Active thrombin produced by the intestinal epithelium controls mucosal biofilms

Motta, Jean-Paul; Denadai‐Souza, Alexandre; Sagnat, David; Guiraud, Laura; Edir, Anissa; Bonnart, Chrystelle; Sebbag, Mireille; Rousset, Perrine; Lapeyre, Ariane; Séguy, Carine; Mathurine-Thomas, Noa; Galipeau, Heather J.; Bonnet, Delphine; Alric, Laurent; Buret, André G.; Wallace, John L.; Dufour, Antoine; Verdú, Elena F.; Hollenberg, Morley D.; Oswald, Éric; Sérino, Matteo; Deraison, Céline; Vergnolle, Nathalie

doi:10.1038/s41467-019-11140-w

Cited by 49 publications

(42 citation statements)

References 56 publications

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“…The role of epithelial‐derived thrombin against the gut microbiota appears to be more complex and less well understood. In this report, epithelial thrombin was shown to cleave microbiota biofilm‐derived proteins, thereby limiting bacterial translocation across the epithelium 46 . Of particular note, luminal thrombin inhibition was sufficient to elicit mucosal injuries and downregulate the expression of genes involved in host‐microbiota interactions 46 .…”

Section: Serine Proteases In a Nutshellmentioning

confidence: 82%

“…Under physiological conditions, matriptase controls claudin‐2 protein expression and its incorporation into the intercellular junction and induces barrier enhancement through downstream activation of mucosal PKCζ 42 . New research unravels an unsuspected role for thrombin, demonstrating that the intestinal epithelium releases thrombin at physiological conditions, which can display a shielding role on gut microbial communities preventing their contact with tissues 46 . The role of epithelial‐derived thrombin against the gut microbiota appears to be more complex and less well understood.…”

Section: Serine Proteases In a Nutshellmentioning

confidence: 99%

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Serine proteases at the cutting edge of IBD: Focus on gastrointestinal inflammation

et al. 2020

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Serine proteases have been long recognized to coordinate many physiological processes and play key roles in regulating the inflammatory response. Accordingly, their dysregulation has been regularly associated with several inflammatory disorders and suggested as a central mechanism in the pathophysiology of digestive inflammation. So far, studies addressing the proteolytic homeostasis in the gut have mainly focused on host serine proteases as candidates of interest, while largely ignoring the potential contribution of their bacterial counterparts. The human gut microbiota comprises a complex ecosystem that contributes to host health and disease. Yet, our understanding of microbially produced serine proteases and investigation of whether they are causally linked to IBD is still in its infancy. In this review, we highlight recent advances in the emerging roles of host and bacterial serine proteases in digestive inflammation. We also discuss the application of available tools in the gut to monitor disease‐related serine proteases. An exhaustive representation and understanding of such functional potential would help in closing existing gaps in mechanistic knowledge.

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Section: Serine Proteases In a Nutshellmentioning

confidence: 82%

Section: Serine Proteases In a Nutshellmentioning

confidence: 99%

Serine proteases at the cutting edge of IBD: Focus on gastrointestinal inflammation

et al. 2020

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“…Five micron paraffin-embedded bladder sections were de-paraffinised in xylene/ethanol. Sections were incubated in lysozyme solution (10 mg/ml, Sigma, France) for 15 minutes at 37°C and exposed to 100 μl of universal bacterial 16 S fluorescent rRNA probe (Eub338, GCTGCCTCCCGTAGGAGT-Cy5’, Eurofins, France) at a concentration of 5 ng/μl, in hybridisation buffer (20 mM Tris-HCl, pH7.4, 0.9 M NaCl, 0.01% SDS) at 46°C for 3 hours [ 57 ]. Sections were then incubated in a 48°C prewarmed saline-sodium citrate wash buffer (30 mM sodium citrate, 300 mM sodium chloride, pH7.4, Invitrogen, France) for 20 minutes.…”

Section: Methodsmentioning

confidence: 99%

Uropathogenic E. coli induces DNA damage in the bladder

et al. 2021

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Urinary tract infections (UTIs) are among the most common outpatient infections, with a lifetime incidence of around 60% in women. We analysed urine samples from 223 patients with community-acquired UTIs and report the presence of the cleavage product released during the synthesis of colibactin, a bacterial genotoxin, in 55 of the samples examined. Uropathogenic Escherichia coli strains isolated from these patients, as well as the archetypal E. coli strain UTI89, were found to produce colibactin. In a murine model of UTI, the machinery producing colibactin was expressed during the early hours of the infection, when intracellular bacterial communities form. We observed extensive DNA damage both in umbrella and bladder progenitor cells. To the best of our knowledge this is the first report of colibactin production in UTIs in humans and its genotoxicity in bladder cells.

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“… 5 This increased thrombin activity in the colon of CD patients can originate either from the general circulation, or from the intestinal epithelium, which we have identified as a source of active thrombin. 9 …”

Section: Introductionmentioning

confidence: 99%

Increased Mucosal Thrombin is Associated with Crohn’s Disease and Causes Inflammatory Damage through Protease-activated Receptors Activation

Motta

Palese

Giorgio

et al. 2020

Journal of Crohn's and Colitis

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Background and Aims Thrombin levels in the colon of Crohn’s disease patients have recently been found to be elevated 100-fold compared to healthy controls. Our aim was to determine whether and how dysregulated thrombin activity could contribute to local tissue malfunctions associated with Crohn’s disease. Methods Thrombin activity was studied in tissues from Crohn’s disease patients and healthy controls. Intracolonic administration of thrombin to wild-type or protease-activated receptor-deficient mice was used to assess the effects and mechanisms of local thrombin upregulation. Colitis was induced in rats and mice by the intracolonic administration of trinitrobenzene sulfonic acid. Results Active forms of thrombin were increased in Crohn’s disease patient tissues. Elevated thrombin expression and activity were associated with intestinal epithelial cells. Increased thrombin activity and expression were also a feature of experimental colitis in rats. Colonic exposure to doses of active thrombin comparable to what is found in inflammatory bowel disease tissues caused mucosal damage and tissue dysfunctions in mice, through a mechanism involving both Protease-Activated Receptors-1 and -4. Intracolonic administration of the thrombin inhibitor Dabigatran, as well as inhibition of protease-activated receptor-1, prevented trinitrobenzene sulfonic acid-induced colitis in rodent models. Conclusions Our data demonstrated that increased local thrombin activity, as it occurs in the colon of patients with inflammatory bowel disease, causes mucosal damage and inflammation. Colonic thrombin and protease-activated receptor-1 appear as possible mechanisms involved in mucosal damage and loss of function and therefore represent potential therapeutic targets for treating inflammatory bowel disease.

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Active thrombin produced by the intestinal epithelium controls mucosal biofilms

Cited by 49 publications

References 56 publications

Serine proteases at the cutting edge of IBD: Focus on gastrointestinal inflammation

Serine proteases at the cutting edge of IBD: Focus on gastrointestinal inflammation

Uropathogenic E. coli induces DNA damage in the bladder

Increased Mucosal Thrombin is Associated with Crohn’s Disease and Causes Inflammatory Damage through Protease-activated Receptors Activation

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