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Suppression of appetite, or hypophagia, is among the most recognizable effects of disease in livestock, with the potential to impair growth, reproduction, and lactation. The continued evolution of the field of immunology has led to a greater understanding of the immune and endocrine signaling networks underlying this conserved response to disease. Inflammatory mediators, especially including the cytokines tumor necrosis factor-α and interleukin-1β, are likely pivotal to disease-induced hypophagia, based on findings in both rodents and cattle. However, the specific mechanisms linking a cytokine surge to decreased feeding behavior are more difficult to pin down and likely include direct effects on appetite centers in the brain, alteration of gastric motility, and modulation of other endocrine factors that influence appetite and satiety. These insights into the mechanisms for disease-induced hypophagia have great relevance for management of neonatal calves, mature cows transitioning to lactation, and cows experiencing mastitis; however, it is not necessarily the case that increasing feed intake by any means possible will improve health outcomes for diseased cattle. We explore conflicting effects of hypophagia on immune responses, which may be impaired by the lack of specific substrates, versus apparent benefits for controlling the growth of some pathogens. Anti-inflammatory strategies have shown promise for promoting recovery of feed intake following some conditions but not others. Finally, we explore the potential for early disease detection through automated monitoring of feeding behavior and consider which strategies may be implemented to respond to early hypophagia.
Maximizing feed intake (FI) in production animals is a common goal to foster optimum production of livestock. However, incidence of disease is inevitable and, in addition to the negative effect on animal well-being, disease challenges our ability to maintain the desired production level, partially through reduced FI. The mechanisms controlling the FI response in diseased animals are complex and should be appreciated within the context of the natural adaptive mechanisms the animal uses to fight off infection. Signaling from the immune system during disease occurs both centrally and peripherally to decrease FI (
Effects of intravenous lipopolysaccharide administration on feed intake, ruminal forage degradability, and liquid parameters and physiological responses in beef cattle.
) are altered by disease insults, further contributing to depressed FI. Even though cytokine effects on feed intake are well documented, it remains difficult to predict the degree and duration of FI depression based on immense variation in factors such as pathogen type and load, immunocompetency, and plane of nutrition (
). For dairy cattle, the transition period introduces overlapping shifts in nutrient flux, immune function, and pathogen exposure that likely contribute to reduced FI. Immune-induced FI depression also commonly occurs in neonatal dairy calves (
The effects of experimentally induced Escherichia coli mastitis and flunixin meglumine administration on activity measures, feed intake, and milk parameters.
, mice were infected with Listeria monocytogenes. One group was fed ad libitum, whereas the other was force-fed to match the intake of noninfected controls. The force-fed animals experienced a 93% mortality rate and a mean survival time of less than half that of infected animals fed ad libitum. Indeed, even animals that were starved for a short period before infection had greater survival than those fed ad libitum pre-infection (
). In a similar manner, mice infected with L. monocytogenes experienced a 100% mortality rate when gavaged with food or glucose, and the researchers determined that the culprit for the death during infection was glucose utilization (
). Conversely, in the same paper, mice infected with influenza virus survived infection when gavaged with food, whereas mice gavaged with phosphate-buffered saline did not survive, demonstrating markedly different effects of food intake for bacterial and viral infections. Even so, additional evidence demonstrates that survival responses to feed restriction vary depending on the bacterial pathogen in fruit flies (
). During this time, the immune system is responding to the injected antigen, adjuvant, or both, as demonstrated by increased cytokine and acute-phase protein concentrations (
The effect of concurrent corticosteroid induced immuno-suppression and infection with the intestinal parasite Trichostrongyulus conubriformis on food intake and utilization in both immunologically naive and competent sheep.
demonstrated immune system involvement in the depression of FI during parasitic infection with Trichostrongylus colubriformis because infected sheep decreased FI compared with animals that were both infected and immunosuppressed. This effect was only evident in young, immunologically naïve sheep—there were no effects of the parasite on FI in mature ewes that had previously established immunity (
The effect of concurrent corticosteroid induced immuno-suppression and infection with the intestinal parasite Trichostrongyulus conubriformis on food intake and utilization in both immunologically naive and competent sheep.
Reducing feed intake during an immune response is a paradoxical response, because the immune system increases its nutrient demands when activated. Immune challenges ranging from vaccination to sepsis increase the basal metabolic rate by an estimated 15 to 57%, depending on the type of insult (
). The nutrient cost of the immune response can have observable effects on nutrient partitioning. For example, beef heifers vaccinated with Mannheimia haemolytica had reduced average daily gain and feed efficiency despite no significant differences in FI over a 15-d period (
), but the reduction in average daily gain and feed efficiency suggest that the consumed energy was partitioned to the immune system rather than growth because FI was not altered. Immune challenges also alter the availability of circulating nutrients. During LPS challenges in cattle, plasma concentrations of AA decline (
Whole body protein deposition and plasma amino acid profiles in growing and/or finishing pigs fed increasing levels of sulfur amino acids with and without Escherichia coli lipopolysaccharide challenge.
Why, then, would a suppression in appetite be a common response to disease? Previous work has pointed to at least 4 plausible benefits. First, animals that are sick are more likely to have ingested pathogens recently, and hypophagia limits the oral introduction of additional pathogens (
). Second, in prey species such as cattle, there would likely be an evolutionary advantage to limiting grazing during disease, simply to avoid predation (
). However, neither of these mechanisms can explain a survival benefit to hypophagia in laboratory-housed mice as described above. A third mechanism that may be more broadly beneficial is the reduced availability of trace minerals (particularly iron) to inhibit bacterial survival due to decreased intake as well as mineral sequestration by acute-phase proteins (
) induced by hypophagia contribute to controlling systemic inflammation, providing a negative feedback on immune-initiated inflammatory signaling. These effects to reduce pathogen burden and alter immune system function may explain why hypophagia is a conserved response to disease. In the next portion of this review, we will uncover specific physiological mechanisms that occur during acute and subacute disease to induce hypophagia.
CYTOKINE REGULATION OF FEED INTAKE
Cytokines are produced by macrophages, lymphocytes, hepatocytes, neuronal cells, bone marrow stromal cells, and a vast array of cell types in the central nervous system (CNS;
) and are key signaling agents of the immune response. Numerous cytokines are produced during the acute phase response, but several cytokine families are most classically recognized as mediators of inflammation, such as tumor-necrosis factor-α, the interleukins, and interferons (
conducted an exhaustive review of various cytokines and their effects on feeding behavior; here we will focus on 2 cytokines that are thought to be most relevant to feeding behavior during disease in livestock.
Hypophagia during disease or infection is typically referred to as a hallmark “sickness behavior.” Our discussion about feeding behavior as affected by immune activity and specific cytokine effects is somewhat confounded by the other behavioral aspects of disease that directly affect food acquisition, and thus require acknowledgment. Somnolence and sleeping is a common product of immune activation (
Role of interleukin-1β and tumour necrosis factor-α in lipopolysaccharide-induced sickness behaviour: A study with interleukin-1 type I receptor-deficient mice.
notes that this overall reduction in locomotor activity is actually an altered motivational state and not a mere consequence of weakness or lack of ability. As we discuss specific actions of cytokines and hormones that are increased during an acute-phase response, some of which may have pleiotropic effects, it is important to recognize that the mechanistic effects on FI may also be confounded by other behavioral changes that the animal experiences during this altered motivational state.
Interleukin-1
Interleukin-1 (IL-1) is produced primarily by macrophages (
). Numerous studies have been conducted to analyze the effects of IL-1 administration on FI, with responses observed in multiple species. Both human and murine isoforms of IL-1 reduced FI in mice (
). However, the effects of i.m. recombinant IL-1β administration in nonlactating dairy cows were transient, with no effect detected until the second day of administration and an immediate return to normal FI posttreatment (
Consistent with a direct role in suppressing FI, IL-1 appears to peripherally affect FI in a dose-dependent manner. Subcutaneous administration of recombinant IL-1β in beef calves caused inappetence with increasing dose (
) injections of IL-1 isoforms reduced rodent food consumption in a dose-dependent manner by decreasing both meal size and duration, but not meal frequency (
). The degree of anorexia caused by disease likely depends on the magnitude of the inflammatory response.
Site-specific responses to IL-1 also provide clues into its mode of action. At least 3.3 µg/kg of BW of i.p. IL-1β were required to reduce FI in mice (
). Continuous i.v. infusions of 20 µg/kg of BW in rats decreased FI during a 4- to 6-d infusion period, which may more accurately reflect an inflammatory disease response compared with bolus injections (
). These differential responses suggest that the most potent action of IL-1 occurs in the CNS; indeed, there is evidence that IL-1 can cross the blood–brain barrier, thus highlighting a potential mechanism for direct peripheral signaling to the CNS during a disease insult (
Other more targeted studies explored the hypothalamus as a potential site of action of IL-1. Interleukin-1 has high affinity for receptors in the ventromedial hypothalamus (
evaluated whether glucose-sensing neurons purported to be responsible for changes in FI may be sensitive to IL-1β. They showed that IL-1β increases activity of the glucose-responsive neurons in the ventromedial hypothalamus that typically increase in firing rate in response to glucose. Inversely, glucose-sensitive neurons that normally decrease firing rate in response to glucose were inhibited by IL-1β in the ventromedial (
). Hypothalamic IL1B expression is correlated with blood glucose concentration and increases in fed versus fasted healthy mice; furthermore, knockout mice lacking an IL-1 receptor more quickly overcome glucose-induced hypophagia (
). These mechanisms provide a clearer picture of the intersection between metabolism and immune function through IL-1 action on the CNS.
Certain treatments can reverse the anorectic effects of IL-1. Infusion of an IL-1 receptor antagonist (IL-1ra, a naturally occurring protein that triggers a negative feedback mechanism) or an IL-1 receptor ligand binding domain attenuated the FI decrease induced by IL-1β or LPS injection (
). Furthermore, TNF-α is produced in adipose tissue, and its production increases with adipose tissue mass (Daniel et al., 2001).
The most extensive evidence for the effects of TNF-α on FI is in mice and rats, pointing to hypophagic effects similar to those of IL-1β. The most dramatic reductions in FI occur during i.c.v. infusions in rats with dose-dependent responses up to 17 µg/kg of BW eliciting a 50% reduction in FI in the short term (
showed no FI effect of 14 µg of TNF-α per kg of BW delivered i.p., which had successfully induced hypophagia via i.c.v. administration. However, when the i.p. dose was increased to ≥75 µg/kg of BW, intake declined 20 to 50% (
Tumor necrosis factor-α has also been shown to influence FI in ruminants. Subcutaneous daily injection of TNF-α at varying stages of lactation decreased FI by 15 to 30% at doses of 1.5 to 3.0 µg/kg of BW (
Daily injection of tumor necrosis factor-α increases hepatic triglycerides and alters transcript abundance of metabolic genes in lactating dairy cattle.
Continuous low-dose infusion of tumor necrosis factor-α in adipose tissue elevates adipose tissue interleukin 10 abundance and fails to alter metabolism in lactating dairy cows.
). The lack of response in the latter study may be a factor of the continuous nature of the infusion, similar to the delayed response noted during continuous i.v. infusion in mice (
). Some animals are also inherently more sensitive to the effect of inflammatory stimuli on TNF-α production. Calves that were genetically predisposed to hyperactive TNF-α production experienced greater FI reduction following LPS exposure and took longer to return to baseline FI levels (
Characterization of calves exhibiting a novel inheritable TNF-α hyperresponsiveness to endotoxin: Associations with increased pathophysiological complications.
