Unraveling anastomotic leak: biological mechanisms underlying intestinal healing after resection

Understanding intestinal healing following resection and anastomosis is a challenging topic due to the complexity of underlying mechanisms. Anastomotic healing follows the fundamental phases of normal wound repair; however, the intestinal anastomosis represents a unique biological environment in which factors such as the structure of the intestines, as well as the microbiome, may modify the healing process. Disruptions in any of the healing phases, such as the inflammatory, proliferative, and remodeling phase, may result in severe complications, characterized by the intraluminal contents leaking out into the extraluminal space, termed an anastomotic leak (AL). Despite decades of surgical advancements, we are still no closer to understanding the underlying AL etiology. It is clear that ALs are multifactorial in nature and contribute to by patient-, technical-, and biological-related factors; however, emerging evidence suggests that biological mechanisms may play a more significant role in AL pathology than originally believed. Evidence points to an interplay between epithelial healing, tissue oxygenation, and the resident microbiome in influencing mucosal healing at the anastomotic site. However, the precise contribution of these factors to failed anastomotic healing and AL etiology remains unclear. In this review, we examine the phases of healing, discuss the existing literature on biological factors affecting anastomotic healing, and describe the advancements made to improve AL rates by targeting the healing response.