Experiencing any one of the metabolic diseases of dairy cows, such as milk fever, ketosis, and displacement of the abomasum, is strongly associated with decreased fertility in the cow. These metabolic problems in the transition dairy cow can have a tremendous negative effect on the immune system of the cow, increasing her susceptibility to retained placenta (RP), metritis, and endometritis. A strong immune system is also required if immune recognition of a conceptus is to occur so that implantation can proceed. Milk fever is often a contributing factor to the development of other metabolic diseases as well. The areas of nutrition to be concentrated on in this review are energy and protein imbalance in early lactation causing ketosis and fatty liver and problems associated with macromineral balance such as milk fever. Though trace mineral imbalances and vitamin deficiencies can also be devastating to fertility and the immune response, proper supplementation will nearly eliminate these as major risk factors for periparturient disorders and therefore will not be a focus of this review.
Epidemiological studies have demonstrated that there is an association between the development of metabolic disease and subsequent development of reproductive disorders (van Dorp et al., 1999; Markusfeld, 1987; Roche, 2006). In a study of New York dairies (2,190 cows), there was a very strong association between parturient hypocalcemia or milk fever and RP. The odds ratio (multiplicative increases in occurrence) suggested that a milk fever cow was 3.2 times more likely to retain her placenta than a cow that had not had milk fever. Hypocalcemia also greatly increased the risk of mastitis (Curtis et al., 1983). Whiteford and Sheldon (2005) also found strong links between hypocalcemia and increased incidence of endometritis. A Swedish study (18,110 Swedish Red and White cows in 924 herds and 14,940 Swedish Friesian cows in 772 herds) found that the risk of ovulatory dysfunction was increased in cows that had suffered ketosis (Emanuelson et al., 1993). Markusfeld (1985) reported that 80% of cows with ketonuria developed metritis. Most of these same risk factors also increase the incidence of mastitis. The emerging story suggests these metabolic diseases impair immune function, predisposing the cow to uterine infection and mastitis (Lewis, 1997; Foldi et al., 2006).
Another argument that can be made is that some uterine disorders may predispose the cow to metabolic disease; for instance, RP is a risk factor for development of ketosis (Correa et al., 1993).
Neutrophil and lymphocyte function are diminished in the periparturient period, especially in the dairy cow (Kehrli et al., 1989 a,b). The onset of milk production imposes tremendous challenges to the mechanisms responsible for energy, protein, and mineral homeostasis in the cow. Negative energy, protein, and/or mineral balance associated with the onset of lactation may be partially responsible for the immunosuppression observed in periparturient dairy cattle. Mastectomy of pregnant dairy cows removes the impact of milk production while presumably maintaining endocrine and other changes associated with late pregnancy and parturition. Mastectomy would be expected to improve immune function in the periparturient dairy cow, if milk production is an immunosuppressive factor. Using 10 mastectomized and 8 intact multiparous Jersey cows (all intact cows developed milk fever), we assessed the ability of neutrophils to kill microbes as assessed by neutrophil myeloperoxidase activity during the periparturient period (Kimura et. al., 1999). Neutrophil myeloperoxidase activity decreased equally before parturition in both groups. While there was a quick recovery of neutrophil myeloperoxidase activity in mastectomized cows, there was no recovery in intact cows after parturition throughout the study, which lasted until d 20 postpartum. Lymphocyte production of gamma-interferon in vitro declined significantly at parturition in intact cows but did not decrease significantly in the mastectomized cows. In intact cows, all T cell subset populations (i.e., CD3, CD4, CD8, and gamma-delta positive cells) decreased as a percentage of total peripheral blood mononuclear cells (PBMC) at the time of parturition while the percentage of monocytes increased. These population changes have previously been shown to be associated with the immune suppression commonly observed in periparturient cows. Mastectomy eliminated these changes in leukocyte subsets (Kimura et al., 2002a).
These results suggest: 1) the mammary gland may produce substances which directly affect immune cell populations, or 2) metabolic demands associated with the onset of lactation negatively impact the composition of circulating PBMC populations. Two metabolic factors were greatly impacted by mastectomy. Mastectomy eliminated hypocalcemia at parturition. Plasma non-esterified fatty acid (NEFA) concentration rose dramatically in intact cows at calving and did not return to baseline level for > 10 d. In contrast, NEFA concentration in mastectomized cow plasma rose only slightly at calving and returned to baseline level one to two days after calving. It is clear that the intact cow mobilizes a much larger amount of body fat than does the mastectomized cow, suggesting negative energy balance coincides with the onset of lactation.
