Olfactory and gustatory function in irritable bowel syndrome
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- Steinbach, S., Reindl, W., Kessel, C. et al. Eur Arch Otorhinolaryngol (2010) 267: 1081. doi:10.1007/s00405-009-1181-7
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Irritable bowel syndrome (IBS) is the most common, functional disorder diagnosed by gastroenterologists. It is still unclear whether IBS has a central etiology, e.g., hyperreactivity of the brain, or a peripheral etiology, e.g., stimulation of olfactory/gustatory receptors on enterochromaffin cells, followed by serotonin release and changed gut motility. Testing the odor identification (ID), odor discrimination (DIS) and odor threshold (THR) as well as the total taste and the taste qualities “sweet”, “sour”, “salty” and “bitter” should be of help for determining the etiology. To our knowledge, this is the first study investigating the olfactory/gustatory function in IBS patients. The olfactory/gustatory function of 43 patients (32 women, 11 men) suffering from IBS as defined by the ROME III criteria was investigated by means of validated tests (Sniffin’ Sticks and taste strips). Compared to normative data, scores of THR were decreased and scores of ID and DIS were increased in IBS patients. Additionally, when compared to normative data, there was no difference in the taste function of IBS patients. Assuming that THR reflects more the peripheral olfactory function, whereas ID and DIS are influenced by central activity, and that taste did not differ in IBS patients compared to normative data, this supports the idea of a central etiology of IBS.
KeywordsIrritable bowel syndromeOlfactionTaste
Irritable bowel syndrome (IBS) is the most common, functional disorder diagnosed by gastroenterologists. The prevalence of IBS in the general population of the USA is approximately 10% [1–3]. Regarding ROME III criteria, IBS is characterized by recurrent abdominal pain or discomfort for at least 3 days per month during the previous 3 months associated with at least two symptoms which can be: improvement with defecation, an onset associated with a change in the frequency of the stool and/or an onset associated with a change in form or appearance of the stool . The pathophysiology of IBS—whether peripheral or central—is still unclear. There are different strategies for explaining IBS. Braun et al.  found an expression of four olfactory receptors in micro-dissected, human, mucosal, enterochromaffin cells. Odorant ligands of these olfactory receptors can cause Ca2+ influx, elevation of intracellular free Ca2+ levels and serotonin release. Serotonin is involved in gut motility and secretion, thus possibly causing diarrhea and vomiting. Also, Kidd et al.  identified transcripts for T2R1 (bitter receptor), OR1G1 (olfactory receptor) as well as transporters for glutamine, glucose and bile salts in enterochromaffin cells. Thus, enterochromaffin cells may be luminal sensors for odorants and taste molecules followed by a regulation of gut motility. Other authors propagate a central etiology with abnormal, visceral pain processing which means an up-regulation of afferent sensitivity to pain. This was based on fMRI studies exploring neural correlates of abdominal pain induced by rectal distension. Some studies described a higher anterior cingulate cortex (ACC) activity and an anterior mid-cingulate cortex (aMCC) activity during painful rectal distension in IBS patients compared to healthy control persons [7–10], and the same number of other studies described a lower activity of, or absence of, ACC or aMCC activity in IBS patients [11–15]. However, whether a higher or lower activity, the studies implicate that IBS patients may have an altered response in brain regions for attentional processes, response selection and emotional and autonomic processes.
In the present, prospective study, the olfactory and gustatory function of IBS patients was studied for the first time. The question arises as to whether IBS patients smell or taste differently to healthy, control persons of the same age. Additionally, measuring the odor identification, odor discrimination and odor threshold of IBS patients should help to answer the question of whether the pathophysiology of IBS is more central or peripheral when considering the idea that odor thresholds reflect peripheral, olfactory function, whereas odor identification and discrimination are indicative of a higher, central, nervous processing of odors.
Patients and methods
Forty-three patients (32 women, 11 men) suffering from IBS as defined by ROME III criteria  were prospectively included in two participating centers from October 2007 to May 2008. Only IBS patients strictly defined by ROME III criteria were included. Thus, out of 96 acquired patients, 43 were left for investigation. All the patients gave their written, informed consent. The study protocol was approved by the Ethics Committee of the Faculty of Medicine at the Technical University of Munich (Number: 1677/06, amendment 3). The women/men had a mean age of 46 ± 16.3/41.2 ± 13.6 (range 21–73 years), a mean height of 168 ± 0.06/180 ± 0.09 cm and a mean weight of 59.2 ± 6.7/83.6 ± 16.2 kg. IBS was diagnosed 10.5 ± 7.3 years ago (range 0.5–30 years). None of the patients had relevant comorbidities such as rhinosinusitis, liver or renal problems, hyperactivity or hypoactivity of the thyroid gland, diabetes or neurological disorders. None of the patients smoked cigarettes influencing olfactory function; 27 patients drank 2.0 ± 0.6 l beer per week.
