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Tu1797 Serotonin-Related Gene Variants in Patients With Irritable Bowel Syndrome and Comorbid Depressive or Anxiety Disorders
AGA Abstracts
stress was higher in IBS vs controls (28±5 vs. 25±6, p=0.003) and in IBS-D vs. the other IBS subtypes (p=0.040). The number of tryptase-positive cells was significantly increased in IBS vs controls (380±181 vs. 243±95/µm, p=0.001) and tended to correlated with stress in IBS (r: 0.30, p=0.056) but not in controls (r: -0.08, p=0.332). In addition, perceived stress explained 9.4% of the variation of tryptase + mast cells. Conclusions:Rome II-IBS patients from a low socieconomical level in Mexico showed an increase in rectal-mucosal tryptase-positive mast cells which correlated moderately with perceived stress. The latter central effect explained small variations in the mucosal degranulated mast cells, thus treatment of stress in IBS may decrease mast cell degranulation and symptoms could improve. This study was supported by a research grant from DGAPA IN210010, UNAM.
Tu1798 High Prevalence of Joint Hypermobility Syndrome in Patients With Functional Gastrointestinal Disorders Valeria Schindler, Jonas Zeitz, Arndt F. van Maren, Michael Scharl, Michael Fried, Daniel Pohl Introduction: Joint hypermobility (JH) is commonly found in the general population. Joint hypermobility syndrome (JHS) constitutes a hereditary disorder of connective tissue in which patients often report non-musculoskeletal symptoms, among them gastrointestinal complaints. Previous studies in Europe and the U.S. have reported a JHS prevalence of 20% in the general population. In addition JHS is assumed to be linked to functional bowel disease. The aim of this study was to assess prevalence of JH and JHS in irritable bowel syndrome (IBS), functional dyspepsia (FD) and functional abdominal pain/bloating (FAP/ FAB). Methods: In a Swiss tertiary ambulatory functional bowel clinic 103 patients were screened for JH and JHS between April 2014 and November 2015. Patients were diagnosed with IBS, FD or FAP/FAB according to Rome III criteria. Overlap of IBS and FD was allowed. JH and JHS were evaluated according to the validated Beighton Score, respectively Brighton Criteria. Results: Two thirds of patients included were female (66%) and median age in the study population was 32 years (range 16-70 years). Positive criteria for JHS were met by 60 (58%) out of 103 patients with functional gastrointestinal disorders. Among 103 patients with a functional intestinal disorder, women were more often diagnosed with JHS than men (66% vs. 47%, p=0.023). Patients with IBS, FD or IBS-FD overlap tended to be more often diagnosed with JHS than FAP/FAB patients (62% vs. 33%, p= 0.063). Distribution of JH, as assessed by the Beighton Score, was not different among subgroups of functional gastrointestinal disorders. However, JH was found in 46 JHS patients compared to 10 in non-JHS patients (77% vs. 23%, p < 0.001). Summary/Conclusions: Our data demonstrate a substantially higher JHS prevalence of more than 50% in functional gastrointestinal disorders, especially IBS and FD, than reported for the general population or patients with organic gastrointestinal diseases. Whereas JH was not different among groups of functional bowel disease, non-hypermobility features in the Brighton Criteria appear to differentiate subgroups of functional bowel disease. These findings emphasize a common underlying pathophysiology between JHS and functional gastrointestinal disorders, providing a basis for future research and possible therapeutic approaches.
