Antimicrobial overproduction sustains intestinal inflammation by inhibiting Enterococcus colonization

Area of Science:

• Microbiology
• Immunology
• Gastroenterology

Background:

• Antimicrobial proteins, such as REG3 family members, are crucial for intestinal barrier integrity.
• Dysregulation of these proteins, particularly overproduction, can negatively impact the gut microbiota and host health.

Approach:

• Investigated the role of heightened secreted REG3 proteins during inflammatory bowel disease (IBD) flares.
• Examined the impact of Enterococcus faecium (Efm) depletion on gut microbiota and intestinal inflammation in mouse models.
• Assessed the involvement of the innate immune receptor NOD2 and its association with bacterial SagA in mediating protective immune responses.

Key Points:

• IBD flares are associated with increased REG3 proteins, leading to Enterococcus faecium depletion.
• Efm administration ameliorates intestinal inflammation via NOD2 activation, involving IL-1β secretion and enhanced T helper cell and innate lymphoid cell responses.
• A common NOD2 variant found in IBD patients abrogated Efm's protective effect.

Conclusions:

• Aberrant antimicrobial activity during inflammation disrupts symbiotic gut microbial relationships.
• Inflammation can self-perpetuate by altering the gut microbiota composition and function.
• Targeting REG3-mediated microbial dysbiosis and NOD2 signaling presents potential therapeutic strategies for IBD.