Prevotella copri leads to colonic barrier dysfunction via the succinate receptor 1-FoxM1-IL-6 axis

Area of Science:

• Microbiome research
• Gut health and disease
• Molecular mechanisms of intestinal inflammation

Background:

• Prevotella copri is a gut bacterium linked to various disorders, but its role in intestinal pathologies is unclear.
• Previous studies suggest an association between P. copri and intestinal issues, yet the underlying mechanisms require elucidation.
• Understanding P. copri's impact on colonic physiology is crucial for addressing gut-related diseases.

Purpose of the Study:

• To investigate the effects of P. copri on colonic physiology in healthy mice.
• To identify the microbial metabolites and signaling pathways involved in P. copri-induced intestinal barrier dysfunction.
• To explore the clinical relevance of these findings in human cohorts.

Main Methods:

• Assessing colonic tight junction protein expression (Occludin, ZO-1) and serum gut permeability markers (LPS, D-LA) in mice colonized with P. copri.
• Identifying the key microbial metabolite responsible for barrier disruption and its receptor (SUCNR1).
• Analyzing the IL-6-STAT3 signaling pathway activation and the role of transcription factor FoxM1 in P. copri or succinate-treated mice.
• Correlating fecal succinate levels with plasma gut permeability markers in human cohorts.

Main Results:

• P. copri colonization compromised intestinal barrier integrity in mice, evidenced by reduced tight junction proteins and increased gut permeability markers.
• Succinate was identified as the primary microbial metabolite mediating P. copri's barrier-disrupting effects, acting through the succinate receptor 1 (SUCNR1).
• Both P. copri and succinate activated the IL-6-STAT3 pathway, leading to Occludin suppression, with FoxM1 identified as a key regulator of IL-6 expression.
• Human cohort analyses revealed positive correlations between fecal succinate and plasma gut permeability markers.

Conclusions:

• P. copri impairs colonic barrier function through succinate production, which activates the IL-6-STAT3 pathway and suppresses Occludin expression.
• The findings elucidate a novel mechanism linking P. copri to intestinal pathology.
• Targeting P. copri abundance or succinate production presents a potential therapeutic strategy for colitis.