Active thrombin produced by the intestinal epithelium controls mucosal biofilms

Published on Dec 1, 2019in Nature Communications11.878
· DOI :10.1038/s41467-019-11140-w
Jean-Paul Motta15
Estimated H-index: 15
(University of Toulouse),
Alexandre Denadai-Souza7
Estimated H-index: 7
(University of Toulouse)
+ 20 AuthorsNathalie Vergnolle62
Estimated H-index: 62
(University of Toulouse)
Proteolytic homeostasis is important at mucosal surfaces, but its actors and their precise role in physiology are poorly understood. Here we report that healthy human and mouse colon epithelia are a major source of active thrombin. We show that mucosal thrombin is directly regulated by the presence of commensal microbiota. Specific inhibition of luminal thrombin activity causes macroscopic and microscopic damage as well as transcriptomic alterations of genes involved in host-microbiota interactions. Further, luminal thrombin inhibition impairs the spatial segregation of microbiota biofilms, allowing bacteria to invade the mucus layer and to translocate across the epithelium. Thrombin cleaves the biofilm matrix of reconstituted mucosa-associated human microbiota. Our results indicate that thrombin constrains biofilms at the intestinal mucosa. Further work is needed to test whether thrombin plays similar roles in other mucosal surfaces, given that lung, bladder and skin epithelia also express thrombin. The roles played by thrombin in the human intestinal mucosa are unclear. Here, the authors show that the commensal microbiota modulates epithelial production of active thrombin, which controls biofilm growth and contributes to protection of the mucosa from bacterial invasion.
  • References (58)
  • Citations (0)
📖 Papers frequently viewed together
56 Citations
4 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
#1Alexandre Denadai-Souza (University of Toulouse)H-Index: 7
#2Chrystelle Bonnart (University of Toulouse)H-Index: 5
Last. Céline Deraison (University of Toulouse)H-Index: 11
view all 11 authors...
While proteases are essential in gastrointestinal physiology, accumulating evidence indicates that dysregulated proteolysis plays a pivotal role in the pathophysiology of inflammatory bowel disease (IBD). Nonetheless, the identity of overactive proteases released by human colonic mucosa remains largely unknown. Studies of protease abundance have primarily investigated expression profiles, not taking into account their enzymatic activity. Herein we have used serine protease-targeted activity-base...
6 CitationsSource
#1Brendan Mallia-Milanes (NIHR: National Institute for Health Research)H-Index: 1
#2Antoine Dufour (UBC: University of British Columbia)H-Index: 17
Last. Simon R. Johnson (NIHR: National Institute for Health Research)H-Index: 28
view all 10 authors...
Dysregulated protease activity is thought to cause parenchymal and airway damage in COPD. Multiple proteases have been implicated in COPD and identifying their substrates may reveal new disease mechanisms and treatments. However as proteases interact with many substrates which may be protease inhibitors or proteases themselves, these webs of protease interactions make the wider consequences of therapeutically targeting proteases difficult to predict. We therefore used a systems approach to deter...
5 CitationsSource
#1Morgane Sébert (University of Toulouse)H-Index: 1
#2Alexandre Denadai-Souza (University of Toulouse)H-Index: 7
Last. Nathalie Vergnolle (University of Toulouse)H-Index: 62
view all 13 authors...
Experimental Approach: Crypts were isolated from human colonic resections and cultured for 6 days, forming human colon organoids. Cultured organoids were exposed to 10 and 50 mU·mL−1 of thrombin, in the presence or not of protease‐activated receptor (PAR) antagonists. Organoid morphology, metabolism, proliferation and apoptosis were followed. Key Results: Thrombin favoured organoid maturation leading to a decreased number of immature cystic structures and a concomitant increased number of larger...
4 CitationsSource
#1Jean-Paul Motta (U of C: University of Calgary)H-Index: 15
#2Thibault Allain (U of C: University of Calgary)H-Index: 5
Last. Andre G. Buret (U of C: University of Calgary)H-Index: 47
view all 10 authors...
5 CitationsSource
#1Christine M. Dejea (Johns Hopkins University)H-Index: 12
#2Payam Fathi (Johns Hopkins University)H-Index: 8
Last. Cynthia L. Sears (Johns Hopkins University)H-Index: 30
view all 18 authors...
Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with precancerous lesions in hereditary CRC remains largely unknown. We studied colonic mucosa of patients with familial adenomatous polyposis (FAP), who develop benign precursor lesions (polyps) early in life. We identified patchy bacterial biofilms composed predominately of Escherichia coli and Bacteroides fragilis . Genes for colibactin...
122 CitationsSource
#1John L. Wallace (U of C: University of Calgary)H-Index: 71
#2Jean-Paul Motta (U of C: University of Calgary)H-Index: 15
Last. Andre G. Buret (U of C: University of Calgary)H-Index: 47
view all 3 authors...
A diverse range of effects of the intestinal microbiota on mucosal defense and injury has become increasingly clear over the past decade. Hydrogen sulfide (H2S) has emerged as an important mediator of many physiological functions, including gastrointestinal mucosal defense and repair. Hydrogen sulfide is produced by gastrointestinal tract tissues and by bacteria residing within the gut and can influence the function of a wide range of cells. The microbiota also appears to be an important target ...
8 CitationsSource
#1Venkat Raghavan Krishnaswamy (Weizmann Institute of Science)H-Index: 2
#2Dvir Mintz (Weizmann Institute of Science)H-Index: 1
Last. Irit Sagi (Weizmann Institute of Science)H-Index: 35
view all 3 authors...
Abstract Cutaneous wound healing is a complex mechanism with multiple processes orchestrating harmoniously for structural and functional restoration of the damaged tissue. Chronic non-healing wounds plagued with infection create a major healthcare burden and is one of the most frustrating clinical problems. Chronic wounds are manifested by prolonged inflammation, defective re-epithelialization and haphazard remodeling. Matrix metalloproteinases (MMPs) are zinc dependent enzymes that play cardina...
13 CitationsSource
#1Jessica L. Mark Welch (MBL: Marine Biological Laboratory)H-Index: 12
#2Yuko Hasegawa (MBL: Marine Biological Laboratory)H-Index: 2
Last. Gary G. Borisy (The Forsyth Institute)H-Index: 90
view all 5 authors...
Knowledge of the spatial organization of the gut microbiota is important for understanding the physical and molecular interactions among its members. These interactions are thought to influence microbial succession, community stability, syntrophic relationships, and resiliency in the face of perturbations. The complexity and dynamism of the gut microbiota pose considerable challenges for quantitative analysis of its spatial organization. Here, we illustrate an approach for addressing this challe...
48 CitationsSource
#1Claire Rolland-Fourcade (University of Toulouse)H-Index: 1
#2Alexandre Denadai-Souza (University of Toulouse)H-Index: 7
Last. Nathalie Vergnolle (University of Toulouse)H-Index: 62
view all 20 authors...
Objectives Proteases are key mediators of pain and altered enteric neuronal signalling, although the types and sources of these important intestinal mediators are unknown. We hypothesised that intestinal epithelium is a major source of trypsin-like activity in patients with IBS and this activity signals to primary afferent and enteric nerves and induces visceral hypersensitivity. Design Trypsin-like activity was determined in tissues from patients with IBS and in supernatants of Caco-2 cells sti...
26 CitationsSource
#1Jitka Petrlova (Lund University)H-Index: 12
#2Finja C. Hansen (Lund University)H-Index: 3
Last. Artur Schmidtchen (NTU: Nanyang Technological University)H-Index: 43
view all 8 authors...
Effective control of endotoxins and bacteria is crucial for normal wound healing. During injury, the key enzyme thrombin is formed, leading to generation of fibrin. Here, we show that human neutrophil elastase cleaves thrombin, generating 11-kDa thrombin-derived C-terminal peptides (TCPs), which bind to and form amorphous amyloid-like aggregates with both bacterial lipopolysaccharide (LPS) and gram-negative bacteria. In silico molecular modeling using atomic resolution and coarse-grained simulat...
14 CitationsSource
Cited By0
#1Barbara Mainoli (U of C: University of Calgary)
#2Simon A. Hirota (U of C: University of Calgary)H-Index: 21
Last. Antoine Dufour (U of C: University of Calgary)H-Index: 2
view all 5 authors...
Crohn’s disease (CD) is a chronic relapsing inflammatory bowel disease (IBD) that may be marked by debilitating symptoms of abdominal pain and obstruction. The etiology and pathogenesis of the disease are not fully understood, and treatment with corticosteroids, biologics, and surgical intervention are the usual therapeutic options. Diagnosis, disease activity, and therapeutic response are currently assessed by endoscopy, cross-sectional imaging, and biomarkers. However, challenges remain regard...