The effects of TNF-α were further isolated by innovative studies that ameliorated the effects of the cytokine. Heat inactivation of TNF-α before administration eliminates its effects entirely in rats (
), demonstrating that the intake depression in that study was not from the i.c.v. infusion procedure alone. Furthermore, administering an antibody specific for TNF-α ameliorated the decline in FI observed in mice not receiving the antibody (
). It is noteworthy that TNF-α blockade counteracts LPS-induced hypophagia, because LPS administration is known to cause a thorough inflammatory response involving several inflammatory mediators capable of contributing to hypophagia. Furthermore, some chronic diseases produce prolonged increases in TNF-α circulation, such as cachexia or tumor growth, but administering a TNF-α receptor inhibitor restores FI (
Evidence suggests that effects of TNF-α on FI reduction may occur both centrally and peripherally. The firing rate of neurons in the ventromedial hypothalamus, a key site for the global regulation of FI (
Although most of the cytokines discussed thus far have been evaluated individually, the reality during an inflammatory response is that multiple cytokines have elevated concentrations. This prompts the question whether the effects of these cytokines may be additive or even synergistic. Due to their strong hypophagic properties individually, the most common combination for testing synergistic responses is IL-1β and TNF-α. In most studies, the combination of IL-1β and TNF-α administered i.v., i.p., or i.c.v. at rates previously shown to have an effect on FI exacerbated the degree of hypophagia compared with the individual cytokines alone (
This synergistic effect may be due in part to how these cytokines potentiate the production of other cytokines. For example, TNF-α stimulates production of IL-1 in mononuclear cells (
). Despite the very clear evidence that IL-1β reduces FI centrally and peripherally, IL-1β knockout mice and wild-type mice both had massive reductions in food intake during LPS administration (
). The anti-inflammatory agent ibuprofen did not alleviate hypophagia induced by LPS and IL-6, but it did overcome FI reduction induced by high-dose TNF-α (
), clearly demonstrating cascading effects of LPS and IL-6 to potentiate other mechanisms of FI reduction. However, the increase in IL-1ra during LPS infusion also demonstrates that inflammatory resolution mechanisms help prevent uncontrolled cytokine release (
). Across studies, when a cytokine is administered in a way that alters FI, other cytokines that are known to have a hypophagic effect are generally not measured, which makes FI responses more difficult to interpret.
OTHER FACTORS AFFECTING FEED INTAKE DURING DISEASE
Leptin
Leptin is a hormone produced by adipose tissue that acts on the hypothalamus to reduce FI (
). Leptin was discovered shortly after the peak of research evaluating cytokine effects on FI, creating a natural bridge to investigate potential synergy across these signals. Early work showed that LPS increased adipose tissue leptin mRNA (
Correlations of norepinephrine release in the paraventricular nucleus with plasma corticosterone and leptin after systemic lipopolysaccharide: Blockade by soluble IL-1 receptor.
showed that LPS did not increase plasma TNF-α or leptin in these endotoxin-insensitive mice, but that TNF-α administration did increase plasma leptin concentration in both LPS-insensitive and wild-type mice. This group went on to show that the TNF receptor is required in adipose tissue for TNF-α-stimulated leptin responses (
Although an important role of leptin is to provide negative feedback on FI, there is evidence that it may potentiate the actions of cytokines to further reduce FI during illness (Figure 1). Leptin induces expression of IL-1β in the mouse brain, including in mice lacking leptin receptors (
). Blocking the IL-1 receptor with an antagonist ameliorates leptin's hypophagic effects, and mice lacking the IL-1 receptor do not experience leptin-induced hypophagia (
Figure 1Putative mechanisms of action of IL-1β and tumor necrosis factor-α (TNF-α) on feed intake. Macrophages produce cytokines when activated, which then bind receptors on glucose-responsive neurons in the hypothalamus to trigger a reduction in feed intake. Peripheral TNF-α also induces adipose tissue leptin production, which further stimulates central production of IL-1β in a unique endocrine-immune crosstalk mechanism. Figure created using BioRender (https://biorender.com/).
). In the limited work conducted in ruminants regarding this topic, TNF-α or LPS effects on plasma leptin are mixed. Two studies reported that TNF-α or LPS failed to increase plasma leptin concentration in sheep and dairy cows (
). In contrast, others demonstrated a marginal ability for LPS challenge to increase peak leptin concentration in sheep (Daniel et al., 2001), and vaccination against respiratory pathogens increased plasma leptin in beef heifers (
Effects of intravenous lipopolysaccharide administration on feed intake, ruminal forage degradability, and liquid parameters and physiological responses in beef cattle.
Intracerebroventricular infusion of leptin elevates the secretion of luteinising hormone without affecting food intake in long-term food-restricted sheep, but increases growth hormone irrespective of bodyweight.
Central infusion of leptin into well-fed and undernourished ewe lambs: Effects on feed intake and serum concentrations of growth hormone and luteinizing hormone.
Intracerebroventricular infusion of leptin elevates the secretion of luteinising hormone without affecting food intake in long-term food-restricted sheep, but increases growth hormone irrespective of bodyweight.
Central infusion of leptin into well-fed and undernourished ewe lambs: Effects on feed intake and serum concentrations of growth hormone and luteinizing hormone.
Effect of intravenous infusion of recombinant ovine leptin on feed intake and serum concentrations of GH, LH, insulin, IGF-1, cortisol, and thyroxine in growing prepubertal ewe lambs.
In the animal sciences, acute-phase proteins (APP) have largely been investigated to understand the immunological or inflammatory status of an animal. The relationship between serum APP concentrations and FI is typically inverse during the initial immune activation (
). A few groups have evaluated statistical relationships between APP and FI. In a large-scale observational study, plasma α-1-acid glycoprotein (AGP) concentration was negatively associated with DMI in postpartum dairy cows (
). Very limited work has been conducted to elucidate whether APP possess a direct role in hypophagia, with that work focusing on AGP. α-1-Acid glycoprotein is produced primarily in the liver during an acute-phase response (
provided evidence that the mechanism of AGP-induced hypophagia was through AGP binding the hypothalamic leptin receptor and activating the intracellular JAK2-STAT3 pathway. This spurred a flurry of recent work in ruminants seeking a mechanistic link between AGP and FI. There was no evidence of hypophagia in sheep subjected to i.c.v. infusion of bovine AGP (
The acute phase protein orosomucoid 1 is upregulated in early lactation but does not trigger appetite-suppressing STAT3 signaling via the leptin receptor.
). The compelling evidence for a mechanistic effect of AGP in rodents but not in ruminants is in some ways similar to the diverging effects of TNF-α on leptin secretion in rodents and ruminants. This suggests different physiological systems that control FI during disease among species. Nevertheless, the possibility that an APP can independently affect FI opens a new realm of possibilities for understanding mechanisms of hypophagia during disease.
Gastrointestinal Motility and Gastric Emptying
Disease and inflammation have a marked effect on gastrointestinal motility and secretions, with consequences for the animal's ability to consume food. Rumination and rumen motility are necessary to reduce particle size for passage through the rumen and promote additional feed consumption. In several studies, administration of endotoxin (
Dose dependency and individual variability in selected clinical, haematological and blood biochemical responses after systemic lipopolysaccharide challenge in cattle.
, 2003) reduced gastrointestinal motility in rodents and small ruminants. In ruminants, the decrease in rumen contraction frequency and amplitude caused by LPS (
Effects of rumen-protected methionine supplementation and bacterial lipopolysaccharide infusion on nitrogen metabolism and hormonal responses of growing beef steers.
Effects of intravenous lipopolysaccharide administration on feed intake, ruminal forage degradability, and liquid parameters and physiological responses in beef cattle.
). It must be pointed out, however, that the effects of an immune response on passage rate and gastric function are confounded with reduced FI, because meals trigger increased gastrointestinal motility. Therefore, an assertion of the ability of cytokines or other immune factors to directly mediate these responses should be interpreted cautiously.
Mechanistically, the action of TNF-α to inhibit gastric motility most likely occurs in the brainstem's dorsal vagal complex (
Another factor potentially contributing to hypophagia experienced during inflammation is the reduction in blood Ca concentration. Blood ionized and total Ca concentrations decline during endotoxin challenge in dairy cows (
Dose dependency and individual variability in selected clinical, haematological and blood biochemical responses after systemic lipopolysaccharide challenge in cattle.
Effects of an oral supplement containing calcium and live yeast on post-absorptive metabolism, inflammation and production following intravenous lipopolysaccharide infusion in dairy cows.
). Calcium is required for smooth muscle contraction, and experimentally binding blood Ca to induce subclinical hypocalcemia reduces ruminal and abomasal contraction frequency, contraction amplitude (
) are not necessarily rescued when Ca is administered during an endotoxin challenge. Additionally, FI is still impaired in cows that do not fall into the subclinical hypocalcemic category during an endotoxin challenge (
Intermittent parenteral administration of endotoxin triggers metabolic and immunological alterations typically associated with displaced abomasum and retained placenta in periparturient dairy cows.
). Although hypocalcemia has very clear effects in reducing ruminal motility and FI, its effects appear to be transitory, and cytokine action (or other signals) during an inflammatory response may have a more powerful and long-lasting role in altering motility and intake.
