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Bovine fescue toxicosis (FT) is caused by grazing ergot alkaloid-producing endophyte ( Epichloë coenophiala )-infected tall fescue. Endophyte’s effects on the animal’s microbiota and metabolism were investigated recently, but its effects  in planta  or on the plant–animal interactions have not been considered. We examined multi-compartment microbiota–metabolome perturbations using multi-‘omics (16S and ITS2 sequencing, plus untargeted metabolomics) in Angus steers grazing non-toxic (Max-Q) or toxic (E+) tall fescue for 28 days and in E+ plants. E+ altered the plant/animal microbiota, decreasing most ruminal fungi, with mixed effects on rumen bacteria and fecal microbiota. Metabolic perturbations occurred in all matrices, with some plant-animal overlap (e.g., Vitamin B6 metabolism). Integrative interactomics revealed unique E+ network constituents. Only E+ had ruminal solids OTUs within the network and fecal fungal OTUs in E+ had unique taxa (e.g.,  Anaeromyces ). Three E+-unique urinary metabolites that could be potential biomarkers of FT and targeted therapeutically were identified.

Integrative interactomics applied to bovine fescue toxicosis