Department of Reproduction, Obstetrics and Herd Health, Faculty of Veterinary Medicine, Ghent University, Belgium Email: Geert.Opsomer@UGent.be
In order to start lactation, dairy cows have to calve. The latter causes reproductive performance of a dairy herd to be the general driving force for milk production. Due to enduring and successful selection in combination with further optimization of the o verall management, dairy farmers have been successful in increasing milk yield of our modern dairy cows. Daily milk yields of over 60 liters and 305-day productions of over 11.000 are rather common nowadays. The steep increase in milk production has for long time been felt to be associated with a significant decline in the reproductive capacity of the animals. Whether this is true or not is very difficult to scientifically research since herd management is a major confounding factor. However, most problems are stated to occur in adult, milk producing animals while reproductive capacity of nulliparous heifers seems relatively unaffected. The latter suggests a deleterious impact of the metabolic status related to the level of milk production.
Successful fertility necessitates easy calving and subsequent uterine involution, early resumption of ovarian activity, successful detection of the correct moment of insemination, easy fertilization and instant growth and development of the embryo, and full maintenance of pregnancy. In order to reach an economically sound calving interval, all these events should happen when the cow is confronted with the deleterious impact of metabolic stress. Metabolic stressors associated with the initiation and maintenance of lactation are known to perturb the finely tuned biological processes of the reproductive axis that are necessary for pregnancy establishment and maintenance.
Modern high yielding dairy cows have been said to have a higher risk to suffer from postpartal uterine diseases. Especially the incidence of subclinical endometritis has been proven to be up to 40% and even more than 25% at insemination, the latter being significantly associated with lower pregnancy results. Managing the inflammatory status of the cow around the moment of calving aiming for a quick immunological response that is sufficient to effectively clean the uterus following parturition, is a main challenge for modern dairy farmers. Besides the importance of calving ease and nutritional aspects to avoid overconditionned cows at calving and an overwhelming negative energy balance, recent studies suggest that the need for glucose to produce milk is that overwhelming in modern dairy cows, that it dominates the function and normal activity of immune cells. On the other hand, at least some cows seem to be confronted with an hyperinflammatory state in the peripartum period. This exorbitant inflammatory status starts in some cows already before calving and is further characterized by its prolonged duration, leading to almost 25% of cows suffering from subclinical endometritis at the moment of insemination.
Resumption of ovarian activity is the next challenge for the cow. This seems to be associated with the duration of the negative energy balance and is therefore generally retarded in high yielding animals. Besides its association with the negative energy balance, managerial factors like nutrition and genetics are known to be involved. Specific ovarian disturbances leading to an extended interval to first ovulation seem to be more prevalent in modern high yielding cows, although there is no general consensus concerning their pathogenesis.
A significant reduction in heat expression by the modern high yielding cow has been named a next significant challenge for the modern dairy farmer. Cows daily producing more than 40 liters of milk are more difficult to detect in heat and hence to inseminate at the correct moment to guarantee an adequate level of fertilization. Multiple underlying reasons have been proposed although without general consensus. Finally, different strategies from timed artificial insemination to the use of sensors to predict the ideal moment of insemination are currently applied.
Fertilization has so far not been indicated as a major problem in modern dairy cattle reproduction. When insemination is performed at the correct moment of the cycle, up to 85-90% of the oocytes will be fertilized. Main challenge however is the sufficient elongation of the young embryo in order to be able to reach enough endometrial cells and to produce a sufficient amount of interferon-tau to interrupt prostaglandin secretion. In up to 30% of the cases, embryos will die and cows will come back in heat. Reasons for this high number of embryo mortality are multiple among which, insufficient support of progesterone both before as well as after fertilization, low oocyte quality following confrontation with toxic metabolites and inflammatory mediators during final maturation, and a deleterious uterine environment are known to be the most important.