IMPLICATIONS IN DAIRY CATTLE
Transition Dairy Cows
The transition period in dairy cattle, defined as 3 wk prepartum to 3 wk postpartum, is a challenging time during which the cow encounters a myriad of potential metabolic and infectious diseases. After parturition, there is a considerable spike in circulating positive APP (
The acute phase protein orosomucoid 1 is upregulated in early lactation but does not trigger appetite-suppressing STAT3 signaling via the leptin receptor.
Effects of prepartum 2,4-thiazolidinedione on insulin sensitivity, plasma concentrations of tumor necrosis factor-α and leptin, and adipose tissue gene expression.
). Although the degree of increase in inflammatory markers depends on quantity and types of disease insults encountered, even apparently healthy cows experience a spike in positive APP postpartum (
). The increase in inflammatory markers in apparently healthy postpartum cows may be tied to naturally occurring tissue damage during parturition, but a multitude of factors may contribute to postpartum inflammation (
). In general, 4 key conditions likely contribute to transition cow inflammation, with plausible mechanisms for each to contribute to hypophagia: (1) uterine disease, (2) mastitis, (3) gastrointestinal inflammation, and (4) lipid mobilization (
Postpartum uterine diseases, such as metritis, arise through a combination of periparturient shifts in immunity and bacterial invasion in the reproductive tract, manifesting over several weeks postpartum (
). As with metritis, prevalence of mastitis is the highest in postpartum cows compared with any other time point in the lactation curve due to a variety of factors (
). Mammary infection can create systemic inflammation evident in increases of hepatic cytokine mRNA abundance and corresponding circulating cytokines and positive APP (
). Further, postpartum dairy cows are subjected to a diet change at parturition that usually includes greater starch concentration and increased diet fermentability, which can induce subclinical gut acidosis. Ruminal acidosis damages the epithelial lining of the rumen and allows LPS to translocate into the bloodstream, creating a systemic immune response (Plaizier et al., 2009,
). In fact, a recent study in postpartum dairy cows found that highly fermentable starch sources in high starch diets increased plasma haptoglobin and TNF-α concentrations (
Diet starch concentration and starch fermentability affect markers of inflammatory response and oxidant status in dairy cows during the early postpartum period.
). There is speculation that these free fatty acids are capable of activating toll-like receptor 4 (TLR-4) on monocytes and macrophages, which then activates nuclear factor-κB and subsequent transcriptional upregulation of cytokine production (
The etiology of all 4 of these disorders in the transition dairy cow is complex and incompletely understood to date. The likelihood of cows encountering one or multiple cases of the inflammatory conditions described during the transition period is high and underscores the need for further investigation into the mechanisms for which the immune response may induce hypophagia during this time period. Many dairy cows experience a marked decline in FI during transition, with a nadir at or slightly after parturition (
) despite an increase in energy demand for milk synthesis. Maximizing peripartum FI is key to promoting a successful lactation, but cows with a greater inflammatory state may have lesser FI than their healthy peers. For example, cows with greater circulating concentrations of IL-1β during the dry period had lesser FI and plasma calcium over the transition period (
With the recognition of the increased inflammatory status in the transition dairy cow, several research groups have administered nonsteroidal anti-inflammatory drugs to cows to potentially alleviate inflammation postpartum. Nonsteroidal anti-inflammatory drugs given to postpartum cows fail to alter (
), which is a surprising response considering the protection from hypophagia in late-lactation cows challenged with mastitis and treated with anti-inflammatory agents (
The effects of experimentally induced Escherichia coli mastitis and flunixin meglumine administration on activity measures, feed intake, and milk parameters.
Proteomic analysis reveals greater abundance of complement and inflammatory proteins in subcutaneous adipose tissue from postpartum cows treated with sodium salicylate.
), demonstrating that inflammation in the transition cow is complex.
