Unique adaptations in neonatal hepatic transcriptome, nutrient signaling, and one-carbon metabolism in response to feeding ethyl cellulose rumen-protected methionine during late-gestation in Holstein cows

Abstract

Background Methionine (Met) supply during late-pregnancy enhances fetal development in utero and leads to greater rates of growth during the neonatal period. Due to its central role in coordinating nutrient and one-carbon metabolism along with immune responses of the newborn, the liver could be a key target of the programming effects induced by dietary methyl donors such as Met. To address this hypothesis, liver biopsies from 4-day old calves (n = 6/group) born to Holstein cows fed a control or the control plus ethyl-cellulose rumen-protected Met for the last 28 days prepartum were used for DNA methylation, transcriptome, metabolome, proteome, and one-carbon metabolism enzyme activities. Results Although greater withers and hip height at birth in Met calves indicated better development in utero, there were no differences in plasma systemic physiological indicators. RNA-seq along with bioinformatics and transcription factor regulator analyses revealed broad alterations in ‘Glucose metabolism’, ‘Lipid metabolism, ‘Glutathione’, and ‘Immune System’ metabolism due to enhanced maternal Met supply. Greater insulin sensitivity assessed via proteomics, and efficiency of transsulfuration pathway activity suggested beneficial effects on nutrient metabolism and metabolic-related stress. Maternal Met supply contributed to greater phosphatidylcholine synthesis in calf liver, with a role in very low density lipoprotein secretion as a mechanism to balance metabolic fates of fatty acids arising from the diet or adipose-depot lipolysis. Despite a lack of effect on hepatic amino acid (AA) transport, a reduction in metabolism of essential AA within the liver indicated an AA ‘sparing effect’ induced by maternal Met. Conclusions Despite greater global DNA methylation, maternal Met supply resulted in distinct alterations of hepatic transcriptome, proteome, and metabolome profiles after birth. Data underscored an effect on maintenance of calf hepatic Met homeostasis, glutathione, phosphatidylcholine and taurine synthesis along with greater efficiency of nutrient metabolism and immune responses. Transcription regulators such as FOXO1, PPARG, E2F1, and CREB1 appeared central in the coordination of effects induced by maternal Met. Overall, maternal Met supply induced better immunometabolic status of the newborn liver, conferring the calf a physiologic advantage during a period of metabolic stress and suboptimal immunocompetence.

Immunometabolism in livestock: triggers and physiological role of transcription regulators, nutrients, and microbiota

“…However, work with sheep receiving a diet with marginal levels of methyl donors in the periconceptional period demonstrated marked alterations in DNA methylation (i.e., an epigenetic mark) in the fetal liver along with altered innate immune and glucose-insulin responses of the offspring at 22 mo of age ( Sinclair et al, 2007 ). In a recent study, it was demonstrated that enhanced post-ruminal supply of methionine in late-pregnant dairy cows not only led to greater calf birth weight ( Alharthi et al, 2018 ), but also marked alterations in immunometabolic networks in the calf liver including downregulation of inflammatory and antioxidant signaling pathways along with fatty acid oxidation and gluconeogenesis ( Palombo et al, 2021 ) ( Figure 3 ). It was noteworthy, however, that these calves had an overall upregulation of immune system pathways, which together suggested a more mature capacity to respond to immune challenges ( Palombo et al, 2021 ).…”

Nutrigenomics in livestock: potential role in physiological regulation and practical applications

“…PPAR), which can affect metabolism in tissues such as the liver (Sauerwein and Häußler 2016). It is now more apparent that TF and target gene networks work in conjunction to alter physiological pathways, not only in the mature animal (Shahzad et al 2014), but also in response to altering the nutrition of the mother during pregnancy (Namous et al 2018;Palombo et al 2021; Table 2).…”

“…the ChIP-X Enrichment Analysis 3 (ChEA3) transcriptionfactor enrichment analysis tool (Keenan et al 2019). Its use in a recent nutrigenomics experiment dealing with RNA sequencing data from liver of neonatal calves born to cows fed normal or greater amounts of methionine (a methyl donor) during the last 30 days of pregnancy led to identification of 72 TF that had statistically significant associations with 568 differentially expressed genes (Palombo et al 2021). Among the TF identified were some with known nutrigenomic potential (Table 1), e.g.…”

“…Enhanced post-ruminal supply of methionine in latepregnancy led to greater calf development in utero and, although hepatic DNA methylation was increased, there were distinct alterations in the hepatic transcriptome, metabolome, and proteome profiles at birthPalombo et al (2021) (Continued on next page)…”

Epigenetic Modifier Supplementation Improves Mitochondrial Respiration and Growth Rates and Alters DNA Methylation of Bovine Embryonic Fibroblast Cells Cultured in Divergent Energy Supply

“…In sheep fed purified diets limited in cobalt and sulfur (thereby limiting the rumen biosynthesis of vitamin B 12 and methionine, respectively) from −60 to +6 days relative to insemination, the male offspring of methyl-donor-deficient ewes had an altered body composition by 22 months of age ( Sinclair et al, 2007 ). In dairy cows, supplementation of individual methyl donors or combinations of methionine, choline, folate, and vitamin B 12 has positively improved milk production, calf birth weight and height, amino acid flow to the calf, and nutrient profiles in milk ( Preynat et al, 2009a , b ; Batistel et al, 2017 ; Alharthi et al, 2018 ; Alharthi et al, 2019 ; Batistel et al, 2019 ; Palombo et al, 2021 ).…”