Campylobacter jejuni genotypes are associated with post-infection irritable bowel syndrome in humans

Authors: PETERS, STEPHANIE - Mayo Clinic; PASCOE, BEN - University Of Bath; WU, ZUOWEI - Iowa State University; BAYLISS, SION - University Of Bath; ZENG, XIMIN - Mayo Clinic; EDWINSON, ADAM - Mayo Clinic; VEERABADHRAN-GURUNAT, S - Mayo Clinic; JAWAHIR, SELINA - Minnesota Department Of Health; CALLAND, JESSICA - University Of Bath; MOURKAS, EVANGELOS - University Of Bath; PATEL, ROBIN - Mayo Clinic; WIENS, TERRA - Minnesota Department Of Health; DECUIR, MARIJKE - Minnesota Department Of Health; BOXRUD, DAVID - Minnesota Department Of Health; SMITH, KIRK - Minnesota Department Of Health; Parker, Craig; FARRUGIA, GIANRICO - Mayo Clinic; ZHANG, QIJING - Iowa State University; SHEPPARD, SAMUEL - University Of Bath; GROVER, MADHUSUDAN - Mayo Clinic

Submitted to: Communications Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/13/2021
Publication Date: 8/30/2021
Citation: Peters, S., Pascoe, B., Wu, Z., Bayliss, S.C., Zeng, X., Edwinson, A., Veerabadhran-Gurunathan, S., Jawahir, S., Calland, J.K., Mourkas, E., Patel, R., Wiens, T., Decuir, M., Boxrud, D., Smith, K., Parker, C.T., Farrugia, G., Zhang, Q., Sheppard, S.K., Grover, M. 2021. Campylobacter jejuni genotypes are associated with post-infection irritable bowel syndrome in humans. Communications Biology. 4. Article 1015. https://doi.org/10.1038/s42003-021-02554-8.
DOI: https://doi.org/10.1038/s42003-021-02554-8

Interpretive Summary: Campylobacter enterocolitis may lead to post-infection irritable bowel syndrome (PI-IBS) and while some C. jejuni strains are more likely than others to cause human disease, genomic and virulence characteristics promoting PI-IBS development remain uncharacterized. We combined pangenome-wide association studies and phenotypic assays to compare C. jejuni isolates from patients who developed PI-IBS with those who did not. Variation in bacterial stress response (Cj0145_phoX), adhesion protein (Cj0628_CapA), and core biosynthetic pathway genes (biotin: Cj0308_bioD; purine: Cj0514_purQ; isoprenoid: Cj0894c_ispH) were associated with PI-IBS development. In vitro assays demonstrated greater adhesion, invasion, IL-8 and TNFa secretion on colonocytes with PI-IBS compared to PI-no-IBS strains. A risk-score for PI-IBS development was generated using 22 genomic markers, four of which were from Cj1631c, a putative heme oxidase gene linked to virulence. Our finding that specific Campylobacter genotypes confer greater in vitro virulence and increased risk of PI-IBS has potential to improve understanding of the complex host-pathogen interactions underlying this condition.

Technical Abstract: Irritable bowel syndrome (IBS) is a chronic, disabling gastrointestinal disorder that affects up to 15% of people worldwide. Patients suffer from chronic symptoms of abdominal pain and alteration in frequency and/or form of the stool. Acute infectious gastroenteritis is a major risk factor for development of this condition with the onset of chronic symptoms often emerging post infection (PI-IBS). Campylobacter enterocolitis may lead to PI-IBS and while some C. jejuni strains are more likely than others to cause human disease, genomic and virulence characteristics promoting PI-IBS development remain uncharacterized. We combined pangenome-wide association studies and phenotypic assays to compare C. jejuni isolates from patients who developed PI-IBS with those who did not. This study provides the first systematic evaluation of bacterial genomics and in vitro virulence using isolates acquired from a prospectively identified cohort of patients developing Campylobacter PI-IBS. Variation in bacterial stress response (Cj0145_phoX), adhesion protein (Cj0628_capA), and core biosynthetic pathway genes (biotin: Cj0308_bioD; purine: Cj0514_purQ; isoprenoid: Cj0894c_ispH) were associated with PI-IBS development. In vitro assays demonstrated greater adhesion, invasion, IL-8 and TNFa secretion on colonocytes with PI-IBS compared to PI-no-IBS strains. A risk-score for PI-IBS development was generated using 22 genomic markers, four of which were from Cj1631c, a putative heme oxidase gene linked to virulence. Our finding that specific Campylobacter genotypes confer greater in vitro virulence and increased risk of PI-IBS has potential to improve understanding of the complex host-pathogen interactions underlying this condition.