Milk-Fed Calves
Milk-fed dairy calves experience a high incidence of gastrointestinal and respiratory disease. Milk consumption is generally not decreased by disease when calves are on a lower plane of nutrition versus a higher plane of nutrition (
; Figure 2) because the nutrient requirements of the calf are generally not met at lower feeding rates. Perhaps one of the simplest ways to determine alterations in feeding behavior in milk-fed calves is through the data obtained with automatic calf feeders, which are generally programmed to provide a relatively high plane of nutrition. Calves experiencing at least one form of disease have fewer unrewarded visits to the calf feeder, decreased intake, and decreased feeding rate (
). However, reducing inflammation through administration of meloxicam at the onset of diarrhea resulted in calves that were 2.6 times more likely to consume their full milk allocation for the 2 wk after diagnosis and treatment (
Figure 2Mean (±SE) daily milk intake of calves on automatic feeders fed a high (n = 28/group) or low (n = 21/group) plane of nutrition. Ill calves were diagnosed on d 0 with respiratory or gastrointestinal issues and are compared with a healthy control of similar age and BW. Differences between sick and healthy calves within each milk allowance: *P < 0.05, +P < 0.10. Figure reproduced from
Unfortunately, few calf studies report inflammatory biomarker concentrations, making it difficult to assess mechanistic causes of alterations in feed-seeking behaviors.
reported no evidence of differences in haptoglobin concentration between diarrheic and healthy calves. In another study in which milk intake was reduced by vaccination, there were inconclusive changes in TNFA mRNA expression in whole blood (
Mastitis is one of the costliest diseases in the dairy industry. Although individual FI is rarely observed in commercial dairy herds that employ group feeding systems, controlled research clearly demonstrates that mastitis can negatively affect FI. Most mastitis studies that reported FI observed a decrease (
), but again it remains unclear whether early stages of mastitis are the primary cause of hypophagia, or if it is secondary to the previously reduced nutrient intake. Unfortunately, data on systemic hypophagic cytokines during mastitis are incredibly limited. Circulating TNF-α concentration has been shown to be stable (
The effects of experimentally induced Escherichia coli mastitis and flunixin meglumine administration on activity measures, feed intake, and milk parameters.
), and inflammatory mediators warrant further investigation as drivers of FI reduction during mastitis.
Vaccination
Vaccination protocols are important for maintaining a healthy dairy herd; however, vaccinations may cause transient reductions in FI resulting from the immune response to the antigen, adjuvant, or both. There are few data sets monitoring FI after vaccination and a lack of quantification of cytokine production over the same period. Several studies highlight a numeric, transient drop in FI in adult dairy cows after vaccination (
Effects of a core antigen vaccine against gram-negative bacteria on physiologic and yield parameters of dairy cows during late lactation and the dry period.
). Vaccination of beef feedlot steers reduced FI in most instances, but it is generally difficult to detect differences in FI over the period of weeks that data were collected (
). Another team vaccinated heifers on the day of arrival or 14 d after arrival, noting a reduction in FI only on d 14, despite increased vaginal temperature at both time points (
Case study: Effects of timing of a modified-live respiratory viral vaccination on performance, feed intake, antibody titer response, and febrile response of beef heifers.
). The lack of evidence of differences in FI on d 0 may have been due to mixing of social groups at the initiation of the trial, but also because heifers were introduced to a new feed monitoring system that may have initially limited their intake. This further illustrates the fact that it is difficult to observe FI reductions if animals' nutritional requirements are not met at baseline. Finally, vaccination in milk-fed calves can reduce milk consumption (
From a management standpoint, recognizing when herd vaccinations will occur may help target adjustments in ration formulation and quantity of feed delivered to maximize efficiency. Another important consideration may be to design dietary formulations for livestock during vaccination to account for reduction in FI and the increase in energy required by the immune response, which may help to ameliorate temporary losses in production efficiency that occur in vaccinated livestock. To date, we are unaware of any data that evaluate such concepts.
Predicting, Detecting, and Responding to Feed Intake Reductions
Attempts have been made to model infection-induced hypophagia.
highlighted the variable characteristics of infection-induced hypophagia, including (1) the lag time after infection, (2) rate of relative FI reduction, (3) magnitude of reduction, (4) duration of the reduction, and (5) rate of relative FI recovery. Models to predict FI during parasitic infection have been created, but in vivo studies are generally lacking to support the model (
) and likely foreshadow the difficulty of developing similar models in transition dairy cows due to the complexity and multiplicity of insults that may occur.
attempted to predict transition dairy cows at risk for low DMI using AGP as a plasma biomarker. Although AGP was negatively associated with DMI postpartum, the prognostic ability of AGP to predict low DMI was marginal.
Perhaps a more relevant approach is to monitor FI to implement intervention strategies for impending disease insults, considering that perturbations in FI can be detected before visual disease diagnosis (
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