Currently, modern research is ongoing to study the effect of the microbiome present in the female genital tract including the uterus, on fertility results. Although the presence of bacteria in clinically health uteri seems to be rather low, differences in the abundance of specific phyla might be associated with the presence of (sub)clinical endometritis and hence with pregnancy results. Furthermore, in dairy cattle prenatal programming of postnatal reproductive capacity might be a next interesting topic to study, since dairy animals are still growing when pregnant as a young animal and produce large amounts of milk when pregnant as an adult.
Session 07: Metabolic status and risk of disease
Mechanisms and impact of inflammatory diseases on reproduction in dairy cows
J. E. P. Santos1 and E. S. Ribeiro2Department of Animal Sciences, University of Florida, Gainesville, USA; 2Department of Animal Biosciences, University of Guelph, Guelph, Canada
Email: Jepsantos@ufl.edu
Approximately 40% of the dairy cows develop one or more clinical diseases in the first 4 to 8 weeks of lactation and they represent 75 to 80% of all first diagnosis of disease in a given lactation. Many of the diseases that affect dairy cows are of inflammatory nature and have long-lasting impacts on reproduction. A conserved mechanism during disease is sickness behavior that cause hypophagia and consequent reduced nutrient intake. Of the important diseases that affect dairy cows, uterine and mammary gland inflammation are among the most common and both metritis and mastitis result in hyperthermia and systemic reactions that result in an acute phase response. Activation of the immune system and acute phase response is costly and alters nutrient partition to repair tissue and combat infection at the expense of tissue accretion, production, and reproduction. In dairy cows, activation of the immune system requires large quantities of glucose, which is in short supply in the first days postpartum. Induced inflammation extensively increases hepatic uptake of amino acids, which limits supply to other peripheral tissues, including the mammary gland. The alterations in nutrient partition induced by disease exacerbate the negative nutrient balance that cows undergo in early lactation. As consequence of negative nutrient balance, the uncoupling of growth-hormone and insulin-like growth factor 1 is extended and splanchnic metabolic signals that communicate nutritional status with hypothalamic centers are depressed. These changes compromise resumption ovarian follicular activity resulting in increased prevalence of anovular cows at the end of the voluntary waiting period. Acute disease compromises oocyte competence either because of hyperthermia or translocation of pathogen-associated molecular patterns that induce apoptosis of follicular cells and hastened progression of oocyte maturation. It’s been suggested that acute uterine diseases might reduce the ovarian reserve and recent work with induced endometritis has shown compromised early embryonic development in dairy cows subjected to in vitro embryo production. Uterine disease causes tissue damage that leaves inflammatory signatures on reproductive tissues even after resolution of the disease. Inflammatory disease before the first postpartum insemination reduced fertilization and embryo development to the morula stage in lactating dairy cows, and impaired early conceptus development in the peri-implantation period with reduced secretion of interferon-τ into the uterine lumen. Concepti from cows diagnosed with disease had inflammation-like changes in the transcriptome, thereby suggesting that either local or systemic effects of disease in early lactation leave a legacy of impacts on the reproductive tract that eventually increase the risk of pregnancy loss. Controlling peripartum diseases is paramount for proper reproduction in dairy cows and that involves integration of multiple aspects of dairy cow management.
Interaction between inflammation and metabolism in periparturient dairy cows
E. Trevisi, A. Minuti and M. MezzettiDepartment of Animal Sciences, Food and Nutrition (DIANA), Facoltà di Scienze Agrarie, Alimentari e Ambientali, Università Cattolica del Sacro Cuore, Piacenza, Italy
Email: erminio.trevisi@unicatt.it
Immune system is made of a variety of cells, molecules and biological processes that interact each other to prevent or counteract biotic (i.e. microbial invasions) and abiotic (i.e. trauma, poisoning) stressors. Innate immunity is the primary defense line. Its activation is accompanied from the release of cytokines that regulate the inflammatory response against harmful stimuli. In normal condition, inflammatory processes occur at local level, allowing the recognition of foreign molecules, the elimination of existing sources of cellular injuries and the restoration of the normal functions of tissues once problem has been solved. In the last decades, severe alterations of innate immune system have been reported during the transition period (TP) of dairy cows. Bovine polymorphonuclear cells (PMN) have an altered abundance in mRNA transcripts encoding for functional genes between -1 and 2 weeks from calving, in comparison to the level found at 4 weeks after calving. A reduced immune competence has been widely assumed as the main phenomena affecting those cells in TP. In fact, PMN of transition cows have a lower production of reactive oxygen metabolites due to an impaired myeloperoxidase activity, and their chemotaxis and phagocytosis are impaired as well.
