Antimicrobial overproduction sustains intestinal inflammation by inhibiting Enterococcus colonization

Area of Science:

• Microbiology
• Immunology
• Gastroenterology

Background:

• Antimicrobial proteins like REG3 are crucial for intestinal barrier integrity.
• Dysregulation of these proteins, including overproduction, can negatively impact the gut microbiota.

Purpose of the Study:

• To investigate the detrimental effects of REG3 protein overproduction in inflammatory bowel disease (IBD).
• To explore the role of Enterococcus faecium (Efm) and its interaction with the NOD2 receptor in mitigating intestinal inflammation.

Main Methods:

• Analysis of REG3 protein levels in IBD patients during flares.
• Efm inoculation in mouse models of intestinal inflammation.
• Investigation of NOD2 activation pathways and downstream immune responses.
• Assessment of Efm's protective capacity in mice with a specific NOD2 gene variant.

Main Results:

• IBD flares are associated with increased secreted REG3 proteins, leading to Efm depletion.
• Efm administration ameliorates intestinal inflammation via NOD2 activation, involving SagA and muropeptides.
• NOD2 activation promotes IL-1β secretion, enhancing IL-22-producing T helper cells and innate lymphoid cells for tissue repair.
• Efm fails to protect mice with an IBD-associated NOD2 variant.

Conclusions:

• Aberrant antimicrobial activity, driven by REG3 overproduction, disrupts beneficial microbial symbiosis in IBD.
• This disruption contributes to inflammation self-perpetuation by impairing protective immune signaling.
• The NOD2 receptor pathway and its interaction with specific microbes like Efm are critical for maintaining gut homeostasis in IBD.