Andrea H. Thurler

Genomic and Clinical Effects Associated with a Relaxation Response Mind-Body Intervention in Patients with Irritable Bowel Syndrome and Inflammatory Bowel Disease

Introduction Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD) can profoundly affect quality of life and are influenced by stress and resiliency. The impact of mind-body interventions (MBIs) on IBS and IBD patients has not previously been examined. Methods Nineteen IBS and 29 IBD patients were enrolled in a 9-week relaxation response based mind-body group intervention (RR-MBI), focusing on elicitation of the RR and cognitive skill building. Symptom questionnaires and inflammatory markers were assessed pre- and post-intervention, and at short-term follow-up. Peripheral blood transcriptome analysis was performed to identify genomic correlates of the RR-MBI. Results Pain Catastrophizing Scale scores improved significantly post-intervention for IBD and at short-term follow-up for IBS and IBD. Trait Anxiety scores, IBS Quality of Life, IBS Symptom Severity Index, and IBD Questionnaire scores improved significantly post-intervention and at short-term follow-up for IBS and IBD, respectively. RR-MBI altered expression of more genes in IBD (1059 genes) than in IBS (119 genes). In IBD, reduced expression of RR-MBI response genes was most significantly linked to inflammatory response, cell growth, proliferation, and oxidative stress-related pathways. In IBS, cell cycle regulation and DNA damage related gene sets were significantly upregulated after RR-MBI. Interactive network analysis of RR-affected pathways identified TNF, AKT and NF-κB as top focus molecules in IBS, while in IBD kinases (e.g. MAPK, P38 MAPK), inflammation (e.g. VEGF-C, NF-κB) and cell cycle and proliferation (e.g. UBC, APP) related genes emerged as top focus molecules. Conclusions In this uncontrolled pilot study, participation in an RR-MBI was associated with improvements in disease-specific measures, trait anxiety, and pain catastrophizing in IBS and IBD patients. Moreover, observed gene expression changes suggest that NF-κB is a target focus molecule in both IBS and IBD—and that its regulation may contribute to counteracting the harmful effects of stress in both diseases. Larger, controlled studies are needed to confirm this preliminary finding. Trial Registration ClinicalTrials.Gov NCT02136745

Brain white matter microstructure is associated with susceptibility to motion-induced nausea.

Nausea is associated with significant morbidity, and there is a wide range in the propensity of individuals to experience nausea. The neural basis of the heterogeneity in nausea susceptibility is poorly understood. Our previous functional magnetic resonance imaging (fMRI) study in healthy adults showed that a visual motion stimulus caused activation in the right MT+/V5 area, and that increased sensation of nausea due to this stimulus was associated with increased activation in the right anterior insula. For the current study, we hypothesized that individual differences in visual motion‐induced nausea are due to microstructural differences in the inferior fronto‐occipital fasciculus (IFOF), the white matter tract connecting the right visual motion processing area (MT+/V5) and right anterior insula. To test this hypothesis, we acquired diffusion tensor imaging data from 30 healthy adults who were subsequently dichotomized into high and low nausea susceptibility groups based on the Motion Sickness Susceptibility Scale. We quantified diffusion along the IFOF for each subject based on axial diffusivity (AD); radial diffusivity (RD), mean diffusivity (MD) and fractional anisotropy (FA), and evaluated between‐group differences in these diffusion metrics. Subjects with high susceptibility to nausea rated significantly (P < 0.001) higher nausea intensity to visual motion stimuli and had significantly (P < 0.05) lower AD and MD along the right IFOF compared to subjects with low susceptibility to nausea. This result suggests that differences in white matter microstructure within tracts connecting visual motion and nausea‐processing brain areas may contribute to nausea susceptibility or may have resulted from an increased history of nausea episodes.

Cyclic Vomiting Syndrome is characterized by altered functional brain connectivity of the insular cortex: a cross‐comparison with migraine and healthy adults

Cyclic Vomiting Syndrome (CVS) has been linked to episodic migraine, yet little is known about the precise brain‐based mechanisms underpinning CVS, and whether these associated conditions share similar pathophysiology. We investigated the functional integrity of salience (SLN) and sensorimotor (SMN) intrinsic connectivity networks in CVS, migraine and healthy controls using brain functional Magnetic Resonance Imaging. CVS, relative to both migraine and controls, showed increased SLN connectivity to middle/posterior insula, a key brain region for nausea and viscerosensory processing. In contrast, this same region showed diminished SMN connectivity in both CVS and migraine. These results highlight both unique and potentially shared pathophysiology between these conditions, and suggest a potential target for therapeutics in future studies.