Tu1796 CD4+ T Cell Derived TNFa Is Elevated in Patients With DiarrheaPredominant Irritable Bowel Syndrome Yasmin Nasser, Carlene Petes, Celine Simmers, Katrina Gee, Stephen Vanner INTRODUCTION: Immune activation may underlie the pathogenesis of irritable bowel syndrome (IBS), but findings have been inconsistent. We hypothesized that this variability is due to the heterogeneity of IBS and/or the sensitivity of serum measurements of immune activation. Our primary aim was to assess whether CD4+ T-cell derived pro-inflammatory cytokines were elevated and if this was confined to subtypes of IBS patients. To gain further insights into potential mechanisms, we assessed homing of CD4+ T cells in IBS as another marker of immune activation and whether immune activation could be related to increased psychological scores, which may reflect increased stress hormone signaling due to HPA axis stimulation. METHODS: IBS patients or healthy volunteers (n=30 per group) were recruited from the outpatient gastroenterology clinic at the Hotel Dieu Hospital and completed validated psychological, symptom severity (IBS-SSS) and quality of life (QOL) questionnaires. CD4+ T cells were isolated from blood and incubated with media or phytohaemagglutinin (PHA) at 5 µg/mL for 24 hrs. Supernatants were analyzed for the production of TNF aby ELISA. Flow cytometry of CD4+ T cells was performed to assess for homing receptors to lymphoid tissue (CD62L) and the gut (b7 integrin). A subset of patients (n=15 control, 14 IBS patients) was re-assessed 3-5 months later. RESULTS: IBS-SSS were in the moderately severe range (269.9 ± 15.32 IBS; 19.1 ± 3.8 Controls, p<0.0001) and were similar between subgroups. A significant increase in PHA-stimulated TNF a was seen in IBS-D but not IBS-C or IBS-M patients when compared to controls (213.2 ± 46.8 pg/mL, n=30 Controls; 639.4 ± 225.9 pg/mL, n= 11 IBS-D; 129.3 ± 31.9 pg/mL, n=11 IBS-C; 148.1 ± 88.0 pg/mL, n=8 IBS-M. p=0.0226, Kruskal-Wallis Test; Control vs. IBS-D). The percentage of CD4+ T cells expressing CD62L was increased in IBS patients when compared to controls (84.1 ± 1.6 IBS; 79.0 ± 2.2 Controls; p=0.058). IBS patients exhibited significantly worse QOL (104.2 ± 7.4 IBS; 2.5 ± 0.7 Controls, p<0.0001), increased anxiety (10.1 ± 0.8 IBS; 4.5 ± 0.6 Controls, p<0.0001), depression (5.6 ± 0.7 IBS; 1.6 ± 0.3 Controls, p<0.0001), and somatization (14.2 ± 0.8 IBS; 4.5 ± 1.2 Controls, p<0.0001) scores when compared to controls; no subgroup differences were noted. CD4+ derived TNFa was not correlated with psychological scores. Longitudinal studies showed that symptom severity and somatization scores, but not immune markers, decreased over time in IBS patients. CONCLUSIONS: IBS-D patients have increased CD4+ T-cell derived TNF a when compared to controls, suggesting different underlying mechanisms in IBS-D compared to other subtypes. The cytokine elevation was not correlated with psychological scores however, suggesting that immune activation in this case is not related to stress hormones.
Tu1799 Differences in Cortisol Responses to Hormone Challenge vs. Visceral Stressor in Irritable Bowel Syndrome Sarah Park, Wendy Shih, Angela Presson, Elizabeth J. Videlock, Emeran A. Mayer, Lin Chang BACKGROUND: Irritable bowel syndrome (IBS) is a stress-sensitive disorder that has been associated with a dysregulated hypothalamic-pituitary-adrenal (HPA) axis in response to hormone stimulation of the pituitary (with corticotropin releasing factor [CRF]) and adrenal cortex (with adrenocorticotropin hormone [ACTH]) and experimental stressors, e.g. a visceral stressor (e.g., flexible sigmoidoscopy [FS]). While hormone challenge measures endocrine regulation of the HPA axis, a visceral stressor activates an integrated brain response, with appraisal of sensory input, which modulates the HPA axis ( endocrineand neuronal regulation). Sex and early adverse life events (EAL) also affect HPA response. AIM: 1) To compare the HPA axis response from hormone challenge with CRF and ACTH, and a visceral stressor between IBS patients and healthy controls (HCs), and 2) To assess the 3-way interaction of IBS, sex, and EAL on these HPA responses. METHODS: Male and female Rome III+ IBS and HCs underwent two studies: 1) hormone challenge with CRF and ACTH on separate days with serial ACTH and cortisol levels and 2) a visceral stressor (FS) on a separate day with serial cortisol levels measured at baseline and following the FS. EAL was measured with the Trauma History questionnaire. Area under the curve (AUC) was calculated for each ACTH and cortisol measure. Linear regression was used to determine whether the association between HPA response to hormone challenge and FS differed by IBS, sex, or EAL status and their 3-way interaction. RESULTS: 48 IBS (71%F, mean age 36 yrs) and 33 HCs (48% F, mean age 33 yrs) participated. CRF-stimulation test: The association between ACTH response to CRF and cortisol response to FS differed between IBS and HCs (p=0.03). In HC's, a greater cortisol response to FS was accompanied by a greater ACTH response to CRF. In contrast, in IBS, a greater cortisol response to FS was accompanied by a lower ACTH response to CRF (Fig 1). ACTH-stimulation test: There was a significant 3-way interaction among ACTH-stimulated cortisol, IBS, and sex in predicting cortisol response to FS (Fig 2, p=0.003). IBS women who had a greater cortisol response to ACTH also had a greater cortisol response to FS. In contrast, IBS men with a lower cortisol response to ACTH had a higher cortisol response to FS. The associations between the ACTH and FS cortisol responses were also opposite in HC men and women. EAL status did not affect the relationships between the hormone challenge and the visceral stressor. CONCLUSIONS: In HCs, the HPA response to a visceral stressor was predicted by the endocrineregulation of the HPA axis. In contrast, the stress response to a visceral stressor in IBS appeared to be significantly affected by neuronal regulation of the HPA axis by brain regions activated in response to enhanced cognitive appraisal and affective responses.
Tu1797 Serotonin-Related Gene Variants in Patients With Irritable Bowel Syndrome and Comorbid Depressive or Anxiety Disorders Agata Mulak, Ewa Waszczuk, Jan A. Beszlej, Marcin Szechinski, Dorota Frydecka, Monika Szewczuk-Boguslawska, Magdalena Grzesiak Background: Serotonin-related genetic polymorphisms have been suggested to be associated with a high prevalence of anxiety and depressive disorders in patients with irritable bowel syndrome (IBS). Aims: To investigate the association of the 44bp insertion/deletion polymorphism in the promoter region (5-HTTLPR) of serotonin transporter gene (SLC6A4), the A218C polymorphism in tryptophan hydroxylase gene (TPH1), and the C1019G polymorphism in serotonin 1A receptor gene (HTR1A) with depressive and anxiety disorders in IBS patients. Methods: Ninety five IBS patients selected according to the Rome II criteria (mean age 49, range 18-73 years, 81 F, 14 M) participated in the study. The lifetime prevalence of depressive and anxiety disorders was assessed by the Munich version of the Composite International Diagnostic Interview (CIDI). The 5-HTTLPR polymorphism was determined using polymerase chain reaction (PCR)-based method. Single nucleotide polymorphisms were detected by minisequencing method. Results: Depressive and anxiety disorders were diagnosed in 54 participants (57%). The IBS patients were divided into 4 subgroups: with no mental disorders (43%), with depressive disorders only (21%), with anxiety disorders only (26%), and with coexisting anxiety-depressive disorders (10%). The IBS patients with depressive disorders were characterized by higher frequencies of the 5-HTTLPR long (L) allele (p=0.013) and the L/L genotype (p=0.03) than the IBS patients with anxiety disorders (no significant differences when compared to the IBS patients with no mental disorders). No statistically significant differences in the THP1 A218C polymorphism between the compared groups were found. A higher frequency of the C allele and a lower frequency of the G/G genotype in the HTR1A C1019G polymorphism were observed in the IBS patients with depressive disorders comparing to the IBS patients with anxiety disorders or no mental disease, but those differences did not reach statistical significance. Conclusions: Our results provide evidence for the involvement of the 5-HTTLPR long allele in the pathophysiology of depressive disorders in IBS. No association was found between the THP1 and HTR1A polymorphisms and the lifetime prevalence of depressive or anxiety disorders in IBS. Supported by KBN No2 P05B07230
AGA Abstracts
S-950
stress was higher in IBS vs controls (28±5 vs. 25±6, p=0.003) and in IBS-D vs. the other IBS subtypes (p=0.040). The number of tryptase-positive cells was significantly increased in IBS vs controls (380±181 vs. 243±95/µm, p=0.001) and tended to correlated with stress in IBS (r: 0.30, p=0.056) but not in controls (r: -0.08, p=0.332). In addition, perceived stress explained 9.4% of the variation of tryptase + mast cells. Conclusions:Rome II-IBS patients from a low socieconomical level in Mexico showed an increase in rectal-mucosal tryptase-positive mast cells which correlated moderately with perceived stress. The latter central effect explained small variations in the mucosal degranulated mast cells, thus treatment of stress in IBS may decrease mast cell degranulation and symptoms could improve. This study was supported by a research grant from DGAPA IN210010, UNAM.
