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772 Staphylococcal Enterotoxin B Triggers a Bystander Immune Response to Food Antigens Leading to Visceral Hypersensitivity
AGA Abstracts Figure 1. Visceromotor response to colorectal distention before OVA re-exposure (BL, baseline), after 4 and 8 OVA challenges and after vehicle/doxantrazole treatment (12 OVA challenges) in SEB/PBS mice (solid blue circles), SEB/OVA (+vehicle) mice (open orange circles), PBS/OVA mice (solid green squares) and SEB/OVA (+doxantrazole) mice (open purple circles). Data are shown as area under the curve of the mice pain responses to colorectal distentions, normalized to the maximum distention response at baseline. Data are reported as mean ± SEM; **P<0.01, ***P<0.001 two-way analysis of variance with Bonferroni post-tests.
Figure 2. Colonic permeability expressed as passage of fluorescein sodium salt (ng fluorescein/mL/cm2) in time in SEB/PBS mice (solid blue circles), SEB/OVA (+vehicle) mice (open orange circles), PBS/OVA mice (solid green squares) and SEB/OVA (+doxantrazole) mice (open purple circles). Data are reported as mean ± SEM; *P<0.05, ***P<0.001 two-way analysis of variance with Bonferroni post-tests.
772 Staphylococcal Enterotoxin B Triggers a Bystander Immune Response to Food Antigens Leading to Visceral Hypersensitivity Javier Aguilera-Lizarraga, Morgane Florens, Dafne Balemans, Stavroula Theofanous, Eluisa Perna, Mira M. Wouters, Guy E. Boeckxstaens
773 A Double-Blind Placebo Controlled Study of Acotiamide Hydrochloride for Efficacy on Gastrointestinal Motility of Patients With Functional Dyspepsia Kumiko Nakamura, Toshihiko Tomita, Tadayuki Oshima, Tomohiro Ogawa, Ken Hara, Takahisa Yamasaki, Takuya Okugawa, Takashi Kondo, Tomoaki Kono, Katsuyuki Tozawa, Yoshio Ohda, Hirokazu Fukui, Jiro Watari, Hiroto Miwa
Background: Bacterial gastroenteritis is a well characterized risk factor to develop irritable bowel syndrome. The mechanism underlying the development of post-infectious irritable bowel syndrome and visceral hypersensitivity (VHS) remains however largely unknown. Previously, we showed that a gastrointestinal infection with Citrobacter rodentium triggers an aberrant immune response to an innocent bystander antigen (ovalbumin, OVA) resulting in mast cell activation and subsequent VHS upon re-exposure to OVA. Here, we hypothesize that not only an active infection but also bacterial products, such as superantigens, are able to trigger such an aberrant immune response leading to activation of mast cells and VHS upon re-exposure to the respective antigen. Material and methods: Three groups of Balb/ c mice were studied (n=8-10/group). Group 1 and 2 received Staphylococcal enterotoxin B (SEB) in the absence (SEB/PBS) or presence (SEB/OVA) of OVA, respectively, during three consecutive days. Group 3 only received OVA dissolved in PBS (PBS/OVA). 5 weeks later, all groups received OVA orally every other day. After the 8th OVA re-exposure, group 2 was randomized to one week treatment with either doxantrazole (mast cell stabilizer) or vehicle. Visceral pain was assessed by recording of the visceromotor response to colorectal distension using abdominal muscle electromyography before OVA re-exposure and after 4, 8 and 12 OVA challenges. VHS was considered when the area under the curve of the responses (normalized to maximum pain at baseline) was >4.56 (=95th percentile). Thereafter, mice were sacrificed and the colonic permeability was studied in Ussing chambers. Ear swelling was assessed after injection of OVA or saline in the ear to exclude the development of allergy. Results: Re-exposure to OVA (at t=5 weeks) did not affect the visceromotor response to colorectal distention in mice that received SEB/PBS or PBS/OVA (Figure 1). In contrast, all mice that received OVA and SEB developed VHS upon re-exposed to OVA (figure 1). Of note, VHS was reversed in 75% of the doxantrazole compared to 0% in the vehicle treated mice. Moreover, OVA re-exposure increased colonic permeability in SEB/ OVA mice compared to SEB/PBS and PBS/OVA mice, an effect that was reversed by doxantrazole (Figure 2). OVA injection did not cause ear swelling in any group (data not shown). Conclusion: Similar to a bacterial infection, SEB induces an aberrant immune response to innocent bystander antigens, leading to mast cell-mediated VHS and increased mucosal permeability upon re-exposure to the respective antigens. Based on this data, we propose that superantigens, either from microbiota in the nasal cavity or the intestine, may be involved in the pathogenesis of irritable bowel syndrome. Future studies evaluating the presence of these superantigens in patients are therefore warranted.
