Host genetic regulation of rumen 6-hydroxymelatonin reduces methane emissions in dairy cattle
- Chenguang Zhang
- Ye Liu
- Guoyan Wang
- Mengqi Huang
- Jun Zhang
- Zongjun Li
- Linhao Zhou
- Guangfu Tang
- Shengru Wu
- Lu Deng
- Junhu Yao
2026-06-08
The mechanisms linking host genetics to ruminal methane emissions remain unclear. Here, we integrated multiomics data from 304 lactating cows and demonstrated that methane emission per dry matter intake (M/D) exhibitd higher heritability ( h 2 = 0.42) than microbiability ( m 2 = 0.19), highlighting the predominant role of host genetics. Mendelian randomization (MR) analysis identified three heritable Prevotella species (including Prevotella_bryantii ) that causally reduce methane emissions. Network suggested that Prevotella_bryantii , which harbors the [NiFe]_Group_1d hydrogenase, exerts this effect by competing with methanogens for H₂. Furthermore, the methane-reducing effect of Prevotella _bryantii was confirmed by in vitro fermentation experiments. To trace the host regulation upstream, the host-derived metabolite 6-hydroxymelatonin was identified as a key regulator that positively influences these Prevotella species by MR analysis, which was further validated by in vitro fermentation and pure bacterial culture experiments. Genome-wide association studies linked ruminal 6-hydroxymelatonin levels to host genetic variants (e.g., 5:106926534) near candidate genes including ITFG 2. Functional studies in bovine hepatocytes revealed that ITFG 2 knockdown activated the mTORC1 pathway, upregulated CYP 1 A 2 expression, and increased 6-hydroxymelatonin synthesis. Furthermore, cattle carrying the TA genotype at 5:106926534 exhibited significantly lower predicted and measured methane emissions. Collectively, this study unveils a pathway whereby host genetics (via ITFG 2/mTORC1) modulate hepatic 6-hydroxymelatonin synthesis, which enriches specific rumen Prevotella that compete with methanogens for hydrogen, thereby reducing methane.