Anna Accarino

Selective dysfunction of mechanosensitive intestinal afferents in irritable bowel syndrome

BACKGROUND/AIMS Experimental studies have shown gut hypersensitivity in irritable bowel syndrome. The aim of this study was to determine whether heightened perception of gut distention in irritable bowel syndrome is related to either decreased gut compliance, altered mechanosensitive afferents, or nonspecific sensory dysfunction. METHODS In 17 patients with irritable bowel syndrome and 15 healthy controls, stimulus-related perception of (1) intestinal balloon distentions, (2) transmucosal electrical nerve stimulation (15 Hz, 100 microseconds), and (3) somatic transcutaneous electrical nerve stimulation (100 Hz, 100 microseconds) was measured. Individual stimuli of 1-minute duration were randomly applied at 5-minute intervals. RESULTS Patients tolerated smaller intestinal volumes than controls (33 +/- 3 mL vs. 43 +/- 4 mL, respectively; mean +/- SE; P < 0.05), whereas both intestinal compliance and perception of transmucosal electrical nerve stimulation were normal (patients tolerated 58 +/- 5 mA and healthy subjects tolerated 69 +/- 5 mA). Interestingly, patients perceived both stimuli more diffusely than controls; 48% +/- 9% distentions and 52% +/- 9% electrical stimuli were perceived over more than one abdominal region vs. 21% +/- 9% and 18% +/- 6%, respectively, in controls (P < 0.05 for both). In contrast to gut distentions, patients showed higher tolerance of somatic stimuli than controls (68 +/- 7 mA vs. 42 +/- 6 mA, respectively; P < 0.05). CONCLUSIONS Patients with irritable bowel syndrome show selective hypersensitivity of intestinal mechanosensitive pathways associated with a nonspecific, probably central dysfunction of viscerosomatic referral.

Abdominal Distention Results From Caudo-ventral Redistribution of Contents

BACKGROUND & AIMS Abdominal bloating is a frequent symptom in various categories of patients; however, its origin is unclear. Our aim was to establish the mechanisms of abdominal bloating. METHODS The study evaluated 56 patients whose predominant symptom was abdominal bloating. Of these, 47 (44 female and 3 male; aged 19-74 years) were diagnosed with functional intestinal disorder by Rome II criteria and 9 (7 female and 2 male; aged 18-64 years) were diagnosed with intestinal dysmotility by gastrointestinal manometry. Computed tomographic scans were obtained before (basal level) and during a severe bloating episode. Control scans were also obtained from 12 healthy subjects (11 female and 1 male; aged 19-62 years). Morpho-volumetric differences between basal and severe bloating scans were measured using an original computer analysis program. RESULTS During severe bloating, patients with dysmotility exhibited anterior wall protrusion (23 +/- 4 mm; P < .001 vs basal) associated with a marked increase in total abdominal volume (1.4 +/- 0.3 L; P = .002 vs basal) and with cephalic displacement of the diaphragm. By contrast, in patients with functional intestinal disorder, total abdominal volume barely increased (0.3 +/- 0.1 L; P < .001 vs dysmotility); in these patients, abdominal distention (14 +/- 2 mm anterior wall protrusion; P < .001 vs basal) was related to diaphragmatic descent (-12 +/- 3 mm; R = -0.62; P < .001). CONCLUSIONS Abdominal distention might be caused by an increase in intra-abdominal volume or abdomino-phrenic displacement and ventro-caudal redistribution of contents.

New insight into intestinal motor function via noninvasive endoluminal image analysis.

BACKGROUND & AIMS Evaluation of small bowel motility by intestinal manometry is invasive and requires expertise for interpretation. Our aim was to use capsule technology for evaluation of small bowel motor function based on a fully computerized image analysis program. METHODS Thirty-six consecutive patients with severe intestinal motor disorders (19 fulfilling manometric criteria of intestinal dysmotility and 17 not) and 50 healthy subjects received the endoscopic capsule (Pillcam; Given Imaging, Yokneam, Israel). Endoluminal image analysis was performed with a computer vision program specifically developed for the detection of contractile patterns (phasic luminal closure and radial wrinkles by wall texture analysis), noncontractile patterns (tunnel and wall appearance by Laplacian filtering), intestinal content (by color decomposition analysis), and endoluminal motion (by chromatic stability). Automatic classification of normal and abnormal intestinal motility was performed by means of a machine-learning technique. RESULTS As compared with healthy subjects, patients exhibited less contractile activity (25% less phasic luminal closures, P < .05) and more noncontractile patterns (151% more tunnel pattern, P < .05), static sequences (56% more static images, P < .01), and turbid intestinal content (94% more static turbid images, P < .01). On cross validation, the classifier identified as abnormal all but 1 patient with manometric criteria of dysmotility and as normal all healthy subjects. Out of the 17 patients without manometric criteria of dysmotility, 11 were identified as abnormal and 6 as normal. CONCLUSIONS Our study shows that endoluminal image analysis, by means of computer vision and machine-learning techniques, constitutes a reliable, noninvasive, and automated diagnostic test of intestinal motor disorders.

