Lactiplantibacillus plantarum TXZ 2-35 protects mice against ulcerative colitis by inhibiting ferroptosis and regulating of intestinal microbiota and lipid metabolites

Abstract Ferroptosis, a newly recognized type of regulated cell death associated with intestinal epithelial dysfunction, can influence the onset and severity of inflammatory bowel disease (IBD). Thus, there is growing interest in the novel therapy targeting of ferroptosis for the treatment of IBD. Here, we investigated the effects of dietary supplementation of viable Lactiplantibacillus plantarum TXZ 2-35 on dextran sulfate sodium (DSS)-induced ulcerative colitis in mice. The results revealed that the disease severity was alleviated by L. plantarum TXZ 2-35 as evidenced by increased body weight, colon length and decreased disease activity index (DAI). Moreover, supplementation with L. plantarum TXZ 2-35 downregulated the levels of inflammation-related cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) in serum, as well as the oxidative enzyme myeloperoxidase (MPO) in the colon. Interestingly, transcriptomic data revealed that ferroptosis-related genes were significantly enriched after TXZ 2-35 supplementation. In addition, TXZ 2-35 restored morphological changes and attenuated the iron content in the colon, accompanied by increased glutathione peroxidase (GSH) and decreased malondialdehyde (MDA), which all together proved that L. plantarum TXZ 2-35 suppressed ferroptosis in colonic epithelial cells. We then sought to determine whether gut microbiota and its metabolites played a role in the process of ferroptosis changing. The results showed that TXZ 2-35 enhanced the abundance and diversity of beneficial bacteria such as Ruminococcus_1, Lachnospiraceae_NK4A136_group, and Anaeroplasma, while reducing levels of Dubosiella. Correlation analysis showed that the decreased level of phospholipid-polyunsaturated fatty acids (PL-PUFAs), gut microbiota metabolites, may be the cause of ferroptosis. In conclusion, our study indicates that TXZ 2-35 has strong potential as a therapeutic adjuvant for ulcerative colitis, through regulating gut microbiota and the metabolites and therefore decreasing ferroptosis.