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Role of Colonic Fermentation in the Perception of Colonic Distention in Irritable Bowel Syndrome and Functional Bloating

2006; Elsevier BV; Volume: 4; Issue: 10 Linguagem: Inglês

10.1016/j.cgh.2006.07.004

1542-7714

M. Di Stefano, Emanuela Miceli, Antonio Missanelli, S. Mazzocchi, Paola Tana, Gino Roberto Corazza,

Biochemical Analysis and Sensing Techniques

Background & Aims: Bloating represents a frequent gastrointestinal symptom, but the pathophysiologic mechanism responsible for its onset is still largely unknown. Patients very frequently attribute the sensation of bloating to the presence of excessive bowel gas, but not all patients with gas-related symptoms exhibit increased intestinal production of gas. It is therefore possible that other still unrecognized mechanisms might contribute to its pathophysiology. Our aim was to evaluate whether a subgroup of patients affected by functional abdominal bloating presents hypersensitivity to colonic fermentation. Methods Sixty patients affected by functional gastrointestinal disorders (11 functional bloating, 36 constipation-predominant, and 13 diarrhea-predominant irritable bowel syndrome) and moderate to severe bloating took part in the study. Twenty sex- and age-matched healthy volunteers were enrolled as a control group. All the subjects underwent a preliminary evaluation of breath hydrogen excretion after oral lactulose. Then, on a separate day, an evaluation of sensitivity thresholds at rectal level was performed with a barostat before and after the induction of colonic fermentation with oral lactulose. A control test with electrolyte solution was also performed. Results Both breath hydrogen excretion and mouth-to-cecum transit time did not differ between the 4 groups studied. Neither electrolyte solution nor lactulose modified sensitivity thresholds in healthy volunteers. In low hydrogen producers, basal perception and discomfort thresholds were similar to high hydrogen producers, but after lactulose both perception and discomfort thresholds were significantly reduced only in low hydrogen producers. Conclusions A subgroup of patients with functional gastrointestinal disorders and moderate to severe bloating might have hypersensitivity to products of colonic fermentation. Background & Aims: Bloating represents a frequent gastrointestinal symptom, but the pathophysiologic mechanism responsible for its onset is still largely unknown. Patients very frequently attribute the sensation of bloating to the presence of excessive bowel gas, but not all patients with gas-related symptoms exhibit increased intestinal production of gas. It is therefore possible that other still unrecognized mechanisms might contribute to its pathophysiology. Our aim was to evaluate whether a subgroup of patients affected by functional abdominal bloating presents hypersensitivity to colonic fermentation. Methods Sixty patients affected by functional gastrointestinal disorders (11 functional bloating, 36 constipation-predominant, and 13 diarrhea-predominant irritable bowel syndrome) and moderate to severe bloating took part in the study. Twenty sex- and age-matched healthy volunteers were enrolled as a control group. All the subjects underwent a preliminary evaluation of breath hydrogen excretion after oral lactulose. Then, on a separate day, an evaluation of sensitivity thresholds at rectal level was performed with a barostat before and after the induction of colonic fermentation with oral lactulose. A control test with electrolyte solution was also performed. Results Both breath hydrogen excretion and mouth-to-cecum transit time did not differ between the 4 groups studied. Neither electrolyte solution nor lactulose modified sensitivity thresholds in healthy volunteers. In low hydrogen producers, basal perception and discomfort thresholds were similar to high hydrogen producers, but after lactulose both perception and discomfort thresholds were significantly reduced only in low hydrogen producers. Conclusions A subgroup of patients with functional gastrointestinal disorders and moderate to severe bloating might have hypersensitivity to products of colonic fermentation. Bloating represents a very frequent symptom in several disorders.1Manning A.P. Thompson W.G. Heaton K.W. et al.Towards positive diagnosis of irritable bowel.Br Med J. 1978; 2: 653-654Crossref PubMed Scopus (1286) Google Scholar, 2Maxton D.G. Morris J.A. Whorwell P.J. Ranking of symptoms by patients with the irritable bowel syndrome.BMJ. 1989; 299: 1138Crossref PubMed Scopus (88) Google Scholar The sensation of bloating might be caused by different mechanisms. In obstructive conditions, the distention of an intestinal tract as a result of the increased intraluminal pressure causes the stimulation of bowel parietal mechanoreceptors3Distrutti E. Azpiroz F. Soldevilla A. et al.Gastric wall tension determines perception of gastric distension.Gastroenterology. 