The olfactory and gustatory function was tested. Additionally, patients answered a questionnaire for assessing their symptoms subjectively—most questions required an answer on visual, analog scales ranging from 0 to 100. Then, they answered the PHQ-D patient health questionnaire.
The “Sniffin’ Stick” test battery is a nasal, chemosensory performance test recommended by the “Working Group Olfaction and Gustation” of the German Society for Otorhinolaryngology, Head and Neck Surgery, and excellently validated [16–18]. It comprises tests for odor identification (ID), odor discrimination (DIS) and odor threshold (THR). Odors are presented in felt-tip pens. The cap is removed and the tip of the pen is positioned approximately 2 cm in front of the patient’s nostrils for 3 s. For ID, 16 pens with different odors are presented. The patient chooses one of four items in a forced-choice procedure that best fits the presented odor (four-alternative forced choice). For DIS, 16 pen triplets are presented. The triplet comprises two pens with the same odor and one with a different odor. The patient has to discriminate the differently smelling pen (three-alternative forced choice). For THR, 16 dilutions were prepared in a series starting from a 4% n-butanol solution. Three pens are presented in randomized order, two containing solvent and one containing the odorant. Patients must identify the pen containing the odorant. The triplets are presented in a staircase, starting at the lowest concentration of the odor. After recognizing the pen containing the odor twice in a presented triplet, a reversal of the staircase is started until the patient can no longer identify the pen containing the odor. The THR is the mean of the last four of seven staircase reversals. The ID and DIS scores can be 0–16, for THR 1–16. The sum of the ID, DIS and THR scores is referred to as TDI (values of 1–48). DIS and THR testing had to be done blindfolded to avoid any visual identification of the pens containing the odorant. Together, the three tests took approximately 30 min.
Gustatory sensitivity was tested by filter-paper taste strips, impregnated at one end with one of four concentrations, i.e. for a sweet taste (0.05, 0.1, 0.2, 0.4 g/ml sucrose), sour taste (0.05, 0.09, 0.165, 0.3 g/ml citric acid), salty taste (0.016, 0.04, 0.1, 0.25 g/ml sodium chloride) and bitter taste (0.0004, 0.0009, 0.0024, 0.006 g/ml quinine-hydrochloride) . After placing one of these taste strips on the tongue, patients had to identify the taste stimuli and answer in a forced-choice procedure (answers included “sweet”, “sour”, “salty” and “bitter”). Testing was done on each side of the tongue, 1.5 cm from the tip of the tongue. The correct identification of each quality scores 0–4 and of all the taste stimuli 0–16. The test took about 10 min.
PHQ-D patient health questionnaire
In this study, the PHQ15, PHQ9 and PHQ7 were analyzed. The PHQ15 is a test for evaluating the severity of somatic symptoms (scores of 5–9 are less severe and scores of >15 very severe) . The PHQ9 evaluates depression (scores of 1–4 very low, 5–9 low, 10–14 moderate, 15–19 less severe, >20 very severe depression) . The PHQ7 or GAD-7 validates generalized anxiety disorders (scores of 1–5 are less severe and scores of >15 very severe) .
Statistical analysis was performed using SPSS software (version 16.0, SPSS Inc., Chicago, IL, USA). Data were presented as mean ± standard deviation. To compare patients with normative data, the one- and two-sample t test was used. For subgroup comparisons, the Mann–Whitney or appropriate two-sample t test was used. To evaluate relations between different measurements, the Chi-square test, the Spearman or the Pearson correlation coefficient respectively were calculated.
All statistical comparisons were made using a two-sided 0.05 level of significance.
Correlation of the olfactory and gustatory function of IBS patients with age, gender and BMI
For all IBS patients, there was a significant correlation between their age and the TDI (r = −0.55, p < 0.01), ID (r = −0.33, p = 0.04), DIS (r = −0.33, p = 0.04) and THR (r = −0.54, p < 0.01). Regarding taste, there was a significant correlation between the age and the quality “bitter” on both sides of the tongue (left: r = −0.38, p = 0.01, right: r = −0.53, p < 0.01) whereas the qualities “sweet”, “sour” and “salty” did not change significantly with age.
