Paying attention to the gut may magnify perceptions of abdominal symptoms and symptom related emotion 12. Irritable bowel syndrome (IBS) is associated with an increased incidence of psychological disorder in patient populations 3, and while the cause and nature of this association are a matter of discussion, several possible mechanisms, both psychological and physiological, have been proposed to account for the finding 456. Although there are many treatment strategies 7, traditional IBS therapy is mainly symptom oriented and often unsatisfactory. Increasing knowledge of brain-gut physiology 8, mechanisms, and neurotransmitters and receptors 9 involved in gastrointestinal motor and sensory function have led to the development of several new therapeutic approaches 1011.

No single medication has proven to be universally effective, and the multiple therapeutic approach of gastrointestinal neurophysiology has led to promising advances in medical and non-medical approaches to IBS. Most studies have examined the association between mood state and IBS symptom severity using between-subjects design. The mechanisms involved suggest an association between mood state and IBS symptom severity within the individual. For example, although self-report measures of symptom severity cannot distinguish between the effect of mood state on physiology and on symptom perception, both mechanisms would lead to a situation in which a worsening of mood would occur before a worsening of IBS symptoms when both are measured longitudinally.

Autonomic imbalance has been proposed as a pathophysiological factor of IBS. Adrenergic neural activity and rectal sensitivity are more pronounced in IBS patients than in normal controls 12. The stress response system includes the sympathetic/adrenomedullary (S/A) system and the hypothalamic-pituitary-adrenal (HPA) axis. The activities of the HPA axis and the S/A system can be biochemically evaluated by measuring catecholamines and cortisol, and we can measure these hormones as objective markers of stress. Recently, as a result of investigating the derivatives of catecholamines that are detectable in saliva, chromogranin A (CgA) was determined to be a useful index of psychological stress. CgA is a member of a family of highly acidic proteins, chromogranins, which are co-stored in the adrenergic neurons and paraneurons and co-released with adrenaline and noradrenaline in response to stimulation 1314. The changes in salivary CgA secretion resulting from exposure to a cognitive task may indicate psychological stress in humans 15.

Colonic stimulation results in brain activation of the somatosensory, insular, anterior cingulate and prefrontal cortices 2. The somatosensory cortex receives direct anatomical projections from the ventral posterior thalamic nucleus, it is generally assumed that the somatosensory cortex is involved in parallel processing of tactile sensory information derived from this thalamic source of input 16. In contrast, psychological stress influences pain thresholds via activation of the prefrontal cortices. Corticotropin releasing hormone is released from the hypothalamus, binding to visceral muscles and causing abnormal movement of the colon 917. A stress marker of the S/A system, CgA, is released in saliva due to negative feelings such as aversive stimuli and psychological stress 1518. Mental activity may modulate gut perception 1819 and override the effect of somatic stimulation on gut perception. For example, afferent signals from muscle stretching might modulate visceral perception and emotion via the spinothalamic pathway.

Skeletal muscle stretching is a unique method for relaxation 202122. The effect of hypnotherapy on IBS has been well documented 23, but specific psychotherapy usually needs long-range training for therapists at much cost. On the other hand, skeletal muscle stretching is simple and applicable in daily practice. Skeletal muscle stretching improved subjective pain scores of the patients with low back pain, and salivary cortisol concentrations were also significantly decreased during exercise 24. However, the effects of skeletal muscle stretching on IBS are still unknown.

We hypothesized that IBS subjects would show abnormal salivary CgA and that skeletal muscle stretching would have beneficial effects on the pathophysiology of IBS.

This is the first study to demonstrate that the salivary CgA level of IBS subjects is higher than that of normal subjects. We also demonstrated that, after stretching, the CgA level of IBS subjects became comparable with that of normal subjects. CgA is a major soluble protein in adrenal medullary chromaffin granules and adrenergic neurons and is co-released with catecholamines, which are considered to be a good index of sympathetic activity 4142. In particular, salivary CgA is reported to be a sensitive and substantial marker of psychological stress, which does not respond well to physical stress 15. The results of this study suggest that abdominal muscle stretching may improve sympathetic arousal in IBS subjects.