It has long been known that hypocalcemia acts as a stressor to the cow. Cows typically exhibit a three- to four-fold increase in plasma cortisol as part of the act of initiation of parturition. However, subclinically hypocalcemic cows may have five- to seven-fold increases in plasma cortisol on the day of calving, and the typical milk fever cow may exhibit plasma cortisol concentrations that are 10- to 15-fold higher than pre-calving plasma cortisol concentration (Horst and Jorgensen, 1982). Cortisol is generally considered a powerful immune suppressive agent and likely exacerbates the immune suppression normally observed in the periparturient period (exacerbates rather than causes because most studies suggest that immune suppression begins one to two weeks before calving [Kehrli et al., 1989a,b: Ishikawa, 1987, Kashiwazaki et al., 1985], and the cortisol surge is fairly tightly confined to the day of calving and perhaps the day after calving).
Most compounds that will activate an immune response bind to receptors on the immune cell surface, which then initiates an increase in intracellular calcium concentration, which acts as a second messenger to alter metabolism within the cell. The source of the calcium for this response is primarily the endoplasmic reticulum and mitochondria of the cell. We have recently demonstrated that hypocalcemia seems to interfere with the activation of immune cells (Kimura et al., 2006). As hypocalcemia begins to occur in the extracellular fluids, there is a decline in intracellular stores of calcium within endoplasmic reticulum as well. Lacking sufficient intracellular stores of calcium, the response of immune cells to activating stimuli is blunted in cows with hypocalcemia.
Two prepartum nutritional factors seem to be key to reducing hypocalcemia (Goff, 2004). High dietary cation-anion difference diets, due to excessive potassium, alkalinize the cow’s tissues, reducing effectiveness of parathyroid hormone on target tissues. The second factor is hypomagnesemia, which reduces parathyroid hormone secretion and impairs tissue recognition of parathyroid hormone. Both problems can subvert normal calcium homeostatic mechanisms, and the animals develop hypocalcemia. Prepartum diets with adjusted cation-anion balance to induce a compensated metabolic acidosis can help prevent milk fever, and the use of these diets has been associated with reduced RP and improved reproductive performance (Wilde, 2006).
Ketosis is diagnosed whenever there are elevated levels of ketones in the blood, urine, or milk of a cow. The disease is always characterized by a decline in blood glucose as well. In lactation, the amount of energy required for maintenance of body tissues and milk production exceeds the amount of energy the cow can obtain from her diet, especially in early lactation when dry matter intake is still low. As a result, the cow must utilize body fat as a source of energy. Every good cow will utilize body reserves in early lactation to help her make milk. However, there is a limit to the amount of fatty acid that can be handled and used for energy by the liver (and to some extent the other tissues of the body). When this limit is reached, the fats are no longer burned for energy but begin to accumulate within the liver cells as triglyceride. Some of the fatty acids are converted to ketones. The appearance of these ketones in the blood, milk, and urine is diagnostic of ketosis. As fat accumulates in the liver, it reduces liver function — and a major function of the liver in the dairy cow is to produce glucose — a major fuel of the immune system.
Use of monensin in dairy cattle can improve supply of gluconeogenic precursors in early lactation. In a large study in Florida, monensin-treated cows were 0.8 times as likely to develop metritis as cows that did not receive monensin (Melendez et al., 2006).
