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other·gastroenterology, immunology, preclinical research, biomedical research·PMC10158566

Crohn’s disease proteolytic microbiota enhances inflammation through PAR2 pathway in gnotobiotic mice

Gut Microbes · 15 authors, 7 centres

AI SUMMARY

FIDELITY 100%

POPULATIONAdult and neonatal germ-free C57BL/6 mice, Nod2−/− mice, and R38E-PAR2 cleavage-resistant mice

INTERVENTIONColonization with Crohn's disease or healthy control fecal microbiota selected for high (HPA) or low (LPA) proteolytic activity

COMPARISONCD-HPA vs CD-LPA vs HC-LPA vs HC-HPA and germ-free controls, across wild-type, Nod2−/−, and R38E-PAR2 mouse strains

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

TRACE TO SOURCE

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TL;DR

Colitis severity was dependent on PAR2 cleavage signaling, as PAR2 cleavage-resistant mice were protected from the colitogenic effect of CD-HPA.

Full summary

831 CHARS

Germ-free C57BL/6, Nod2−/−, and R38E-PAR2 cleavage-resistant mice were colonized with human microbiota from Crohn's disease patients selected for high (CD-HPA) or low (CD-LPA) fecal proteolytic activity, or from healthy controls (HC-HPA or HC-LPA). Colitis was induced with low-dose dextran sodium sulfate. Fecal proteolytic, elastolytic, and mucolytic activity were measured, and microbial community assessed by 16S rRNA gene sequencing with PICRUSt2 functional prediction. Immune function was evaluated by inflammatory gene expression using NanoString and by histology. CD-HPA-colonized C57BL/6 and Nod2−/− mice had higher colitis severity than CD-LPA-colonized counterparts. Importantly, PAR2 cleavage-resistant mice colonized with CD-HPA were protected from exacerbated colitis, indicating PAR2 signaling as a required pathway.

PICO

PPOPULATION

Adult and neonatal germ-free C57BL/6 mice, Nod2−/− mice, and R38E-PAR2 cleavage-resistant mice

IINTERVENTION

Colonization with Crohn's disease or healthy control fecal microbiota selected for high (HPA) or low (LPA) proteolytic activity

OOUTCOME

Colitis severity, fecal proteolytic activity, inflammatory gene expression, microbiota composition, histological immune infiltrate

STUDY TYPE

other

SPECIALTY

gastroenterology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10158566

Crohn’s disease proteolytic microbiota enhances inflammation through PAR2 pathway in gnotobiotic mice

Gut Microbes

READ THE FULL PAPER

ABSTRACT

ABSTRACT Emerging evidence implicates microbial proteolytic activity in ulcerative colitis (UC), but whether it also plays a role in Crohn’s disease (CD) remains unclear. We investigated the effects of colonizing adult and neonatal germ-free C57BL/6 mice with CD microbiota, selected based on high (CD-HPA) or low fecal proteolytic activity (CD-LPA), or microbiota from healthy controls with LPA (HC-LPA) or HPA (HC-HPA). We then investigated colitogenic mechanisms in gnotobiotic C57BL/6, and in mice with impaired Nucleotide-binding Oligomerization Domain-2 (NOD2) and Protease-Activated Receptor 2 (PAR2) cleavage resistant mice ( Nod2 −/− ; R38E-PAR2 respectively). At sacrifice, total fecal proteolytic, elastolytic, and mucolytic activity were analyzed. Microbial community and predicted function were assessed by 16S rRNA gene sequencing and PICRUSt2. Immune function and colonic injury were investigated by inflammatory gene expression (NanoString) and histology. Colonization with HC-LPA or CD-LPA lowered baseline fecal proteolytic activity in germ-free mice, which was paralleled by lower acute inflammatory cell infiltrate. CD-HPA further increased proteolytic activity compared with germ-free mice. CD-HPA mice had lower alpha diversity, distinct microbial profiles and higher fecal proteolytic activity compared with CD-LPA. C57BL/6 and Nod2 −/− mice, but not R38E-PAR2, colonized with CD-HPA had higher colitis severity than those colonized with CD-LPA. Our results indicate that CD proteolytic microbiota is proinflammatory, increasing colitis severity through a PAR2 pathway.

CITATION EXPORT

Alba Santiago, Amber Hann, Marco Constante et al.. Crohn’s disease proteolytic microbiota enhances inflammation through PAR2 pathway in gnotobiotic mice. Gut Microbes. (2023). https://doi.org/10.1080/19490976.2023.2205425

AUTHORS

15 · 7 CENTRES

Alba Santiago, Amber Hann, Marco Constante, Sara Rahmani, Josie Libertucci, Kyle Jackson, Gaston Rueda, Laura Rossi, Rithwik Ramachandran, Wolfram Ruf, Jon Schertzer, Alberto Caminero, Premysl Bercik, Heather Jean Galipeau, Elena Francisca Verdu

aDepartment of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada
bSchool of Biomedical Engineering, McMaster University, Ontario, Canada
cDepartment of Chemical Engineering, McMaster University, Ontario, Canada
dDepartment of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada
eCenter for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany
fDepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
gDepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada