Publications by authors named "Wendy Sundt"

4 Publications

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Serine proteases as luminal mediators of intestinal barrier dysfunction and symptom severity in IBS.

Gut 2020 01 28;69(1):62-73. Epub 2019 Mar 28.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.

Objective: The intestinal lumen contains several proteases. Our aim was to determine the role of faecal proteases in mediating barrier dysfunction and symptoms in IBS.

Design: 39 patients with IBS and 25 healthy volunteers completed questionnaires, assessments of in vivo permeability, ex vivo colonic barrier function in Ussing chambers, tight junction (TJ) proteins, ultrastructural morphology and 16 s sequencing of faecal microbiota rRNA. A casein-based assay was used to measure proteolytic activity (PA) in faecal supernatants (FSNs). Colonic barrier function was determined in mice (ex-germ free) humanised with microbial communities associated with different human PA states.

Results: Patients with IBS had higher faecal PA than healthy volunteers. 8/20 postinfection IBS (PI-IBS) and 3/19 constipation- predominant IBS had high PA (>95th percentile). High-PA patients had more and looser bowel movements, greater symptom severity and higher in vivo and ex vivo colonic permeability. High-PA FSNs increased paracellular permeability, decreased occludin and increased phosphorylated myosin light chain (pMLC) expression. Serine but not cysteine protease inhibitor significantly blocked high-PA FSN effects on barrier. The effects on barrier were diminished by pharmacological or siRNA inhibition of protease activated receptor-2 (PAR-2). Patients with high-PA IBS had lower occludin expression, wider TJs on biopsies and reduced microbial diversity than patients with low PA. Mice humanised with high-PA IBS microbiota had greater in vivo permeability than those with low-PA microbiota.

Conclusion: A subset of patients with IBS, especially in PI-IBS, has substantially high faecal PA, greater symptoms, impaired barrier and reduced microbial diversity. Commensal microbiota affects luminal PA that can influence host barrier function.
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http://dx.doi.org/10.1136/gutjnl-2018-317416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765451PMC
January 2020

Sex differences in NSAID-induced perturbation of human intestinal barrier function and microbiota.

FASEB J 2018 Jun 13:fj201800560R. Epub 2018 Jun 13.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.

Intestinal barrier function and microbiota are integrally related and play critical roles in maintenance of host physiology. Sex is a key biologic variable for several disorders. Our aim was to determine sex-based differences in response to perturbation and subsequent recovery of intestinal barrier function and microbiota in healthy humans. Twenty-three volunteers underwent duodenal biopsies, mucosal impedance, and in vivo permeability measurement. Permeability testing was repeated after administration of indomethacin, then 4 to 6 wk after its discontinuation. Duodenal and fecal microbiota composition was determined using 16S rRNA amplicon sequencing. Healthy women had lower intestinal permeability and higher duodenal and fecal microbial diversity than healthy men. Intestinal permeability increases after indomethacin administration in both sexes. However, only women demonstrated decreased fecal microbial diversity, including an increase in Prevotella abundance, after indomethacin administration. Duodenal microbiota composition did not show sex-specific changes. The increase in permeability and microbiota changes normalized after discontinuation of indomethacin. In summary, women have lower intestinal permeability and higher microbial diversity. Intestinal permeability is sensitive to perturbation but recovers to baseline. Gut microbiota in women is sensitive to perturbation but appears to be more stable in men. Sex-based differences in intestinal barrier function and microbiome should be considered in future studies.-Edogawa, S., Peters, S. A., Jenkins, G. D., Gurunathan, S. V., Sundt, W. J., Johnson, S., Lennon, R. J., Dyer, R. B., Camilleri, M., Kashyap, P. C., Farrugia, G., Chen, J., Singh, R. J., Grover, M. Sex differences in NSAID-induced perturbation of human intestinal barrier function and microbiota.
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http://dx.doi.org/10.1096/fj.201800560RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219825PMC
June 2018

Constipation-Predominant Irritable Bowel Syndrome Females Have Normal Colonic Barrier and Secretory Function.

Am J Gastroenterol 2017 Jun 21;112(6):913-923. Epub 2017 Mar 21.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.

Objectives: The objective of this study was to determine whether constipation-predominant irritable bowel syndrome (IBS-C) is associated with changes in intestinal barrier and secretory function.

