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Anastomotic leak rates have not improved over several decades despite improvements in surgical techniques and patient care. The gut microbiome has been implicated in the development of leaks. The exact mechanisms by which tissue oxygenation affects gut microbial composition and anastomotic healing physiology are unclear. Also, commonly used carbon dioxide (CO 2) is a known vasodilator that improves tissue oxygen tension. We performed a systematic review to determine the influence of hyperoxia, hypoxia, and hypercapnia on the gut microbiome and anastomotic healing. A literature search was performed in MEDLINE, EMBASE, and COCHRANE to identify studies investigating the effects of hyperoxia, hypoxia, and hypercapnia on anastomotic healing and gut microbiota published between 1998 and 2018. Two reviewers screened the articles for eligibility and quality. Fifty-three articles underwent full text review, and a narrative synthesis was undertaken. Hyperoxia is associated with better anastomotic healing, increased gastrointestinal oxygen tension, and may reduce gut anaerobes. Hypoxia is associated with poor healing and increased gut anaerobes. However, it is unclear if hypoxia is the most important predictor of anastomotic leaks. Low pressure CO 2 pneumoperitoneum and mild systemic hypercapnia are both associated with increased gastrointestinal oxygen tension and may improve anastomotic healing. We found no studies which investigated the effect of hypercapnia on gut microbiota in the context of anastomotic healing. Tissue oxygenation influences gut anastomotic healing, but little evidence exists to demonstrate the influence on the gut microbiome in the context of healing. Further studies are needed to determine if anastomotic microbiome changes with altered tissue oxygenation and if this affects healing and leak rates. If confirmed, altering tissue oxygenation through hyperoxia or hypercapnia could be feasible means of altering the microbiome such that anastomotic leak rates reduce. [ABSTRACT FROM AUTHOR]