The fresh cow is also in negative protein balance shortly after calving. Generally this is not perceived to be as big a problem as the negative energy balance of early lactation, but the typical cow will lose 37 lb of body protein during the first two weeks of lactation. Much of this body protein is being used to support the amino acid and glucose requirements of milk production (Paquay et al., 1972). Therefore, in many respects, the dairy cow in early lactation is in a physiological state comparable to that of humans and rodents with prolonged protein-calorie restriction. Glutamine is the most abundant free amino acid in human muscle and plasma and is utilized at high rates by rapidly dividing cells, including leucocytes, to provide energy and optimal conditions for nucleotide biosynthesis. As such, it is considered to be essential for proper immune function. In humans, plasma glutamine is known to fall in patients with untreated diabetes mellitus, in diet-induced metabolic acidosis, and in the recovery period following high-intensity intermittent exercise (Walsh et al., 1998). Interestingly, plasma glutamine does not seem to be depressed in the dairy cow at calving – when body fat mobilization is rapidly increasing and presumably protein catabolism would also be increasing rapidly. However, plasma glutamine does decrease as the cow progresses into the early weeks of lactation (Zhu et al., 2000; Meijer et al., 1995).
Does the relative calorie-protein deficiency of the early lactation cow impact her immune response? In humans, protein-calorie restriction has severe effects on cell-mediated immunity. There is often widespread atrophy of lymphoid tissues, and this can cause a 50% decline in the number of circulating T cells. Surprisingly, antibody responses are intact, and phagocytosis of bacteria is relatively normal. However, destruction of bacteria within the phagocytes is impaired (Roitt, 1991).
There is some concern from studies done in human diabetics suffering from ketoacidosis that circulating ketone bodies may be affecting the immune system directly (Gregory et al., 1993). Several studies have looked at the effect addition of ketones and/or glucose to media used to culture normal bovine leukocytes might have on their function. Franklin et al. (1991) examined the effects of beta-hydroxybutyrate, acetoacetate, acetone, acetate, butyrate, and glucose on in vitro lymphocyte proliferation of lymphocytes stimulated with concanavalin A, phytohemagglutinin-P, or pokeweed mitogen. Ketones, butyrate, and glucose at concentrations occurring in vivo had minimal effects on bovine lymphocyte proliferation in vitro. Only very high levels of beta-hydroxybutyrate inhibited proliferation. Nonnecke et al. (1992) examined the effect of ketones and glucose on in vitro lymphocyte immunoglobulin secretion. Results from experiments evaluating effects of glucose concentrations on IgM secretion indicated that plasma glucose concentration associated with the ketotic state (1.66 mM, a plasma glucose concentration associated with the ketotic state), compared with normal plasma glucose concentration (3.33 mM), did not affect total or antigen-specific IgM secretion. Adding a mixture of ketones to the culture media which approximated plasma levels of severely ketotic cows inhibited mitogen-induced IgM secretion in 11.1 mM glucose-supplemented cultures but not in cultures with 3.33 or 1.66 mM glucose. High ketones and high plasma glucose would be more likely in the human ketoacidotic state and could help explain the immune deficits observed in diabetics. These data indicate that effects of ketones and acetate on IgM secretion are dependent on the concentration of glucose in culture and suggest that changes in plasma glucose, ketone, and acetate concentrations associated with bovine ketosis do not alter IgM secretion in vivo. Sartorelli et al. (2000), working with sheep, determined that beta-hydroxybutyrate (but not other ketones) at concentrations seen in mild ketosis could decrease bactericidal activity. Hoeben et al. (1997) found that butyrate at a level consistent with mild ketosis (1 to 2.5 mM) was able to reduce respiratory burst activity of bovine neutrophils. However, it remains unclear how butyrate affects the cells.
A few studies have been done on lymphocytes isolated directly from normal cows and cows with clinical and subclinical ketosis and then placed into culture. Leukocytes of cows with clinical symptoms and the highest concentration of ketones and free fatty acids in blood responded with the lowest levels of interferons alpha and gamma to three interferon inducers: Newcastle disease virus, phytohemagglutinin and concanavalin A. Depression in interferon PHA stimulated synthesis correlated with a very low mitogenic response of blood lymphocytes. A correlation between the stage of ketosis and the level of interferon production in milk leukocytes was also observed (Kandefer-Szerszen et al., 1992).
Zerbe et al. (2000) examined the relationship between liver triacylglycerol (TAG) content and immunophenotypical and functional properties of neutrophils of dairy cows in the peripartum period. Increased liver TAG content, > 40mg/g, which was considered the upper level of normal, went in parallel with a reduced expression of function-associated surface molecules on blood neutrophils. Moreover, in cows with high liver TAG levels, the antibody-independent and -dependent cellular cytotoxicity (AICC, ADCC) of blood neutrophil preparations was markedly reduced. Neutrophil preparations of cows with high liver TAG also were less capable of reactive oxygen species generation after stimulation with phorbol myristate acetate.