1999; 116: 1035-1042Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar; in pregnancy or in conditions associated with voluminous ascites, the stimulation of abdominal wall stretch receptors or the compression of various internal organs is the probable cause of the symptom.4Rao S.S. Belching, bloating, and flatulence: how to help patients who have troublesome abdominal gas.Postgrad Med. 1997; 101: 263-269Crossref PubMed Scopus (25) Google Scholar On the contrary, in functional bowel disorders the mechanism responsible for the onset of bloating is still largely unknown. Patients very frequently attribute the sensation of bloating to the presence of excessive bowel gas.5Strocchi A. Levitt M.D. Intestinal gas.in: Sleisenger M.H. Fortran J.S. Gastrointestinal disease. Saunders, Philadelphia1993: 1035-1042Google Scholar Accordingly, we recently showed that breath hydrogen (H2) excretion is increased in a subgroup of patients with gas-related symptoms.6Di Stefano M. Strocchi A. Malserviti S. et al.Non-absorbable antibiotics for managing intestinal gas production and gas-related symptoms.Aliment Pharmacol Ther. 2000; 14: 1001-1008Crossref PubMed Scopus (96) Google Scholar Nevertheless, the close relationship between amounts of intestinal gas and bloating onset and severity has been questioned, and a sure link between symptom and gas production was described only for flatulence.7Levitt M.D. Furne J. Olsson S. The relation of passage of gas and abdominal bloating to colonic gas production.Ann Intern Med. 1996; 124: 422-424Crossref PubMed Scopus (89) Google Scholar In fact, in our article,6Di Stefano M. Strocchi A. Malserviti S. et al.Non-absorbable antibiotics for managing intestinal gas production and gas-related symptoms.Aliment Pharmacol Ther. 2000; 14: 1001-1008Crossref PubMed Scopus (96) Google Scholar patients affected by functional diseases as a group exhibited significantly higher mean breath H2 excretion than healthy volunteers, but a wide overlap of results was evident, suggesting that the absolute amount of intraluminal gas is not the only crucial factor for symptom onset. This observation indicates that other still unrecognized mechanisms might contribute to the pathophysiology of bloating. Recently, a large body of evidence showed that visceral sensitivity plays a pivotal role in the pathophysiology of functional diseases.8Drossman D.A. Camilleri M. Mayer E.A. et al.AGA technical review on irritable bowel syndrome.Gastroenterology. 2002; 123: 2108-2131Abstract Full Text Full Text PDF PubMed Scopus (1226) Google Scholar, 9Camilleri M. Coulie B. Tack J.F. Visceral hypersensitivity: facts, speculations, and challenges.Gut. 2001; 48: 125-131Crossref PubMed Scopus (187) Google Scholar It was demonstrated that relaxation of the gastric fundus might be induced by colonic fermentation of lactulose10Ropert A. Cherbut C. Roze C. et al.Colonic fermentation and proximal gastric tone in humans.Gastroenterology. 1996; 111: 289-296Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar and mechanical distention of the esophagus, the antropyloric region, and the duodenum,11De Ponti F. Azpiroz F. Malagelada J.R. Relaxatory response of canine proximal stomach to esophageal and duodenal distension.Dig Dis Sci. 1989; 34: 873-881Crossref PubMed Scopus (49) Google Scholar, 12Azpiroz F. Malagelada J.R. Perception and reflex relaxation of the stomach in response to gut distension.Gastroenterology. 1990; 98: 1193-1198PubMed Scopus (112) Google Scholar, 13De Ponti F. Azpiroz F. Mlagelada J.R. Reflex gastric relaxation in response to distension of the duodenum.Am J Physiol. 