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Is It the Brain-Gut or the Gut-Brain That Drives Irritable Bowel Syndrome (IBS) and Functional Dyspepsia (FD)?
AGA Abstracts
group. Only 37% of the PPI group had documented indication for PPI use. Conclusions: SBP is common problem with cirrhotic patients. There are many risk factors associated with developing SBP, and one of these may be the use of PPIs. Our study found that the use of PPIs and lower ascitic albumin level may predispose patients to more severe infections and increase mortality. This is an important consideration when prescribing PPIs in cirrhotic patients.
Su1341 Is It the Brain-Gut or the Gut-Brain That Drives Irritable Bowel Syndrome (IBS) and Functional Dyspepsia (FD)? Natasha A. Koloski, Michael Jones, Jamshid S. Kalantar, Martin D. Weltman, Jessa Zaguirre, Nicholas J. Talley BACKGROUND: Although irritable bowel syndrome (IBS) and functional dyspepsia (FD) are extremely common, the exact etiology of these conditions remains unknown. Psychological factors, however, are thought to play an important role in these disorders, possibly through the brain-gut axis. No prospective studies have evaluated whether it is the brain driving the gut or the gut driving the brain in IBS and FD, and whether this is the same in both disorders. AIMS: In a 12-year longitudinal, prospective, population-based followup cohort study, we aimed to determine the directionality of the brain-gut mechanism in both IBS and FD. We hypothesised that anxiety and depression drive the new onset of both FD and IBS. METHODS: Participants (n=1775) were a random population sample from Penrith, Australia who responded to a valid survey on functional gastrointestinal symptoms in 1997 and agreed to be contacted for future research. Of these n=1002 completed the 12-year follow-up survey (response rate = 64%). Among those followed, n=44 met Rome II criteria for new onset IBS and n=23 for new onset FD, respectively. Controls (n=626) did not meet Rome II criteria for any functional gastrointestinal disorder (FGID). Clinically elevated levels of psychological distress (anxiety and depression) were defined as a score of ≥4 out of 12 on the valid Delusions Symptom States Inventory (DSSI). RESULTS: Among people free of a FGID at baseline, clinically elevated levels of anxiety (OR=2.7; 95%CI1.16.4, P=0.03) and depression (OR=4.5; 95%CI 1.7-11.6, P=0.002) at baseline were significant independent predictors of developing new onset FD 12 years later. This was particularly the case with respect to anxiety for dysmotility-like dyspepsia (OR=3.4; 95%CI 1.1-10.8, P=0.036), but not IBS with respect to anxiety (OR=1.4; 95%CI 0.6-3.1, P=0.40) or depression (OR=2.1; 95%CI0.8-5.3, P=0.13). Although not significant, in contrast we found a trend for an IBS diagnosis at baseline to be predictive of clinically elevated levels of anxiety (OR= 2.7; 95%CI 0.9-7.5, P=0.066) at follow-up among people who did not have clinically elevated levels of psychological distress at baseline. The odds ratio was highest for diarrhea predominant IBS with respect to anxiety (OR=4.3; 95%CI 0.6-31.0, P=0.15). IBS was not predictive of depression (OR=1.5; 95%CI 0.3-6.9, P=0.59) and FD was not predictive of anxiety (OR=1.4; 95%CI 0.5-3.7, P=0.50) or depression (OR=0.9; 95%CI 0.2-4.0, P=0.89) at follow-up. CONCLUSIONS: The central nervous system appears to be a key driver of new FD symptoms but not IBS. Whether IBS itself may be a driver of psychological distress deserves further study.