Methods: A total of 19 IBS-C patients and 18 healthy volunteers (all females) underwent saccharide excretion assay (0.1 g C mannitol and 1 g lactulose), measurements of duodenal and colonic mucosal barrier (transmucosal resistance (TMR), macromolecular and Escherichia coli Bio-Particle translocation), mucosal secretion (basal and acetylcholine (Ach)-evoked short-circuit current (Isc)), in vivo duodenal mucosal impedance, circulating endotoxins, and colonic tight junction gene expression.

Results: There were no differences in the in vivo measurements of barrier function between IBS-C patients and healthy controls: cumulative excretion of C mannitol (0-2 h mean (s.e.m.); IBS-C: 12.1 (0.9) mg vs. healthy: 13.2 (0.8) mg) and lactulose (8-24 h; IBS-C: 0.9 (0.5) mg vs. healthy: 0.5 (0.2) mg); duodenal impedance IBS-C: 729 (65) Ω vs. healthy: 706 (43) Ω; plasma mean endotoxin activity level IBS-C: 0.36 (0.03) vs. healthy: 0.35 (0.02); and in colonic mRNA expression of occludin, zonula occludens (ZO) 1-3, and claudins 1-12 and 14-19. The ex vivo findings were consistent, with no group differences: duodenal TMR (IBS-C: 28.2 (1.9) Ω cm vs. healthy: 29.8 (1.9) Ω cm) and colonic TMR (IBS-C: 19.1 (1.1) Ω cm vs. healthy: 17.6 (1.7) Ω cm); fluorescein isothiocyanate (FITC)-dextran (4 kDa) and E. coli Bio-Particle flux. Colonic basal Isc was similar, but duodenal basal Isc was lower in IBS-C (43.5 (4.5) μA cm) vs. healthy (56.9 (4.9) μA cm), P=0.05. Ach-evoked ΔIsc was similar.

Conclusions: Females with IBS-C have normal colonic barrier and secretory function. Basal duodenal secretion is decreased in IBS-C.
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http://dx.doi.org/10.1038/ajg.2017.48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502210PMC
June 2017

Prevalence, Risk Factors, and Outcomes of Irritable Bowel Syndrome After Infectious Enteritis: A Systematic Review and Meta-analysis.

Gastroenterology 2017 04 6;152(5):1042-1054.e1. Epub 2017 Jan 6.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Background & Aims: Foodborne illness affects 15% of the US population each year, and is a risk factor for irritable bowel syndrome (IBS). We evaluated risk of, risk factors for, and outcomes of IBS after infectious enteritis.

Methods: We performed a systematic review of electronic databases from 1994 through August 31, 2015 to identify cohort studies of the prevalence of IBS 3 months or more after infectious enteritis. We used random-effects meta-analysis to calculate the summary point prevalence of IBS after infectious enteritis, as well as relative risk (compared with individuals without infectious enteritis) and host- and enteritis-related risk factors.

Results: We identified 45 studies, comprising 21,421 individuals with enteritis, followed for 3 months to 10 years for development of IBS. The pooled prevalence of IBS at 12 months after infectious enteritis was 10.1% (95% confidence interval [CI], 7.2-14.1) and at more than 12 months after infectious enteritis was 14.5% (95% CI, 7.7-25.5). Risk of IBS was 4.2-fold higher in patients who had infectious enteritis in the past 12 months than in those who had not (95% CI, 3.1-5.7); risk of IBS was 2.3-fold higher in individuals who had infectious enteritis more than 12 months ago than in individuals who had not (95% CI, 1.8-3.0). Of patients with enteritis caused by protozoa or parasites, 41.9% developed IBS, and of patients with enteritis caused by bacterial infection, 13.8% developed IBS. Risk of IBS was significantly increased in women (odds ratio [OR], 2.2; 95% CI, 1.6-3.1) and individuals with antibiotic exposure (OR, 1.7; 95% CI, 1.2-2.4), anxiety (OR, 2; 95% CI, 1.3-2.9), depression (OR, 1.5; 95% CI, 1.2-1.9), somatization (OR, 4.1; 95% CI, 2.7-6.0), neuroticism (OR, 3.3; 95% CI, 1.6-6.5), and clinical indicators of enteritis severity. There was a considerable level of heterogeneity among studies.

Conclusions: In a systematic review and meta-analysis, we found >10% of patients with infectious enteritis develop IBS later; risk of IBS was 4-fold higher than in individuals who did not have infectious enteritis, although there was heterogeneity among studies analyzed. Women-particularly those with severe enteritis-are at increased risk for developing IBS, as are individuals with psychological distress and users of antibiotics during the enteritis.
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http://dx.doi.org/10.1053/j.gastro.2016.12.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367939PMC
April 2017