IBS patients with a lower BMI had a significantly better score in TDI (r = −0.41, p = 0.01), ID (r = −0.42, p < 0.01) and THR (r = −0.31, p = 0.05) than IBS patients with a higher BMI. For DIS and the qualities “sweet”, “sour”, “salty” and “bitter”, this was not significant.
Correlation of the olfactory and gustatory function of IBS patients with the subjective assessment and the PHQ-D
IBS patients assessed their subjective olfactory and gustatory function on a scale from 0 (anosmia, ageusia) to 100 (hyperosmia, hypergeusia) at 76.7 ± 20.1 and 75.9 ± 21.6. There was no significant correlation between the subjective olfactory and gustatory assessment and the TDI, ID, DIS, THR or between the total value and values for the qualities “sweet”, “sour”, “salty” and “bitter”. On a scale from 0 (none) to 100 (high), patients rated the frequency of parosmia as 15.8 ± 25.9 and the frequency of phantosmia as 6.4 ± 18.5.
Correlation of the olfactory and gustatory function of IBS patients with normative data
Comparison of the olfactory function of IBS patients with normative data
36.06 ± 4.17
37.1 ± 3.52b
13.68 ± 1.62
14.2 ± 1.81b
12.91 ± 1.92
13.7 ± 1.88b
9.39 ± 2.56
9.2 ± 2.58b
35.16 ± 4.52
35.47 ± 2.55c
13.49 ± 1.56
14.12 ± 1.35c
12.46 ± 1.96
13.5 ± 1.69c
9.08 ± 3.09
7.9 ± 1.18c
Age > 55
29.83 ± 6.77
34.28 ± 2.68d
12.06 ± 2.31
14.5 ± 1.08d
10.66 ± 2.50
13.2 ± 1.54d
7.44 ± 3.51
6.57 ± 1.68d
Comparison of the gustatory function of IBS patients with normative data
Patients, left side of tongue
Patients, right side of tongue
12.4 ± 2.3
11.53 ± 3.1
11.79 ± 3.4
3.3 ± 0.8
3.29 ± 1.0
3.34 ± 1.0
3 ± 0.8
2.26 ± 1.0
2.66 ± 1.0
3.1 ± 0.9
3.16 ± 1.1
2.89 ± 1.2
3 ± 1.1
2.82 ± 1.2
2.92 ± 1.3
Correlation of the olfactory and gustatory function of IBS patients with the IBS type
As known from literature, the best olfactory function is present between the ages of 20–40 years and then it begins to decline monotonically [18, 23]. At an older age, olfactory receptor cells are more susceptible to neurotoxic substances, the number of olfactory receptor cells decreases and regeneration is reduced . As regards taste, the taste function decreases with age, but the loss of taste is much less pronounced than that of olfaction [25–27].
The qualities “bitter” and “sour” are more affected in age-related taste loss than “sweet” or “salty” . Additionally, women in all age groups have better results than men in various different olfactory tests [18, 23]. Simchen et al.  reported a higher capability of smelling and tasting in normal weight individuals (<65 years) compared to overweight subjects. Richardson et al.  showed that morbidly obese individuals are more likely to have an olfactory dysfunction than moderately obese individuals. Thus, the olfactory and gustatory function of the IBS patients in the present study correlated to age, gender and BMI was within an expected range.
There was no significant correlation between the subjective olfactory and gustatory assessment of the IBS patients assessed by the IBS patients themselves on a visual analog scale and the values of the TDI, ID, DIS, THR or between the total taste value and the values for the qualities “sweet”, “sour”, “salty” and “bitter”.
Regarding IBS, there is a high prevalence of non-gastrointestinal, functional diseases such as fibromyalgia, chronic fatigue syndrome and psychological disorders (depression and anxiety) [31, 32]. Somatic symptoms, i.e. depression and anxiety disorders tested by PHQ15, PHQ9 and PHQ7 in the present study, did not show a significant correlation to the olfactory and gustatory function of the IBS patients. This is in congruence with investigations by Landis et al.  and Pentzek et al. , who could not show a significant correlation between depression and the olfactory function. However, Pause et al.  observed that patients with major depression exhibit a decrease in olfactory sensitivity. Also, Pollatos et al.  described a significant correlation between the Beck Depression Inventory score and the odor threshold in healthy subjects with depression symptoms. The overall olfactory function in their subjects, however, was within the normal range.