1987; 252: G595-G601PubMed Google Scholar thus suggesting the existence of long reflexes. On the contrary, no data are available on the effect of colonic fermentation on bowel sensitivity. Our hypothesis, therefore, was that in a subgroup of patients affected by irritable bowel syndrome (IBS) or functional abdominal bloating (FB), hypersensitivity to colonic fermentation might be responsible for bloating onset. Sixty patients (45 women; mean age, 35 ± 5 years; range, 19–58 years) affected by functional gastrointestinal disorders took part in the study. Eleven were affected by FB (8 women; mean age, 34 ± 6 years; range, 21–45 years); 36 were affected by constipation-predominant irritable bowel syndrome (IBS-C) (24 women; mean age, 36 ± 8 years; range, 24–51 years); 13 were affected by diarrhea-predominant irritable bowel syndrome (IBS-D) (7 women; mean age, 32 ± 8 years; range, 23–45 years). The diagnosis was made according to Rome II criteria.14Thompson W.G. Longstreth G.F. Drossman D.A. et al.Functional bowel disorder and functional abdominal pain.Gut. 1999; 45: II43-II47Crossref PubMed Scopus (2043) Google Scholar A careful anamnestic evaluation, clinical examination, colonoscopy/barium enema, routine biochemistry, upper abdominal ultrasonography, fecal occult blood test, and microbiologic stool tests excluded the presence of inflammatory diseases. The patients were asked to grade the intensity (0, absent; 1, mild; 2, moderate; 3, severe and interfering with daily activities) of bloating, according to a previously adopted procedure,15Stanghellini V. Tosetti C. Paternico A. et al.Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia.Gastroenterology. 1996; 110: 1036-1042Abstract Full Text Full Text PDF PubMed Scopus (576) Google Scholar, 16Tack J. Piessevaux H. Coulie B. et al.Role of impaired gastric accommodation to a meal in functional dyspepsia.Gastroenterology. 1998; 115: 1346-1352Abstract Full Text Full Text PDF PubMed Scopus (942) Google Scholar and patients with moderate or severe score were enrolled. Similarly, patients were asked to grade the severity of abdominal pain, abdominal distention, bowel habit abnormality, and flatulence. Twenty (14 women; mean age, 33 ± 2 years; range, 24–43 years) sex- and age-matched healthy volunteers, members of the medical or paramedical staff or students, were also enrolled as a control group. None of them had a history or symptoms of gastrointestinal disease. None of the enrolled subjects had previously undergone therapeutic courses of antibiotics or drugs interfering with gut motility and sensitivity during the months preceding the study. All subjects gave their informed consent, and the protocol was approved by the local ethics committee. A preliminary evaluation of breath H2 and methane (CH4) excretion was performed in all patients and healthy volunteers by monitoring breath H2 and CH4 excretion, the main pathway for H2 consumption,17Levitt M.D. Berggren T. Hastings J. et al.Hydrogen (H2) catabolism in the colon of the rat.J Lab Clin Med. 1974; 84: 163-167PubMed Google Scholar after oral lactulose administration. CH4 excretion was evident only in 3 subjects (1 IBS-C, 1 IBS-D, 1 FB), so we did not consider CH4 results for analysis. Subjects were divided into low or high H2 producers on the basis of a cumulative breath H2 excretion value lower or higher than 5000 ppm/min, in accordance with previous results.6Di Stefano M. Strocchi A. Malserviti S. et al.Non-absorbable antibiotics for managing intestinal gas production and gas-related symptoms.Aliment Pharmacol Ther. 2000; 14: 1001-1008Crossref PubMed Scopus (96) Google Scholar, 18Di Stefano M. Malservisi S. Veneto G. et al.Rifaximin versus chlortetracycline in the short term treatment of small intestinal bacterial overgrowth.Aliment Pharmacol Ther. 2000; 14: 551-556Crossref PubMed Scopus (137) Google Scholar All subjects then underwent a rectal barostat test (Figure 1A) to determine the rectal sensitivity threshold. The test consisted of a fasting evaluation of rectal perception and discomfort thresholds evaluated by mechanical distention, followed by the oral administration of a 250-mL solution containing 10 g of lactulose, a nonabsorbable carbohydrate, fermented by colonic flora, to induce colonic fermentation. After the administration of the lactulose solution, we monitored breath H2 excretion, and when a sustained increase of breath H2 excretion was detected, indicating the arrival of the test solution in the colon and the beginning of its fermentation by the colonic flora, a second series of mechanical distentions was performed to test whether lactulose modified rectal sensitivity thresholds. To exclude the possible interfering effect of the delivery to the colon of preexisting fermentable substrates or of the release of preformed H2 entrapped in the feces,19Di Stefano M. Miceli E. Malservisi S. et al.Mixing of the intestinal content and variations of fermentation capacity do not affect the results of hydrogen breath test.Am J Gastroenterol. 