key: cord-0076914-2m4ie82s
authors: Niu, Xueting; Ding, Yuexia; Chen, Shengwei; Gooneratne, Ravi; Ju, Xianghong
title: Effect of Immune Stress on Growth Performance and Immune Functions of Livestock: Mechanisms and Prevention
date: 2022-04-02
journal: Animals (Basel)
DOI: 10.3390/ani12070909
sha: 70f39a5c68bb13d6456f07d3a3635bfdb894c81f
doc_id: 76914
cord_uid: 2m4ie82s

SIMPLE SUMMARY: Immune stress is an important stressor in domestic animals that leads to decreased feed intake, slow growth, and reduced disease resistance of pigs and poultry. Especially in high-density animal feeding conditions, the risk factor of immune stress is extremely high, as they are easily harmed by pathogens, and frequent vaccinations are required to enhance the immunity function of the animals. This review mainly describes the causes, mechanisms of immune stress and its prevention and treatment measures. This provides a theoretical basis for further research and development of safe and efficient prevention and control measures for immune stress in animals. ABSTRACT: Immune stress markedly affects the immune function and growth performance of livestock, including poultry, resulting in financial loss to farmers. It can lead to decreased feed intake, reduced growth, and intestinal disorders. Studies have shown that pathogen-induced immune stress is mostly related to TLR4-related inflammatory signal pathway activation, excessive inflammatory cytokine release, oxidative stress, hormonal disorders, cell apoptosis, and intestinal microbial disorders. This paper reviews the occurrence of immune stress in livestock, its impact on immune function and growth performance, and strategies for immune stress prevention.

Stress refers to a series of nonspecific responses when the body is stimulated by external and internal abnormal stimuli [1] . In animal husbandry, common stresses include housing density, weaning, immunization, capture, transportation, and exposure to ammonia, temperature, humidity, noise, and high doses of pathogens [2] . Different stresses cause specific biological changes and endanger the animal's health. Immune stress (IS) is also called immune stimulation. Specifically, in immunology, it refers stimulation of the body by an antigen eliciting an immune response. In a narrow sense, it refers to the systemic nonspecific adaptive immune response following inoculation with an antigen. In a broad sense, it refers to the frequent infection of various pathogenic microorganisms in the body under poor sanitary conditions, resulting in continuous activation of the immune system by invading pathogenic microorganisms and eliciting a nonspecific adaptive response [3] .

In recent years, due to the large-scale and high-density farming environment and livestock genetic improvement, animals are vulnerable to a range of pathogens. Therefore, animals require to be vaccinated more frequently. Immunization can protect livestock from pathogens, but it can also stimulate immunity as a special stress factor, which can lead to a series of adverse phenomena such as fever, depression, anorexia, intestinal There are abundant glucocorticoid receptors in the hippocampus which can inhibit the stress response of the HPA axis when bound to glucocorticoid [31] [32] [33] . In contrast, COR can suppress the immune system by targeting genes related to cytokines, chemokines, inflammatory proteins and their receptors, and also affect cell adhesion. At the transcriptional level, COR binds to its receptors, inhibits the transcriptional activity of AP-1 and NF-κB, thereby inhibiting the expression of various cytokines [34] . It can also directly act on immune cells such as macrophages, mast cells, and basophils, thereby inhibiting their immune function, inducing apoptosis of B and T lymphocytes and dendritic cells, inhibiting their proliferation, differentiation, and migration, reducing humoral and cellular immune function, and causing immunosuppression [35, 36] . The mechanism of IS effects on the neuro-endocrine-immune system is shown in Figure 1 . 

The effect of IS on animal immune function is bidirectional. It may enhance or suppress immune function, which depends largely on stress intensity and duration of stress [37] . It is generally believed that short-term (acute) stress can enhance the immune function of livestock, while long-term, low-intensity (chronic) stress can cause immunosuppression [37, 38] .