Background and Aims: Acotiamide hydrochloride trihydrate (acotiamide) is widely used to improve the dyspeptic symptoms in patients with functional dyspepsia (FD). The mechanism of action has been reported by several animal studies. However, few human studies are available for the mechanistic aspects of effects of acotiamide. Accordingly, we assessed the effects of acotiamide on gastric accommodation and gastric emptying, gastrointestinal symptoms as well as HR-QOL by placebo-controlled study. Patients and Methods: We conducted a randomized, double-blind placebo-controlled study. Fifty Japanese FD patients (33 men and 17 women; mean age 51.9 ± 19.3 yrs and 53.8 ± 10.5 yrs, respectively) were randomly allocated to receive either a placebo (n=25) or acotiamide 100 mg ×3/day for 2 weeks (n=25). At baseline and at 2 weeks of treatment, we evaluated the patients' gastric motility (using scintigraphy with a meal of curry/rice and radiolabeled 99mTc [37 MBq] to determine the accommodation and emptying values), their dyspeptic symptoms (Gastrointestinal Symptom Rating Scale [GSRS]), quality of life [SF-8], and their anxiety and depression (Hospital Anxiety and Depression Scale [HADS]). For the scintigraphy, the radioactivity in the upper-third and whole stomach was assessed, and its percentage was calculated to evaluate gastric accommodation. Results: Four patients failed to complete the medication regimen, and thus data from 24 placebo patients and 22 acotiamide patients were analyzed. Acotiamide significantly increased gastric accommodation compared to the placebo (pre: 29.6 ± 14.8%, post: 35.1 ± 13.4%, p<0.05 vs. pre: 38.5 ± 15.1%, post: 35.6 ± 15.0%, N.S; respectively). Acotiamide significantly accelerated the gastric emptying (50% half-emptying time) (pre: 52.3 ± 15.3 min, post: 46.9 ± 14.2 min, p<0.05 vs. pre: 52.2 ± 16.3 min, post: 51.1±16.8 min, N.S). Acotiamide significantly improved the GSRS scores compared to placebo (pre: 2.5 ± 0.6, post: 2.1 ± 0.6, p<0.05 vs. pre: 2.6 ± 0.8, post: 2.3 ± 0.7, N.S). In general, the QOL (Physical and Mental summary scores) outcomes were not significantly different between the two groups, but acotiamide significantly improved the HADS anxiety score compared to placebo (pre: 5.4 ± 3.5, post: 4.3 ± 2.0, p<0.05 vs. pre: 4.9 ± 3.0, post: 4.3 ± 2.8, N.S.). Conclusions: Our placebo-controlled study demonstrated that acotiamide significantly increased both gastric accommodation and gastric emptying in Japanese FD patients. Acotiamide also improved the patients' dyspeptic symptoms and the anxiety score.
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AGA Abstracts
Figure 2. Colonic permeability expressed as passage of fluorescein sodium salt (ng fluorescein/mL/cm2) in time in SEB/PBS mice (solid blue circles), SEB/OVA (+vehicle) mice (open orange circles), PBS/OVA mice (solid green squares) and SEB/OVA (+doxantrazole) mice (open purple circles). Data are reported as mean ± SEM; *P<0.05, ***P<0.001 two-way analysis of variance with Bonferroni post-tests.
772 Staphylococcal Enterotoxin B Triggers a Bystander Immune Response to Food Antigens Leading to Visceral Hypersensitivity Javier Aguilera-Lizarraga, Morgane Florens, Dafne Balemans, Stavroula Theofanous, Eluisa Perna, Mira M. Wouters, Guy E. Boeckxstaens
773 A Double-Blind Placebo Controlled Study of Acotiamide Hydrochloride for Efficacy on Gastrointestinal Motility of Patients With Functional Dyspepsia Kumiko Nakamura, Toshihiko Tomita, Tadayuki Oshima, Tomohiro Ogawa, Ken Hara, Takahisa Yamasaki, Takuya Okugawa, Takashi Kondo, Tomoaki Kono, Katsuyuki Tozawa, Yoshio Ohda, Hirokazu Fukui, Jiro Watari, Hiroto Miwa
Background: Bacterial gastroenteritis is a well characterized risk factor to develop irritable bowel syndrome. The mechanism underlying the development of post-infectious irritable bowel syndrome and visceral hypersensitivity (VHS) remains however largely unknown. Previously, we showed that a gastrointestinal infection with Citrobacter rodentium triggers an aberrant immune response to an innocent bystander antigen (ovalbumin, OVA) resulting in mast cell activation and subsequent VHS upon re-exposure to OVA. Here, we hypothesize that not only an active infection but also bacterial products, such as superantigens, are able to trigger such an aberrant immune response leading to activation of mast cells and VHS upon re-exposure to the respective antigen. Material and methods: Three groups of Balb/ c mice were studied (n=8-10/group). Group 1 and 2 received Staphylococcal enterotoxin B (SEB) in the absence (SEB/PBS) or presence (SEB/OVA) of OVA, respectively, during three consecutive days. Group 3 only received OVA dissolved in PBS (PBS/OVA). 