2003; 98: 1584-1587PubMed Google Scholar a control test (Figure 1B) was performed in 8 healthy volunteers and 24 patients with functional gastrointestinal disorders (8 with FB, 8 with IBS-C, and 8 with IBS-D). The 2 groups were age- and sex-matched. The control test consisted of a fasting threshold evaluation followed by the oral administration of a 250-mL electrolyte nonfermentable, nonabsorbable solution. Ten g of barium was added to the electrolyte solution, and the second series of distentions were performed after the arrival of the barium in the cecum at x-ray. During the control test no significant increase of breath H2 excretion was detected. To avoid prolonged intestinal gas production as a result of the presence of nonabsorbable or slowly fermentable material in the colonic lumen, the subject ate a meal consisting of only rice, meat, and olive oil the evening before the test.20Kotler O.P. Holt P.R. Rosensweig N.S. Modification of the breath hydrogen test increased sensitivity for the detection of carbohydrate malabsorption.J Lab Clin Med. 1982; 100: 798-805PubMed Google Scholar This meal was then followed by a 12-hour fasting period. Breath testing started between 8:30 and 9:30 am after thorough mouthwashing with 40 mL of 1% chlorhexidine solution.21Thompson D.G. O’Brien J.D. Hardie J.M. lnfluence of the oropharyngeal microflora on the measurements of exhaled breath hydrogen.Gastroenterology. 1986; 191: 853-860Google Scholar Smoking22Rosenthal A. Solomons N.W. Time-course of cigarette smoke contamination of clinical hydrogen breath-analysis tests.Clin Chem. 1983; 29: 1980-1981PubMed Google Scholar and physical exercise23Payne D.L. Welsh J.D. Claypool P.L. Breath hydrogen (H2) response to carbohydrate malabsorption after exercise.J Lab Clin Med. 1983; 102: 147-150PubMed Google Scholar were not allowed for 1 hour before and throughout the test. Sampling of alveolar air was performed by means of a commercial device (Gasampler; Quintron Instrument, Milwaukee, WI) that allows the first 500 mL of dead space air to be separated and discarded, while the remaining 700 mL of end-alveolar air is collected in a gas-tight bag. Subjects were instructed to avoid deep inspiration and not to hyperventilate before exhalation. A gas chromatograph dedicated to the detection of H2 and CH4 in air samples was used for breath sample analysis (model DP12; Quintron Instrument). The accuracy of the detector was ±2 ppm with a linear response range between 2–150 ppm of H2 and between 2–50 ppm of CH4. Ten g of lactulose in a 250-mL water solution was administered per os after fasting, and air samples were then collected every 15 minutes for a 4-hour period. To estimate cumulative gas production, the area under the time-concentration curve was calculated,24Kotler O.P. Holt P.R. Rosensweig N.S. Modification of the breath hydrogen test increased sensitivity for the detection of carbohydrate malabsorption.J Lab Clin Med. 1982; 100: 798-805PubMed Google Scholar and to evaluate mouth-to-cecum transit time, an increase of hydrogen breath excretion of 10 ppm over fasting value in at least 3 consecutive samples was considered.25LaBrooy S.J.L. Male P.J. Beavis A.K. et al.Assessment of reproducibility of the lactulose H2 breath test as a measure of mouth to caecum transit time.Gut. 1983; 24: 893-896Crossref PubMed Scopus (140) Google Scholar A double lumen polyvinyl tube (Salem sump tube 14 Ch; Sherwood Medical, St Louis, MO) with an adherent, infinitely compliant plastic bag (800-mL capacity, 17-cm maximal diameter), finely folded, was inserted through the rectum to the rectal-sigmoid junction level and secured with adhesive tape. The polyvinyl tube was connected to a computer-driven programmable volume-displacement barostat device (G & J Electronics Inc, Toronto, Ontario, Canada). The barostat device maintains a constant preselected pressure within the bag, changing the intrabag volume of air by an electronic feedback mechanism.26Azpiroz F. Malagelada J.R. Gastric tone measured by an electronic barostat in health and postsurgical gastroparesis.Gastroenterology. 