Early in lactation, the cow does experience a rise in blood NEFA content. Stulnig et al. (2000) demonstrated that increased serum free fatty acid concentrations could affect T lymphocyte activation under in vivo conditions. They infused humans with various saturated and unsaturated fatty acids over a period of hours, isolated lymphocytes from these people, and assessed the ability of the cells to respond to stimuli using a rise in intracellular calcium as a measure of lymphocyte activation. Increasing serum FFA by lipid infusion inhibited calcium response of both CD4(+) and CD8(+) subsets. Could the rise in serum NEFA observed in the periparturient cow be a major factor causing the immunosuppression associated with the ketotic cow? Evidence already exists that these fatty acids can have effects on hepatic function (Mashek et al., 2005), so it is likely they can affect immune cell function.
Little to no work has been done to examine this issue in cattle. However, in humans suffering from severe infection causing sepsis (various degrees of fever, increased white blood cell [WBC] count, and acute phase protein production), the resting energy expenditure (determined by indirect calorimetry) increased progressively over the first week of the infection to around 40% above normal and was still elevated three weeks from the onset of illness. As an aside, over a three-week period, patients lost 13% of their total body protein (Plank and Hill, 2000).
No such measurements have been reported for cattle. However, if we are allowed to extrapolate and speculate, we can go through a few calculations. Maintenance energy for a 600 kg dairy cow is approximately 9.7 Mcal net energy/day. If the cow must also increase energy expenditure 40% to mount an inflammatory response, the energy requirement increases by nearly 4 Mcal/day. This is roughly equivalent to a requirement that the cow consume an additional 2.4 kg of diet (assuming a diet that provided 1.65 Mcal NEL/kg). Can the periparturient cow, already in negative energy balance, be expected to successfully mount a rapid immune response? If she is in fact in negative protein balance as well, will her immune system produce the immunoglobulins and acute phase proteins necessary to fight an infection while it is still in the acute phase to prevent it from escalating to a clinical infection?
We have confirmed studies begun by Gunnink (1984) that suggested RP was caused by an impaired immune response. Gunnink’s theory suggested the fetal placenta must be recognized as “foreign” tissue and rejected by the immune system after parturition to cause expulsion of the placenta. We followed up on this report with the hypothesis that impaired neutrophil function causes RP. We examined the ability of neutrophils to recognize fetal cotyledon tissue as assessed by a chemotaxis assay, which utilized a placental homogenate obtained from a spontaneously expelled placenta as the chemoattractant. Neutrophil killing ability was also estimated by determining myeloperoxidase activity in isolated neutrophils. Blood samples were obtained from 142 periparturient dairy cattle in two herds. Twenty cattle developed RP (14.1%). Neutrophils isolated from blood of cows with RP had significantly lower neutrophil function in both assays prior to calving, and this impaired function lasted for one to two weeks after parturition. Addition of antibody directed against interleukin-8 (IL-8) to the cotyledon preparation used as a chemoattractant inhibited chemotaxis by 41%, suggesting one of the chemoattractants present in the cotyledon at parturition is IL-8. At calving, plasma IL-8 concentration was lower in RP cows (51 ± 12 pg/ml) than in cows expelling the placenta normally (134 ± 11 pg/ml) (Kimura et al., 2002b). These data suggest neutrophil function determines whether or not the cow will develop RP. These data also suggest that depressed production of IL-8 may be a factor affecting neutrophil function in cows developing RP. This suppressed immune system could also explain why cows with RP are more susceptible to mastitis. Retained placenta probably does not cause mastitis but is symptomatic of a depressed immune system.
Cows developing RP were demonstrated to have reduced levels of antioxidants in their blood (Brzezinska-Slebodzinska et al., 1994), which could be exacerbated by feeding excessive dietary iron (Campbell and Miller, 1998). A profound decrease in plasma content of vitamin E and beta-carotene, another antioxidant, begins to occur about two weeks before calving and does not recover until several weeks after parturition, suggesting the periparturient period may represent a period of increased oxidative stress to the cow (Goff and Stabel, 1990). It is interesting to note that deficiency of two nutrients, vitamin E and selenium, well known as anti-oxidants and known to be risk factors for RP and metritis (Harrison et al., 1984), can also cause increased risk of mastitis (Smith et al., 1984; Weiss et al., 1997). It would appear that the likely mediator of both decreased RP and decreased mastitis when animals become replete with these nutrients is an improved immune system.
