Abstract
Acute ruminal acidosis (ARA) occurs after an excessive intake of rapidly fermentable carbohydrates and is characterized by the overproduction of D-lactate in the rumen that reaches the bloodstream. Lameness presentation, one of the primary consequences of ARA in cattle, is associated with the occurrence of laminitis and aseptic polysynovitis. Fibroblast-like synoviocytes (FLS) are predominant cells of synovia and play a key role in the pathophysiology of joint diseases, thus increasing the chances of the release of pro-inflammatory cytokines. Increased D-lactate levels and disturbances in the metabolism of carbohydrates, pyruvates, and amino acids are observed in the synovial fluid of heifers with ARA-related polysynovitis prior to neutrophil infiltration, suggesting an early involvement of metabolic disturbances in joint inflammation. We hypothesized that D-lactate induces metabolic reprogramming, along with an inflammatory response, in bovine exposed FLS. Gas chromatography-mass spectrometry (GC-MS)-based metabolomics revealed that D-lactate disrupts the metabolism of bovine FLS, mainly enhancing glycolysis and gluconeogenesis, pyruvate metabolism, and galactose metabolism. The reverse-transcription quantitative PCR (RT-qPCR) analysis revealed an increased expression of metabolic-related genes, including hypoxia-inducible factor 1 (HIF-1)α, glucose transporter 1 (Glut-1), L-lactate dehydrogenase subunit A (L-LDHA), and pyruvate dehydrogenase kinase 1 (PDK-1). Along with metabolic disturbances, D-lactate also induced an overexpression and the secretion of IL-6. Furthermore, the inhibition of HIF-1, PI3K/Akt, and NF-κB reduced the expression of IL-6 and metabolic-related genes. The results of this study reveal a potential role for D-lactate in bFLS metabolic reprogramming and support a close relationship between inflammation and metabolism in cattle.
Highlights
Acute ruminal acidosis (ARA) is a well-known metabolic syndrome in cattle caused by excessive intake of rapidly fermentable carbohydrates, which alters ruminal microbiota composition [1, 2]
The chemical structure of the derivative product was used for metabolite identification. Carbohydrates and their metabolites were the primary compounds detected in bovine FLS (bFLS) (Supplementary Figure 1A), with 30 (32.6%) carbohydrates identified, including arabinose, fructose, galactitol, gluconic acid, glucose, glucose-1-phosphate, glucose-6-phosphate, glycerol, hexose, lactose, mannitol, mannose, melibiose, N-acetyl-Dhexosamine, sucrose, and UDP-N-acetylglucosamine
High energy diets rich in available carbohydrates favor acidotic states, the consequences of which include the occurrence of laminitis, a diffuse, aseptic inflammation of the corium, and aseptic polysynovitis, which contributes to lameness [3, 9]
Summary
Acute ruminal acidosis (ARA) is a well-known metabolic syndrome in cattle caused by excessive intake of rapidly fermentable carbohydrates, which alters ruminal microbiota composition [1, 2]. Distension of the tarsocrural joints in dairy heifers with ARA has been observed [9,10,11,12] and is characterized by generalized sterile neutrophilic polysynovitis [9] This acute joint reaction is considered to be a part of the clinical complex interpreted as acute laminitis, and the clinical consequence is still unclear, it most likely contributes to claw pain and lameness [9,10,11]
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