IS significantly increases the plasma concentrations of COR, PEG2, IL-6, TNF-α, and IL-1β [39] . IS induced by LPS increases IL-1, IL-2, IL-6, immunoglobulin G (IgG), and immunoglobulin A (IgA) levels in broiler serum [40] . LPS-induced IS can strongly inhibit C4BPA (a cycle inhibitor of the classical and MBL pathways of the complement system activation pathways) in peripheral blood mononuclear cells (PBMC) in pigs, thereby enhancing the activation of the complement system [41] . Chickens vaccinated with Eimeria tenella express high IgG and sIgA levels [42] . LPS and human serum albumin (HuSA) used to construct a broiler IS model found that IS significantly increases total immunoglobulin, immunoglobulin M (IgM), IgA, and IgG levels in the serum, indicating that IS enhances the broiler humoral immune response [43] . Similarly, IS significantly increases serum IgA levels in Linwu ducks [44] , the spleen and thymus index of broilers [45] , while LPS-induced IS increases the ratio of CD4 + /CD8 + in duck spleen and thymus [46] . IS can increase the concentration of IL-1β, PGE2, and COR in piglet plasma and promote the proliferation of peripheral blood lymphocytes, an indication of enhanced cellular immune function in piglets [47] [48] [49] , similarly to another study which also showed proliferation of lymphocytes and increased ratio of CD4 + /CD8 + in peripheral blood lymphocytes of chickens, and a significant increase in serum TNF-a, IL-6, IL-1, and IgG levels [50, 51] . Thus, all of the above studies confirm that IS can enhance the immune function of livestock fairly quickly so that the body can better resist a pathogen invasion.

In contrast to acute IS, chronic IS causes suppression of cellular immunity in livestock. Chronic IS increases serum ATCH, COR, and expression of Caspase-3 and Caspase-9 in immune cells, decreases the ratio of Bcl-2 to Bax, decreases the index of immune organs (bursa, thymus, and spleen) and the number of neutrophils, CD4 + cells, and CD8 + cells, and induces apoptosis of immune cells [52] [53] [54] . Chronic IS also affects humoral immunity, a decrease in serum IgG levels and lysozyme activity in livestock [55, 56] . Chronic IS also affects intestinal immunity. Chronic IS markedly damages the intestinal structure of livestock, enhances lymphocyte apoptosis in intestinal Peyer's nodules, reduces intestinal IgA-secreting cells (ASC) and secretory immunoglobulin A (sIgA), causing destruction of the intestinal immune barrier [54] and also the intestinal mechanical barrier by downregulating tight junction proteins and inducing intestinal epithelial cell apoptosis, and the intestinal microbial barrier by interfering with the composition of intestinal microorganisms, with all these effects culminating in serious damage to intestinal immune function [57] [58] [59] . Thus, chronic IS inhibits the body's intestinal, cellular, and humoral immunities.

Although the impact of acute and chronic IS based on the intensity and duration of stress is different, the effects on the livestock growth performance such as the decrease in average daily feed intake (ADFI) and average daily gain (ADG) and increased feed meat ratio (FCR) are somewhat similar.

IS significantly decreases the ADFI of livestock [45, 47, 53, 60] . It is believed that this could be due to a reduced feed intake caused by secretion of specific hormones and inflammatory factors. The brain-gut axis plays a vital role in the loss of appetite caused by IS. The hypothalamus, especially its arcuate nucleus (ARC) that is involved in energy perception and integration. In ARC, neuropeptide Y (NPY) and, agouti-related peptide (AgRP), a neuropeptide produced by the AgRP/NPY neuron, and also gamma-aminobutyric acid (GABA) can increase food intake, while POMC, cocaine-and amphetamine-regulated transcripts (CART) reduce food intake [61] . While intestinal hormones (leptin, cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), resistin, and growth hormone-releasing peptide) can initiate most of the signal transduction and communication in the gut-brain axis, they can also regulate appetite by activating or inhibiting hypothalamic neurons [62] .

In IS, a large number of inflammatory factors released by the peripheral immune system enter the circulation. These can induce adipocytes to synthesize and secrete leptin [63, 64] and transport it to the brain. With assistance from IL-1β, leptin binds to the leptin receptor in hypothalamic neurons [65] , stimulates POMC neurons in ARC neurons to produce anorexic peptide POMC, and inhibits AgRP/NPY neurons from producing appetite peptides NPY and AgRP [20, 66, 67] . LPS-induced IS can significantly increase resistin and GLP-1 and decrease ghrelin in animals [68] [69] [70] . Excess GLP-1 can overactivate GLP-1 receptors in the CNS, gastrointestinal tract (GIT), and pancreas, activate GLP-1 receptors in the CNS, all of which can lead to a fullness feeling in the animal. GLP1 can also reduce the speed of gastric emptying and hinder gastric acid secretion, thereby increasing gastric dilatation, limiting excessive food consumption, and enhancing satiety [68] .