Su1340 Enhanced Auditory Brainstem Responses in Children With Irritable Bowel Syndrome and Parental Bonding Style Shizuka Seino, Satoshi Watanabe, Namiko Itoh, Konosuke Sasaki, Shoko Miura, Kaori Shoji, Kanoko Kozawa, Kunihiko Nakai, Hiroshi Sato, Motoyori Kanazawa, Shin Fukudo Background: The pathophysiology of irritable bowel syndrome (IBS) in childhood is not completely understood. Onset of IBS may be associated with neural hypersensitivity and/ or environmental factors in childhood. An earlier study in IBS adults reported the hypersensitivity evaluated with event-related potential. However, there has be no report on auditory brainstem response (ABR) in children with gastrointestinal symptoms (GIS). We hypothesized that children with GIS may show exaggerated ABR response and that they may receive more irrelevant parental bonding from their parents. Methods: One hundred and forty-one pairs of a mother and her child participated in this study. ABR was measured in the children at the age of 7 years. The experimental session consist of two blocks. Each block started with a 75dB click noise in the right ear and 45dB white noise masking the opposite ear via headphones. These sounds exchanged side to side. Stimuli of 75dB were presented at 0.1s duration with a frequency of 20Hz and an interval of 50 ms. The mothers scored the Child Somatization Inventory (CSI) and Parental Bonding Instrument (PBI). Results: Female children with GIS on the CSI showed significantly shorter latency of the 3 wave in the left than those without GIS (p=0.04). Female children with GIS had trend towards a shorter latency of the 3 wave in the right than those without GIS (p=0.056). Male children with GIS did not show significantly shorter latency of the 3 wave. The mothers of children with GIS reported significantly lower maternal care than those of children without GIS (p=0.017) and significantly higher overprotection than those of children without GIS (p=0.037). The number of GIS significantly correlated with the peak latency of the 3 wave on the left side (rho = -0.19, p=0.028). CSI score (except GIS), parental care, and the latency of 3 wave in the right side are the predictable parameter to GIS. Conclusion: This is the first neurological finding that depicts excitatory properties of the brainstem in children with GI symptoms. These results support the hypotheses that individuals who may develop IBS later have exaggerated brainstem response during childhood and that they receive more irrelevant parental bonding from their parents.
Su1342 Anxiety Predisposes for Impaired Steroid Sensitivity in Patients With Inflammatory and Irritable Bowel Disease Tobias Liebregts, Birgit Adam, Julia G. Junne, Gerald Holtmann, Guido Gerken, Jost Langhorst
Su2088 Characterization and Quantification of a New Esophago-LES Reflex Ivan M. Lang, Bidyut K. Medda, Reema Lamba, Reza Shaker
Background: Low-grade inflammation may contribute to the manifestation of symptoms in at least a subgroup of patients with IBS (Liebregts et al. Gastroenterology 2007). Psychological stress has been postulated to be associated with greater resistance to molecules that normally terminate the inflammatory cascade. In both irritable bowel syndrome and inflammatory bowel diseases anxiety is discussed to have a negative influence on the clinical course of disease. The underlying mechanisms are yet not fully understood. We hypothesized that patients with ulcerative colitis (UC) or IBS and concomitant psychological co-morbidity are less susceptible to steroids. Thus we aimed to quantitate steroid sensitivity [50% inhibitory concentration (IC50) for dexamethasone] of LPS stimulated peripheral blood mononuclear cells (PBMC) and anxiety scores in patients with IBS and UC in remission compared to healthy controls (HC). Methods: Sixteen patients with UC in remission (defined by a clinical Rachmilewitz Index < 5), 30 patients with IBS (ROME II) and 26 age and gender matched healthy controls were included in the study. Patients were not on corticosteroid medication for at least 2 months and had never been on other immunomodulating drugs. Peripheral blood mononuclear cells (PBMC) were isolated by density gradient centrifugation, stimulated with E. coli LPS and cultured for 24 hours in the presence or absence of various concentrations of dexamethasone (10-5M to 10-8M). Cell free culture supernatants were obtained and analyzed for TNF-α, IL-1β and IL-10 levels by ELISA. Steroid sensitivity was determined by calculating IC50's for dexamethasone. Psychological stress, namely anxiety was assessed utilizing a standardized questionnaire (HADS). A subscale of anxiety was calculated and responders who score ≥11 were considered as having a clinically relevant psychological disorder. Results: Anxiety was found in 18 IBS and 6 UC patients. IBS patients with anxiety showed significantly (p<0.05) higher IC50's for TNF-α (9.42±0.82 10-7M) and IL1β (8.6±0.91 10-7M) compared to IBS without anxiety (TNF-α 8.59±.68 10-7M; IL-1β 7.56±.58 10-7M). Patients with UC and anxiety also demonstrated increased IC50's for TNFα (3.81±0.36 vs. 1.86±0.46 10-6M) and IL-1β (4.93±0.48 vs. 2.67±0.49 10-6M) compared to UC patients without concomitant anxiety. Both UC and IBS patients demonstrated decreased steroid sensitivity compared to healthy controls (TNF-α: 7.33±0.75 10-7M, IL-1β: 6.71±0.88 10-7M), while UC was associated with a greater steroid resistance than IBS. Summary and Conclusion: Anxiety is associated with impaired steroid sensitivity in UC and IBS. These data indicate a modulating role of psychological co-morbidity for immune activation and clinical manifestation in patients with functional and inflammatory bowel disease.
