personality Inventory (MMPI), and Profile of Mood States-Second Edition (POMS2) or its shortened version [11, 12]. The MAS, SDS, and MMPI tests determine a subject’s personality traits, namely and respectively the tendency for anxiety, depression, and multifaceted personality. In contrast, the POMS2 or its shortened version is a test that does not evaluate personality traits but rather changes in mood over time, such as the last few hours or days. The advantage of this test, which is used in various fields, such as medical care, mental health, and sports or exercise, is that it measures multiple mood states at the same time with a single questionnaire [13]. However, since subjective factors strongly influence the mood or psychological evaluations, it is desirable to perform these questionnaire-based tests in combination with an objective evaluation.

One objective assessment of stress status is to measure biomarkers that have been suggested to reflect stress status. To evaluate the stress state more accurately, it is necessary to measure biomarkers in biological samples, such as blood and tissues, in a state with no stress load other than stress stimulation. Thus, since invasive blood collection involves mental stress, it is desirable to use biological samples, such as urine, saliva, tears, and sweat, that can be collected noninvasively. Recently, attention has been focused on saliva, which is easy to collect. Stress-related biomarkers cortisol, chromogranin A, oxytocin, and secretory immunoglobulin A (s-IgA) have been identified in saliva. These salivary biomarkers have been measured in many stress-related clinical studies [14].

The purpose of the present study was to evaluate the stress status in patients with chronic constipation. To achieve this goal, 84 adult female patients with chronic constipation (constipation group) and 20 healthy adult female volunteers (control group) were enrolled. All subjects were then subjectively evaluated for their mood using a shortened version of POMS2 and objectively evaluated by measuring salivary stress markers (cortisol, chromogranin A, oxytocin, and s-IgA).

Statistical Analysis

All analytical data were nonparametric data with no normal distribution. Therefore, those data are shown as box plots. The box represents the median ± interquartile range (IQR), and the whiskers of the box represent the 1.5 × IQR range. Statistical significance between the constipation and healthy control groups in all analyses was assessed using the nonparametric Mann–Whitney U test using EZR 1.52 software. The significance level was accepted at P < 0.05.

Discussion

The purpose of the present study was to evaluate the stress status in patients with constipation. To achieve this goal, 84 adult female patients with chronic constipation and 20 healthy adult female volunteers were enrolled. Both a subjective emotional profile test using the shortened POMS2 version and objective analysis of some stress markers in saliva were performed in all subjects.

There have been several reports on the relationship between constipation and stress. Heymen et al. performed an MMPI to assess personality differences in patients with chronic pelvic floor disorders, including constipation, and found significantly higher scores for hypochondriasis, depression, and hysteria in the constipation group [5]. From this result, they suggested that patients with constipation may manifest their psychologic distress as physical symptoms. Using a bowel disease questionnaire, Jiang et al. reported that the abdominal bloating and distention observed in constipation and irritable bowel syndrome caused somatic distress in patients [15]. In an epidemiological study investigating comorbidities in patients with chronic constipation using a self-reported gastrointestinal symptom questionnaire, patients with chronic constipation were more likely to have ischemic heart disease and depression or anxiety [6]. In cohort studies using a self-administered structured questionnaire to clarify the association between psychological stress and constipation, psychological stress was strongly associated with the development of constipation in children [8] and adolescents [9]. In a case- control study, which investigated the relationship between the onset of functional constipation and life stress in male university students using a self-administered questionnaire, life stress was reported to be strongly associated with functional constipation [10]. These reports show that there is a positive correlation between stress and constipation, that is, various psychological stresses such as depression, anxiety, and distress are associated with the onset and exacerbation of constipation. In addition, the data suggest that patients with constipation are prone to psychological stress-sensitive hypochondriasis. However, PONS2, which was used in all patients with constipation enrolled in this study, is not a personality tendency test, but a mood assessment over a period of time, such as the past few hours or days. The POMS2 has been well-established for standardization, reliability, and validity [11, 12]. In the present study, all negative mood subscale scores (AH, CB, DD, FI, and TA) in the constipation group were higher than those in the control group. This result suggests that negative mood predominates in patients with constipation over positive mood, and is also supported by the fact that the TMD scores were higher in patients with constipation than in controls. This shows that the patients with constipation are experiencing negative mood psychological stress such as depression, malaise, and anxiety. However, the positive mood subscale scores (VA and F) were not significantly different between the two groups, indicating that the high negative mood was not due to impaired positive emotions. In other words, the data suggest that positive emotions were retained. Stress has been suggested to be either a triggering or aggravating factor for many diseases and pathological conditions, including a variety of psychological symptoms, such as anxiety, tension, depression, lethargy, anger, confusion, and fatigue [16]. Therefore, understanding the mood states of patients with constipation using the POMS2 provides important information for the treatment of constipation. A unique feature of this study was the combination of the subjective evaluation with an objective measure of stress-related biomarkers in saliva to make the questionnaire-based POMS2 test more precise.