Ghrelin, the only known peripherally derived appetite hormone, activates the hypothalamic growth hormone secretagogue receptor (GHSR-1a) [61] , mediates the activation of AgRP/NPY neurons in ARC [71] , and inhibits the satiety POMC neurons [72] , promoting appetite. Therefore, a decline in the level of ghrelin leads to a decrease in appetite. The mechanism of appetite suppression by IS is shown in Figure 2 . 

Mucosal integrity, digestive enzymes, transport proteins, and microbes of the intestines play a major role in the digestion and absorption of nutrients. Nutrient absorption mostly occurs in the small intestine (SI). Iintestinal villi height (VH) growth will increase the contact area between the nutrients and SI, resulting in improved absorption rate of nutrients. This is supported by shallower crypt depth (CD) which facilitates the proliferation of intestinal epithelial cells to further improve absorption from the SI. Thus, both VH and CD, and the ratio of VH/CD (known as V/C) are often used to evaluate intestinal absorptive capacity [73] . Furthermore, intestinal microbes can ferment indigestible substrates such as dietary fiber and endogenous intestinal mucus to produce short-chain fatty acids (SCFA) which are easily absorbed [74] . Thus, intestinal microbial composition is important for optimal intestinal function. IS can seriously affect intestinal health. LPS-induced IS can reduce VH and enhance CD and reduce alkaline phosphatase (AKP) activity in the duodenum and jejunum, and also decrease the number of duodenal sodium-dependent glucose cotransporter 1 (SGLT1) and the plasma D-xylose level [75] . IS decreases the level of lactase, maltase, and sucrase markedly in the jejunum and ileum of piglets [76, 77] . Furthermore, IS increases SI interleukin-8 (IL-8) secretion, ROS production, and TNF-α mRNA abundance, but decreases the level of SGLT1, excitatory amino acid transporter 1 (EAAC1), H + /peptide cotransport 1 (PEPT-1), and intestinal fatty acid binding protein 2 (I-FABP2) in the intestine of weaned piglets [78] . It was also found that the abundance and distribution of tight junction proteins (zonula occluden-1 (ZO-1), Occludin, and claudin-1) mRNA in the SI declines when exposed to IS [79] . IS makes duck SI walls thinner, lowers the V/C value, reduces the expression of tight junction proteins (ZO-1, Occludin, and Claudin-1), and enhances intestinal permeability [44] . IS not only downregulates the expression of digestive enzymes (maltase, AKP, and Na-K-ATPase) and tight junction proteins (CLDN-1, OCLD, ZO-1, ZO-3, EpCAM, and JAM2), but also reduces the phosphorylation of mTOR protein in the jejunum and inhibits the proliferation of jejunum cells [80] . IS causes rumen and intestinal flora disorders in livestock, resulting in SI damage, reduced intestinal flora diversity, and an increased harmful-to-beneficial bacteria ratio [56, [81] [82] [83] [84] [85] [86] .

Intestinal injury cause inflammation, oxidation, apoptosis, and autophagy. IS induces the expression of key genes related to TLR4 and the nucleotide-binding oligodomain proteins (NODs) signaling pathway and increases the expression of inflammatory factors (IL-1β, IL-2, IL-6, IL-8, INF-γ, and TNF-α), iNOS, and COX-2 in the SI [44, [76] [77] [78] 87] . IS also reduces SI superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and increases malondialdehyde (MDA) and reactive oxygen species' (ROS) levels [44, 86] . In addition, IS induces the expression of apoptosis-related genes (Caspase-3, Caspase-8, Bax, A20, and MT) and autophagy-related pathway key proteins (PTEN-induced putative kinase 1 and parkin), increases the ratio of light chain 3-II (LC3-II) to LC3-I in the intestine, all of which leads to apoptosis and autophagy in the SI [44, 80] .

As mentioned above, IS can lead to a release of a large number of inflammatory cytokines and chemokines by peripheral immune cells. Inflammatory cytokines in the SI and over-recruited immune cells mediate SI damage and decrease ADFI, mediating the destruction of SI integrity and apoptosis of epithelial cells [88] . However, there is little research on the mechanism of the changes of intestinal digestive enzymes and related transporters caused by IS. Some believe that the changes of digestive enzymes and transporters are closely related to the release of glucocorticoids [89] . Thus, in general, IS causes microbial flora disorders, reduces intestinal digestive enzymes and transporters, and damages SI structural integrity, culminating in digestive and absorption disorders.