Nevertheless, immunosuppression could not fully account for typical phenomena affecting bovine immune system during peripartum.
In fact, inflammatory events occurring around calving suggest innate immune system to provide an effective response against stressors. Such inflammations commonly assume a systemic connotation in transition cows, suggesting an impaired capacity of immune system to restore homeostasis. Systemic inflammations imply an impairment of hepatic function driven by the acute phase response. During acute phase, the liver produces more α-globulins, known as positive acute phase proteins (APP; i.e. haptoglobin, ceruloplasmin and serum amyloid alpha). Conversely, it reduces the syntheses of other proteins (i.e. albumin, retinol binding protein, paraoxonase and lipoproteins) known as negative APP and sequester minerals (as zinc and iron) from the blood. Systemic inflammation could induce fever and induce an anorexic stimulus as a side effect of the massive concentrations of cytokines circulating in the body, and an oxidative stress could occur due to impaired capacity of the liver to manage antioxidant compounds.
Nevertheless, systemic inflammations are not reflected from any clinical symptoms in most of the animals. Despite that, systemic inflammations around calving could induce severe consequences in early lactation. Such consequences include an altered control of appetite, an increased likelihood in developing mastitis and a delayed resumption of ovarian function. Immune alterations could depend on a specific adaptation of immune cells to the sudden changes occurring in TP (i.e. alterations in endocrine asset, limitations of maternal immune responses against the allogeneic conceptus, alterations in energy metabolism with sudden utilization of body reserves and in reduction-oxidation balance). When peripartal alterations exceed the control of homeorhetic and homeostatic mechanisms a physiological imbalance (PI) condition could occur, aggravating the immune dysfunction around calving and increasing the duration of inflammatory processes. Genotype could also have a contribution in regulating inflammatory processes, as highly selected dairy cows seem to be less capable than autochthonous breeds to dampen massive inflammatory responses occurring in early lactation. PI conditions could arise from the repeated exposure to stressing events in peripartum. Among the most relevant stressing factors a frequent regrouping of the animals, an inadequate environment at calving time (i.e. overcrowding, climatic stress), nutritional upsets (i.e. unbalanced diets or feeds containing contaminants as mycotoxins) and a suboptimal physiological status in late gestating animals (i.e. excessive accumulation of body fat) could be listed. Sudden changes of diet occurring in peripartum are also involved in the development of inflammations. In fact, altered rumen and/or gut permeability that accompanies diet changes could allow the absorption of immunogenic compounds (i.e. lipopolysaccharides, ammines). A wide range of anti-inflammatory strategies has been listed to reduce negative effects of uncontrolled inflammations in TP. The post partal administration of nonsteroidal anti-inflammatory agents with mild side effects (i.e. aspirin) has been proposed to improve both performance and metabolism of cows.
