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Elucidation of Proteus mirabilis as a Key Bacterium in Crohn's Disease Inflammation
Jingwan Zhang1, Emily C Hoedt2, Qin Liu1
1Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
Background & Aims:
Proteus spp, Gram-negative facultative anaerobic bacilli, have recently been associated with Crohn's disease (CD) recurrence after intestinal resection. We investigated the genomic and functional role of Proteus as a gut pathogen in CD.
Methods:
Proteus spp abundance was assessed by ure gene-specific polymerase chain in 54 pairs of fecal samples and 101 intestinal biopsies from patients with CD and healthy controls. The adherence, invasion, and intracellular presence of 2 distinct isolates of Proteus mirabilis in epithelial cells were evaluated using immunofluorescence and electron microscopy. Intracellular gene expression profiles and regulated pathways were analyzed by RNA sequencing and KEGG pathway analysis. Biologic functions of 2 isolates of P mirabilis were determined by in vitro cell culture, and in vivo using conventional mice and germ-free mice.
Results:
Proteus spp were significantly more prevalent and abundant in fecal samples and colonic tissue of patients with CD than controls. A greater abundance of the genus Fusobacterium and a lesser abundance of the genus Faecalibacterium were seen in patients with CD with a high Proteus spp abundance. All 24 Proteus monoclones isolated from patients with CD belonged to members of P mirabilis lineages and 2 isolates, recovered from stool or mucosa, were used in further studies. Mice gavaged with either P mirabilis strain had more severe colonic inflammation. Co-culture of the isolates with epithelial cell lines showed bacterial adherence, invasion, increased production of pro-inflammatory cytokines IL-18 and IL-1α, and cell necrosis. Both isolates induced key pro-inflammatory pathways, including NOD-like receptor signaling, Jak-STAT signaling, and MAPK signaling, and induced pro-inflammatory genes and activated inflammation-related pathways in gnotobiotic mice.
Conclusions:
P mirabilis in the gut is associated with CD and can induce inflammation in cells and animal models of colitis. P mirabilis can act as a pathobiont and play a crucial role in the pathogenesis of CD.
Insights
Proteus mirabilis bacteria are linked to Crohn's disease (CD) recurrence. This study shows P. mirabilis can cause gut inflammation and may be a key factor in CD development.
Area of Science:
- Microbiology
- Gastroenterology
- Immunology
Background:
- Proteus species (spp.) are Gram-negative bacilli increasingly associated with Crohn's disease (CD) recurrence post-surgery.
- This study investigates the role of Proteus as a gut pathogen in CD pathogenesis.
Purpose of the Study:
- To assess the prevalence and abundance of Proteus spp. in patients with CD compared to healthy controls.
- To evaluate the pathogenic mechanisms of Proteus mirabilis, including adherence, invasion, and inflammatory responses in epithelial cells and animal models.
Main Methods:
- Quantified Proteus spp. abundance using ure gene-specific polymerase chain reaction in fecal samples and intestinal biopsies.
- Assessed bacterial adherence, invasion, and intracellular presence in epithelial cells via microscopy.
- Analyzed gene expression and pathways using RNA sequencing and KEGG analysis.
- Evaluated in vitro and in vivo functions using cell cultures and mouse models.
Main Results:
- Proteus spp. were significantly more prevalent in CD patients' gut samples.
- Proteus mirabilis isolates adhered to and invaded epithelial cells, inducing pro-inflammatory cytokines (IL-18, IL-1α) and necrosis.
- P. mirabilis induced key inflammatory pathways (NOD-like receptor, Jak-STAT, MAPK) and exacerbated colitis in mice.
Conclusions:
- Proteus mirabilis is associated with Crohn's disease and can induce gut inflammation.
- P. mirabilis functions as a pathobiont, playing a significant role in CD pathogenesis.
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