The protease code of the bacterial gut microbiota: ecological regulation, barrier disruption, and rewiring host defense and signaling

Abstract The human gastrointestinal tract is home to a dense and diverse microbial ecosystem that functions as a complex superorganism. Yet, the enzymatic machinery responsible for orchestrating this coexistence remains underexplored. Among these enzymes, microbial peptidases (proteases) represent pivotal effectors of the host-microbe interface. Far from acting merely as nonspecific digestive degraders, these proteases serve as highly specific signaling enzymes that can tip the balance between eubiosis and dysbiosis, functioning as critical architects of biofilm structure while also acting as potent virulence factors. This review provides a focused analysis of the microbial proteolytic landscape. We first examine how these enzymes govern community dynamics through the remodeling of biofilm protein matrices and the quenching of peptide-based quorum sensing. At the host-microbe boundary, we detail the hierarchical dismantling of barriers: from mucinases that compromise the protective mucus layer, to the systematic cleavage of adherens junctions by key effectors including enterotoxigenic Bacteroides fragilis toxin, Campylobacter jejuni HtrA, and Porphyromonas gingivalis gingipains. Finally, we explore how proteases transcend physical destruction to manipulate cellular signaling, subverting mucosal immunity via immunoglobulin A cleavage and driving inflammation through the activation of protease-activated receptors.