title: Morphine Promotes Colonization of Anastomotic Tissues with Collagenase - Producing Enterococcus faecalis and Causes Leak.
abstract: Despite ever more powerful antibiotics, newer surgical techniques, and enhanced recovery programs, anastomotic leaks remain a clear and present danger to patients. Previous work from our laboratory suggests that anastomotic leakage may be caused by Enterococcus faecalis strains that express a high collagenase phenotype (i.e., collagenolytic). Yet the mechanisms by which the practice of surgery shifts or selects for collagenolytic phenotypes to colonize anastomotic tissues remain unknown.
  
  
  
  Here, we hypothesized that morphine, an analgesic agent universally used in gastrointestinal surgery, promotes tissue colonization with collagenolytic E. faecalis and causes anastomotic leak. To test this, rats were administered morphine in a chronic release form as would occur during routine surgery or vehicle. Rats were observed for 6 days and then underwent exploratory laparotomy for anastomotic inspection and tissue harvest for microbial analysis. These results provide further rationale to enhanced recovery after surgery (i.e., ERAS) programs that suggest limiting or avoiding the use of opioids in gastrointestinal surgery.
  
  
  
  Results demonstrated that compared to placebo-treated rats, morphine-treated rats demonstrated markedly impaired anastomotic healing and gross leaks that correlated with the presence of high collagenase-producing E. faecalis adherent to anastomotic tissues. To determine the direct role of morphine on this response, various isolates of E. faecalis from the rats were exposed to morphine and their collagenase activity and adherence capacity determined in vitro. Morphine increased both the adhesiveness and collagenase production of four strains of E. faecalis harvested from anastomotic tissues, two that were low collagenase producers at baseline, and two that were high collagenase producers at baseline.
  
  
  
  These results provide further rationale to enhanced recovery after surgery (i.e., ERAS) programs that suggest limiting or avoiding the use of opioids in gastrointestinal surgery.
authors.affiliation: Department of Surgery, Pritzker School of Medicine, University of Chicago, 5841 S Maryland Ave, MC 6040, Chicago, IL, 60605, USA.
authors.forename: Baddr A
authors.initials: BA
authors.lastname: Shakhsheer
authors.affiliation: Department of Surgery, Pritzker School of Medicine, University of Chicago, 5841 S Maryland Ave, MC 6040, Chicago, IL, 60605, USA.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Versten
authors.affiliation: Department of Surgery, Pritzker School of Medicine, University of Chicago, 5841 S Maryland Ave, MC 6040, Chicago, IL, 60605, USA.
authors.forename: James N
authors.initials: JN
authors.lastname: Luo
authors.affiliation: Department of Surgery, Pritzker School of Medicine, University of Chicago, 5841 S Maryland Ave, MC 6040, Chicago, IL, 60605, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Defazio
authors.affiliation: Department of Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
authors.forename: Robin
authors.initials: R
authors.lastname: Klabbers
authors.affiliation: Department of Surgery, Pritzker School of Medicine, University of Chicago, 5841 S Maryland Ave, MC 6040, Chicago, IL, 60605, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Christley
authors.affiliation: Department of Surgery, Pritzker School of Medicine, University of Chicago, 5841 S Maryland Ave, MC 6040, Chicago, IL, 60605, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zaborin
authors.affiliation: Department of Surgery, Pritzker School of Medicine, University of Chicago, 5841 S Maryland Ave, MC 6040, Chicago, IL, 60605, USA.
authors.forename: Kristina L
authors.initials: KL
authors.lastname: Guyton
authors.affiliation: Department of Surgery, Pritzker School of Medicine, University of Chicago, 5841 S Maryland Ave, MC 6040, Chicago, IL, 60605, USA.
authors.forename: Monika
authors.initials: M
authors.lastname: Krezalek
authors.affiliation: Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Smith
authors.affiliation: Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Nadim J
authors.initials: NJ
authors.lastname: Ajami
authors.affiliation: Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Petrosino
authors.affiliation: Department of Surgery, Pritzker School of Medicine, University of Chicago, 5841 S Maryland Ave, MC 6040, Chicago, IL, 60605, USA.
authors.forename: Irma D
authors.initials: ID
authors.lastname: Fleming
authors.affiliation: Department of Surgery, Pritzker School of Medicine, University of Chicago, 5841 S Maryland Ave, MC 6040, Chicago, IL, 60605, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Belogortseva
authors.affiliation: Department of Surgery, Pritzker School of Medicine, University of Chicago, 5841 S Maryland Ave, MC 6040, Chicago, IL, 60605, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Zaborina
authors.affiliation: Department of Surgery, Pritzker School of Medicine, University of Chicago, 5841 S Maryland Ave, MC 6040, Chicago, IL, 60605, USA. jalverdy@surgery.bsd.uchicago.edu.
authors.forename: John C
authors.initials: JC
authors.lastname: Alverdy
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D057868:Anastomotic Leak / Q000382:microbiology*; D000818:Animals; D017364:Collagenases; D013505:Digestive System Surgical Procedures / Q000009:adverse effects*; D013293:Enterococcus faecalis / Q000201:enzymology / Q000254:growth & development*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D017208:Rats, Wistar; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine; D017364:Collagenases
keywords: Anastomotic leak; Enterococcus faecalis; Morphine