Although the reduction of feed intake, digestion, and absorption are the most important factors in IS-induced growth suppression of livestock, the redistribution of nutrients also plays a role [90] . After the regulation of multiple hormones (growth hormone (GH), thyroid hormone, IGF-1, and GC) and cytokines, the body will redirect nutrients originally used for muscle synthesis and growth to the immune system to maintain a highly activated immune system to prevent diseases, resulting in an increase in FCR [90] [91] [92] [93] [94] [95] .

The activation of the HPA axis caused by IS leads to an increase in the secretion of catabolic hormones such as ACTH and CORT and a decrease in the secretion of anabolic hormones such as GH and IGF-1. In addition, a large number of inflammatory cytokines are secreted, which inhibits the synthesis of energy and promotes the decomposition of energy [96] . Mechanistically, the proinflammatory cytokines released by the body during IS directly act on the thermoregulatory center via the blood-brain barrier, resulting in an increase in body heat production and a reduction in body heat dissipation, which results in an increase in body temperature [7, 97] . IS increases energy consumption because in thermostatic animals, the metabolic rate needs to be raised by 10-12.5% to increase the body temperature by 1 • C [98] .

In carbohydrate metabolism, IS promotes gluconeogenesis and glycogen hydrolysis in the liver, resulting in an increase in glucose production, a reduction in the uptake of glucose in peripheral tissues such as skeletal muscle and myocardium, resulting in an increase in blood glucose concentration. Because a lot of aerobic energy and hence oxygen is required for the immune response, an anaerobic situation is created that results in the conversion of glucose into lactic acid [3, 52] .

In protein metabolism, IS increases skeletal muscle protein degradation rate, reduces skeletal muscle protein deposition, speeds up peripheral protein decomposition, enhances liver degradation of valine, leucine and isoleucine, and produces a large amount of liver acute phase protein (APP). In addition, the induction of inflammatory cytokines upregulates the expression of liver proteins involved in immune defense function, amino acid catabolism, ion transport, wound healing, and hormone secretion [92, 99] .

In lipid metabolism, IS induces the degradation of a large number of lipoproteins in the body and produces a series of inflammatory factors such as TNF-α, which can inhibit the synthesis of fatty acids (FA) in adipose tissue and promote fat degradation [100] . TNF-α also stimulates the liver to synthesize FA de novo and lipolysis in adipose tissue. In addition, the AMP-dependent protein kinase (AMPK) lipid metabolism pathway is activated, inhibiting the activity of acetyl-CoA carboxylase (ACC), thereby reducing the conversion of malonate-CoA. This activates carnitine palmitoyltransferase-1 (CPT-1), which in turn enhances the activity of CPT-1 and the expression of peroxisome proliferator-activated receptor-α (PPARα) mRNA, thereby stimulating liver lipid metabolism, accelerating FA oxidation and reducing fat deposition [101] .

Thus, IS reduces the appetite of livestock, redistributing nutrients in the body to the immune system, resulting in a decline of ADFI, enhancing catabolism, reducing intestinal digestion and absorption function, all of which finally leads to a decline in growth performance of livestock and poultry, resulting in economic loss to the livestock industry.

IS can cause the activation of the OPG/RANKL pathway in tibia and increase the expression of inflammatory cytokines. Furthermore, IS can enhance the generation of osteoclasts, leading to impairment of bone development [102] . IS can reduce chicken muscle pH, which can result in pale muscle [95] . Mechanistically, IS can lead to accumulation of lactic acid in muscle, resulting in a lowering of muscle pH, which can lead to an increase in protein denaturation and muscle fiber damage, damaging the hydration and texture of meat [103] . In addition, protein denaturation may lead to a decrease in light transmittance to the meat's surface, resulting in pallor meat [104] . IS can also lead to a sharp decline in lactation of cows [105] due to inhibition of the release of prolactin, GH, and IGF-I, resulting in reduced milk quality and yield [106] . LPS-induced IS decreases the feed intake and egg laying rate in hens, leading to a significant increase in eggshell thickness, strength, and a reduction in albumin quality and content [107] .

Because of intensive farming, the frequency of IS has increased, resulting in a negative impact on the animal industry. It is particularly important to develop safe and effective techniques to prevent and alleviate the effects of IS. Controlling stress, improving management, and resisting the stress response by nutritional intervention are the most popular methods used currently.

