Chronic Microcystin-LR Exposure Induces Colorectal Inflammation Associated with Macrophage Infiltration and...

Microcystin-LR (MC-LR), one of the most prevalent cyanobacterial toxins in freshwater environments, has raised increasing concern because of its potential health risks asso-ciated with long-term exposure through contaminated drinking water and food, as well as inhalation of bloom-derived aerosols. Although intestinal toxicity has emerged as an important consequence of MC-LR exposure, the mechanisms underlying chronic colorectal inflammation remain incompletely understood. In the present study, mice were continuously exposed to MC-LR at 0, 1, 60, or 120 μg/L through drinking water for 15 months to investigate the effects of prolonged exposure on colorectal injury, inflammatory responses, macrophage infiltration, and glycolytic metabolism. Chronic MC-LR exposure did not significantly alter body weight or water consumption, whereas exposure to 60 and 120 μg/L MC-LR significantly shortened colon length. Histopathological examination revealed pronounced colorectal mucosal injury in the 60 and 120 μg/L groups, characterized by mucosal epithelial cell shedding, inflammatory cell infiltration, and disorganization of the crypt architecture. Consistently, MC-LR exposure markedly increased the expression of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α and promoted the accumulation of F4/80-positive macrophages in colorectal tissues. Given that inflammatory macrophage activation is closely coupled to glycolysis-associated metabolic remodeling and that HIF-1α serves as a key transcriptional regulator linking inflammatory responses to glycolytic metabolism, we further examined HIF-1α and related metabolic markers. Prolonged MC-LR exposure increased HIF-1α expression together with the glycolysis-associated proteins HK2, PKM, and LDHA and was accompanied by increased lactate accumulation, indicating a glycolysis-associated metabolic phenotype in colorectal tissues. Collectively, these findings suggest that chronic MC-LR exposure may promote colorectal toxicity through a potential sequential inflammatory-HIF-1α-glycolytic remodeling axis, in which macrophage-associated inflammation is accompanied by HIF-1α upregulation and subsequent glycolysis-associated metabolic reprogramming. This immunometabolic alteration may further contribute to the persistence of colorectal inflammation and tissue injury during long-term MC-LR exposure.