Peripartum hypophosphatemia is associated with a hindgut-centered microbiota-metabolite-host axis in transition dairy cows.

The transition period in dairy cows is accompanied by profound shifts in mineral homeostasis and gut microbial ecology. While endocrine regulation of hypocalcemia has been extensively characterized, adaptive responses to hypophosphatemia-and the potential involvement of the gut microbiota-have received far less attention. Twenty-four Holstein dairy cows were randomly assigned to control or low-phosphorus groups. Hypophosphatemia was induced by dietary supplementation with 300 g/d synthetic zeolite from 21 days prepartum to 3 days postpartum. Blood and feces samples were collected at -21, -7, 0, 1, and 3 d relative to calving for longitudinal analysis of physiology, hindgut microbiome and plasma metabolomics to investigate host-microbiome adaptation to peripartum hypophosphatemia in dairy cows. Cows with hypophosphatemia exhibited pronounced compositional remodeling of their hindgut microbiota and extensive, persistent alterations in their plasma metabolome, with glycerophospholipid metabolism being a consistently affected pathway. Integrated correlation and mediation analyses revealed close associations between hindgut microbial variation, host metabolic reprogramming, and circulating phosphorus dynamics. In addition, a plasma feature putatively annotated as α-methyl-m-tyrosine (AMT) was identified as a candidate statistical mediator associated with the observed relationships between Lachnospiraceae_NK3A20_group abundance with systematic phosphorus concentrations. Collectively, these findings indicate that peripartum hypophosphatemia in dairy cows is accompanied by coordinated host metabolic and hindgut microbial remodeling, supporting a hindgut-centered host-metabolite-microbiome framework for understanding phosphorus adaptation during early lactation.