In order to determine which kind of vaccines are necessary for an individual farm, it is important evaluate the endemic infectious agents in the region, the age of the animal, genetic and health status of the breeding animals, the distance to other farms, and the level of biosecurity to be implemented in the farm [108] . In poultry production, vaccines for Newcastle disease (ND), infectious bronchitis, and infectious bursal disease are used in most countries [109] . Furthermore, vaccine programs should be designed based on other impact factors such as interaction between different vaccines, interference with maternal antibodies, vaccine type, vaccination method, and vaccination frequency. Unnecessary vaccination should be avoided to prevent excessive stimulation of the animal immune system [109, 110] .

Combined immunization is a scheme worthy of consideration. Combined immunization refers to simultaneous injection with two or more antigens in combination to reduce animal stress [111] . Some have used an inactivated vaccine against serotype 4 and 8 bluetongue disease to immunize sheep and found that simultaneous double-injected booster vaccination yields the highest median serotype-specific neutralization antibody 26 weeks after the first vaccination and a positive serum antibody level at a maximum even after one year [112] . Trivalent vaccine (Mycoplasma hyopneumoniae, porcine circovirus type 2 (PCV2) and porcine reproductive and respiratory syndrome virus (PRRSV)) used in pigs has a protective effect on the infection of three pathogens, and the effect is similar to that of a monovalent vaccine, and their growth performance is superior to the uninfected pigs [113] . Similarly, a combined vaccine (Mycoplasma hyopneumoniae and PRRSV) is effective in pigs [114] . A recombinant herpesvirus of turkey laryngotracheitis vaccine (rHVT) combined with chicken embryo origin laryngotracheitis vaccine (CEO) provides stronger protection than rHVT alone does. rHVT can reduce the virulence return and replication of CEO, which is safer than CEO alone. rHVT-CEO vaccination strategy is another way to achieve better disease control [115] .

In general, combined immunization can exert a positive effect without interfering with the effects of each vaccine and reduce the number of immunizations, reducing crossinfection, stress, and improving health and production efficiency.

Improving the hygiene of the feeding environment and strengthening farm management can minimize the occurrence of IS. Good hygiene conditions can reduce the contact chance between the animal and pathogenic microorganisms in the environment, thereby reducing the excessive stimulation of the host immune system [116] . A decrease in feeding density has also been used to prevent IS. High-density feeding has been shown to increase IS and thereby affect the growth performance of geese. A reasonable stocking density is not only good for animal welfare but also for better animal growth [117] . Currently, other measures such as "all-in, all-out", group feeding, and improvement in uniformity of animals are widely implemented in poultry farms, which have reduced the chance of poultry contact with bacteria and viruses and thereby reduced the occurrence of IS.

Alleviating animal IS through nutritional regulation has been highlighted in recent years because animals consume more when under IS. This is because of the amount of nutrients required to synthesize immune effector molecules [118] . The addition of amino acids, fats, vitamins, and plant extracts in feed have been shown to alleviate IS and enhance host resistance to IS.

IS not only increases amino acid requirements of the host but also affects amino acid balance. Adding L-arginine to the diet can effectively alleviate the damage to the intestinal mucosal barrier caused by IS in order to maintain intestinal integrity [54, 119] . Mechanistically, L-arginine inhibits the TLR4 signaling pathway, decreases the percentage of CD14 + cells with resultant overexpression of proinflammatory factors in animals in IS [9] . In addition, other amino acids and their derivatives, such as glutamic acid [76] , glutamate precursor α-ketoglutarate [120, 121] , L-theanine [122] , cysteine [123] , N-acetylcysteine [77, 124, 125] , glycine [126] , glycyl-glutamine [88] , glutamine [127] , and asparagine [128, 129] have been used as anti-IS additives in feed.

Polyunsaturated FA can relieve IS by reducing the release of inflammatory factors. Adding conjugated oleic acid to the diet can inhibit the production of IL-1β, enhance proliferation of lymphocytes by inhibiting the expression of PGE2, and thereby improve the growth performance of pigs [130] . n3 FA can also reduce the expression of PGE2 and the level of inflammatory cytokines in the serum induced by LPS [131] . Fish oil can reduce the release of inflammatory cytokines and improve the growth performance in IS pigs [47, 132] . While adding fish oil to the diet can increase cellular immunity and reduce the inflammation index in animals exposed to IS [133] , increasing the ratio of n3 to n6 fatty acids in the diet can inhibit the inflammatory response, thereby improving the animals' performance [134] .