Wider nutritional strategies to optimize dairy cow’s immunity during TP should be focused on reducing the PI degree related to calving, as this condition could be referred as a common denominator between immune dysfunction and diseases. In example, feeding cows with excessive amounts of energy during dry period could increase the deposition of body fat, inducing a severe mobilization of nonesterified fatty acids in early lactation. In these conditions, the severity of the acute phase response, as well as the likelihood of metabolic diseases in early lactation are known to increase. Moreover, nutrients as fatty acids are directly involved in immune modulation. Omega-3 and omega-6 fatty acids are precursors of oxylipids exerting both pro and antinflammatory actions. An increased availability of dietary omega-3 fatty acids from late pregnancy to early lactation could improve the omega-3/omega-6 balance in the body, improving the immune regulation. Conjugated linoleic acid (CLA) is another immune modulator. The administration of cis-9 trans-11 and trans-10 cis-12 CLA isomers around calving reduce the inflammation and the negative energy balance in early lactation. Finally, plant extracts (i.e. Aloe arborescens, Echinacea spp.) and specific nutrients as methionine and choline, could further provide an aid in modulating immune system around calving, sorting beneficial effects on health and performances. In a wider perspective, the nutritional optimization could mitigate the immune alterations of transition cows. Despite that, minimize the occurrence of stressing events during the whole peripartal period could be the best strategy to alleviate immune dysfunctions and prevent overexuberant inflammations around calving.
Session 07: Metabolic status and risk of disease
Amino acids and the regulation of oxidative stress and immune function in dairy cows
D. N. Coleman1, V. Lopreiato2 and J. J. Loor11Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA; 2Department of Health Science, Interdepartmental Services Centre of Veterinary for Human and Animal Health, Magna Græcia University of Catanzaro, Catanzaro, Italy
Email: jloor@illinois.edu
Introduction Dairy cows undergo a number of metabolic, endocrine, physiologic, and immune adaptations during the periparturient period. Historically, these aspects of dairy cow biology were studied in isolation, but the mechanistic interplay among these systems is now well-recognized. Metabolically, for example, the increase in mobilization of adipose depots as parturition approaches not only increases the risk of triacylglycerol accumulation in the liver, but also could trigger inflammation, oxidative stress, immune dysfunction, and reductions in liver function. Both, the degree and length of time during which these systems remain out of balance could render cows more susceptible to disease incidence, poor reproductive outcomes, and less efficient. Therefore, there continues to be interest on approaches that might synergistically help cows modulate metabolism and immune responses during the periparturient period.
Justification Nutrition during the periparturient period is one feasible way to modulate biological adaptations. In the context of
“immunometabolism”, varying the post-ruminal supply of micronutrients [e.g. B vitamins, folic acid, choline, trace minerals, amino acids (AA)] has been a focus of research for a number of years. Recognition of the “functional role” of certain nutrients on biological aspects unrelated to metabolism has sparked interest on determining their “immunomodulator” potential. Classical studies in non-ruminants established a crucial role for glutamine and glutamate in immune cell metabolism and function (e.g. lymphocytes, macrophages, neutrophils). At the cellular level these AA along with essential (e.g. methionine, histidine, threonine), semi-essential (arginine), and non-essential (serine, glycine) AA not only interact through common biochemical pathways to help immune cells meet energy needs (Figure), but also are important for synthesis of nucleotides, antioxidants, and polyamines. Those compounds impact a number of cellular processes across cell types and organs. From a nutritional standpoint, the 1-carbon metabolism pathway (Figure) represents an example of an interconnected route through which a number of AA could impact molecular events such as epigenetic regulation, i.e. control of gene transcription. An important “nutrient sensor” that is sensitive to AA supply is the mechanistic target of rapamycin (mTOR). Although mTOR has been primarily studied in the context of bovine milk protein synthesis, a growing body of literature in non-ruminants underscores its involvement in the immunometabolic response.
Objectives To provide an overview of immune system responses in the periparturient cow followed by more specific discussion of the immunometabolic role of specific AA. Available molecular data on immune cells and immune-responsive organs in dairy cows are discussed in the context of AA transport, cellular sensors, and signalling mechanisms that might impact responses to increases in the supply of specific AA. With nutritional management during the periparturient period continuing to be an active area of research, it is important to develop a systems understanding of the potential role that dietary AA may play in modulating immune and metabolic responses during this period.