1987; 92: 934-943Abstract Full Text PDF PubMed Scopus (331) Google Scholar To initially unfold the balloon, it was inflated with a fixed volume of 250 mL of air for 2 minutes with the subject in a recumbent position and then deflated completely. After a 10-minute equilibration period, the patients were asked to maintain the right lateral position. After determination of minimal distending pressure, defined as the lowest intrabag pressure that provided an intrabag volume of 30 mL or more, sequential ramp distentions were performed in stepwise increments of 2 mm Hg starting from the minimal distending pressure, each lasting for 2 minutes. Subjects were instructed to score their perception of rectal sensations induced by each distending stimulus at the end of every distending step by using a graphic rating scale that combined verbal descriptors on a scale graded from 0–6.27Notivol R. Coffin B. Azpiroz F. et al.Gastric tone determines the sensitivity of the stomach to distension.Gastroenterology. 1995; 108: 330-336Abstract Full Text PDF PubMed Scopus (169) Google Scholar During stepwise ramp distentions, the perception threshold was defined as the first level of intrabag pressure that evoked a perception score of 1 or more, and the discomfort threshold was defined as the first level of intrabag pressure that evoked a perception score of 5 or more.28Tack J. Caenepeel P. Fischler B. et al.Symptoms associated with hypersensitivity to gastric distension in functional dyspepsia.Gastroenterology. 2001; 121: 526-535Abstract Full Text Full Text PDF PubMed Scopus (495) Google Scholar Rectal compliance was calculated as the slope of the pressure-volume curve obtained by stepwise ramp distentions (mL/mm Hg); only those levels of distention for which data were available in at least 75% of subjects were considered.29Tack J. Vos R. Janssens J. et al.Influence of tegaserod on proximal gastric tone and on the perception of gastric distension.Aliment Pharmacol Ther. 2003; 18: 1031-1037Crossref PubMed Scopus (90) Google Scholar Data are presented as mean ± standard deviation values. All variables showed a nonparametric distribution and were analyzed by nonparametric analysis of variance (ANOVA). Spearman coefficient was calculated to estimate the level of association between 2 variables. Differences were considered to be significant at the 5% level. Figure 2 shows time-H2 breath excretion mean curves in the 3 groups of patients and healthy volunteers. Cumulative breath H2 excretion after lactulose administration in healthy volunteers (3255 ± 750 ppm/min) and IBS-C (5291 ± 3276 ppm/min), IBS-D (3252 ± 1839 ppm/min), and FB patients (4689 ± 2757 ppm/min) showed no significant difference by ANOVA. Moreover, orocecal transit time was not different between IBS-C, IBS-D, and FB patients and healthy volunteers (120 ± 45, 108 ± 36, 105 ± 52, and 120 ± 21 min, respectively; ANOVA = NS). None of the subjects had diarrhea or bowel movement after such a low-dose oral lactulose administration. Figure 3 shows perception and discomfort thresholds before and after the administration of electrolyte solution. Electrolyte solution induced no major modification of sensitivity thresholds in patients or healthy volunteers; in particular, the extent of the threshold modification, if any, was never higher than 2 mm Hg, corresponding to 1 distention. These results replicate those previously obtained in a different cohort of patients with lactose malabsorption.30Di Stefano M, Miceli E, Missanelli A, et al. Hypersensitivity to colonic fermentation is responsible for intolerance symptoms onset in patients with lactose malabsorption. Gut 205;54(Suppl VII):A133.Google Scholar Accordingly, a significant modification of the threshold was defined as a difference between fasting and post-solution value >2 mm Hg, corresponding to at least 2 steps in the distention protocol. Table 1 shows basal and post-lactulose perception and discomfort thresholds in the subgroups of patients and in healthy