Tu1798 High Prevalence of Joint Hypermobility Syndrome in Patients With Functional Gastrointestinal Disorders Valeria Schindler, Jonas Zeitz, Arndt F. van Maren, Michael Scharl, Michael Fried, Daniel Pohl Introduction: Joint hypermobility (JH) is commonly found in the general population. Joint hypermobility syndrome (JHS) constitutes a hereditary disorder of connective tissue in which patients often report non-musculoskeletal symptoms, among them gastrointestinal complaints. Previous studies in Europe and the U.S. have reported a JHS prevalence of 20% in the general population. In addition JHS is assumed to be linked to functional bowel disease. The aim of this study was to assess prevalence of JH and JHS in irritable bowel syndrome (IBS), functional dyspepsia (FD) and functional abdominal pain/bloating (FAP/ FAB). Methods: In a Swiss tertiary ambulatory functional bowel clinic 103 patients were screened for JH and JHS between April 2014 and November 2015. Patients were diagnosed with IBS, FD or FAP/FAB according to Rome III criteria. Overlap of IBS and FD was allowed. JH and JHS were evaluated according to the validated Beighton Score, respectively Brighton Criteria. Results: Two thirds of patients included were female (66%) and median age in the study population was 32 years (range 16-70 years). Positive criteria for JHS were met by 60 (58%) out of 103 patients with functional gastrointestinal disorders. Among 103 patients with a functional intestinal disorder, women were more often diagnosed with JHS than men (66% vs. 47%, p=0.023). Patients with IBS, FD or IBS-FD overlap tended to be more often diagnosed with JHS than FAP/FAB patients (62% vs. 33%, p= 0.063). Distribution of JH, as assessed by the Beighton Score, was not different among subgroups of functional gastrointestinal disorders. However, JH was found in 46 JHS patients compared to 10 in non-JHS patients (77% vs. 23%, p < 0.001). Summary/Conclusions: Our data demonstrate a substantially higher JHS prevalence of more than 50% in functional gastrointestinal disorders, especially IBS and FD, than reported for the general population or patients with organic gastrointestinal diseases. Whereas JH was not different among groups of functional bowel disease, non-hypermobility features in the Brighton Criteria appear to differentiate subgroups of functional bowel disease. These findings emphasize a common underlying pathophysiology between JHS and functional gastrointestinal disorders, providing a basis for future research and possible therapeutic approaches.
