- Email: [email protected]
370 AJM300, an Oral α4 Integrin Antagonist, for Active Ulcerative Colitis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2A Study
compared with t-test for continuous variables (i.e., age) and chi-squared test for categorical variables (i.e., gender, body mass index, IBS subtype). Intragroup differences of IBS symptoms, evaluated pre- and post-diet, were assessed with paired t-test, intergroup differences with one-way ANOVA with post-hoc Tukey multiple comparison test. Results. Baseline socio-demographic and clinical characteristics did not differ between the three groups. After the diets, FOD-NG and FOD-GF groups showed a significant improvement of bloating, abdominal distension, and pain (p-values equal to 0.000 in the former group and from 0.001 to 0.008 in the latter), whereas the controls had a slight, but not significant, improvement. One-way ANOVA showed comparable severity of bloating and frequency of abdominal distension/pain in the three groups pre-diet (p=0.217), but a difference in the same symptoms post-diet (p=0.000). Tukey test showed a greater improvement of IBS symptoms in the two test diet groups vs. the controls, and only a trend favoring the FOD-NG group vs. the FODGF group. Conclusions. IBS patients have considerable benefit of restricting FODMAPs in the diet. Gluten avoidance in addition to a FODMAP restricted diet does not seem to add any significant benefit. 1) Halmos EP et al., Gastroenterology 2013; 2) Catassi C et al., Nutrients 2013.
AGA Abstracts
ductal tree (arrowhead), and growing into the islet. Similarly, DNTβRII pancreas (D-F) regeneration model show extensive ductal network within the islets and numerous BrdU+/ insulin+ cells and duct cells in the islet (dotted circle) (inset shows magnified confocal view)
375 AAV6-Sox9-cre viral duct infusion technique showed a high level of duct lineage labeling on whole mount (A,B) and section (c). In comparison to sham control (D) partial pancreatectomy DNTβRII pancreas (E) showed duct lineage-tagged intra-islet cells (red) appear as yellow beta cells when stained for insulin in green with confocal imaging (arrows)
Human Gut Microbial Clusters Correlate With Anatomical Brain Signatures: A Pilot Study Jennifer S. Labus, Emeran A. Mayer, Muriel Derrien, Johan E. Van Hylckama Vlieg, Boris Le Nevé, Denis Guyonnet, Remi Brazeilles, John D. Van Horn, Carinna Torgerson, Cody Ashe-McNalley, Kirsten Tillisch
370
Introduction: The role of the gut microbiota in brain function is of increasing interest. Preclinical studies show that gut microbes influence affective behaviors as well as brain neurochemistry. It is unknown if patterns of predominant microbial composition, such as previously described Prevotella and Bacteroides dominant clusters, are associated with distinct neural circuitry. In this study of healthy women we combine analysis of large-scale anatomical brain connectivity using multivariate pattern analysis recognition methods with analysis of stool microbial composition. Methods. Stool samples were collected from 40 healthy women. 16s RNA profiling was performed and analyzed using QIIME. Weighted Unifrac distance was used to identify stool microbial clusters. Structural and diffusion tensor imaging (DTI) brain images were obtained. Segmentation and regional parcellation (165 regions) was performed in Freesurfer. Regional gray matter metrics included volume, cortical thickness, surface area and mean curvature. Deterministic tractography using TrackVis measured fiber density between regions. Sparse Partial Least Square-Discrimination Analysis was applied to discriminate microbiota clusters using structural and DTI-connectivity data. Results: Microbial clustering revealed two microbiota clusters, supported by a coefficient (Silhouette index >0.4). The two clusters were as previously demonstrated i.e a Prevotella dominant (n=7) and a Bacteroides dominant (n=33). The gray matter based classifier with two brain signatures/components comprising 5 gray matter metrics achieved greater than 90% accuracy in discriminating the two microbial clusters based on leave one out cross-validation. Signature 1, comprised by left (L) cerebellum, L nucleus accumbens, and right (R) anterior occipital sulcus volumes and cortical thickness in the R fronto-marginal gyrus, explained 46% of the variance. Signature 2, explaining an additional 26% of variance, was comprised of L inferior precentral sulcus and R tranverse frontopolar gyri volumes, and mean curvature of the L frontomarginal gyrus, superior temporal gyrus and intermedius sulcus. The DTI-based classifier showed 2 brain signatures comprised by 5 connectivities each with > 90% accuracy in discriminating clusters. Bidirectional connectivities included L nucleus accumbens to orbital gyrus, R orbital gyrus to R gyrus rectus, R pallidum to R anterior cingulate sulcus and gyrus, and L mid posterior cingulate gyrus to L postecentral gyrus. The two signatures accounted for 87% of the variance in the data set. Conclusions. In this pilot study in healthy women, a relationship between aspects of brain structure and microbial composition was observed. If confirmed in a larger sample, these data may provide new mechanistic insights into the relationship between brain structure and gut microbiota.
