Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, United States of America.
Department of Veterinary Preventive Medicine, College of Veterinary Medicine, The Ohio State University, Columbus, OH, United States of America.
PLoS One. 2023 Aug 10;18(8):e0289165. doi: 10.1371/journal.pone.0289165. eCollection 2023.
Hyperketonemia (HYK) in early lactation can have a different impact on health and productivity depending on the timing of HYK onset. While specific metabolites measured during the dry period may serve as biomarkers of HYK, the correlations between metabolites represent a challenge for the use of metabolic profiles dataset, and little has been explored on HYK. This exploratory cohort study aimed a) to characterize the correlations among metabolites measured during the late dry period in dairy cows, and b) to identify biomarkers in the late dry period associated with the onset of HYK at the first (wk1) and second (wk2) week of lactation. Individual blood samples from 440 Holstein dairy cows were collected at 21 ± 3 days before expected parturition. From each sample, 36 different metabolites were measured in serum and plasma. Hyperketonemia was diagnosed in wk1 and wk2 of lactation based on the blood concentration of beta-hydroxybutyrate (BHB > 1.2 mmol/L). Principal component analysis (PCA) was performed to reduce metabolites to a smaller number of uncorrelated components. Multivariable logistic regression models were applied to assess the associations between principal components (PC) and HYK at wk1 only (HYK+ wk1), wk2 only (HYK+ wk2), or both weeks (HYK+ wk1-2). The incidence of HYK was 16.2% in the first week, 13.0% in the second week, and 21.2% within the first two weeks of lactation. The results of PCA highlighted 10 PCs from which two were associated with HYK+ wk1 as compared with cows without HYK during the first two weeks of lactation (non-HYK); the PC a2 led by bilirubin and non-esterified fatty acids (OR = 1.29; 95%CI: 1.02-1.68), and the PC a5 led by alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) (OR = 2.77; 95%CI: 1.61-4.97). There was no evidence of an association between any PC and HYK+ wk2 (vs. non-HYK cows). Cows with elevated PC a5 (led by ALP and GGT) in the dry period were 3.18 times more likely to be HYK+ wk1 than HYK+ wk2 (OR: 3.18, 95%CI: 1.34-8.73; P = 0.013). Overall, the main hypothesis generated by our exploratory study suggests that cows with biomarkers of liver dysfunction (ALP, GGT, bilirubin) assessed by PCA at 3 weeks before calving are more likely to develop HYK during the first week of lactation compared to the second week. In addition, results suggest that cows with HYK in both of the first two weeks of lactation had an overall metabolic disbalance during the onset of the late dry period, which based on PCs, encompass biomarkers related to glucogenic and ketogenic metabolic pathways as well as liver dysfunction and fatty liver. Further research is needed to determine the underlying mechanisms associated with the different adaptations between cows that develop HYK during the first and second week of lactation.
奶牛泌乳早期的高酮血症（HYK）的发病时间不同，对健康和生产力的影响也不同。虽然在干奶期测量的特定代谢物可以作为 HYK 的生物标志物，但代谢物之间的相关性为代谢谱数据集的使用带来了挑战，而关于 HYK 的研究还很少。本探索性队列研究旨在：a）描述奶牛干奶后期测量的代谢物之间的相关性；b）确定与泌乳第 1 周（wk1）和第 2 周（wk2） HYK 发病相关的干奶后期生物标志物。从预计分娩前 21 ± 3 天开始，从 440 头荷斯坦奶牛中采集个体血液样本。从每个样本中，测量了血清和血浆中的 36 种不同的代谢物。根据血液中 β-羟丁酸（BHB>1.2mmol/L）的浓度，在泌乳第 1 周和第 2 周诊断 HYK。主成分分析（PCA）用于将代谢物减少到更小数量的不相关成分。多元逻辑回归模型用于评估主成分（PC）与仅在第 1 周（HYK+wk1）、仅在第 2 周（HYK+wk2）或前两周（HYK+wk1-2）发生 HYK 之间的关联。在第 1 周，16.2%的奶牛发生 HYK，第 2 周，13.0%的奶牛发生 HYK，在泌乳的前两周内，21.2%的奶牛发生 HYK。PCA 的结果突出了 10 个与 HYK+wk1 相关的 PC，与前两周内无 HYK 的奶牛相比（非 HYK）；由胆红素和非酯化脂肪酸（OR=1.29；95%CI：1.02-1.68）主导的 PC a2，和由碱性磷酸酶（ALP）和γ-谷氨酰转移酶（GGT）主导的 PC a5（OR=2.77；95%CI：1.61-4.97）。没有证据表明任何 PC 与 HYK+wk2（与非 HYK 奶牛相比）之间存在关联。在干奶期 PC a5（由 ALP 和 GGT 主导）升高的奶牛在 HYK+wk1 时发生 HYK 的可能性是 HYK+wk2 的 3.18 倍（OR：3.18，95%CI：1.34-8.73；P=0.013）。总体而言，我们的探索性研究提出的主要假设表明，在分娩前 3 周通过 PCA 评估的具有肝功能障碍生物标志物（ALP、GGT、胆红素）的奶牛在泌乳第 1 周发生 HYK 的可能性高于第 2 周。此外，结果表明，在泌乳的前两周内都发生 HYK 的奶牛在干奶后期发病时整体代谢失衡，根据 PCs，包括与糖异生和生酮代谢途径以及肝功能障碍和脂肪肝相关的生物标志物。需要进一步研究以确定与在泌乳第 1 周和第 2 周发生 HYK 的奶牛之间不同适应相关的潜在机制。
