Macrophages in Intestinal Wound Healing: Dichotomous Effects and Therapeutic Opportunities

Anastomotic leakage (AL) is a significant complication associated with elevated morbidity and mortality rates following colorectal surgery. This complication primarily arises due to impaired wound healing. Anastomotic and intestinal wound healing is generally divided into three phases: inflammation, proliferation, and remodeling. The physiological transition between these phases is primarily orchestrated by macrophages, which are key regulators of inflammation and tissue repair. They undergo sequential phenotypic changes from pro-inflammatory to anti-inflammatory states and are involved in the phagocytosis of bacteria or debris, but also attract fibroblasts for collagen production and deposition. Importantly, they can promote local perfusion by secreting pro-angiogenic and growth factors. Failure of this transition from pro- to anti-inflammatory properties is associated with AL, scarring, and fibrosis. Intestinal macrophages represent the largest pool of resident myeloid cells and are promising cellular targets for therapeutic interventions. In this narrative review, we focus on intestinal and anastomotic wound healing, highlight the dichotomous role of macrophages, and discuss potential therapeutic strategies. A detailed understanding of macrophage polarization, recruitment, and targeted modulation may enhance wound healing and prevent complications such as AL.