AJM300, an Oral α4 Integrin Antagonist, for Active Ulcerative Colitis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2A Study Mamoru Watanabe, Naoki Yoshimura, Satoshi Motoya, Keiichi Tominaga, Ryuichi Iwakiri, Kenji Watanabe, Toshifumi Hibi Introduction: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. Selective inhibition of lymphocyte trafficking has been proven a promising treatment for UC, although all the drug candidates are monoclonal antibodies. AJM300, an orally active, small molecule α4 integrin antagonist, is known to inhibit the binding of α4β1/α4β7 integrin-expressing cells to VCAM-1/MAdCAM-1, and evaluated in patients with moderately active UC. Methods: A multicenter, randomized, double-blind, placebo-controlled phase 2a study was conducted to evaluate the efficacy and safety of AJM300 in 102 Japanese patients with moderately active UC. Patients with the Mayo Clinic score of 6-10, an endoscopic subscore ≥2 and a rectal bleeding subscore ≥1 were enrolled. An additional inclusion criterion was documentation of inadequate response or intolerance to 5-ASA or corticoids. Patients were randomly assigned to receive AJM300 at a dose of 960 mg or placebo three times daily for 8 weeks. The primary endpoint was a clinical response at week 8, defined as a reduction of the Mayo Clinic score of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. The key secondary endpoints were clinical remission (defined as the Mayo Clinic score ≤ 2, with no subscore >1) and mucosal healing (defined as an endoscopic subscore of 0 or 1) at week 8. These endpoints were analyzed with logistic regression adjusted for stratification factor. Results: The primary endpoint, clinical response at week 8, was 62.7% versus 25.5% in the AJM300 group and placebo group, respectively (odds ratio [OR], 5.35; 95% confidence interval [CI], 2.23 to 12.82; p=0.0002). The secondary endpoints, clinical remission at week 8 was 23.5% versus 3.9% (OR, 7.81; 95% CI, 1.64 to 37.24; P=0.0099), and mucosal healing at week 8 was 58.8% versus 29.4% (OR, 4.65; 95% CI, 1.81 to 11.90; P=0.0014) in the AJM300 group and placebo group, respectively. A significant increase in peripheral lymphocyte counts (as the pharmacodynamics) at week 2 (mean, 2655/μL versus 1810/μL in the AJM300 group and placebo group, respectively; difference, 845/μL; 95% CI, 467 to 1222) and week 4 (mean, 2746/μL versus 1759/μL; difference, 986/μL; 95% CI, 638 to 1335) was observed in the AJM300 group only, without any change in neutrophil counts. Neither serious adverse event (including PML) nor serious infection was observed. Although more cases showed the abnormal laboratory test values in the AJM300 group, all the changes were mild and recovered without any treatment. Conclusion: This is the first study that demonstrated the clinical benefit of an oral α4 integrin antagonist for inflammatory bowel disease. AJM300 is well tolerable and significantly effective in patients with moderately active UC.
