Transcriptomic and metabolomic correlates of increased colonic permeability in post-infection irritable bowel syndrome.

BACKGROUND AND AIM: Post-infection irritable bowel syndrome (PI-IBS) is well-known epidemiologically; however, its physiological and molecular characteristics are not well studied. We aimed to determine the physiological phenotypes, colonic transcriptome, fecal microbiome, and metabolome in PI-IBS. METHODS: Fifty-one Rome III Campylobacter PI-IBS patients and 39 healthy volunteers (HV) were enrolled. Participants completed questionnaires, in vivo intestinal permeability, gastrointestinal transit, and rectal sensation. Fecal samples were collected for shotgun metagenomics, untargeted metabolomics, and sigmoid colonic biopsies for bulk RNAseq. Differential gene expression, differences in microbiota composition and metabolite abundance were determined. Gene and metabolite clusters were identified via weighted gene correlation network analysis and correlations with clinical and physiological parameters determined. RESULTS: PI-IBS (59% F, 46±2 yrs.) and HV (64% F, 42±2 yrs.) demographics were comparable. Mean IBS-symptom severity score was 227; 94% were non-constipation. 2-24h lactulose excretion was increased in PI-IBS, suggesting increased colonic permeability (4.4±0.5 mg vs. 2.6±0.3 mg, p=0.01). Colonic transit and sensory thresholds were similar between the two groups. Overall, expression of 2036 mucosal genes and 223 fecal metabolites were different, with changes more prominent in females. Fecal N-acetylputrescine was increased in PI-IBS and associated with colonic permeability, worse diarrhea, and negatively correlated with abundance of Collinsella aerofaciens. Histamine and N-acetyl histamine positively associated with 2-24 hr lactulose excretion. Eight weighted gene coexpression modules significantly correlated with phenotypes (sex, stool frequency, colonic permeability, transit). CONCLUSIONS: Campylobacter PI-IBS patients demonstrate higher colonic permeability which associated with changes in polyamine and histamine metabolites. Female patients demonstrated greater molecular changes.

Intestinal chemosensitivity in irritable bowel syndrome associates with small intestinal TRPV channel expression.

BACKGROUND: Irritable bowel syndrome (IBS) patients often experience meal-associated symptoms. However, the underlying mechanisms are unclear. AIM: To determine small intestinal mechanisms of lipid-induced symptoms and rectal hypersensitivity in IBS METHODS: We recruited 26 IBS patients (12 IBS-C, 14 IBS-D) and 15 healthy volunteers (HV). In vivo permeability was assessed using saccharide excretion assay. Rectal sensitivity was assessed using a barostat before and after small bowel lipid infusion; symptoms were assessed throughout. Next, an extended upper endoscopy with probe-based confocal laser endomicroscopy (pCLE) was performed with changes induced by lipids. Duodenal and jejunal mucosal biopsies were obtained for transcriptomics. RESULTS: Following lipid infusion, a higher proportion of HV than IBS patients reported no pain, no nausea, no fullness and no urgency (P < 0.05 for all). In a model adjusted for sex and anxiety, IBS-C and IBS-D patients had lower thresholds for first rectal sensation (P = 0.0007) and pain (P = 0.004) than HV. In vivo small intestinal permeability and mean pCLE scores were similar between IBS patients and HV. Post-lipid, pCLE scores were higher than pre-lipid but were not different between groups. Baseline duodenal transient receptor potential vanilloid (TRPV) 1 and 3 expression was increased in IBS-D, and TRPV3 in IBS-C. Duodenal TRPV1 expression correlated with abdominal pain (r = 0.51, FDR = 0.01), and inversely with first rectal sensation (r = -0.48, FDR = 0.01) and pain (r = -0.41, FDR = 0.02) thresholds. CONCLUSION: Lipid infusion elicits a greater symptom response in IBS patients than HV, which is associated with small intestinal expression of TRPV channels. TRPV-mediated small intestinal chemosensitivity may mediate post-meal symptoms in IBS.

Post-infection Irritable Bowel Syndrome.

Epidemiologic data support that acute gastrointestinal infection is one of the strongest risk factors for development of irritable bowel syndrome (IBS). Risk of post-infection IBS (PI-IBS) seems to be greater with bacterial and protozoal than viral enterocolitis. Younger individuals, women, and those with severe enterocolitis are more likely to develop PI-IBS. Disease mechanisms in animal models and humans involve chronic perturbation of intestinal microbiome, epithelial and neuronal remodeling, and immune activation. These mechanisms can lead to luminal (increased proteolytic activity, altered bile acid composition) and physiologic (increased permeability, transit changes, and visceral hypersensitivity) alterations that can mediate PI-IBS symptoms.

