Active thrombin produced by the intestinal epithelium controls mucosal biofilms

Area of Science:

• Gastroenterology
• Microbiology
• Proteomics

Background:

• Proteolytic homeostasis is crucial at mucosal surfaces, yet the specific enzymes and their physiological roles remain unclear.
• Understanding the regulation of mucosal surfaces by enzymes is essential for maintaining gut health and host-microbe interactions.

Purpose of the Study:

• To investigate the role of thrombin in maintaining proteolytic homeostasis at the intestinal mucosa.
• To determine the impact of thrombin inhibition on the gut epithelium and its associated microbiota.

Main Methods:

• Analysis of thrombin expression in healthy human and mouse colon epithelia.
• Inhibition of luminal thrombin activity and assessment of resulting damage (macroscopic, microscopic, transcriptomic).
• Investigation of thrombin's effect on the structure and spatial segregation of microbiota biofilms.

Main Results:

• Healthy colon epithelia are a significant source of active thrombin, regulated by commensal microbiota.
• Inhibition of luminal thrombin led to intestinal damage and altered gene expression related to host-microbiota interactions.
• Thrombin inhibition disrupted microbiota biofilm spatial organization, enabling bacterial invasion and translocation across the epithelium.
• Thrombin was shown to cleave the biofilm matrix of reconstituted mucosa-associated human microbiota.

Conclusions:

• Thrombin acts as a key regulator, constraining bacterial biofilms at the intestinal mucosal surface.
• These findings highlight a novel role for thrombin in maintaining gut barrier integrity and host-microbe symbiosis.
• Further research is warranted to explore thrombin's function on other mucosal surfaces like the lung, bladder, and skin.