Intestinal Lactobacillus murinus-derived small RNAs target porcine polyamine metabolism

Lijuan Fan, Bingnan Liu, Youxia Wang, Bin Tang, Tianqi Xu, Jian Fu, Chuanlong Wang,

 Yuan Liu, Liangpeng Gegeliangpeng, Hong Wei, and Wenkai Ren

PNAS;  October 3, 2024; 121 (41) e2413241121

https://doi.org/10.1073/pnas.2413241121

Significance

Polyamine metabolism participates in various processes of host physiology and disease. The roles of intrinsic factors in polyamine metabolism have been well clarified, but the effects of extrinsic factors, such as gut microbes, on polyamine metabolism remain elusive. Here, we found the intestinal Lactobacillus murinus -derived small RNAs in extracellular vesicles down-regulate host polyamine metabolism by inhibiting the expression of enzymes in polyamine metabolism. The intestinal microbiota-derived small RNAs–host polyamine metabolism axis is associated with the pathogenesis of colitis and colorectal cancer. These findings enhance our understanding of polyamine metabolism and suggest possible avenues for therapeutic interventions in polyamine-related diseases.

Abstract

Gut microbiota plays a vital role in host metabolism; however, the influence of gut microbes on polyamine metabolism is unknown. Here, we found germ-free models possess elevated polyamine levels in the colon. Mechanistically, intestinal Lactobacillus murinus-derived small RNAs in extracellular vesicles down-regulate host polyamine metabolism by targeting the expression of enzymes in polyamine metabolism. In addition, Lactobacillus murinus delays recovery of dextran sodium sulfate-induced colitis by reducing polyamine levels in mice. Notably, a decline in the abundance of small RNAs was observed in the colon of mice with colorectal cancer (CRC) and human CRC specimens, accompanied by elevated polyamine levels. Collectively, our study identifies a specific underlying mechanism used by intestinal microbiota to modulate host polyamine metabolism, which provides potential intervention for the treatment of polyamine-associated diseases.

See https://www.pnas.org/doi/10.1073/pnas.2413241121

Figure 3

L. murinus (F5) diminishes level of polyamines in vivo. (A) LEfSe analysis shows bacterial taxa that are significantly different in abundance between mice with or without colistin administration (n = 10). (B) Spearman’s correlation between the top 10 species and metabolomic data of putrescine, spermidine, and spermine in the serum and colon (n = 10). (C and D) The level of putrescine, spermidine, spermine, and polyamines in the serum (C) and colon (D) of mice colonized with or without F5 (n = 8 to 12). (E and F) The level of putrescine, spermidine, spermine, and polyamines in the serum (E) and colon (F) of GF mice monocolonized with or without F5 (n = 12). Data were analyzed by unpaired t test or Mann–Whitney U test (F: Putrescine) and represented as mean ± SD (C–F). *P < 0.05; **P < 0.01; ****P < 0.0001.