Associations between Circulating IGF-1 Concentrations, Disease Status and the Leukocyte Transcriptome in Early Lactation Dairy Cows

D Claire Wathes,Conrad Ferris,Leslie Foldager,Haruko Takeda,Laura Buggiotti,Zhangrui Cheng,Klaus L Ingvartsen,Mark A Crowe,Miel Hostens,Clément Grelet,Lijing Tang,Cinzia Marchitelli,Mazdak Salavati,Frank Becker,Federica Signorelli

doi:10.3390/ruminants1020012

Abstract

Peripartum dairy cows commonly experience negative energy balance (EB) and immunosuppression together with high incidences of infectious and metabolic disease. This study investigated mechanisms linking EB status with immune defense in early lactation. Data were collected from multiparous Holstein cows from six herds and leukocyte transcriptomes were analyzed using RNA sequencing. Global gene expression was related to circulating IGF-1 (as a biomarker for EB) by subdividing animals into three groups, defined as IGF-1 LOW (<35 ng/mL, n = 35), MODERATE (35–100 ng/mL, n = 92) or HIGH (>100 ng/mL, n = 43) at 14 ± 4 days in milk (DIM). Differentially expressed genes between groups were identified using CLC Genomics Workbench V21, followed by cluster and KEGG pathway analysis, focusing on the comparison between LOW and HIGH IGF-1 cows. LOW cows were older and had significantly lower dry matter intakes and EB values, whereas HIGH cows produced more milk. During the first 35 DIM, 63% of LOW cows had more than one health problem vs. 26% HIGH cows, including more with clinical mastitis and uterine infections. Gene expression analysis indicated that leukocytes in LOW cows switched energy metabolism from oxidative phosphorylation to aerobic glycolysis (PGM, LDH, and PDK4). Many antimicrobial peptides were up-regulated in LOW cows (e.g., PTX3, DMBT1, S100A8, and S100A9) together with genes associated with inflammation, platelet activation and the complement cascade. HIGH cows had greater expression of genes regulating T and B cell function and the cytoskeleton. Overall, results suggested an ongoing cycle of poor EB and higher infection rates in LOW IGF-1 cows which was reflected in altered leukocyte functionality and reduced milk production.

Highlights

The requirement of the mammary gland for metabolizable energy and protein in the immediate post-calving period exceeds intake by approximately 25% [1]
Our study has linked transcriptomic analysis of circulating leukocytes to the IGF-1 concentration, used as a biomarker of metabolic function. This has confirmed changes in metabolic pathways in LOW compared to HIGH IGF-1 cows, with immune cells switching their energy metabolism from oxidative phosphorylation to aerobic glycolysis, and making greater use of the pentose phosphate shunt
Our analysis has extended the range of candidate genes and pathways regulating immunity which were differentially affected

Summary

Introduction

The requirement of the mammary gland for metabolizable energy and protein in the immediate post-calving period exceeds intake by approximately 25% [1] This results in reduced availability of amino acids and glucogenic compounds, whereas ketogenic and lipogenic compounds are generally increased [2,3,4]. The associated period of negative energy balance (NEB) may last for several weeks, extending into months in severe cases [6] During this period, the liver co-ordinates the extensive changes in metabolic pathways required via up-regulation of genes involved in fatty acid oxidation and gluconeogenesis, and down-regulation of triacylglycerol synthesis [7,8]. This may be associated with the development of hepatic steatosis, which compromises glucose production and increases inflammatory responses [9]

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