Advances in the Intestinal Toxicity of Microcystin‐LR

Microcystin-LR (MC-LR), the most prevalent and toxic microcystin congener, is a persistent cyanotoxin that reaches humans mainly through contaminated water and food. Because the intestine is the first tissue exposed after ingestion, it is both a portal of systemic uptake and a direct toxicological target. This review integrates evidence on intestinal distribution and absorption, exposure-dependent toxic phenotypes, and molecular mechanisms. Acute or high-dose exposure predominantly causes villus erosion, epithelial apoptosis, cytoskeletal collapse, and rapid barrier failure, whereas repeated exposure at low or environmentally relevant doses produces low-grade inflammation, fibrosis, microbiota and metabolite dysregulation, and increased susceptibility to colitis and colorectal tumor progression. Mechanistically, organic anion-transporting polypeptide-mediated uptake and inhibition of protein phosphatase 2A (PP2A) act as upstream events that promote protein hyperphosphorylation and interconnected oxidative stress, DNA damage, tight-junction disassembly, inflammatory signaling, and dysregulated proliferation, apoptosis, migration, and invasion. Recent multiomics and fecal microbiota transplantation studies further support a bidirectional microbiota-barrier-immune axis in local and systemic effects. Quantitative interpretation nevertheless remains limited by heterogeneous dose metrics, short experiments, nonphysiological exposure routes, and scarce human longitudinal data. Future studies should prioritize environmentally realistic chronic and mixture exposures, human intestinal organoids and organ-on-chip systems, causal PP2A pathway perturbation, longitudinal biomonitoring, and harmonized benchmark-dose analyses.