Melatonin Protects Against Colistin‐Induced Intestinal Inflammation and Microbiota Dysbiosis

ABSTRACT Colistin is renowned as a last‐resort antibiotic due to the emergence of multidrug‐resistant pathogens. However, its potential toxicity significantly hampers its clinical utilization. Melatonin, chemically known as N ‐acetyl‐5‐hydroxytryptamine, is an endogenous hormone produced by the pineal gland and possesses diverse biological functions. However, the protective role of melatonin in alleviating antibiotic‐induced intestinal inflammation remains unknown. Herein, we reveal that colistin stimulation markedly elevates intestinal inflammatory levels and compromises the gut barrier. In contrast, pretreatment with melatonin safeguards mice against intestinal inflammation and mucosal damage. Microbial diversity analysis indicates that melatonin supplementation prevents a reduction in the abundance of Erysipelotrichales and Bifidobacteriales , as well as an increase in Desulfovibrionales abundance, following colistin exposure. Remarkably, short‐chain fatty acids (SCFAs) analysis shows that propanoic acid contributes to the protective effect of melatonin on colistin‐induced intestinal inflammation. Furthermore, the protection effects of melatonin and propanoic acid on LPS‐induced cellular inflammation in RAW 264.7 cells are confirmed. Mechanistic investigations suggest that intervention with melatonin and propanoic acid can repress the activation of the TLR4 signal and its downstream NF‐κB and MAPK signaling pathways, thereby mitigating the toxic effects of colistin. Our work highlights the unappreciated role of melatonin in preventing the potential detrimental effects of colistin on intestinal health and suggests a combined therapeutic strategy to effectively manage intestinal infectious diseases.