Tu1796 CD4+ T Cell Derived TNFa Is Elevated in Patients With DiarrheaPredominant Irritable Bowel Syndrome Yasmin Nasser, Carlene Petes, Celine Simmers, Katrina Gee, Stephen Vanner INTRODUCTION: Immune activation may underlie the pathogenesis of irritable bowel syndrome (IBS), but findings have been inconsistent. We hypothesized that this variability is due to the heterogeneity of IBS and/or the sensitivity of serum measurements of immune activation. Our primary aim was to assess whether CD4+ T-cell derived pro-inflammatory cytokines were elevated and if this was confined to subtypes of IBS patients. To gain further insights into potential mechanisms, we assessed homing of CD4+ T cells in IBS as another marker of immune activation and whether immune activation could be related to increased psychological scores, which may reflect increased stress hormone signaling due to HPA axis stimulation. METHODS: IBS patients or healthy volunteers (n=30 per group) were recruited from the outpatient gastroenterology clinic at the Hotel Dieu Hospital and completed validated psychological, symptom severity (IBS-SSS) and quality of life (QOL) questionnaires. CD4+ T cells were isolated from blood and incubated with media or phytohaemagglutinin (PHA) at 5 µg/mL for 24 hrs. Supernatants were analyzed for the production of TNF aby ELISA. Flow cytometry of CD4+ T cells was performed to assess for homing receptors to lymphoid tissue (CD62L) and the gut (b7 integrin). A subset of patients (n=15 control, 14 IBS patients) was re-assessed 3-5 months later. RESULTS: IBS-SSS were in the moderately severe range (269.9 ± 15.32 IBS; 19.1 ± 3.8 Controls, p<0.0001) and were similar between subgroups. A significant increase in PHA-stimulated TNF a was seen in IBS-D but not IBS-C or IBS-M patients when compared to controls (213.2 ± 46.8 pg/mL, n=30 Controls; 639.4 ± 225.9 pg/mL, n= 11 IBS-D; 129.3 ± 31.9 pg/mL, n=11 IBS-C; 148.1 ± 88.0 pg/mL, n=8 IBS-M. p=0.0226, Kruskal-Wallis Test; Control vs. IBS-D). The percentage of CD4+ T cells expressing CD62L was increased in IBS patients when compared to controls (84.1 ± 1.6 IBS; 79.0 ± 2.2 Controls; p=0.058). IBS patients exhibited significantly worse QOL (104.2 ± 7.4 IBS; 2.5 ± 0.7 Controls, p<0.0001), increased anxiety (10.1 ± 0.8 IBS; 4.5 ± 0.6 Controls, p<0.0001), depression (5.6 ± 0.7 IBS; 1.6 ± 0.3 Controls, p<0.0001), and somatization (14.2 ± 0.8 IBS; 4.5 ± 1.2 Controls, p<0.0001) scores when compared to controls; no subgroup differences were noted. CD4+ derived TNFa was not correlated with psychological scores. Longitudinal studies showed that symptom severity and somatization scores, but not immune markers, decreased over time in IBS patients. CONCLUSIONS: IBS-D patients have increased CD4+ T-cell derived TNF a when compared to controls, suggesting different underlying mechanisms in IBS-D compared to other subtypes. The cytokine elevation was not correlated with psychological scores however, suggesting that immune activation in this case is not related to stress hormones.
Tu1799 Differences in Cortisol Responses to Hormone Challenge vs. Visceral Stressor in Irritable Bowel Syndrome Sarah Park, Wendy Shih, Angela Presson, Elizabeth J. Videlock, Emeran A. Mayer, Lin Chang BACKGROUND: Irritable bowel syndrome (IBS) is a stress-sensitive disorder that has been associated with a dysregulated hypothalamic-pituitary-adrenal (HPA) axis in response to hormone stimulation of the pituitary (with corticotropin releasing factor [CRF]) and adrenal cortex (with adrenocorticotropin hormone [ACTH]) and experimental stressors, e.g. a visceral stressor (e.g., flexible sigmoidoscopy [FS]). While hormone challenge measures endocrine regulation of the HPA axis, a visceral stressor activates an integrated brain response, with appraisal of sensory input, which modulates the HPA axis ( endocrineand neuronal regulation). Sex and early adverse life events (EAL) also affect HPA response. AIM: 1) To compare the HPA axis response from hormone challenge with CRF and ACTH, and a visceral stressor between IBS patients and healthy controls (HCs), and 2) To assess the 3-way interaction of IBS, sex, and EAL on these HPA responses. METHODS: Male and female Rome III+ IBS and HCs underwent two studies: 1) hormone challenge with CRF and ACTH on separate days with serial ACTH and cortisol levels and 2) a