Long-term environmental levels of microcystin-LR exposure induces colorectal chronic inflammation, fibrosis and barrier disruption via CSF1R/Rap1b signaling pathway

Microcystin-LR (MC-LR) is a very common toxic cyanotoxins threating ecosystems and the public health. This study aims to explore the long-term effects and potential toxicity mechanisms of MC-LR exposure at environmental levels on colorectal injury. We performed histopathological, biochemical indicator and multi-omics analyses in mice with low-dose MC-LR exposure for 12 months. Long-term environmental levels of MC-LR exposure caused epithelial barrier disruption, inflammatory cell infiltration and an increase of collagen fibers in mouse colorectum. Integrated proteotranscriptomics revealed differential expression of genes/proteins, including CSF1R, which were mainly involved in oxidative stress-induced premature senescence and inflammatory response. MC-LR induced chronic inflammation and fibrosis through oxidative stress and CSF1R/Rap1b signaling pathway were confirmed in cell models. We found for the first time that long-term environmental levels of MC-LR exposure caused colorectal chronic inflammation, fibrosis and barrier disruption via a novel CSF1R/Rap1b signaling pathway. Moreover, MC-LR changed the gut microbiota and microbial-related metabolites in a vicious cycle aggravating colorectal injury. These findings provide novel insights into the effects and toxic mechanisms of MC-LR and suggest strategies for the prevention and treatment of MC-caused intestinal diseases.