Prior studies have identified an esophago-LES relaxation reflex (ELRR) of the distal esophagus mediated peripherally, but the proximal esophagus has not been studied. AIMS: To determine whether distension of the proximal esophagus effects LES tone and whether this response is centrally or peripherally mediated. METHODS: Eight cats were decerebrated, the trachea intubated, chest opened and the animal placed on a ventilator (20/min, tidal volume of 15ml/kg), the phrenic nerves cut, the diaphragm removed from the lower esophagus, EMG electrodes placed in the geniohyoideus, thyrohyoideus, cricopharyngeus (CP) and cricothyroideus, a strain gauge sewn onto the LES under tension, and the femoral artery and vein cannulated. The esophagus was distended between 1 and 2cm using a balloon for 6 sec at 2, 5, 8, 11, 14 and 17cm from the UES and responses of the larynx, hyoid, UES and LES recorded before and after bilateral cervical vagotomy. RESULTS: We found that the esophageal distension caused CP excitation and LES relaxation at all levels of the esophagus. The threshold stimulus of the CP response did not differ with region of the esophagus, but the threshold stimulus of the LES relaxation response was greatest at the proximal esophagus which steadily decreased aborally (Table). Vagotomy eliminated the CP response at all levels of the esophagus and blocked the LES response from the proximal half of the esophagus (Table). In the distal half of the esophagus, vagotomy reduced the number of animals responding with the ELRR, and in those animals responding with the ELRR vagotomy significantly increased the threshold stimulus (Table). CONCLUSIONS: An ELRR of the proximal esophagus exists, but it is less sensitive than the ELRR of the lower esophagus. The ELRR of the proximal esophagus is centrally and vagally mediated, but the ELRR of the distal esophagus is not. However, the vagus nerves provide increased sensitivity of the ELRR of the distal esophagus. Effect of vagotomy on threshold for excitation of ELRR
Values are mean±SE (N) cm of esophageal distension at thresold for ELRR. N, number of animals; NR, no response at maximum distension; *, P<0.05 for a difference from contol.
Su1343 Irritable Bowel Syndrome and Early Life Trauma Are Associated With an Enhanced HPA Axis Response to Hormone Stimulation Melissa Alberto, Wendy Shih, Angela P. Presson, Arlene Licudine, Emeran A. Mayer, Lin Chang Background: Irritable bowel syndrome (IBS) is considered a stress-sensitive disorder. However, reports about stimulated hypothalamic-pituitary-adrenal (HPA) axis responses have either been conflicting (psychological stress, corticotropin releasing factor [CRF] stimulation
AGA Abstracts
S-462
group. Only 37% of the PPI group had documented indication for PPI use. Conclusions: SBP is common problem with cirrhotic patients. There are many risk factors associated with developing SBP, and one of these may be the use of PPIs. Our study found that the use of PPIs and lower ascitic albumin level may predispose patients to more severe infections and increase mortality. This is an important consideration when prescribing PPIs in cirrhotic patients.
Su1341 Is It the Brain-Gut or the Gut-Brain That Drives Irritable Bowel Syndrome (IBS) and Functional Dyspepsia (FD)? Natasha A. Koloski, Michael Jones, Jamshid S. Kalantar, Martin D. Weltman, Jessa Zaguirre, Nicholas J. Talley BACKGROUND: Although irritable bowel syndrome (IBS) and functional dyspepsia (FD) are extremely common, the exact etiology of these conditions remains unknown. Psychological factors, however, are thought to play an important role in these disorders, possibly through the brain-gut axis. No prospective studies have evaluated whether it is the brain driving the gut or the gut driving the brain in IBS and FD, and whether this is the same in both disorders. AIMS: In a 12-year longitudinal, prospective, population-based followup cohort study, we aimed to determine the directionality of the brain-gut mechanism in both IBS and FD. We hypothesised that anxiety and depression drive the new onset of both FD and IBS. METHODS: Participants (n=1775) were a random population sample from Penrith, Australia who responded to a valid survey on functional gastrointestinal symptoms in 1997 and agreed to be contacted for future research. Of these n=1002 completed the 12-year follow-up survey (response rate = 64%). Among those followed, n=44 met Rome II criteria for new onset IBS and n=23 for new onset FD, respectively. Controls (n=626) did not meet Rome II criteria for any functional gastrointestinal disorder (FGID). Clinically elevated levels of psychological distress (anxiety and depression) were defined as a score of ≥4 out of 12 on the valid Delusions Symptom States Inventory (DSSI). RESULTS: Among people free of a FGID at baseline, clinically elevated levels of anxiety (OR=2.7; 95%CI1.16.4, P=0.03) and depression (OR=4.5; 95%CI 1.7-11.6, P=0.002) at baseline were significant independent predictors of developing new onset FD 12 years later. This was particularly the case with respect to anxiety for dysmotility-like dyspepsia (OR=3.4; 95%CI 1.1-10.8, P=0.036), but not IBS with respect to anxiety (OR=1.4; 95%CI 0.6-3.1, P=0.40) or depression (OR=2.1; 95%CI0.8-5.3, P=0.13). Although not significant, in contrast we found a trend for an IBS diagnosis at baseline to be predictive of clinically elevated levels of anxiety (OR= 2.7; 95%CI 0.9-7.5, P=0.066) at follow-up among people who did not have clinically elevated levels of psychological distress at baseline. The odds ratio was highest for diarrhea predominant IBS with respect to anxiety (OR=4.3; 95%CI 0.6-31.0, P=0.15). IBS was not predictive of depression (OR=1.5; 95%CI 0.3-6.9, P=0.59) and FD was not predictive of anxiety (OR=1.4; 95%CI 0.5-3.7, P=0.50) or depression (OR=0.9; 95%CI 0.2-4.0, P=0.89) at follow-up. CONCLUSIONS: The central nervous system appears to be a key driver of new FD symptoms but not IBS. Whether IBS itself may be a driver of psychological distress deserves further study.