Characteristics and Risk Factors of Post-Infection Irritable Bowel Syndrome After Campylobacter Enteritis.

BACKGROUND & AIMS: Campylobacter is the leading cause of bacterial gastroenteritis in the United States. We investigated the prevalence of postinfection irritable bowel syndrome (PI-IBS) in a cohort with culture-confirmed Campylobacter cases; risk factors for PI-IBS based on clinical factors; and shifts in IBS patterns postinfection in patients with pre-existing IBS. METHODS: The Minnesota Department of Health collects data on symptoms and exposures upon notification of Campylobacter cases. From 2011 through 2019, we sent surveys (the Rome III and IBS symptom severity surveys) to 3586 patients 6 to 9 months after Campylobacter infection. The prevalence of PI-IBS was estimated and risk factors were assessed using multivariable logistic regression. RESULTS: There were 1667 responders to the survey, 249 of whom had pre-existing IBS. Of the 1418 responders without pre-existing IBS, 301 (21%) subsequently developed IBS. Most of these individuals had IBS-mixed (54%), followed by IBS-diarrhea (38%), and IBS-constipation (6%). The mean IBS symptom severity score was 218 (indicating moderate severity). Female sex, younger age, bloody stools, abdominal cramps, and hospitalization during acute enteritis were associated with increased risk, whereas fever was protective for the development of PI-IBS. Antibiotic use and exposure patterns were similar between PI-IBS and control groups. Among patients with IBS-mixed or IBS-diarrhea before infection, 78% retained their subtypes after infection. In contrast, only 50% of patients with IBS-constipation retained that subtype after infection, whereas 40% transitioned to IBS-mixed. Of patients with pre-existing IBS, 38% had increased frequency of abdominal pain after Campylobacter infection. CONCLUSIONS: In a cohort of patients with Campylobacter infection in Minnesota, 21% developed PI-IBS; most cases reported mixed IBS or diarrhea of moderate severity. Demographic and clinical factors during acute enterocolitis are associated with PI-IBS development. Campylobacter infection also can result in a switch of a pre-existing IBS phenotype.

Comparing Clinical, Imaging, and Physiological Correlates of Intestinal Pseudo-Obstruction: Systemic Sclerosis vs Amyloidosis and Paraneoplastic Syndrome.

INTRODUCTION: Intestinal pseudo-obstruction is characterized by impaired transit and luminal dilation in the absence of mechanical obstruction. Our study aims to describe the clinical, radiographic, and physiological findings in pseudo-obstruction associated with systemic sclerosis (SSc), amyloidosis, and paraneoplastic syndrome. METHODS: A retrospective cohort of patients evaluated at our institution between January 1, 2008, and August 1, 2018, was assembled. Clinical, imaging, and physiological characteristics were abstracted from electronic medical records. RESULTS: We identified 100 cases of pseudo-obstruction (55 SSc, 27 amyloidosis, and 18 paraneoplastic). Female population predominance was seen in SSc (71%) vs male population in amyloidosis (74%). Most common symptom was abdominal bloating in all 3 groups. Vomiting was more common in SSc than amyloidosis (73% vs 46%, P = 0.02). Diarrhea was more common in amyloidosis and SSc compared with paraneoplastic (81% and 67% vs 28%, P < 0.01). Weight loss (>5%) was more common in SSc compared with amyloidosis and paraneoplastic (78% vs 31% and 17%, P < 0.0001). Only small bowel dilation was seen in 79%, 40%, and 44% and only large bowel dilation in 2%, 44%, and 44% of patients in SSc, amyloidosis, and paraneoplastic, respectively. Five of 8 SSc patients had myopathic and 3 of 5 paraneoplastic had neuropathic involvement on gastroduodenal manometry. DISCUSSION: SSc-associated pseudo-obstruction demonstrates female population predominance and presents with vomiting, diarrhea, and weight loss. Amyloidosis-associated pseudo-obstruction shows male population predominance. Small bowel is more commonly involved than large bowel on both imaging and transit studies in SSc. Myopathic involvement was more common in SSc, contrary to neuropathic in paraneoplastic syndrome.