5 weeks later, all groups received OVA orally every other day. After the 8th OVA re-exposure, group 2 was randomized to one week treatment with either doxantrazole (mast cell stabilizer) or vehicle. Visceral pain was assessed by recording of the visceromotor response to colorectal distension using abdominal muscle electromyography before OVA re-exposure and after 4, 8 and 12 OVA challenges. VHS was considered when the area under the curve of the responses (normalized to maximum pain at baseline) was >4.56 (=95th percentile). Thereafter, mice were sacrificed and the colonic permeability was studied in Ussing chambers. Ear swelling was assessed after injection of OVA or saline in the ear to exclude the development of allergy. Results: Re-exposure to OVA (at t=5 weeks) did not affect the visceromotor response to colorectal distention in mice that received SEB/PBS or PBS/OVA (Figure 1). In contrast, all mice that received OVA and SEB developed VHS upon re-exposed to OVA (figure 1). Of note, VHS was reversed in 75% of the doxantrazole compared to 0% in the vehicle treated mice. Moreover, OVA re-exposure increased colonic permeability in SEB/ OVA mice compared to SEB/PBS and PBS/OVA mice, an effect that was reversed by doxantrazole (Figure 2). OVA injection did not cause ear swelling in any group (data not shown). Conclusion: Similar to a bacterial infection, SEB induces an aberrant immune response to innocent bystander antigens, leading to mast cell-mediated VHS and increased mucosal permeability upon re-exposure to the respective antigens. Based on this data, we propose that superantigens, either from microbiota in the nasal cavity or the intestine, may be involved in the pathogenesis of irritable bowel syndrome. Future studies evaluating the presence of these superantigens in patients are therefore warranted.
Background and Aims: Acotiamide hydrochloride trihydrate (acotiamide) is widely used to improve the dyspeptic symptoms in patients with functional dyspepsia (FD). The mechanism of action has been reported by several animal studies. However, few human studies are available for the mechanistic aspects of effects of acotiamide. Accordingly, we assessed the effects of acotiamide on gastric accommodation and gastric emptying, gastrointestinal symptoms as well as HR-QOL by placebo-controlled study. Patients and Methods: We conducted a randomized, double-blind placebo-controlled study. Fifty Japanese FD patients (33 men and 17 women; mean age 51.9 ± 19.3 yrs and 53.8 ± 10.5 yrs, respectively) were randomly allocated to receive either a placebo (n=25) or acotiamide 100 mg ×3/day for 2 weeks (n=25). At baseline and at 2 weeks of treatment, we evaluated the patients' gastric motility (using scintigraphy with a meal of curry/rice and radiolabeled 99mTc [37 MBq] to determine the accommodation and emptying values), their dyspeptic symptoms (Gastrointestinal Symptom Rating Scale [GSRS]), quality of life [SF-8], and their anxiety and depression (Hospital Anxiety and Depression Scale [HADS]). For the scintigraphy, the radioactivity in the upper-third and whole stomach was assessed, and its percentage was calculated to evaluate gastric accommodation. Results: Four patients failed to complete the medication regimen, and thus data from 24 placebo patients and 22 acotiamide patients were analyzed. Acotiamide significantly increased gastric accommodation compared to the placebo (pre: 29.6 ± 14.8%, post: 35.1 ± 13.4%, p<0.05 vs. pre: 38.5 ± 15.1%, post: 35.6 ± 15.0%, N.S; respectively). Acotiamide significantly accelerated the gastric emptying (50% half-emptying time) (pre: 52.3 ± 15.3 min, post: 46.9 ± 14.2 min, p<0.05 vs. pre: 52.2 ± 16.3 min, post: 51.1±16.8 min, N.S). Acotiamide significantly improved the GSRS scores compared to placebo (pre: 2.5 ± 0.6, post: 2.1 ± 0.6, p<0.05 vs. pre: 2.6 ± 0.8, post: 2.3 ± 0.7, N.S). In general, the QOL (Physical and Mental summary scores) outcomes were not significantly different between the two groups, but acotiamide significantly improved the HADS anxiety score compared to placebo (pre: 5.4 ± 3.5, post: 4.3 ± 2.0, p<0.05 vs. pre: 4.9 ± 3.0, post: 4.3 ± 2.8, N.S.). Conclusions: Our placebo-controlled study demonstrated that acotiamide significantly increased both gastric accommodation and gastric emptying in Japanese FD patients. Acotiamide also improved the patients' dyspeptic symptoms and the anxiety score.
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AGA Abstracts