Su1340 Enhanced Auditory Brainstem Responses in Children With Irritable Bowel Syndrome and Parental Bonding Style Shizuka Seino, Satoshi Watanabe, Namiko Itoh, Konosuke Sasaki, Shoko Miura, Kaori Shoji, Kanoko Kozawa, Kunihiko Nakai, Hiroshi Sato, Motoyori Kanazawa, Shin Fukudo Background: The pathophysiology of irritable bowel syndrome (IBS) in childhood is not completely understood. Onset of IBS may be associated with neural hypersensitivity and/ or environmental factors in childhood. An earlier study in IBS adults reported the hypersensitivity evaluated with event-related potential. However, there has be no report on auditory brainstem response (ABR) in children with gastrointestinal symptoms (GIS). We hypothesized that children with GIS may show exaggerated ABR response and that they may receive more irrelevant parental bonding from their parents. Methods: One hundred and forty-one pairs of a mother and her child participated in this study. ABR was measured in the children at the age of 7 years. The experimental session consist of two blocks. Each block started with a 75dB click noise in the right ear and 45dB white noise masking the opposite ear via headphones. These sounds exchanged side to side. Stimuli of 75dB were presented at 0.1s duration with a frequency of 20Hz and an interval of 50 ms. The mothers scored the Child Somatization Inventory (CSI) and Parental Bonding Instrument (PBI). Results: Female children with GIS on the CSI showed significantly shorter latency of the 3 wave in the left than those without GIS (p=0.04). Female children with GIS had trend towards a shorter latency of the 3 wave in the right than those without GIS (p=0.056). Male children with GIS did not show significantly shorter latency of the 3 wave. The mothers of children with GIS reported significantly lower maternal care than those of children without GIS (p=0.017) and significantly higher overprotection than those of children without GIS (p=0.037). The number of GIS significantly correlated with the peak latency of the 3 wave on the left side (rho = -0.19, p=0.028). CSI score (except GIS), parental care, and the latency of 3 wave in the right side are the predictable parameter to GIS. Conclusion: This is the first neurological finding that depicts excitatory properties of the brainstem in children with GI symptoms. These results support the hypotheses that individuals who may develop IBS later have exaggerated brainstem response during childhood and that they receive more irrelevant parental bonding from their parents.