388 Effects of the Herbal Drug STW 5 and Its Individual Components on Human Intestinal Motility Shady Allam, Dagmar Krueger, Olaf Kelber, Ihsan Ekin Demir, Gueralp O. Ceyhan, Florian Zeller, Michael Schemann Background and Aims: STW5 consists of hydroethanolic extracts from iberis amara, chamomile, peppermint, caraway, liquorice, lemon balm, angelica, greater celandine and milk thistle and is clinically used to treat functional gut disorders. We recently reported that STW5 and the individual extracts have region-specific effects in guinea pig stomach and increase intestinal chloride secretion. These actions may be involved in its clinical efficacy. We now studied the so far unknown effects of STW5 and its components on human intestinal motility. Methods: In vitro motility effects of STW5 were studied in 575 circular (CM) or longitudinal muscle (LM) strip preparations of human small or large intestinal specimens from 114 patients undergoing abdominal surgery. Parameters were tonic contractions (muscle tone, MT) and phasic contractions (Motility index, MI). Results: STW5 significantly and dose dependently (64-5120μg/ml) reduced MT. Effects were more predominant in large vs. small intestine and in CM vs. LM. At 5120μg/ml (which is still sub-therapeutic), STW5 had regionspecific effects on MI reduction of duodenum and jejunum (66.1±16.2%, n=6, p=0.004 vs. ileum CM, -35.3±80.2%, n=6, p=0.6). Both regions showed comparable reduction in MT (-5.5±2.2 vs. -6.8±1.1mN respectively n=6, p=0.6). In large intestinal CM; MI was transiently increased (158.9±40.6%, n=11, p<0.05) followed by a complete inhibition of phasic contractility. Reduction in MT was significantly higher in large than in small intestine (-13.8±3.4 vs. -6.2±1.2mN, n=12, p=0.01). In small intestine, all extracts (except milk thistle and iberis amara) reduced MT and MI. In duodenum and jejunum, G.celandine increased MI by 119.4±85.4% (n=9, p=0.001) but decreased MI in the ileum (35.5±14.1%, n=7, p=0.001). In large intestine, peppermint, liquorice and angelica reduced MT and MI, thereby mimicking STW5 actions. Additionally, caraway and lemon balm decreased MT while G.celandine increased it. The spasmolytic effect of STW5 was significantly inhibited by the TRPA1 blocker HC030031, a blocker of SOCs (SK&F96365) and a TRPC3 antagonist (Pyr3, all 10μM) by
374 Effects of Low-Fodmap and Gluten-Free Diets in Irritable Bowel Syndrome Patients. A Double-Blind Randomized Controlled Clinical Study Daria Piacentino, Sara Rossi, Valeria Alvino, Rosanna Cantarini, Danilo Badiali, Nadia Pallotta, Enrico Corazziari There is increasing evidence of the efficacy of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) for the treatment of Irritable Bowel Syndrome (IBS) [1]. It has also been observed that non-celiac patients with IBS-like symptoms may benefit of a gluten-free diet, being indicative of non-celiac gluten sensitivity (NCGS). The overlap between IBS and NCGS is not infrequent [2]. Aim. To assess in IBS patients the effect on bloating, abdominal distension, and abdominal pain of three types of diet: 1) low FODMAP and gluten-free (FOD-GF); 2) low-FODMAP and normal-gluten (FOD-NG); 3) normal-FODMAP and normal-gluten (controls). Subjects and Methods. Sixty IBS outpatients (F=37, age range=21-67 years), matching Rome III criteria, were consecutively recruited. At enrollment, patients filled out a visual analogue scale (VAS), ranging from 0 ("no or mild bloating") to 10 ("very severe bloating"), to rate the severity of bloating and a 2-week daily diary card to calculate the number of days with abdominal distension or pain. At the end of the diary completion, they were randomly and blindly assigned to one of the three dietary protocols (20 patients to each), which they followed for 4 weeks. During the last 2 weeks of the diet they filled out a second diary card and at the end they rated again the severity of bloating. All data were analyzed by an investigator blinded to the diet assignment. Baseline socio-demographic and clinical characteristics of the three groups were
AGA Abstracts
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AGA Abstracts
ductal tree (arrowhead), and growing into the islet. Similarly, DNTβRII pancreas (D-F) regeneration model show extensive ductal network within the islets and numerous BrdU+/ insulin+ cells and duct cells in the islet (dotted circle) (inset shows magnified confocal view)
375 AAV6-Sox9-cre viral duct infusion technique showed a high level of duct lineage labeling on whole mount (A,B) and section (c). In comparison to sham control (D) partial pancreatectomy DNTβRII pancreas (E) showed duct lineage-tagged intra-islet cells (red) appear as yellow beta cells when stained for insulin in green with confocal imaging (arrows)
Human Gut Microbial Clusters Correlate With Anatomical Brain Signatures: A Pilot Study Jennifer S. Labus, Emeran A. Mayer, Muriel Derrien, Johan E. Van Hylckama Vlieg, Boris Le Nevé, Denis Guyonnet, Remi Brazeilles, John D. Van Horn, Carinna Torgerson, Cody Ashe-McNalley, Kirsten Tillisch
370