Modification of small bowel mechanosensitivity by intestinal fat

BACKGROUND Lipids may exacerbate symptoms induced by gut stimuli. AIM To determine the mechanism whereby fat exerts this effect. SUBJECTS Twenty four healthy subjects were studied during fasting. METHODS We measured perception (0–6 scale) in response to jejunal balloon distension and transmucosal electrical nerve stimulation; phasic stimuli (one minute) were randomly applied at five minute intervals during intestinal infusion (2 ml/min) of saline and then Intralipid 2 kcal/min (high fat; n=8 subjects), Intralipid 0.5 kcal/min (low fat; n=8), or saline (n=8). RESULTS Intestinal lipids increased the perception of jejunal distension regardless of concentration (by 53% with high fat, 49% with low fat, and 17% with saline; p<0.05 for both fat loads). This effect could not be attributed to changes in intestinal compliance as intraballoon pressures remained unchanged during lipid infusion (2% change; NS). Sensitisation induced by lipids seemed to be specifically related to intestinal mechanoreceptors because electrical stimulation, which non-specifically activates gut afferents, was perceived equally during saline and lipid administration (10%, 11%, and 15% change during high fat, low fat, and saline, respectively; NS). CONCLUSION Physiological amounts of lipids heighten intestinal sensitivity by modulating intestinal mechanoreceptor response.

Reduction of butyrate- and methane-producing microorganisms in patients with Irritable Bowel Syndrome.

The pathophysiology of irritable bowel syndrome (IBS) remains unclear. Here we investigated the microbiome of a large cohort of patients to identify specific signatures for IBS subtypes. We examined the microbiome of 113 patients with IBS and 66 healthy controls. A subset of these participants provided two samples one month apart. We analyzed a total of 273 fecal samples, generating more than 20 million 16S rRNA sequences. In patients with IBS, a significantly lower microbial diversity was associated with a lower relative abundance of butyrate-producing bacteria (P = 0.002; q < 0.06), in particular in patients with IBS-D and IBS-M. IBS patients who did not receive any treatment harboured a lower abundance of Methanobacteria compared to healthy controls (P = 0.005; q = 0.05). Furthermore, significant correlations were observed between several bacterial taxa and sensation of flatulence and abdominal pain (P < 0.05). Altogether, our findings showed that IBS-M and IBS-D patients are characterized by a reduction of butyrate producing bacteria, known to improve intestinal barrier function, and a reduction of methane producing microorganisms a major mechanism of hydrogen disposal in the human colon, which could explain excess of abdominal gas in IBS.

Anal gas evacuation and colonic microbiota in patients with flatulence: effect of diet

Objective To characterise the influence of diet on abdominal symptoms, anal gas evacuation, intestinal gas distribution and colonic microbiota in patients complaining of flatulence. Design Patients complaining of flatulence (n=30) and healthy subjects (n=20) were instructed to follow their usual diet for 3 days (basal phase) and to consume a high-flatulogenic diet for another 3 days (challenge phase). Results During basal phase, patients recorded more abdominal symptoms than healthy subjects in daily questionnaires (5.8±0.3 vs 0.4±0.2 mean discomfort/pain score, respectively; p=<0.0001) and more gas evacuations by an event marker (21.9±2.8 vs 7.4±1.0 daytime evacuations, respectively; p=0.0001), without differences in the volume of gas evacuated after a standard meal (262±22 and 265±25 mL, respectively). On flatulogenic diet, both groups recorded more abdominal symptoms (7.9±0.3 and 2.8±0.4 discomfort/pain, respectively), number of gas evacuations (44.4±5.3 and 21.7±2.9 daytime evacuations, respectively) and had more gas production (656±52 and 673±78 mL, respectively; p<0.05 vs basal diet for all). When challenged with flatulogenic diet, patients’ microbiota developed instability in composition, exhibiting variations in the main phyla and reduction of microbial diversity, whereas healthy subjects’ microbiota were stable. Taxa from Bacteroides fragilis or Bilophila wadsworthia correlated with number of gas evacuations or volume of gas evacuated, respectively. Conclusions Patients complaining of flatulence have a poor tolerance of intestinal gas, which is associated with instability of the microbial ecosystem.

Impaired intestinal gas propulsion in manometrically proven dysmotility and in irritable bowel syndrome

Background  Intestinal manometry is the current gold standard for diagnosing small bowel dysmotility; however, the functional significance of abnormal manometry is unknown. Our aim was to determine whether, and to what extent, intestinal gas propulsion is impaired in patients with manometrically proven dysmotility compared with healthy controls and patients with IBS.