Tu1448 Gabapentin/Pregabalin Improves Symptoms in Patients With Upper GI Functional Disease and Gut Dysmotility

G A A b st ra ct s shown the GI pharmacological effects of allyl isothiocyanate (AITC), a pungent ingredient of wasabi and a TRPA1 channel activator. It was found that 1) AITC impairs tight junction barrier in primary cultures of rat stomachs (Capsaicin 2014, DOI: 10.5772/57289), and 2) no gastric damage by AITC was observed in ex-vivo rat stomachs (Gastroenterology, 138 (5), S-721, 2010). Therefore, this study is to establish a rodent model of impaired gastric motility resulting from gastric low-grade inflammation by AITC, which is reliable produce to evaluate therapeutic agents of FD. METHODS: Gastric low-grade inflammation: Male SD rats were used after 18 h-fasting. Stomachs mounted on ex-vivo chambers under urethaneanesthetized rats treated with omeprazole, were perfused with 50 mM HCl. Vascular permeability (Pontamine Sky blue) was measured during and 90 min after exposure to AITC (0.33~30 mM) for 30 min. A-967079 (10 mM), a TRPA1 channel blocker, was co-applied with AITC. Gastric motility: Male ddY mice were used after 15 h-fasting. Gastric motility was measured by 13C-acetic acid breath test in conscious mice. AITC (1-100 mg/kg, p.o.) was given 30 min before the measurement of motility. Prokinetic agents including itopride (30, 100 mg/kg), mosapride (0.1-1 mg/kg), and neostigmine (30 μg/kg), or a therapeutic agent for FD acotiamide (10, 30 mg/kg) was given s.c. 40 min before the measurement. RESULTS: Gastric low-grade inflammation: AITC increased vascular permeability in exvivo rat stomachs in concentration-dependent manner, which is obviously increased over 10 mM of AITC. However, increased vascular permeability induced by AITC was not inhibited by A-967079. Gastric motility: AITC (%30 mg/kg) impaired gastric motility in dose-dependent manner in conscious mice, those impaired motility was reversible to normal levels for 24 h after treatment of AITC. Decreased gastric motility induced by AITC (80 mg/ kg) was restored by the pretreatment of itopride, mosapride (1 mg/kg), or neostigmine. Acotiamide (100 mg/kg) also recovered decrease of gastric motility. Gastric macroscopic damage was not observed at the end of the experiments and 24 h after treatment of AITC (80 mg/kg). CONCLUSION: These results suggest that AITC induced gastric low-grade inflammation in the rodent stomach, which is independent on TRPA1 channels and no gastric mucosal damage. In addition, AITC produced the impaired gastric motility in conscious mice, whose phenomenon was reversible by prokinetic agents and a therapeutic agent for FD. This rodent model might be useful tool to develop new therapeutic agents for FD.

From Heave to Leave: Understanding Cyclic Vomiting Syndrome

Cyclic vomiting syndrome (CVS) is an idiopathic functional gastrointestinal disorder that has been underrecognized in the adult population. Nausea, vomiting, and abdominal pain are common presentations to gastrointestinal nursing. There are multiple differential diagnoses the clinician must consider prior to a diagnosis of CVS to recognize the disorder. CVS occurs in 4 phases: (a) interepisodic, (b) prodromal, (c) vomiting, and (d) recovery. Each phase has specific treatment guidelines. There is no specific “cure” for CVS; proper management is key. Increasing awareness of CVS is paramount to its detection. CVS has been examined in the pediatric population and has often been considered a pediatric disorder. More recently, it has come to be recognized in the adult population. Proper care and management of these patients allow for better support for patients and their families who are often on the primary caregivers. Nurses are often on the front lines of care and knowledge of CVS from the beginning should lead to shortened hospital stays and optimal patient care.

Genomic Determinants of a Relaxation Response Resiliency Program in Inflammatory Bowel Disease and Irritable Bowel Syndrome

G A A b st ra ct s exogenous application of proteases on neuronal excitability (decrease in rheobase and/or increased number of action potentials discharged at twice the rheobase) were studied. Incubation of neurons with supernatants from diarrhea predominant IBS patients induced hyperexcitability compared to controls (n = 18 cells). Mean action potential discharge increased by > 100% compared to controls (mean = 1.6 ± 0.4 control vs. 4.3 ± 0.9 PI-IBS, n = 11 and 9 cells respectively, p = 0.014). In contrast, the effect of supernatants from constipation predominant IBS patients did not differ from controls. To determine if cysteine proteases may be important mediators in the supernatant, the effects of exogenous cysteine proteases (cathepsin-s 500 nM) were studied and the effect of the cysteine protease inhibitor E-64 (100 μM) was determined. Incubation of neurons in cysteine proteases for 2 hours increased excitability in patch clamp recordings. Action potential discharge increased by more than 100% (mean = 1.5 ± 0.2 control vs. 3.8 ± 0.6 cathepsin-s, n = 12 and 11 respectively, p = 0.002). When enemas containing cathepsins (500 nM) were applied rectally for 2 hours, visceromotor reflexes evoked by rectal distentions (0 60 mmHg) were significantly increased compared to vehicle enemas (p = 0.039). In patch clamp studies, the increased action potential discharge mediated by the incubation with cysteine proteases was blocked by E-64 (mean = 3.8 ± 0.6 cathepsin-s vs. 1.9 ± 0.4 cathepsin-s plus E-64, n = 11 and 14 cells respectively, p = 0.017). To test the selectivity of this inhibitor, the effects of the serine protease trypsin was studied. Incubation in trypsin (50 nM) for 2 hours also increased excitability but this effect was not blocked by E-64, suggesting E-64 was selective for cysteine proteases. IBS supernatant from diarrhea predominant IBS patients was then incubated with E-64 and compared to supernatant alone. Action potential discharge was decreased ~ 100% by E-64 (p< 0.05) and the rheobase increased 20% (did not reach significance) compared to supernatant alone. These data demonstrate that supernatants from diarrhea-predominant IBS patients increase the intrinsic excitability of colonic DRG neurons. Cysteine proteases appear to be important mediators underlying this effect and could play a role in generating visceral hyperalgesia.