Introduction: The role of the gut microbiota in brain function is of increasing interest. Preclinical studies show that gut microbes influence affective behaviors as well as brain neurochemistry. It is unknown if patterns of predominant microbial composition, such as previously described Prevotella and Bacteroides dominant clusters, are associated with distinct neural circuitry. In this study of healthy women we combine analysis of large-scale anatomical brain connectivity using multivariate pattern analysis recognition methods with analysis of stool microbial composition. Methods. Stool samples were collected from 40 healthy women. 16s RNA profiling was performed and analyzed using QIIME. Weighted Unifrac distance was used to identify stool microbial clusters. Structural and diffusion tensor imaging (DTI) brain images were obtained. Segmentation and regional parcellation (165 regions) was performed in Freesurfer. Regional gray matter metrics included volume, cortical thickness, surface area and mean curvature. Deterministic tractography using TrackVis measured fiber density between regions. Sparse Partial Least Square-Discrimination Analysis was applied to discriminate microbiota clusters using structural and DTI-connectivity data. Results: Microbial clustering revealed two microbiota clusters, supported by a coefficient (Silhouette index >0.4). The two clusters were as previously demonstrated i.e a Prevotella dominant (n=7) and a Bacteroides dominant (n=33). The gray matter based classifier with two brain signatures/components comprising 5 gray matter metrics achieved greater than 90% accuracy in discriminating the two microbial clusters based on leave one out cross-validation. Signature 1, comprised by left (L) cerebellum, L nucleus accumbens, and right (R) anterior occipital sulcus volumes and cortical thickness in the R fronto-marginal gyrus, explained 46% of the variance. Signature 2, explaining an additional 26% of variance, was comprised of L inferior precentral sulcus and R tranverse frontopolar gyri volumes, and mean curvature of the L frontomarginal gyrus, superior temporal gyrus and intermedius sulcus. The DTI-based classifier showed 2 brain signatures comprised by 5 connectivities each with > 90% accuracy in discriminating clusters. Bidirectional connectivities included L nucleus accumbens to orbital gyrus, R orbital gyrus to R gyrus rectus, R pallidum to R anterior cingulate sulcus and gyrus, and L mid posterior cingulate gyrus to L postecentral gyrus. The two signatures accounted for 87% of the variance in the data set. Conclusions. In this pilot study in healthy women, a relationship between aspects of brain structure and microbial composition was observed. If confirmed in a larger sample, these data may provide new mechanistic insights into the relationship between brain structure and gut microbiota.
AJM300, an Oral α4 Integrin Antagonist, for Active Ulcerative Colitis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2A Study Mamoru Watanabe, Naoki Yoshimura, Satoshi Motoya, Keiichi Tominaga, Ryuichi Iwakiri, Kenji Watanabe, Toshifumi Hibi Introduction: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. Selective inhibition of lymphocyte trafficking has been proven a promising treatment for UC, although all the drug candidates are monoclonal antibodies. AJM300, an orally active, small molecule α4 integrin antagonist, is known to inhibit the binding of α4β1/α4β7 integrin-expressing cells to VCAM-1/MAdCAM-1, and evaluated in patients with moderately active UC. Methods: A multicenter, randomized, double-blind, placebo-controlled phase 2a study was conducted to evaluate the efficacy and safety of AJM300 in 102 Japanese patients with moderately active UC. Patients with the Mayo Clinic score of 6-10, an endoscopic subscore ≥2 and a rectal bleeding subscore ≥1 were enrolled. An additional inclusion criterion was documentation of inadequate response or intolerance to 5-ASA or corticoids. Patients were randomly assigned to receive AJM300 at a dose of 960 mg or placebo three times daily for 8 weeks. The primary endpoint was a clinical response at week 8, defined as a reduction of the Mayo Clinic score of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. The key secondary endpoints were clinical remission (defined as the Mayo Clinic score ≤ 2, with no subscore >1) and mucosal healing (defined as an endoscopic subscore of 0 or 1) at week 8. These endpoints were analyzed with logistic regression adjusted for stratification factor. Results: The primary endpoint, clinical response at week 8, was 62.7% versus 25.5% in the AJM300 group and placebo group, respectively (odds ratio [OR], 5.35; 95% confidence interval [CI], 2.23 to 12.82; p=0.0002). The secondary endpoints, clinical remission at week 8 was 23.5% versus 3.9% (OR, 7.81; 95% CI, 1.64 to 37.24; P=0.0099), and mucosal healing at week 8 was 58.8% versus 29.4% (OR, 4.65; 95% CI, 1.81 to 11.90; P=0.0014) in the AJM300 group and placebo group, respectively. A significant increase in peripheral lymphocyte counts (as the pharmacodynamics) at week 2 (mean, 2655/μL versus 1810/μL in the AJM300 group and placebo group, respectively; difference, 845/μL; 95% CI, 467 to 1222) and week 4 (mean, 2746/μL versus 1759/μL; difference, 986/μL; 95% CI, 638 to 1335) was observed in the AJM300 group only, without any change in neutrophil counts. Neither serious adverse event (including PML) nor serious infection was observed. Although more cases showed the abnormal laboratory test values in the AJM300 group, all the changes were mild and recovered without any treatment. Conclusion: This is the first study that demonstrated the clinical benefit of an oral α4 integrin antagonist for inflammatory bowel disease. AJM300 is well tolerable and significantly effective in patients with moderately active UC.