volunteers. After lactulose administration, patients with IBS-C exhibited a significant reduction of both perception and discomfort threshold. Patients with IBS-D exhibited a significant reduction of discomfort threshold. Patients with FB and healthy volunteers exhibited post-solution thresholds similar to fasting values.Table 1Perception and Discomfort Thresholds (mm Hg Above Minimal Distending Pressure) in Patients and Healthy Volunteers Before and After LactuloseBasalLactuloseP valuePerception threshold Healthy volunteers9.2 ± 2.59.3 ± 2.1NS IBS-C4.3 ± 4.12.5 ± 3.2.0003 IBS-D3.1 ± 4.13.1 ± 3.2NS FB2.7 ± 2.92.0 ± 2.4NSDiscomfort threshold Healthy volunteers21.4 ± 2.321.4 ± 3.1NS IBS-C13.0 ± 5.79.2 ± 5.8.00001 IBS-D12.0 ± 5.88.9 ± 5.9.0059 FB12.9 ± 7.110.0 ± 5.4NS Open table in a new tab In each group of patients, however, post-lactulose modification of sensitivity threshold values showed considerable variability, as shown in Figure 4. A reduction of perception threshold was present in a minority of patients, but a reduction of discomfort threshold was present in 19 of 36 (53%) IBS-C patients, in 7 of 13 (54%) IBS-D patients, and in 6 of 11 (55%) FB patients. A substantial portion of patients exhibiting the discomfort threshold modification were characterized by a normal or low hydrogen production, suggesting an important pathophysiologic role of factors other than an increased intestinal gas production or the underlying clinical condition. As can be seen in Figure 4, 24 of 36 (66%) IBS-C patients, 2 of 13 (15%) IBS-D patients, and 5 of 11(45%) FB patients were high H2 producers. Accordingly, we subdivided the whole patient group according to breath H2 excretion, and a post hoc analysis was performed; 29 patients proved to be low H2 producers (2797 ± 1398 ppm/min), and 31 proved to be high H2 producers (8890 ± 3920 ppm/min). In low H2 producers, mean basal perception (4.1 ± 4.2 mm Hg) and discomfort thresholds (13.7 ± 5.5 mm Hg) were not significantly different than in high H2 producers (3.7 ± 3.5 mm Hg and 9.0 ± 3.4 mm Hg). In patients with low H2-production, both post-lactulose perception (2.9 ± 3.3; P = .043) and discomfort (9.6 ± 6.2; P < .0001) thresholds were significantly reduced (Figure 5); on the contrary, no significant difference was evident in high hydrogen producers (2.0 ± 2.4 for perception threshold, 8.8 ± 4.8 for discomfort threshold). In none of the subgroups of patients was post-lactulose modification of either perception or discomfort threshold significantly correlated with severity of symptoms (data not shown). Lactulose induced no significant difference in rectal compliance, because distention of the rectum with progressively higher intrabag pressure produced similar and progressively larger intrabag volumes in all the subjects (data not shown). Bloating is a very frequent symptom of both inflammatory and functional diseases, but its pathophysiology is still largely unknown. Previous results showed that among bloating patients, a subgroup is characterized by increased breath H2 excretion, whereas another subgroup presents breath H2 excretion overlapping that of healthy volunteers.6Di Stefano M. Strocchi A. Malserviti S. et al.Non-absorbable antibiotics for managing intestinal gas production and gas-related symptoms.Aliment Pharmacol Ther. 2000; 14: 1001-1008Crossref PubMed Scopus (96) Google Scholar This observation suggests that other still unrecognized mechanisms might have a role in the pathophysiology of bloating; therefore, the aim of our study was to analyze the role of visceral sensitivity and colonic gas production. First, we analyzed whether an increased excretion of intestinal gas with breath was present in the subgroups of IBS and FB patients with respect to healthy volunteers. Unfortunately, only 3 patients proved to be methane producers, so we cannot analyze the role of this gas. However, the lack of methane production in our patients makes it possible to hypothesize that this gas is not crucial for the events analyzed in this article. Our results showed that cumulative breath H2 excretion after lactulose was not significantly different between the groups. It is possible that the method used to evaluate cumulative breath H2 excretion after lactulose was severely affected by a considerable difference in mouth-to-cecum transit time among the