Pathway links dairy cow genes and liver metabolites to methane reduction by rumen microbes
Background: How do dairy cow genes affect methane emissions?
A study published in the Proceedings of the National Academy of Sciences (PNAS) reports that 6-hydroxymelatonin, produced in the liver of dairy cows, promotes the growth of rumen bacteria and contributes to lower methane production. The researchers analyzed genomic, rumen microbial genomic, and metabolomic data from 304 lactating Holsteins, then traced the pathway from host genes to microbial fermentation using in vitro fermentation and bovine liver-cell experiments. The key is a link between liver metabolism and rumen microbes.
Methane produced by rumen microbes is both a greenhouse gas and a source of feed-energy loss. Alongside feed adjustments and additives, breeding livestock for lower methane emissions is under study. But how specific genetic variants affect emissions through metabolites and microbes remains poorly understood. This study sought to clarify that process.
Key findings: A pathway connecting a liver metabolite to hydrogen-using bacteria
The main measure was methane emissions per kilogram of dry matter intake (M/D), meaning methane produced per kilogram of feed consumed after excluding its water content. M/D was not measured directly in the 304 cows; it was predicted using an existing artificial neural network model. Estimated heritability in this cohort was 0.42, while the proportion of variance explained by microbiome information was 0.19. These are estimates for this cohort and model; they do not mean that genes determine 42% of an individual cow’s emissions.
Mendelian randomization (MR), which uses genetic variants to estimate causal relationships, linked three Prevotella species to lower M/D. The genome of Prevotella bryantii strain B14 contained a [NiFe] group 1d hydrogenase gene, and network analysis supported the possibility that this bacterium competes with methane-producing microbes for hydrogen. When the strain was added to an in vitro rumen fermentation system, hydrogen and methane production also decreased.
The researchers identified 6-hydroxymelatonin as a host-derived metabolite involved in regulating these bacteria. In in vitro fermentation at 39°C for 6 hours, adding 0.1 mM had no significant effect on gas production, while 1 mM significantly reduced methane. Total gas production did not change significantly. In pure culture, 1.5 mM most clearly promoted the growth of P. bryantii B14, but the same effect was not observed at 2 mM.
The upstream regulatory pathway was examined in bovine liver cells. Suppressing ITFG2 expression activated mechanistic target of rapamycin complex 1 (mTORC1), a cellular metabolic signaling complex, and increased expression of CYP1A2, a melatonin-metabolizing enzyme, and synthesis of 6-hydroxymelatonin. Treatment with rapamycin, an mTORC1 inhibitor, blocked these increases. These findings should be distinguished from experiments testing methane reduction by genetically manipulating live dairy cows.
Implications and outlook: A candidate marker for breeding, with further validation needed
At variant 5:106926534 near ITFG2, the TA genotype was associated with lower predicted M/D. Measurements in 31 dairy cows on a separate farm using automated head chambers over 14 days showed the same direction of association. Measured M/D was significantly lower in the 14 TA cows than in the 17 AA cows, but daily absolute methane emissions and dry matter intake did not differ significantly. The result therefore does not establish a reduction in total emissions.
The findings add evidence for low-methane breeding research that considers host genetics, liver metabolites, and rumen microbes together. However, exactly how the variant changes ITFG2 expression and how the metabolite promotes bacterial growth remain unresolved. The tendency toward increases in P. bryantii and associated hydrogenases in TA cows did not reach statistical significance. Replication in other ruminants, as well as the long-term effects and safety of administering the metabolite to live animals, also require follow-up.
The study design and results are available in the full PNAS article.
Proceedings of the National Academy of Sciences, Volume 123, Issue 25, June 2026. SignificanceThis study reveals a host-genetic pathway that regulates rumen microbial fermentation to mitigate methane emissions from livestock—a major contributor to climate change. We demonstrate how specific cow genes influence the production of a liver ...
Breeding organizations could evaluate variant 5:106926534 as a candidate marker for selecting low-methane dairy cows. This would involve comparing genotype with measured M/D in larger independent cohorts and tracking daily absolute methane emissions, milk yield, feed intake, and health indicators together. The current results cannot guarantee the effectiveness of selecting a particular genotype or the preservation of productivity.
For feed and microbiome research, 6-hydroxymelatonin and P. bryantii are candidates for follow-up experiments. However, there is no basis for converting the in vitro concentrations into doses for use on farms. Researchers would also need to assess whether effects persist in the rumen and how treatment affects animal health and economic viability. This study identifies specific targets and a pathway for those evaluations.