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.

High-Dimensional Clustering of 4000 Irritable Bowel Syndrome Patients Reveals Seven Distinct Disease Subsets.

BACKGROUND AND AIMS: Irritable bowel syndrome (IBS) is a pain disorder classified by bowel habits, disregarding other factors that may influence the clinical course. The aim of this study was to determine if IBS patients can be clustered based on clinical, dietary, lifestyle, and psychosocial factors. METHODS: Between 2013 and 2020, the Mayo Clinic Biobank surveyed and received 40,291 responses to a questionnaire incorporating Rome III criteria. Factors associated with IBS were determined and latent class analysis, a model-based clustering, was performed on IBS cases. RESULTS: We identified 4021 IBS patients (mean 64 years; 75% women) and 12,063 controls. Using 26 variables separating cases from controls, the optimal clustering revealed 7 latent clusters. These were characterized by perceived health impairment (moderate or severe), psychoneurological factors, and bowel dysfunction (diarrhea or constipation predominance). Health impairment clusters demonstrated more pain, with the severe cluster also having more psychiatric comorbidities. The next 3 clusters had unique enrichment of psychiatric, neurological, or both comorbidities. The bowel dysfunction clusters demonstrated less abdominal pain, with diarrhea cluster most likely to report pain improvement with defecation. The constipation cluster had the highest exercise score and consumption of fruits, vegetables, and alcohol. The distribution of clusters remained similar when Rome IV criteria were applied. Physiologic tests were available on a limited subset (6%), and there were no significant differences between clusters. CONCLUSIONS: In this cohort of older IBS patients, 7 distinct clusters were identified demonstrating varying degrees of gastrointestinal symptoms, comorbidities, dietary, and lifestyle factors. Further research is required to assess whether these unique clusters could be used to direct clinical trials and individualize patient management.

Impact of Rome IV criteria on the prevalence of post-infection irritable bowel syndrome.

BACKGROUND: The Rome IV irritable bowel syndrome (IBS) criteria include changes to the description and frequency of abdominal pain. Existing studies have demonstrated a lower prevalence and greater severity in IBS patients identified using Rome IV than Rome III criteria. Our aim was to investigate the prevalence of post-infection IBS (PI-IBS) using Rome IV criteria in a population-based cohort of laboratory-confirmed C. jejuni infection cases. METHODS: The Minnesota Department of Health (MDH) requires notification of Campylobacter cases and interviews patients to gather information on clinical symptoms. For this study, the Rome IV diagnostic questionnaire was utilized 6-9 months after infection to determine the development of PI-IBS. The survey responses were analyzed for the prevalence of IBS and symptom severity. KEY RESULTS: Surveys were completed by 391 participants (31% response rate). Twenty-three patients had pre-existing IBS, and 18 did not complete enough questions to categorize their case status. Of the 350 remaining participants, 58 (17%) met Rome IV criteria. An additional 47 patients would have met the Rome III IBS criteria for pain frequency, driving the cumulative prevalence to 30%. The mean IBS Symptom Severity Score (IBS-SSS) in Rome IV patients was significantly higher than in Rome III (p < 0.05). With Rome IV, IBS-diarrhea was the most common subtype. CONCLUSIONS & INFERENCES: Rome IV criteria resulted in a 19% lower prevalence of PI-IBS than earlier reported Rome III-based prevalence in a similar population. Rome IV defined PI-IBS patients have greater symptom severity but similar distribution of IBS subtypes.

Systematic review of squamous cell carcinoma of the gallbladder.

BACKGROUND: Although gallbladder cancer is the most common biliary tract malignancy, squamous cell carcinoma of the gallbladder (GBSCC) is extremely uncommon, comprising approximately 1-4% of all malignant gallbladder tumors. Given its rare incidence, there are currently no established treatment guidelines for GBSCC. METHODS: We reviewed the current data available through a comprehensive search of PubMed/MEDLINE and Embase. RESULTS: Although the clinical presentations of GBSCC and gallbladder adenocarcinoma (GBAC) are similar, GBSCCs are oftentimes larger and present with a higher histologic grade and more advanced pathological stage. Due to these aggressive features, the overall prognosis of GBSCC is significantly worse than GBAC, even after R0 resection. CONCLUSION: A combination of radical cholecystectomy with negative surgical margins along with systemic chemotherapy and/or radiotherapy appears to be the best treatment strategy based on the current limited literature. Mutational profiling using next-generation sequencing (NGS) can help clinicians identify and treat actionable mutations of this rare tumor.