Patients with IBS show more psychiatric disorders and pathologic behavioral patterns than normal subjects 443. A correlation between CgA secretion and the depression score was observed in this study. This result suggests a potential mechanism connecting events in the nervous system (central or enteric) with IBS symptoms. Noradrenaline in the brain plays a crucial role in anxiety, and colorectal distention induces noradrenaline release in the hippocampus 44. Not only central but also peripheral adrenergic/noradrenergic functions may contribute to the pathophysiology of IBS. Elsenbruch et al. reported that IBS patients demonstrated significantly greater postprandial increases in plasma noradrenaline and systolic blood pressure 45. In inflammatory bowel diseases, disturbed adrenergic regulation of interleukin-10 (IL-10) could be part of the mechanism underlying the modulation of disease activity due to psychological stress 46. Disturbed autonomic or neuroendocrine modulation of cytokine production, may play a role in the pathogenesis of IBS 9. Increased salivary CgA in IBS subjects suggests that IBS subjects have sympathetic arousal due to increased signaling to the gut afferent neurons.

IBS symptoms are generally worsened by stress and often improve with physical exercise and medications affecting serotonin function 474849. Sugano et al. reported that the skeletal muscle stretching program improved subjective pain scores of the patients with low back pain and that salivary cortisol concentrations were also significantly decreased up to 90 min after exercise 24. Exercise may have beneficial effects on IBS symptoms 50.

CgA secretion before stretching was negatively correlated with the stress score of normal subjects. Additionally, the anxiety score was reduced after stretching in the normal subjects. Psychological factors influencing symptom reporting have been identified in the constructs of visceral perceptional amplification and alexithymia 51. From a psychological viewpoint, IBS may be conceived as an abnormal cognitive processing of emotional stimuli, via verbal responses, and a tendency to perceive somatic stimuli as evidence of symptoms of disease.

Ghoncheh et al. examined the psychological and physical effect of passive muscle stretching and yoga stretching exercises for relaxation 22. Muscle relaxation displayed higher levels of relaxation states, physical relaxation, disengagement and higher levels of joy as a post-training effect 52. Muscle stretching provides sensation contrasts for learning relaxation in addition to fostering relaxation through the stretching of muscles 53. Muscle stretching for patients with IBS may be of benefit to the patients and could be used as part of a multi-component approach to the treatment of IBS.

Evidence of a physiological component of IBS is based on gender differences in GI symptoms, central nervous system pain processing, and specific effects of estrogen and progesterone on gut function 5455. Additional factors may play a role, including gender-related differences in neuroendocrine, S/A system, and stress reactivity, which are related to bowel function and pain. Although gender differences in the therapeutic benefits of serotonergic agents have been observed 56, less is known about potential differences in responsiveness to non-drug therapies for IBS. Multiple comparisons between CgA and gender related information suggest that stretch intervention may have gender dependent effects on IBS.

The following three points can be cited as limitations of this study. The first is that sample size was very small. The levels of CgA found in our subjects were somewhat different from the reported mean value 39, and our findings could not exclude the effect of the sample size. Additionally, we could not examine the effects on subtypes of IBS (i.e. constipation-predominant or diarrhea-predominant), because the sample sizes of the subtypes were too small to analyze them separately. However, a long follow-up study 57 proved the inconsistency of IBS subtypes, suggesting that whole IBS analysis is more important than subtype analysis. The second limitation is that the duration of muscle stretching might be too short. The duration of the effect of contraction-relaxation stretching on range of motion (ROM) in the lower extremities is 15 min and the increase in ROM usually remains for 90 min 58. Proprioceptive neuromuscular facilitation (PNF) stretching techniques produced greater increases in ROM than static or dynamic stretching exercises. The stretching hold time at the hip is 3–10 sec in one hold-relax PNF stretch 59. There is no study that clarifies the stretch duration required of the abdominal muscle for relaxation. Thus, it will be necessary to examine how long we should stretch the abdominal muscles for IBS treatment. Lastly, we could not analyze the effect of lifestyle and medical history on CgA in this study. Many stress-related biomarkers are affected by lifestyle or medical history 60. Such relationships might contribute to increased knowledge about strategies to prevent progression of IBS.

Our results suggested that it is possible to improve IBS pathophysiology by passive abdominal muscle stretching using a biochemical index of the activity of the S/A system (salivary CgA). In this study, we verified only the effects of stretching and presence of IBS on CgA levels. Further study of the S/A system and muscle stretching in IBS is warranted.

IBS: irritable bowel syndrome; CgA: chromogranin A; GSRS: Gastrointestinal Symptoms Rating Scale; STAI: State Trait AnxietyInventory; SDS: Self-rating Depression Scale; ANOVA: analysis ofvariance; S/A: sympathetic/adrenomedullary.

The authors declare that they have no competing interests.

TH was the main investigator and wrote the first draft of the manuscript. SF supervised the study, analyzed the data and wrote the final draft of the manuscript. MT and TT supervised the study. KS, MO and KS contributed to the study design. KS contributed to the data collection. All authors contributed to the preparation of the article and approved the final manuscript.