patients. However, mouth-to-cecum transit time was not significantly different between the groups. Consequently, these results excluded the possibility that an accelerated transit time could be responsible for an apparent increase of gas production. Both in patients and in healthy volunteers similar values of perception and discomfort thresholds were detectable before and after the administration of an inert solution able to deliver a fair amount of liquid as far as the colon. Therefore, an increased bowel filling does not induce a modification of visceral sensitivity. During the test, no increase of breath hydrogen excretion was evident after electrolyte solution, thus confirming that the fermentation process, and therefore increased intraluminal gas, did not induce intestinal distention in this phase of the study. On the contrary, during lactulose fermentation, a reduction of discomfort thresholds was present in IBS patients. However, a wide range of variability was evident in all the groups, and more than half the subjects in each group exhibited a threshold reduction induced by intestinal fermentation. We thus hypothesized that a defect of visceral sensitivity induced by colonic fermentation could be important in a subgroup of bloaters, and a post hoc analysis was performed. As shown in Figure 4, among the subgroup of patients exhibiting a reduction of sensitivity thresholds after lactulose fermentation, a considerable number of patients proved to be low H2 breath excretors. We were thus able to confirm that an increase of intestinal gas production does not necessarily have to be present to induce bloating. We then subdivided our cohort of patients according to the presence of a high or normal cumulative breath hydrogen excretion, and a significant reduction of sensitivity thresholds was evident only in the low H2 excretor group. This finding is very interesting; because it is produced on the basis of a post hoc analysis, it needs confirmation, but it also opens a fascinating scenario. The inhibitory effect of nitric oxide on colonic motor function is already known,31Mizuta Y. Takahashi T. Owyang C. Nitrergic regulation of colonic transit in rats.Am J Physiol. 1999; 277: G275-G279PubMed Google Scholar and it was recently shown that another gas, methane, might trigger small bowel contractility in guinea pig ileum and slows intestinal transit in dogs.32Pimentel M. Lin H.C. Enayati P. et al.Methane, a gas produced by enteric bacteria, slows intestinal transit and augments small intestinal contractile activity.Am J Physiol Gastrointest Liver Physiol. 2006; 290: G1089-G1095Crossref PubMed Scopus (348) Google Scholar Even if similar demonstrations should be first performed in the colon, which is the normal site of methane production, these and our data support the hypothesis of a modulatory role of intraluminal gas on intestinal sensory motor function. The modification of both perception and discomfort threshold was not correlated to symptom severity. The absence of correlation between threshold modification and bloating is not surprising, because our patients were selected among those with moderate to severe bloating, and most of them had a score of 3. Unfortunately, we were not able to show a link between this alteration and clinical manifestations. In low H2 producers, basal perception and discomfort threshold values were not significantly different than in high H2 producers; this result excludes the hypothesis that a more severe visceral hypersensitivity in low H2 producers might be responsible for our findings. The reduction of sensitivity thresholds might be due to a sensitizing effect of lactulose at colonic level, but this is not the case, because it should also be present in healthy volunteers. Moreover, we measured sensitivity thresholds at rectal level, when gas production was taking place at cecum level; this excluded the role of an irritating effect of gas at the site of the measurement. Besides gas, hypersensitivity to fermentation might be due to the release of other fermentation products, mainly short-chain fatty acids (SCFAs). Colonic perfusion of SCFAs induces a reduction of gastric tone,10Ropert A. Cherbut C. Roze C. et al.Colonic fermentation and proximal gastric tone in humans.Gastroenterology. 