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Multi-omics and intervention analyses reveal a hindgut microbiota–secondary bile acid–mammary axis linked to milk yield in dairy cows

ABSTRACT: Background In large scale dairy farming systems, maintaining stable milk yield post-lactation peak is crucial for dairy farms’ economic benefits. While sufficient evidence shows the microbiota profoundly impacts host production efficiency, the specific mechanisms by which hindgut microbiota support mid lactation milk performance via host-microbe interactions remain unclear. This study focused on the hindgut microbial ecosystem. By analyzing hindgut microbial composition and metabolic differences between high and low yield cows during mid-lactation, and conducting metabolite intervention, we clarified the biological mechanism by which hindgut microbiota regulates milk production through host interactions. Results Shotgun metagenomics, untargeted metabolomics, and targeted metabolomics of high versus normal-yield cows revealed that high-yield animals harbored distinct hindgut microbial communities enriched in bile salt hydrolase–positive taxa, and elevated levels of deoxycholic acid (DCA). Fecal microbiota transplantation from high-yield donors into antibiotic-treated recipient mice increased their milk production, accompanied by a shift in circulating bile acid profiles towards higher DCA. Oral administration of DCA to antibiotic-treated mice partially recapitulated these mammary and lactation phenotypes, supporting a causal contribution of bile acids downstream of the microbiota. In lactating cows, supplementation with a rumen-protected DCA formulation enhanced cumulative energy-corrected milk yield and tended to increase daily milk yield. DCA can directly upregulate the expression of genes related to the cell cycle progression in dairy cow mammary glands, thereby promoting and maintaining the activity of mammary epithelial cells in mid-lactation cows to support milk production. Conclusions Our multi-layered evidence demonstrates that hindgut microbiota-derived secondary bile acids, particularly DCA, act along a gut–mammary axis to enhance mammary epithelial function and lactation performance in dairy cows. These findings broaden the conceptual framework of microbiota–epithelial crosstalk and suggest microbial bile acid metabolism as a tractable target to improve lactation efficiency in ruminants.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS14549 | MetaboLights | 2026-05-22

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS14549_LC-MS_negative_reverse-phase.txt	Txt
	a_MTBLS14549_LC-MS_positive_reverse-phase.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS14549_LC-MS_negative_reverse-phase_v2_maf.tsv	Tabular
	m_MTBLS14549_LC-MS_positive_reverse-phase_v2_maf.tsv	Tabular

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Project description:BackgroundIn large scale dairy farming systems, maintaining stable milk yield post-lactation peak is crucial for dairy farms’ economic benefits. While sufficient evidence shows the microbiota profoundly impacts host production efficiency, the specific mechanisms by which hindgut microbiota support mid lactation milk performance via host-microbe interactions remain unclear. This study focused on the hindgut microbial ecosystem. By analyzing hindgut microbial composition and metabolic differences between high and low yield cows during mid-lactation, and conducting metabolite intervention, we clarified the biological mechanism by which hindgut microbiota regulates milk production through host interactions.ResultsShotgun metagenomics, untargeted metabolomics, and targeted metabolomics of high versus normal-yield cows revealed that high-yield animals harbored distinct hindgut microbial communities enriched in bile salt hydrolase–positive taxa, and elevated levels of deoxycholic acid (DCA). Fecal microbiota transplantation from high-yield donors into antibiotic-treated recipient mice increased their milk production, accompanied by a shift in circulating bile acid profiles towards higher DCA. Oral administration of DCA to antibiotic-treated mice partially recapitulated these mammary and lactation phenotypes, supporting a causal contribution of bile acids downstream of the microbiota. In lactating cows, supplementation with a rumen-protected DCA formulation enhanced cumulative energy-corrected milk yield and tended to increase daily milk yield. DCA can directly upregulate the expression of genes related to the cell cycle progression in dairy cow mammary glands, thereby promoting and maintaining the activity of mammary epithelial cells in mid-lactation cows to support milk production.ConclusionsOur multi-layered evidence demonstrates that hindgut microbiota-derived secondary bile acids, particularly DCA, act along a gut–mammary axis to enhance mammary epithelial function and lactation performance in dairy cows. These findings broaden the conceptual framework of microbiota–epithelial crosstalk and suggest microbial bile acid metabolism as a tractable target to improve lactation efficiency in ruminants.

Project description:BACKGROUND: The lactating mammary gland responds to changes in milking frequency by modulating milk production. This response is locally regulated and, in dairy cows, the udder is particularly sensitive during early lactation. Relative to cows milked twice-daily throughout lactation, those milked four-times-daily for just the first 3 weeks of lactation produce more milk throughout that lactation. We hypothesized that the milk yield response would be associated with increased mammary cell turnover and changes in gene expression during frequent milking and persisting thereafter. Cows were assigned to unilateral frequent milking (UFM; left udder halves milked twice-daily; right udder halves milked four-times daily) on days 1 to 21 of lactation, followed by twice-daily milking for the remainder of lactation. Relative to udder halves milked twice-daily, those milked four-times produced more milk during UFM; the difference in milk yield declined acutely upon cessation of UFM after day 21, but remained significantly elevated thereafter. We obtained mammary biopsies from both udder halves on days 21, 23, and 40 of lactation. RESULTS: Mammary cell proliferation and apoptosis were not affected by milking frequency. We identified 75 genes that were differentially expressed between paired udder halves on day 21 but exhibited a reversal of differential expression on day 23. Among those genes, we identified four clusters characterized by similar temporal patterns of differential expression. Two clusters (11 genes) were positively correlated with changes in milk yield and were differentially expressed on day 21 of lactation only, indicating involvement in the initial milk yield response. Two other clusters (64 genes) were negatively correlated with changes in milk yield. Twenty-nine of the 75 genes were also differentially expressed on day 40 of lactation. CONCLUSIONS: Changes in milking frequency during early lactation did not alter mammary cell population dynamics, but were associated with coordinated changes in mammary expression of at least 75 genes. Twenty-nine of those genes were differentially expressed 19 days after cessation of treatment, implicating them in the persistent milk yield response. We conclude that we have identified a novel transcriptional signature that may mediate the adaptive response to changes in milking frequency.

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Multi-omics and intervention analyses reveal a hindgut microbiota–secondary bile acid–mammary axis linked to milk yield in dairy cows

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