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Pleurocidin is an antimicrobial peptide derived from the mucous membranes of the skin or intestinal secretions of Pseudopleuronectes americanus that has antimicrobial and immunomodulatory activities. Ulcerative colitis is recognized as a widespread human disease that may be influenced by environmental and genetic factors. Evidence emphasizes the critical role of the gut microbiota in UC. Synthetic Pleurocidin was analyzed by a combination of liquid chromatography and mass spectrometry. Pleurocidin pharmacological effects were evaluated by DAI score, colon histological score, cytokine levels, and tight junction protein expression in mice. The preliminary molecular mechanism was explored by the levels of key proteins in the NF-κB and MAPK inflammatory signaling pathways in colon tissues. The main analytical methods such as immunohistochemistry, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and Western blot were used. We then used 16S rRNA gene sequences to characterize the gut microbiota. Firstly, our study demonstrated that rectal injection of Pleurocidin at 5 mg/kg body weight alleviated clinical symptoms and colonic histopathological changes in UC mice caused by DSS. Secondly, Pleurocidin altered the abnormal levels of inflammatory and immune-related cytokines in serum, modulated the significant down-regulation of tight junction proteins, and inhibited the expression of NF-κB and MAPK inflammatory signaling pathway-related proteins. Finally, Pleurocidin can regulate gut microbiota, increase the relative abundance of beneficial bacteria and reduce the relative abundance of harmful bacteria. In conclusion, Pleurocidin alleviates UC symptoms in mice, and its effects on the gut microbiome may be potential pathways. It is providing a promising therapeutic option for UC., (Copyright © 2024 Elsevier B.V. All rights reserved.)

PR39 is an antimicrobial peptide (AMP) with a variety of biological functions, including antimicrobial, wound healing, leukocyte chemotaxis, angiogenesis, and immunomodulation; however, its therapeutic efficacy in colitis (IBD) has rarely been reported. For this reason, the present study aimed to investigate the therapeutic effect of PR39 on IBD and its underlying mechanisms. In this experiment, a mouse model of ulcerative colitis (UC) was induced with 3 % dextran sulfate (DSS) and administered by rectal injection of PR39. The results of the study showed that 5 mg/kg of PR39 was able to ameliorate the clinical manifestations of DSS-induced UC mice by improving the clinical symptoms, colonic tissue damage, up-regulating the expression of tight junction proteins, and alleviating the systemic inflammation in mice in various ways. The mechanism of action may involve inhibition of the phosphorylation level of proteins related to the NF-κB/MAPK signaling pathway and modulation of the relative abundance of potentially pathogenic (Bacteroides, Pseudoflavonifractor, Barnesiella, and Oscillibacter) and potentially beneficial bacteria (Candidatus_Saccharibacteria, Desulfovibrio, Saccharibacteria) in the intestinal flora. The results enriched the biological functions of PR-39 and also suggested that PR-39 may be able to be used as a novel drug for the treatment of IBD., (Copyright © 2023 Elsevier B.V. All rights reserved.)