Influencing Calf Epigenetics

The gastrointestinal tract of calves is a complex ecosystem that is densely populated by trillions of commensal bacteria, fungi, archaea, and viruses. Recent research has highlighted the importance of these microorganisms in the development and maintenance of normal intestinal development and physiology, including digestion and nutrient uptake, metabolism, tissue development, and immunity.

Epigenetic Regulation

Epigenetic modifications enable bovine cells to alter gene expression without changing the genetic code. This mechanism is what allows mammals to adapt to environmental cues. Calves contain what are termed eukaryotic cells. Within these cells DNA is bound to histone proteins and organized into a compact structure called chromatin. 

In general, epigenetic modifications allow relaxation of the chromatin to activate gene transcription. Epigenetic modifications that regulate chromatin accessibility include post-translational modification of histones, DNA acetylation, and DNA methylation.

This mechanism can happen through multiple potential mechanisms.

• Microbial byproducts influence the availability of chemical donors for DNA or histone modifications.
• Regulation of epigenetic modifying enzyme expression and/or activity.
• Activation of host-cell natural processes that direct epigenetic pathways.

Microbiota-Gene Expression Relationship

Epigenetic-modifying enzymes require a substrate to catalyze changes to chromatin.  Generally, these rely on methyl and acetyl donors. While many of these donor substrates can be generated from natural processes within the animal, the microbiota is an additional source of these compounds.

Microbiota can synthesize many biological compounds including several that serve as epigenetic substrates, co-factors, or regulators of epigenetic enzyme activity.

The neonatal intestine is uniquely sensitive to initial microbial colonization after birth. This critical window important for post-natal tissue development and establishing normal immune responses. Early microbial colonization has been found to be associated with altered DNA methylation in genes associated with immunity, metabolism, and vascular regulation. 

Neonatal colonization also helps to protect against pulmonary and enteric disease by preventing accumulation of natural killer T cells in the lungs and intestines. As an industry we need to emphasize the importance of microbiota-epigenome cross talk during early life stages and that timing, density, and diversity of microbial colonization are likely to influence genetic merit into adulthood.

On-Farm Application

All these scientific terms about genetics can see overwhelming! Let’s talk a little bit about how to take what we have learned and apply it on farm?

• Nutrition: feeding calves a higher plane of nutrition
  • Feeding calves a higher plane of nutrition (>20 % protein, >20% fat) during the preweaning period has been found to mediate the growth response of the mammary gland. This result is probably activated by intracellular cascades of hormones, growth factors, etc. because of feeding more nutrients to the animal.
  • Feeding beef calves 20% of their body weight in milk vs. 10% resulted in increased granulosa cells (GC) and higher follicle counts at 8 months of age, suggesting that a higher plane of nutrition early in life may impact overall reproduction. It is thought that this result may be a consequence of interferon regulated immunological pathways.
• Modification of Gut Flora: early and effective colonization of beneficial gut microbiota
  • Colostrum provides many compounds necessary to the colonization of the GIT and development of the immune system.
    • Beneficial microbes found in colostrum have the first chance at colonizing the GIT.
    • IgA screens and selects which types of bacteria are allowed to colonize.
    • miRNAs found in colostrum act as signaling molecules to stimulate intestinal epithelial cell proliferation, stem cell activity, and development of the immune system
    • Prebiotics found in colostrum feed commensal probiotics allowing them to flourish.
  • Probiotic use early in life densifies the population of helpful microbial species such as Lactobacillus and Bifidobacterium spp.
  • Prebiotic feed ingredients can nourish and support gut microbiome diversity as well as prepare the immune system for defense.
  • Gut microbiota has been found to alter acetylation and methylation in various tissues including the colon, liver, and adipose tissue.
• Feeding methyl donors and/or short chain fatty acids (SCFA):
  • Increasing the availability of methyl donors is one way to improve gene modification. Examples of methyl donors include rumen protected choline and betaine. These methyl donors will tag onto histones and influence gene expression.
    • Rumen protected choline reduces oxidative stress during heat stress.
    • Betaine is an osmolyte (helps maintain osmotic pressure and homeostasis within cells) and a methyl donor.
  • SCFA are the byproducts of microbial fermentation in the GIT. Some SCFA inhibit histone deacetylases (HDACs), compounds that take acetyl groups off histones and suppress gene expression. 
  • SCFA activate G-protein-coupled receptors (GPCRs) which regulate metabolism, inflammation, and disease.
  • SCFA are a major player in the maintenance of gut and immune homeostasis.

I feel like one of the biggest challenges we face in the livestock production industry is applying new science findings on farm. I recently had the opportunity to do just that in a calf study looking at how we can influence immunity and gene expression by giving calves a prebiotic, probiotic, postbiotic on day 1. We saw both immune benefit as well as improved average daily gain. You can learn more about our approach in my previous blog post Effects of Sync on Immune Protection.

Sources:

Röttgen, V., Tümmler, LM., Koczan, D. et al. Early milk-feeding regimes in calves exert long-term effects on the development of ovarian granulosa cells. BMC Genomics 24, 485 (2023). https://doi.org/10.1186/s12864-023-09589-7

Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L. The role of short-chain fatty acids in health and disease. Adv Immunol. 2014;121:91-119. doi: 10.1016/B978-0-12-800100-4.00003-9. PMID: 24388214.

Vailati-Riboni M, Bucktrout RE, Zhan S, et al. Higher plane of nutrition pre-weaning enhances Holstein calf mammary gland development through alterations in the parenchyma and fat pad transcriptome. BMC Genomics. 2018 Dec;19(1):900. DOI: 10.1186/s12864-018-5303-8. PMID: 30537932; PMCID: PMC6290502.

Woo V, Alenghat T. Epigenetic regulation by gut microbiota. Gut Microbes. 2022 Jan-Dec;14(1):2022407. doi: 10.1080/19490976.2021.2022407. PMID: 35000562; PMCID: PMC8744890.