To substantiate the IBS patients’ reports, the olfactory and gustatory function of IBS patients was tested and the olfactory and gustatory test scores were compared with the test scores of healthy, age-related control persons.
Regarding THR, the scores of THR were lower in the IBS patients than in the control persons. However, this tendency was only significant in the age group 36–55. Regarding TDI, ID and DIS, the scores of IBS patients were higher than those of the control persons. However, this tendency was only significant for the age group older than 55 years.
Assuming that THR reflects the function of the peripheral olfactory system to a higher degree than other olfactory tests [37, 38], this might indicate that the function of the peripheral, nasal, olfactory system in IBS patients seems to be less sensitive than in healthy control persons. Assuming that the peripheral olfactory system of the nose has the same olfactory receptor contribution as elsewhere in the body, the hypothesis of peripheral pathophysiology in IBS with a higher serotonin release from enterochromaffin cells followed by a higher gut motility is not self-explanatory. Taste function did not differ either between the IBS patients and healthy control persons. Thus, the peripheral pathophysiology of IBS with enterochromaffin cells acting as sensors for the taste quality “bitter” is not self-explanatory either. The only significant difference between IBS patients and healthy controls on the left side of the tongue for the quality “sour” could not be confirmed for the right side of the tongue for the same patients/persons. Mueller et al.  observed that the percentage of correctly identified taste strips for the highest concentrations was 100% for “sweet”, 99% for “sour”, 96% for “salty” and 99% for “bitter”. For the lowest concentrations, it was 54% for “sweet”, 36% for “sour”, 51% for “salty” and 52% for “bitter”. This might explain that “sour” in the lowest concentration was more difficult to identify. Maybe this is the reason for the discrepancy in the test results between the left and right side of the tongue of IBS patients for the quality “sour”.
The present study may support the central etiology of IBS, due to finding a better ID and DIS of IBS patients compared to healthy control persons. Although there are different patterns of brain activity in fMRI studies in IBS patients during rectal distension (activation or deactivation in the ACC and aMCC), there is a difference compared with healthy volunteers [7–15]. Higher activity in fMRI studies of ACC and aMCC during painful, rectal distension in IBS patients could mean an up-regulation of visceral, afferent input to the brain—increased anticipation or hypervigilance/attention—or a negative, affective reaction to the visceral sensory stimulus, or both. Lower activity or an absence of the activity of ACC or aMCC could mean a decreased, descending anti-nociceptive response through pathways originating at the level of the ACC, ceiling effects or differential sensitization of the lateral versus the medial pain system . For testing ID and DIS, cognitive performance (verbal communication, memory, attention) is necessary. Thus, overlapping brain regions may be involved in processing the affective and cognitive dimensions of the olfactory sensation, or the visceral sensation in IBS patients under rectal distension. Blomhoff et al.  and Berman et al.  investigated event-related potentials to auditory stimuli in IBS patients and found a perceptual hyperreactive response to auditory stimuli. Andresen et al.  found an altered cerebral response pattern in the fMRI of IBS patients after auditory stimuli, compared with control persons. Auditory stimuli are transmitted via the eighth cranial nerve directly to the brain without connecting to a visceral sensory input. Thus, there seems to be an enhanced, pre-attentive brain reactivity in IBS, reflecting a generalized change in emotional sensitivity and affective reactivity without limitation to visceral processing.
Wilder-Smith et al.  compared the fMRI of IBS patient subgroups (obstipated, diarrhea) and healthy control persons under rectal pain processing. They could show a significantly different brain activation response to rectal pain with and without counterirritation in obstipated patients compared with diarrheic patients and also compared with healthy volunteers. Although there was no significant correlation between the TDI, ID, DIS and THR values or between the taste testing values with the IBS subtypes, the mean average TDI, ID and THR values were best for obstipated IBS patients, lower for diarrheic IBS patients and the least for mixed-type IBS patients. This can be explained by different brain activation responses shown by the investigations of Wilder-Smith et al. . Favouring the peripheral pathophysiology of IBS, one would expect the diarrheic IBS patients to have a better THR than the obstipated IBS patients. A better olfactory function would correlate with a higher response to olfactory molecules and a higher release of serotonin by enterochromaffin cells, thus causing a higher gut motility.
In conclusion, scores of odor identification and odor discrimination were better in IBS patients than in healthy controls, whereas scores of odor threshold were lower in IBS patients than in controls. The gustatory function did not differ between IBS patients and healthy controls. This tendency might support a central etiology of IBS rather than a peripheral pathophysiology.
Conflict of interest statement