388 Effects of the Herbal Drug STW 5 and Its Individual Components on Human Intestinal Motility Shady Allam, Dagmar Krueger, Olaf Kelber, Ihsan Ekin Demir, Gueralp O. Ceyhan, Florian Zeller, Michael Schemann Background and Aims: STW5 consists of hydroethanolic extracts from iberis amara, chamomile, peppermint, caraway, liquorice, lemon balm, angelica, greater celandine and milk thistle and is clinically used to treat functional gut disorders. We recently reported that STW5 and the individual extracts have region-specific effects in guinea pig stomach and increase intestinal chloride secretion. These actions may be involved in its clinical efficacy. We now studied the so far unknown effects of STW5 and its components on human intestinal motility. Methods: In vitro motility effects of STW5 were studied in 575 circular (CM) or longitudinal muscle (LM) strip preparations of human small or large intestinal specimens from 114 patients undergoing abdominal surgery. Parameters were tonic contractions (muscle tone, MT) and phasic contractions (Motility index, MI). Results: STW5 significantly and dose dependently (64-5120μg/ml) reduced MT. Effects were more predominant in large vs. small intestine and in CM vs. LM. At 5120μg/ml (which is still sub-therapeutic), STW5 had regionspecific effects on MI reduction of duodenum and jejunum (66.1±16.2%, n=6, p=0.004 vs. ileum CM, -35.3±80.2%, n=6, p=0.6). Both regions showed comparable reduction in MT (-5.5±2.2 vs. -6.8±1.1mN respectively n=6, p=0.6). In large intestinal CM; MI was transiently increased (158.9±40.6%, n=11, p<0.05) followed by a complete inhibition of phasic contractility. Reduction in MT was significantly higher in large than in small intestine (-13.8±3.4 vs. -6.2±1.2mN, n=12, p=0.01). In small intestine, all extracts (except milk thistle and iberis amara) reduced MT and MI. In duodenum and jejunum, G.celandine increased MI by 119.4±85.4% (n=9, p=0.001) but decreased MI in the ileum (35.5±14.1%, n=7, p=0.001). In large intestine, peppermint, liquorice and angelica reduced MT and MI, thereby mimicking STW5 actions. Additionally, caraway and lemon balm decreased MT while G.celandine increased it. The spasmolytic effect of STW5 was significantly inhibited by the TRPA1 blocker HC030031, a blocker of SOCs (SK&F96365) and a TRPC3 antagonist (Pyr3, all 10μM) by
374 Effects of Low-Fodmap and Gluten-Free Diets in Irritable Bowel Syndrome Patients. A Double-Blind Randomized Controlled Clinical Study Daria Piacentino, Sara Rossi, Valeria Alvino, Rosanna Cantarini, Danilo Badiali, Nadia Pallotta, Enrico Corazziari There is increasing evidence of the efficacy of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) for the treatment of Irritable Bowel Syndrome (IBS) [1]. It has also been observed that non-celiac patients with IBS-like symptoms may benefit of a gluten-free diet, being indicative of non-celiac gluten sensitivity (NCGS). The overlap between IBS and NCGS is not infrequent [2]. Aim. To assess in IBS patients the effect on bloating, abdominal distension, and abdominal pain of three types of diet: 1) low FODMAP and gluten-free (FOD-GF); 2) low-FODMAP and normal-gluten (FOD-NG); 3) normal-FODMAP and normal-gluten (controls). Subjects and Methods. Sixty IBS outpatients (F=37, age range=21-67 years), matching Rome III criteria, were consecutively recruited. At enrollment, patients filled out a visual analogue scale (VAS), ranging from 0 ("no or mild bloating") to 10 ("very severe bloating"), to rate the severity of bloating and a 2-week daily diary card to calculate the number of days with abdominal distension or pain. At the end of the diary completion, they were randomly and blindly assigned to one of the three dietary protocols (20 patients to each), which they followed for 4 weeks. During the last 2 weeks of the diet they filled out a second diary card and at the end they rated again the severity of bloating. All data were analyzed by an investigator blinded to the diet assignment. Baseline socio-demographic and clinical characteristics of the three groups were
AGA Abstracts
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