Hypoxia-biofilm-immunometabolism axis in cryptoglandular anal fistula: An integrated pathophysiological and therapeutic paradigm

Cryptoglandular anal fistula (CAF) remains a persistent clinical challenge in colorectal surgery, with high recurrence rates reflecting fundamental gaps in our understanding of its pathophysiology.This narrative review proposes an integrated paradigm extending beyond the classical cryptoglandular theory.We hypothesize that CAF formation may represent an adaptive mechanism reducing sepsis risk from deep-space infections, but this process establishes a pathological, self-sustaining 'hypoxia-biofilm microenvironment' within the intersphincteric space.We propose that local immune cells undergo immunometabolic reprogramming (Warburg effect), driving an interleukin (IL)-1β/IL-8/IL-17-dominated inflammatory storm, while hypoxia-inducible factor-1α activation promotes epithelial-mesenchymal transition and pathological fibrosis, potentially contributing to a non-healing state.This model reinterprets the variable success rates of surgical approaches through the lens of microenvironmental disruption and suggests that therapeutic principles, adequate intersphincteric drainage with oxygen exposure require prospective validation.Future strategies targeting biofilms, immunometabolism, cellular senescence, and hypoxia may fundamentally modulate fistula pathobiology, offering new avenues for overcoming this refractory disease.