Microbial and Metabolite Signatures of Stress Reactivity in Ulcerative Colitis Patients in Clinical Remission Predict Clinical Flare Risk.

BACKGROUND: Stress reactivity (SR) is associated with increased risk of flares in ulcerative colitis (UC) patients. Because both preclinical and clinical data support that stress can influence gut microbiome composition and function, we investigated whether microbiome profiles of SR exist in UC. METHODS: Ninety-one UC subjects in clinical and biochemical remission were classified into high and low SR groups by questionnaires. Baseline and longitudinal characterization of the intestinal microbiome was performed by 16S rRNA gene sequencing and fecal and plasma global untargeted metabolomics. Microbe, fecal metabolite, and plasma metabolite abundances were analyzed separately to create random forest classifiers for high SR and biomarker-derived SR scores. RESULTS: High SR reactivity was characterized by altered abundance of fecal microbes, primarily in the Ruminococcaceae and Lachnospiraceae families; fecal metabolites including reduced levels of monoacylglycerols (endocannabinoid-related) and bile acids; and plasma metabolites including increased 4-ethyl phenyl sulfate, 1-arachidonoylglycerol (endocannabinoid), and sphingomyelin. Classifiers generated from baseline microbe, fecal metabolite, and plasma metabolite abundance distinguished high vs low SR with area under the receiver operating characteristic curve of 0.81, 0.83, and 0.91, respectively. Stress reactivity scores derived from these classifiers were significantly associated with flare risk during 6 to 24 months of follow-up, with odds ratios of 3.8, 4.1, and 4.9. Clinical flare and intestinal inflammation did not alter fecal microbial abundances but attenuated fecal and plasma metabolite differences between high and low SR. CONCLUSIONS: High SR in UC is characterized by microbial signatures that predict clinical flare risk, suggesting that the microbiome may contribute to stress-induced UC flares.

High Perceived Stress is Associated With Increased Risk of Ulcerative Colitis Clinical Flares.

BACKGROUND & AIMS: Although perceived stress (PS) has been associated with symptomatic flares in inflammatory bowel disease, clinical and physiological measures associated with perceived stress and flare are not known. The aim of this study was to identify physiological factors associated with perceived stress in ulcerative colitis (UC) subjects, and their relationship with flare. METHODS: Patients with UC in clinical remission (Simple Colitis Clinical Activity Index [SCCAI] score <5) underwent clinical and behavioral assessments, morning salivary cortisol measurements, autonomic nervous system activity testing (heart rate variability, electrodermal activity) at baseline with patient-reported SCCAI every 2 weeks over 1 to 2 years and fecal calprotectin at time of flare. Clinical flares (SCCAI ≥5) and biochemical flares (SCCAI ≥5 with fecal calprotectin ≥250 µg/g) were evaluated. RESULTS: One hundred ten patients with UC were enrolled, with mean follow-up of 65.6 weeks. Patients with UC with higher and lower PS were determined. Although the high PS group had 3.6 times higher odds of a clinical flare than the low PS group, no significant differences in biochemical flares were observed between the low and high PS groups. The high vs low PS group differed in tonic sympathetic arousal as indexed by significantly greater baseline electrodermal activity (4.3 vs 3.4 microsiemens; P = .026) in the high PS group, but not in terms of heart rate variability and morning cortisol levels. Increased fecal calprotectin was associated with cardioautonomic measures, suggesting lower parasympathetic activity. CONCLUSIONS: Increased PS assessed at baseline is associated with tonic sympathetic arousal and greater odds of clinical flares in patients with UC.

Patient Experience and Satisfaction with an e-Health Care Management Application for Inflammatory Bowel Diseases.

BACKGROUND: Rising healthcare expenditures have been partially attributed to suboptimal management of inflammatory bowel diseases (IBD). Electronic health interventions may help improve care management for IBD patients, but there is a need to better understand patient perspectives on these emerging technologies. AIMS: The primary aim was to evaluate patient satisfaction and experience with the UCLA eIBD mobile application, an integrative care management platform with disease activity monitoring tools and educational modules. The secondary objective was to capture patient feedback on how to improve the mobile application. METHODS: We surveyed IBD patients treated at the UCLA Center for Inflammatory Bowel Diseases. The patient experience survey assessed the patients' overall satisfaction with the application, perception of health outcomes after participation in the program, and feedback on educational modules as well as areas for application improvement. RESULTS: 50 patients were included. The responses indicated that the patients were greatly satisfied with the ease of patient-provider communication within the application and appointment scheduling features (68%). A majority of respondents (54%) also reported that program participation resulted in improved perception of disease control and quality of life. Lastly, a majority of participants (79%) would recommend this application to others. CONCLUSIONS: Mobile tools such as UCLA eIBD have promising implications for integration into patients' daily lives. This patient satisfaction study suggests the feasibility of using this mobile application by patients and providers. We further showed that UCLA eIBD and its holistic approach led to improved patient experience and satisfaction, which can provide useful recommendations for future electronic health solutions.

The Colonic Mucosal MicroRNAs, MicroRNA-219a-5p, and MicroRNA-338-3p Are Downregulated in Irritable Bowel Syndrome and Are Associated With Barrier Function and MAPK Signaling.

BACKGROUND & AIMS: Alterations in microRNA (miRNA) and in the intestinal barrier are putative risk factors for irritable bowel syndrome (IBS). We aimed to identify differentially expressed colonic mucosal miRNAs, their targets in IBS compared to healthy controls (HCs), and putative downstream pathways. METHODS: Twenty-nine IBS patients (15 IBS with constipation [IBS-C], 14 IBS with diarrhea [IBS-D]), and 15 age-matched HCs underwent sigmoidoscopy with biopsies. A nCounter array was used to assess biopsy specimen-associated miRNA levels. A false discovery rate (FDR) < 10% was considered significant. Real-time polymerase chain reaction (PCR) was used to validate differentially expressed genes. To assess barrier function, trans-epithelial electrical resistance (TEER) and dextran flux assays were performed on Caco-2 intestinal epithelial cells that were transfected with miRNA-inhibitors or control inhibitors. Protein expression of barrier function associated genes was confirmed using western blots. RESULTS: Four out of 247 miRNAs tested were differentially expressed in IBS compared to HCs (FDR < 10%). Real-time PCR validation suggested decreased levels of miR-219a-5p and miR-338-3p in IBS (P = .026 and P = .004), and IBS-C (P = .02 and P = .06) vs. HCs as the strongest associations. Inhibition of miR-219a-5p resulted in altered expression of proteasome/barrier function genes. Functionally, miR-219a-5p inhibition enhanced the permeability of intestinal epithelial cells as TEER was reduced (25-50%, P < .05) and dextran flux was increased (P < .01). Additionally, inhibition of miR-338-3p in cells caused alterations in the mitogen-activated protein kinase (MAPK) signaling pathway genes. CONCLUSION: Two microRNAs that potentially affect permeability and visceral nociception were identified to be altered in IBS patients. MiR-219a-5p and miR-338-3p potentially alter barrier function and visceral hypersensitivity via neuronal and MAPK signaling and could be therapeutic targets in IBS.