Collagen degradation and MMP9 activation by Enterococcus faecalis contribute to intestinal anastomotic leak

Abstract

Even under the most expert care, a properly constructed intestinal anastomosis can fail to heal resulting in leakage of its contents, peritonitis and sepsis. The cause of anastomotic leak remains unknown and its incidence has not changed in decades. Here, we demonstrate that the commensal bacterium Enterococcus faecalis contributes to the pathogenesis of anastomotic leak through its capacity to degrade collagen and to activate tissue matrix metalloprotease-9 (MMP9) in host intestinal tissues. We demonstrate in rats that leaking anastomotic tissues were colonized by E. faecalis strains that showed an increased collagen-degrading activity and also an increased ability to activate host MMP9, both of which contributed to anastomotic leakage. We demonstrate that the E. faecalis genes gelE and sprE were required for E. faecalis-mediated MMP9 activation. Either elimination of E. faecalis strains through direct topical antibiotics applied to rat intestinal tissues or pharmacological suppression of intestinal MMP9 activation prevented anastomotic leak in rats. In contrast, the standard recommended intravenous antibiotics used in patients undergoing colorectal surgery did not eliminate E. faecalis at anastomotic tissues nor did they prevent leak in our rat model. Finally, we show in humans undergoing colon surgery and treated with the standard recommended intravenous antibiotics, that their anastomotic tissues still contained E. faecalis and other bacterial strains with collagen-degrading/MMP9 activity. We suggest that intestinal microbes with the capacity to produce collagenases and to activate host metalloproteinase MMP9 may break down collagen in the gut tissue contributing to anastomotic leak.

Are gut bacteria associated with the development of anastomotic leaks?

“…Pathogens with the dual capacity to degrade collagen and cleave MMP9, such as E. faecalis, appear to be associated with anastomotic leak in a rat model [29]. Intestinal microbiota seem to contribute to the amplification of MMP9, hypoxia-inducible factor 1-alpha (HIF-1 alpha), and inflammation during anastomotic surgery [29]; an effect that is again amplified by devascularization [29]. Data demonstrate that MMP9 expression in tissues exposed to both anastomosis and devascularization can be attenuated when rats are exposed to a topical antibiotic solution (ciprofloxacin, metronidazole, and neomycin).…”

“…Finally these authors could demonstrate that among commensal microbiota, Enterococcus faecalis strains with enhanced collagen-degrading activity and the capacity to activate host intestinal tissue matrix metalloproteinase 9 (MMP9) contribute to the pathogenesis of anastomotic leak [29]. Pathogens with the dual capacity to degrade collagen and cleave MMP9, such as E. faecalis, appear to be associated with anastomotic leak in a rat model [29].…”

“…Either this or pharmacological suppression of intestinal MMP9 activation prevented AL in rats. A clinical trial investigating the role of microbes in anastomotic healing to the left colon and rectum has begun [29].…”

“…The use of non-microbicidal drugs to create microenvironmental conditions that suppress the virulence of pathogens is an attractive strategy to minimize the negative consequences of intestinal microbiome disruption caused by antibiotic use [14,28,29,32,33]. It has been shown previously that phosphate is depleted in the intestinal tract following surgical injury, that this depletion is a major "cue" that triggers bactericidal virulence, and that the maintenance of luminal phosphate abundance in the gut prevents virulence expression [12,14,32,33].…”

Doit-on continuer à imposer une stomie d’amont systématique après une anastomose colorectale ?

“…Face à ces cellules intestinales à duréed ev ie très brèveo nt rouvel em icrobiote intestinal dont la complexité est progressivement mise en lumière [7]. Certaines bactéries ont un effet eutrophique sur la muqueuse intestinale comme Faecobacterium prausnitzii et Escherichia coli nissle,d 'autres ont un effet délétèrec omme les bactéries réductrices des sulfates dont le métabolisme produit un excès de sulfites, Clostridium difficile ou certaines souches d'Enterococcus faecalis capables de dégrader le collagène et de perturber ainsi la cicatrisation.…”