Gas Distribution Within the Human Gut: Effect of Meals

BACKGROUND AND AIMS: Patients frequently complain of gas symptoms precipitated by meals, but the effect of early digestion on intestinal gas content remains unknown. Our aim was to determine the influence of meals on intestinal gas volume and distribution.METHODS:First, we developed a CT image analysis program, based on independent software modules, to measure gas content within the gut. The system was validated in nine healthy subjects by taking helical abdominal CT scans before and after rectal infusion of known volumes of air (100–400 mL). In 15 healthy subjects, intestinal gas distribution was measured in fast and early postcibal CT scans. The postcibal scan was taken 99 ± 22 minutes after a 597 ± 57 kcal meal.RESULTS:The volume of gas infused per rectum was detected with an accuracy of 100.4 ± 3.0%. During fasting, intestinal gas volume was 94 ± 7 mL (excluding two extreme outliers). After the meal, gas content within the gut increased by 64.7% (up to 149 ± 21 mL, P < 0.01 vs fast) and the increment occurred in the colon (59 ± 9 mL precibal vs 121 ± 20 mL postcibal, P < 0.001), while other gut compartments remained unchanged.CONCLUSION:Ingestion of a meal activated gas metabolism and increased gas content within the gut. The increment occurred early, presumably prior to colonic fermentation of food substrates and was localized in the distal gut, suggesting that gas had a proximal origin and was propelled caudally.

Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy

Haematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of all known patients suffering from mitochondrial neurogastrointestinal encephalomyopathy who underwent allogeneic haematopoietic stem cell transplantation between 2005 and 2011. Twenty-four patients, 11 males and 13 females, median age 25 years (range 10-41 years) treated with haematopoietic stem cell transplantation from related (n = 9) or unrelated donors (n = 15) in 15 institutions worldwide were analysed for outcome and its associated factors. Overall, 9 of 24 patients (37.5%) were alive at last follow-up with a median follow-up of these surviving patients of 1430 days. Deaths were attributed to transplant in nine (including two after a second transplant due to graft failure), and to mitochondrial neurogastrointestinal encephalomyopathy in six patients. Thymidine phosphorylase activity rose from undetectable to normal levels (median 697 nmol/h/mg protein, range 262-1285) in all survivors. Seven patients (29%) who were engrafted and living more than 2 years after transplantation, showed improvement of body mass index, gastrointestinal manifestations, and peripheral neuropathy. Univariate statistical analysis demonstrated that survival was associated with two defined pre-transplant characteristics: human leukocyte antigen match (10/10 versus <10/10) and disease characteristics (liver disease, history of gastrointestinal pseudo-obstruction or both). Allogeneic haematopoietic stem cell transplantation can restore thymidine phosphorylase enzyme function in patients with mitochondrial neurogastrointestinal encephalomyopathy and improve clinical manifestations of mitochondrial neurogastrointestinal encephalomyopathy in the long term. Allogeneic haematopoietic stem cell transplantation should be considered for selected patients with an optimal donor.

Anal gas evacuation and colonic microbiota in patients with flatulence

Objective To characterise the influence of diet on abdominal symptoms, anal gas evacuation, intestinal gas distribution and colonic microbiota in patients complaining of flatulence. Design Patients complaining of flatulence (n=30) and healthy subjects (n=20) were instructed to follow their usual diet for 3 days (basal phase) and to consume a high-flatulogenic diet for another 3 days (challenge phase). Results During basal phase, patients recorded more abdominal symptoms than healthy subjects in daily questionnaires (5.8±0.3 vs 0.4±0.2 mean discomfort/pain score, respectively; p=<0.0001) and more gas evacuations by an event marker (21.9±2.8 vs 7.4±1.0 daytime evacuations, respectively; p=0.0001), without differences in the volume of gas evacuated after a standard meal (262±22 and 265±25 mL, respectively). On flatulogenic diet, both groups recorded more abdominal symptoms (7.9±0.3 and 2.8±0.4 discomfort/pain, respectively), number of gas evacuations (44.4±5.3 and 21.7±2.9 daytime evacuations, respectively) and had more gas production (656±52 and 673±78 mL, respectively; p<0.05 vs basal diet for all). When challenged with flatulogenic diet, patients’ microbiota developed instability in composition, exhibiting variations in the main phyla and reduction of microbial diversity, whereas healthy subjects’ microbiota were stable. Taxa from Bacteroides fragilis or Bilophila wadsworthia correlated with number of gas evacuations or volume of gas evacuated, respectively. Conclusions Patients complaining of flatulence have a poor tolerance of intestinal gas, which is associated with instability of the microbial ecosystem.