1996; 111: 289-296Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar suggesting the activation of the mucosal chemoreceptor is able to interfere with remote viscera. There is no study dealing with the effect of SCFAs on intestinal sensitivity, so we can only hypothesize a possible role in symptom occurrence. However, a strict relationship was recently shown between visceral perception and parietal tone, because increased parietal tone enhances perception of motor activity.33Piessevaux H. Tack J. Wilmer A. et al.Perception of changes in wall tension of the proximal stomach in humans.Gut. 2001; 49: 203-208Crossref PubMed Scopus (99) Google Scholar Perfusion of SCFAs in the proximal colon accelerates colonic transit, inducing propulsive high-amplitude contractions migrating from mid to distal colon.34Fukumoto S. Tatewaki M. Yamada T. et al.Short-chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats.Am J Physiol Regul Integr Comp Physiol. 2003; 284: R1269-R1276PubMed Google Scholar It is, therefore, possible that increased parietal tone associated with high-amplitude contractions might mediate an increased local sensitivity. SCFAs might also act through a pH reduction, but we think this was not the case, because colonic perfusion of SCFA solution at a controlled pH of 5.6–6.1 showed a similar effect on gastric tone to oral administration of lactulose.10Ropert A. Cherbut C. Roze C. et al.Colonic fermentation and proximal gastric tone in humans.Gastroenterology. 1996; 111: 289-296Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar Moreover, an HCl solution at the same pH as the SCFA solution (pH, 2.8) had no stimulatory effect on colonic transit, disproving a pH-dependent effect.34Fukumoto S. Tatewaki M. Yamada T. et al.Short-chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats.Am J Physiol Regul Integr Comp Physiol. 2003; 284: R1269-R1276PubMed Google Scholar Whether intraluminal gas modifies sensitivity thresholds by acting on chemoreceptors or mechanoreceptors cannot be clarified from our results. Because esophageal, antropyloric, and duodenal mechanic distention exerts a similar effect at gastric level,11De Ponti F. Azpiroz F. Malagelada J.R. Relaxatory response of canine proximal stomach to esophageal and duodenal distension.Dig Dis Sci. 1989; 34: 873-881Crossref PubMed Scopus (49) Google Scholar, 12Azpiroz F. Malagelada J.R. Perception and reflex relaxation of the stomach in response to gut distension.Gastroenterology. 1990; 98: 1193-1198PubMed Scopus (112) Google Scholar, 13De Ponti F. Azpiroz F. Mlagelada J.R. Reflex gastric relaxation in response to distension of the duodenum.Am J Physiol. 1987; 252: G595-G601PubMed Google Scholar it could be argued that similar results might be due to the mere distention of the viscera as a result of the increased content of intraluminal gas and not to the nature of what distends the viscera. In our opinion this is not the case, because if distention is the triggering stimulus, a similar stimulus was also applied to the healthy volunteers, who did not exhibit threshold variations. Moreover, it was previously shown that a very brief period of time is present between the increase of colonic gas production and gastric tone reduction, suggesting that gastric dilation takes place when small amounts of gas are produced and, therefore, a chemoreceptor rather than a mechanoreceptor activation.10Ropert A. Cherbut C. Roze C. et al.Colonic fermentation and proximal gastric tone in humans.Gastroenterology. 1996; 111: 289-296Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar Moreover, the amount of intraluminal hydrogen in low producers was very low. A subject with a cumulative hydrogen excretion of 5000 ppm/min produces about 0.1 mL of hydrogen per minute, thus a value of 48 mL during the 240 minutes of the test, about 50% of which is reabsorbed and excreted with breath.35Christl S.U. Murgatroyd P.R. Gibson G.R. et al.Production, metabolism and excretion of hydrogen in the large intestine.Gastroenterology. 1992; 102: 1269-1277PubMed Google Scholar Therefore, it seems unlikely that such a small amount of gas can be responsible for bowel distention. In conclusion, a subgroup of patients with functional disorders and hypersensitivity to colonic fermentation might exist. Further studies are needed to better explain which neural pathway will represent the target for treatment in this condition.