Gut microbiota-derived ornithine aggravates hypofibrinogenemia induced by tigecycline via disturbing fibrinogen mRNA stability.

Authors

Yu-Qiong He, Fang Huang, Jing-Ming Zhang, Wen-Kang Cao, Jun-Xiao Song, Xue-Chun Zhang, Dong-Jie Li, Fu-Ming Shen, Can-Can Zhou

Published in

International journal of biological macromolecules. Pages 155018. Oct 25, 2026. Epub Oct 25, 2026.

Abstract

Tigecycline has been regarded as the last resort strategy for complex infections caused by multidrug-resistant pathogens. Nonetheless, due to hypofibrinogenemia its clinical use may have to be suspended. However, the mechanisms of hypofibrinogenemia induced by tigecycline are still unknown. In this study, untargeted metabolomics were conducted in a prospective patient cohort by using feces samples from patients with and without hypofibrinogenemia following tigecycline administration. We found a significant difference in fecal metabolic profile between patients with and without hypofibrinogenemia, especially ornithine. Transferring gut microbiota from subjects with hypofibrinogenemia induced ornithine accumulation and exhibited coagulation dysfunction in the recipient mice. Next, we demonstrated that co-treatment with ornithine and tigecycline upregulated the m6A modification, accelerated cell senescence, and decreased the mRNA stability of FGA and FGB, thereby reducing fibrinogen levels in HepG2 cells. Interestingly, knockdown of methyltransferase-like 3 (METTL3) increased fibrinogen levels by enhancing the stability of mRNAs associated with fibrinogen synthesis, whereas overexpression of METTL3 showed the reverse effects. Notably, YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) was involved in the regulation of FGA and FGB mRNA stability in the METTL3-mediated m6A modification process. The results of animal experiments also verified that excessive ornithine could aggravate tigecycline-induced fibrinogen reduction and decrease blood coagulation activity in a METTL3-dependent manner. Collectively, our study demonstrated that gut microbiota-derived ornithine aggravates hypofibrinogenemia induced by tigecycline via regulation fibrinogen mRNA stability. Our study provides novel insights and preventive therapeutic strategies against tigecycline-induced hypofibrinogenemia.

PMID:
42927812
Bibliographic data and abstract were imported from PubMed on 26 Oct 2026.

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