The use of saliva to measure stress-related substances compared to blood has obvious advantages in terms of sample collection, including speed, ease, subject mobility, and noninvasiveness. In the present study, salivary cortisol, chromogranin A, oxytocin, and s-IgA were selected as stress markers to objectively and easily assess stress status in constipated patients. The stress response system includes the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenomedullary (SAM) system, whose activities can be biochemically evaluated by measuring cortisol and catecholamines, respectively [17]. Psychological and physical stress has been reported to increase HPA axis activity and subsequently increase salivary cortisol levels [18]. Subjects under chronic episode stress have been reported to have higher scores for “FI” and “TA” in the shortened POMS test, and also had higher salivary cortisol levels [19].

Chromogranin A is an acidic glycoprotein stored and coreleased with catecholamines by exocytosis from the adrenal medulla and sympathetic nerve endings [20]. Catecholamine levels are commonly used as a sensitive biochemical index of stress. Still, it is difficult to measure their concentrations in the saliva due to generally low levels and rapid degradation. Therefore, salivary chromogranin A is used as an alternative marker for catecholamines. Salivary chromogranin A levels are commonly measured as reliable biological markers of changes in the SAM system activity caused by prolonged psychosocial stress [21]. Chromogranin A levels in saliva have been reported to increase with computer-controlled psychological stress [22]. It has also been suggested that it reflects psychological stress more quickly and sensitively than cortisol [21, 22].

The neuropeptide oxytocin not only plays a role in uterine contractions during parturition and milk production during lactation but is also released within multiple regions of the brain, affecting behavior and neuroendocrine responses to stress [23]. Several studies suggest that oxytocin is involved in the central regulation of the response to stress through the regulation of the corticotropin-releasing hormone; i.e., oxytocin is associated with an inhibitory effect on adrenocorticotropic hormone secretion followed by impaired corticosterone secretion [24]. Evidence from rodent models suggests that both acute and chronic oxytocin administration reduces physiological and behavioral stress responsiveness [25]. In humans, stress responses have been reported to be attenuated by exogenous oxytocin administration [26]. These findings suggest that oxytocin plays a role in relieving stress.

S-IgA is a protein present in the mucus of mucous membranes, such as the oral cavity, nasal cavity, and digestive organs. It is mainly responsible for the local immune system of the mucosa [27]. Thus, s-IgA in the saliva is a marker of the immune system, but since the immune system is closely related to stress, it has also been used as a stress marker in recent years. For example, it has been reported that s-IgA in saliva generally decreases under chronic academic stress [28] and temporarily increases or decreases depending on the type of stress situation under acute psychosocial stress [14].

In this study, salivary cortisol and chromogranin A levels in the constipation group were significantly higher than in the control group. In contrast, the oxytocin levels in the constipation group tended to be lower than in the control group. These results suggest that patients with constipation are more stressed than healthy people. However, contrary to our expectations, the salivary levels of s-IgA were significantly higher in patients with constipation than in healthy individuals. Although the cause cannot be elucidated in this study, it is worth noticing that the reflection of the psycho- immune response may differ depending on the type and condition of stress [14]. Because the present study targeted patients with constipation, it is possible that in our study s-IgA worked more as an immune system marker rather than as a psychological stress marker for constipation [29]. This hypothesis is supported by the fact that constipation is known to cause abnormalities in the intestinal environment, such as intestinal inflammation and disturbance of the intestinal flora [30]. Therefore, the constipation patients enrolled in this study may have elevated s-IgA levels, reflecting their biological defense response to these abnormalities. It is necessary to examine the characteristics of s-IgA as a stress marker in more detail in the future.

The combined results of subjective emotional profile test using the POMS2 version and objective analysis of some stress markers in saliva suggest that patients with constipation are more stressed than healthy individuals. Not only does stress cause constipation, but the constipation caused by stress causes new stress, which in turn exacerbates constipation. Thus, constipation and stress are presumed to have a “negative spiral” relationship that exacerbates constipation. In this study, the stress status of patients with chronic constipation was clarified by both subjective and objective evaluations. Considering that psychological stress induces or exacerbates constipation [5, 8, 9, 10] it is important to understand the current state of stress in these patients.

Conclusion

We evaluated the stress status of constipation patients by comparing 84 adult female patients with chronic constipation with 20 healthy adult female volunteers. Both the subjective emotional profile test using the shortened POMS2 version and objective analysis of some stress markers in saliva were used as stress assessments in constipation. The results showed that constipated patients were more stressed and had negative emotions, such as anxiety, depression, tension, and fatigue than healthy individuals. By combining both these assessments, our approach to understanding the stress status of patients with constipation will provide important and useful information for the treatment and prevention of constipation and constipation worsening cases.