Summary of Study ST002094
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001102. The data can be accessed directly via it's Project DOI: 10.21228/M8840R This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Study ID | ST002094 |
| Study Title | Commensal intestinal microbiota regulates host luminal proteolytic activity and intestinal barrier integrity through β-glucuronidase activity (Part 1) |
| Study Type | MS |
| Study Summary | Proteases constitute the largest enzyme gene family in vertebrates with intracellular and secreted proteases having critical roles in cellular and organ physiology. Intestinal tract contains diverse set of proteases mediating digestion, microbial responses, epithelial and immune signaling. Transit of chyme through the intestinal tract results in significant suppression of proteases. Although endogenous protease inhibitors have been identified, the broader mechanisms underlying protease regulation in the intestinal tract remains unclear. The objective of this study was to determine microbial regulation of proteolytic activity in intestinal tract using phenotype of post-infection irritable bowel syndrome, a condition characterized by high fecal proteolytic activity. Proteases of host pancreatic origin (chymotrypsin like pancreatic elastase 2A, 3B and trypsin 2) drove proteolytic activity. Of the 14 differentially abundant taxa, high proteolytic activity state was characterized by complete absence of the commensal Alistipes putredinis. Germ free mice had very high proteolytic activity (10-fold of specific-pathogen free mice) which dropped significantly upon humanization with microbiota from healthy volunteers. In contrast, high proteolytic activity microbiota failed to inhibit it, a defect that corrected with fecal microbiota transplant as well as addition of A. putredinis. These mice also had increased intestinal permeability similar to that seen in patients. Microbiota β-glucuronidases mediate bilirubin deconjugation and unconjugated bilirubin is an inhibitor of serine proteases. We found that high proteolytic activity patients had lower urobilinogen levels, a product of bilirubin deconjugation. Mice colonized with β-glucuronidase overexpressing E. coli demonstrated significant inhibition of proteolytic activity and treatment with β-glucuronidase inhibitors increased it. The findings establish that specific commensal microbiota mediates effective inhibition of host pancreatic proteases and maintains intestinal barrier function through the production of β-glucuronidases. This suggests an important homeostatic role for commensal intestinal microbiota. |
| Institute | Mayo Clinic |
| Department | Biomedical Statistics and Informatics |
| Last Name | Dasari |
| First Name | Surendra |
| Address | 200 First Street SW, Rochester, MN, 55905, USA |
| Dasari.Surendra@mayo.edu | |
| Phone | 507-284-0513 |
| Submit Date | 2022-02-17 |
| Num Groups | 2 |
| Total Subjects | 7 |
| Raw Data Available | Yes |
| Raw Data File Type(s) | d |
| Analysis Type Detail | LC-MS |
| Release Date | 2022-03-09 |
| Release Version | 1 |
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Treatment:
| Treatment ID: | TR002190 |
| Treatment Summary: | A total of 52 PI-IBS patients defined by Rome III criteria and 38 healthy volunteers were recruited. Those with a history of abdominal surgery (except hernia, C-section, hysterectomy, appendectomy or cholecystectomy), inflammatory bowel disease, microscopic colitis, or celiac disease were excluded. Additionally, recruited volunteers were not pregnant at the time of the study. Use of tobacco or alcohol for the duration of the study was prohibited. Following medications were prohibited 7 days prior to study participation: those affecting gastrointestinal transit, serotonergic agents, anti-cholinergic agents, antimuscarinics, narcotics, peppermint oil, antibiotics or new probiotics. Ingestion of artificial sweeteners such as SplendaTM (sucralose), Nutrasweet TM (aspartame), lactulose or mannitol was prohibited for 2 days before the start and during the study. All subjects taking part in the study were asked to complete the Hospital Anxiety and Depression Scale (HADS) and a 7-day bowel diary. All participants completed the Hospital anxiety and depression scale (HADS). PI-IBS patients also completed the Symptom Checklist-90 (SCL-90), IBS Symptom severity scale (IBS-SSS), IBS-quality of life (IBS-QoL) questionnaire as well as the Long Bowel Disease questionnaire (BDQ). Mayo Clinic Institutional Review Board approved human studies and all participants provided a written informed consent (IRB protocol: 12-006529; ClinicalTrials.gov identifier: NCT03266068). |
