Mechanistic Investigation of Gut Microbiome-Mediated Drug Metabolism in Cattle Across Nigerian Agro-ecological Zones

The gastrointestinal microbiome is increasingly recognised as a critical determinant of drug metabolism, with microbial communities capable of activating prodrugs, degrading active compounds, and generating pharmacologically active metabolites. In cattle, the rumen microbiome represents an extraordinarily complex ecosystem that may substantially influence the bioavailability and disposition of orally administered pharmaceuticals. This study investigated microbiome-mediated drug metabolism in cattle across contrasting agro-ecological zones in Nigeria, including the Sudan savannah of Sokoto State, the derived savannah of Nasarawa State, and the rainforest zone of Edo State. Forty-five cattle, 15 per zone, received standardised oral administration of selected probe drugs including metronidazole, sulphadimidine, and paracetamol. Rumen fluid was collected by stomach tube for 16S rRNA metagenomic sequencing and ex vivo drug incubation assays. Plasma pharmacokinetics were characterised by validated HPLC. Statistical modelling was used to correlate microbiome compositional and functional features with drug disposition parameters. Significant zone-dependent variation in rumen microbacterial community composition was identified, with Firmicutes to Bacteroidetes ratios differing significantly across zones. Metronidazole reduction to hydroxymetronidazole was significantly faster in rumen fluid from Sudan savannah animals, correlating with higher relative abundance of Clostridium and Ruminococcus genera. Sulphadimidine acetylation capacity also varied significantly by zone. These findings establish a mechanistic link between agro-ecological zone, rumen microbiome composition, and drug metabolism in Nigerian cattle, with implications for zone-specific dosing recommendations and the impact of antibiotic perturbation on microbiome-drug interactions. Keywords: rumen microbiome, drug metabolism, pharmacokinetics, agro-ecological zones, Nigeria.