visceral stressor (FS) on a separate day with serial cortisol levels measured at baseline and following the FS. EAL was measured with the Trauma History questionnaire. Area under the curve (AUC) was calculated for each ACTH and cortisol measure. Linear regression was used to determine whether the association between HPA response to hormone challenge and FS differed by IBS, sex, or EAL status and their 3-way interaction. RESULTS: 48 IBS (71%F, mean age 36 yrs) and 33 HCs (48% F, mean age 33 yrs) participated. CRF-stimulation test: The association between ACTH response to CRF and cortisol response to FS differed between IBS and HCs (p=0.03). In HC's, a greater cortisol response to FS was accompanied by a greater ACTH response to CRF. In contrast, in IBS, a greater cortisol response to FS was accompanied by a lower ACTH response to CRF (Fig 1). ACTH-stimulation test: There was a significant 3-way interaction among ACTH-stimulated cortisol, IBS, and sex in predicting cortisol response to FS (Fig 2, p=0.003). IBS women who had a greater cortisol response to ACTH also had a greater cortisol response to FS. In contrast, IBS men with a lower cortisol response to ACTH had a higher cortisol response to FS. The associations between the ACTH and FS cortisol responses were also opposite in HC men and women. EAL status did not affect the relationships between the hormone challenge and the visceral stressor. CONCLUSIONS: In HCs, the HPA response to a visceral stressor was predicted by the endocrineregulation of the HPA axis. In contrast, the stress response to a visceral stressor in IBS appeared to be significantly affected by neuronal regulation of the HPA axis by brain regions activated in response to enhanced cognitive appraisal and affective responses.
Tu1797 Serotonin-Related Gene Variants in Patients With Irritable Bowel Syndrome and Comorbid Depressive or Anxiety Disorders Agata Mulak, Ewa Waszczuk, Jan A. Beszlej, Marcin Szechinski, Dorota Frydecka, Monika Szewczuk-Boguslawska, Magdalena Grzesiak Background: Serotonin-related genetic polymorphisms have been suggested to be associated with a high prevalence of anxiety and depressive disorders in patients with irritable bowel syndrome (IBS). Aims: To investigate the association of the 44bp insertion/deletion polymorphism in the promoter region (5-HTTLPR) of serotonin transporter gene (SLC6A4), the A218C polymorphism in tryptophan hydroxylase gene (TPH1), and the C1019G polymorphism in serotonin 1A receptor gene (HTR1A) with depressive and anxiety disorders in IBS patients. Methods: Ninety five IBS patients selected according to the Rome II criteria (mean age 49, range 18-73 years, 81 F, 14 M) participated in the study. The lifetime prevalence of depressive and anxiety disorders was assessed by the Munich version of the Composite International Diagnostic Interview (CIDI). The 5-HTTLPR polymorphism was determined using polymerase chain reaction (PCR)-based method. Single nucleotide polymorphisms were detected by minisequencing method. Results: Depressive and anxiety disorders were diagnosed in 54 participants (57%). The IBS patients were divided into 4 subgroups: with no mental disorders (43%), with depressive disorders only (21%), with anxiety disorders only (26%), and with coexisting anxiety-depressive disorders (10%). The IBS patients with depressive disorders were characterized by higher frequencies of the 5-HTTLPR long (L) allele (p=0.013) and the L/L genotype (p=0.03) than the IBS patients with anxiety disorders (no significant differences when compared to the IBS patients with no mental disorders). No statistically significant differences in the THP1 A218C polymorphism between the compared groups were found. A higher frequency of the C allele and a lower frequency of the G/G genotype in the HTR1A C1019G polymorphism were observed in the IBS patients with depressive disorders comparing to the IBS patients with anxiety disorders or no mental disease, but those differences did not reach statistical significance. Conclusions: Our results provide evidence for the involvement of the 5-HTTLPR long allele in the pathophysiology of depressive disorders in IBS. No association was found between the THP1 and HTR1A polymorphisms and the lifetime prevalence of depressive or anxiety disorders in IBS. Supported by KBN No2 P05B07230
AGA Abstracts
S-950