Su1342 Anxiety Predisposes for Impaired Steroid Sensitivity in Patients With Inflammatory and Irritable Bowel Disease Tobias Liebregts, Birgit Adam, Julia G. Junne, Gerald Holtmann, Guido Gerken, Jost Langhorst
Su2088 Characterization and Quantification of a New Esophago-LES Reflex Ivan M. Lang, Bidyut K. Medda, Reema Lamba, Reza Shaker
Background: Low-grade inflammation may contribute to the manifestation of symptoms in at least a subgroup of patients with IBS (Liebregts et al. Gastroenterology 2007). Psychological stress has been postulated to be associated with greater resistance to molecules that normally terminate the inflammatory cascade. In both irritable bowel syndrome and inflammatory bowel diseases anxiety is discussed to have a negative influence on the clinical course of disease. The underlying mechanisms are yet not fully understood. We hypothesized that patients with ulcerative colitis (UC) or IBS and concomitant psychological co-morbidity are less susceptible to steroids. Thus we aimed to quantitate steroid sensitivity [50% inhibitory concentration (IC50) for dexamethasone] of LPS stimulated peripheral blood mononuclear cells (PBMC) and anxiety scores in patients with IBS and UC in remission compared to healthy controls (HC). Methods: Sixteen patients with UC in remission (defined by a clinical Rachmilewitz Index < 5), 30 patients with IBS (ROME II) and 26 age and gender matched healthy controls were included in the study. Patients were not on corticosteroid medication for at least 2 months and had never been on other immunomodulating drugs. Peripheral blood mononuclear cells (PBMC) were isolated by density gradient centrifugation, stimulated with E. coli LPS and cultured for 24 hours in the presence or absence of various concentrations of dexamethasone (10-5M to 10-8M). Cell free culture supernatants were obtained and analyzed for TNF-α, IL-1β and IL-10 levels by ELISA. Steroid sensitivity was determined by calculating IC50's for dexamethasone. Psychological stress, namely anxiety was assessed utilizing a standardized questionnaire (HADS). A subscale of anxiety was calculated and responders who score ≥11 were considered as having a clinically relevant psychological disorder. Results: Anxiety was found in 18 IBS and 6 UC patients. IBS patients with anxiety showed significantly (p<0.05) higher IC50's for TNF-α (9.42±0.82 10-7M) and IL1β (8.6±0.91 10-7M) compared to IBS without anxiety (TNF-α 8.59±.68 10-7M; IL-1β 7.56±.58 10-7M). Patients with UC and anxiety also demonstrated increased IC50's for TNFα (3.81±0.36 vs. 1.86±0.46 10-6M) and IL-1β (4.93±0.48 vs. 2.67±0.49 10-6M) compared to UC patients without concomitant anxiety. Both UC and IBS patients demonstrated decreased steroid sensitivity compared to healthy controls (TNF-α: 7.33±0.75 10-7M, IL-1β: 6.71±0.88 10-7M), while UC was associated with a greater steroid resistance than IBS. Summary and Conclusion: Anxiety is associated with impaired steroid sensitivity in UC and IBS. These data indicate a modulating role of psychological co-morbidity for immune activation and clinical manifestation in patients with functional and inflammatory bowel disease.
Prior studies have identified an esophago-LES relaxation reflex (ELRR) of the distal esophagus mediated peripherally, but the proximal esophagus has not been studied. AIMS: To determine whether distension of the proximal esophagus effects LES tone and whether this response is centrally or peripherally mediated. METHODS: Eight cats were decerebrated, the trachea intubated, chest opened and the animal placed on a ventilator (20/min, tidal volume of 15ml/kg), the phrenic nerves cut, the diaphragm removed from the lower esophagus, EMG electrodes placed in the geniohyoideus, thyrohyoideus, cricopharyngeus (CP) and cricothyroideus, a strain gauge sewn onto the LES under tension, and the femoral artery and vein cannulated. The esophagus was distended between 1 and 2cm using a balloon for 6 sec at 2, 5, 8, 11, 14 and 17cm from the UES and responses of the larynx, hyoid, UES and LES recorded before and after bilateral cervical vagotomy. RESULTS: We found that the esophageal distension caused CP excitation and LES relaxation at all levels of the esophagus. The threshold stimulus of the CP response did not differ with region of the esophagus, but the threshold stimulus of the LES relaxation response was greatest at the proximal esophagus which steadily decreased aborally (Table). Vagotomy eliminated the CP response at all levels of the esophagus and blocked the LES response from the proximal half of the esophagus (Table). In the distal half of the esophagus, vagotomy reduced the number of animals responding with the ELRR, and in those animals responding with the ELRR vagotomy significantly increased the threshold stimulus (Table). CONCLUSIONS: An ELRR of the proximal esophagus exists, but it is less sensitive than the ELRR of the lower esophagus. The ELRR of the proximal esophagus is centrally and vagally mediated, but the ELRR of the distal esophagus is not. However, the vagus nerves provide increased sensitivity of the ELRR of the distal esophagus. Effect of vagotomy on threshold for excitation of ELRR
Values are mean±SE (N) cm of esophageal distension at thresold for ELRR. N, number of animals; NR, no response at maximum distension; *, P<0.05 for a difference from contol.
Su1343 Irritable Bowel Syndrome and Early Life Trauma Are Associated With an Enhanced HPA Axis Response to Hormone Stimulation Melissa Alberto, Wendy Shih, Angela P. Presson, Arlene Licudine, Emeran A. Mayer, Lin Chang Background: Irritable bowel syndrome (IBS) is considered a stress-sensitive disorder. However, reports about stimulated hypothalamic-pituitary-adrenal (HPA) axis responses have either been conflicting (psychological stress, corticotropin releasing factor [CRF] stimulation
AGA Abstracts
S-462