At calving, the cow’s reproductive tract is exposed to bacteria, even in the cleanest of environments. The cow survives because her WBC provide protection from infection. Neutrophils provide the first line of defense, moving out of the blood whenever and wherever bacteria invade body tissue. Once in the infected tissue, the neutrophils ingest the bacteria and release enzymes and free radical compounds onto the bacteria to kill them. Occasionally, the neutrophils don’t succeed in killing the intruder. The immune system then calls on macrophages and lymphocytes, which work together to produce antibodies and other antibacterial factors. Production of these factors takes a little more time but will eventually eliminate most infections the neutrophils can’t handle.
In immune-compromised cows, the bacteria are not kept in check and grow to large numbers in the uterus, causing a condition known as metritis. Around 20 to 30% of cows will develop metritis, which is characterized by a foul-smelling, red-brown, watery discharge from the uterus within 10 to 14 days after calving. It is often, but not always, accompanied by a fever. Hammon et al. (2006) demonstrated that neutrophils of cows with metritis are significantly less able to kill bacteria (measured by a neutrophil iodination assay) than neutrophils from cows without metritis. The surprise was that poor neutrophil function was evident in these cows the day of calving — before lactation began and before any bacteria could have entered the uterus.
Endometritis is a uterine problem characterized by inflammation of the lining of the uterus lasting more than three to four weeks after calving. Studies suggest 40 to 50% of cows can have endometritis at four weeks after calving. These cows are less likely to be successfully bred back. An interesting study by Kim et al. (2005) compared the peripartum immune responses of dairy cows that developed endometritis by four weeks postpartum (n = 11) to cows that did not develop this disease (n = 19). Blood samples were collected one week before calving, just after or during calving, and then at weeks 1, 2, 3, and 4 postpartum. The leukocytes from cows that developed endometritis were significantly less phagocytic than those from control cows at all sampling time points (P < 0.01). In the study of Hammon et al. (2006), cows with endometritis and subclinical endometritis had poorer neutrophil function than cows with a healthy uterus — from the time they calved until the diagnosis of endometritis was made four weeks later. Cows in this study developing metritis, or diagnosed with subclinical or clinical endometritis, had higher NEFA levels in their blood than did cows with a healthy uterus. Surprisingly, the NEFA levels were significantly higher for at least two weeks prior to calving, suggesting these cows were mobilizing body fat even before calving. Individual cow feed intake data revealed those cows that were going to develop uterine health problems ate significantly less feed than cows that would maintain a healthy uterus, and this difference in feed intake existed at least one week prior to calving. Urton et al. (2005) were able to demonstrate that feeding behavior prior to calving was a major risk factor for metritis. In this study, for every 10 min/day reduction in time spent eating in the weeks prior to calving, the risk of developing metritis doubled. Though uterine diseases are diagnosed in early lactation, it now appears that the health of the uterus is greatly influenced by feed intake and avoidance of negative energy at the end of the dry period.
If we are going to reduce uterine disease, we must look back to the dry cow. To improve feed intake in the critical period around the time of calving, we must offer palatable rations in a cool, uncrowded environment with plenty of bunk space (28 to 30 inches per cow) to encourage intake. Clean maternity pens, clean obstetrical equipment when assisting calving, and clean stalls can reduce exposure to bacteria; even a strong immune system can be overwhelmed by a large bacterial load in the uterus. Feed to avoid metabolic disorders. Reducing dietary potassium in the dry cow ration and adding chloride or sulfate to the diet in a palatable form to reduce hypocalcemia improves feed intake in early lactation and helps keep WBC functioning. Maintain adequate fiber in dry and fresh cow diets to avoid displaced abomasum. Keep cows from getting too fat, as fat cows seem to suffer the greatest decline in feed intake prior to calving.
Jesse P. Goff
Iowa State University
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