Vitamins are necessary for animal metabolism and growth, acting in a variety of ways. Vitamins act to minimize stress, inflammation, and, in general, immune function regulation. Vitamin C can regulate the inflammatory response and oxidative stress caused by LPS and reduce hippocampal cell apoptosis [135] . Vitamin C can also alleviate the damage caused by IS in piglets [136] . Under stress conditions, the requirements for vitamin C are increased, and therefore it is widely used in animal feed to alleviate the health impacts of IS. Adding high doses of vitamin E can increase the feed intake of laying hens during IS and also increase the level of antibodies after vaccination for NDV and avian influenza virus [137] . Vitamin E can inhibit the increase in proinflammatory cytokines, PGE2, and cortisol caused by IS [131, 138] . In vitro studies have shown that vitamin A can improve intestinal barrier integrity and reverse LPS-induced intestinal barrier damage by enhancing the expression of tight junction proteins [139] .

Trace elements affect immune regulation and can function to reduce stress. For example, MgSO 4 significantly attenuates LPS-induced acute lung injury, apoptosis, oxidative stress (reducing MDA levels), and lung inflammation [140] and inhibits the NF-κB signaling pathway in mice [141] . Chromium yeast can effectively reduce IL-1β, TNF-α, and COR in piglet serum, thereby alleviating IS [142] . Clinoptilolite (aluminosilicate containing sodium, potassium, and calcium) can inhibit the infiltration and hyperactivation of neutrophils in broilers and reduce plasma and SI mucosal inflammatory cytokines, thereby reducing the inflammatory response caused by LPS [10] . Copper also has an anti-IS additive effect [143, 144] .

Probiotics, also known as microecological preparations, are a group of active microorganisms or metabolites that benefit the host. The role of probiotics is to improve intestinal health and immune function by regulating the colonization and composition of the intestinal flora, intestinal pH, and also improving communication through the intestinal-brain axis pathway [145] . Feeding some probiotics (Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium thermophilum, and Enterococcus faecium) in the diet can alleviate intestinal inflammation, oxidative stress, and morphological damage caused by enterotoxigenic E. coli and enhance the growth performance of piglets [146] . Adding Bacillus subtilis to broiler diets can normalize the expression of gut barrier-related genes (JAM2, occludin, ZO1, and MUC2) under IS [147] . Fermentation products of Bacillus subtilis not only reduce the expression of LPS-induced SI inflammation genes but also enhance the expression of intestinal barrier genes, thereby improving the growth performance of broilers under IS [58] . In addition, probiotics such as Bacillus amyloliquefaciens [55] , Lactobacillus casei [148] , Lactobacillus acidophilus [149] , Lactobacillus delbrueckii [150] , Enterococcus faecalis [151] , Clostridium butyricum [151] , and also their fermentation products, can alleviate IS.

Several low-molecular-weight secondary metabolites of plants can also play a role in modulating immune stress along with their antibacterial, antiviral, anti-inflammatory, and anti-tumor functions. Since many plant extracts exhibit low toxicity, high safety, and health improvement functions, it has become a research hotspot in the field of feed additives. Table 1 shows the more important IS resistance plant extracts reported in recent years. These plant extracts include esters, phenols, polysaccharides, glycosides, flavonoids, alkaloids, and crude plant extracts [16, 40, [152] [153] [154] [155] [156] [157] [158] . Anti-IS mechanisms of plant extract can be categorized into three types, namely (1) relieving inflammation and oxidative stress by inhibiting inflammatory response and oxidative pathways, (2) maintaining intestinal balance by regulating intestinal barrier-related proteins and promoting intestinal cell proliferation, and (3) maintaining hormone balance by regulating the endocrine system. Inhibits the activities of inflammatory factors (IFN-γ, IL-1β, IL-2, IL-4, IL-6, and IL-10) and nitrogen oxides (NOx).

[164]

Thymol Enhances the barrier function of epithelial cells, reduces the production of ROS and expression of proinflammatory cytokine genes.

[78]

Sesamol Reduces MCP-1, inhibits NF-κB and inflammatory cytokines TNF-α and IL-1β, prevents lipid peroxidation in serum and liver, increases catalase and glutathione reductase activities. [165, 166] Curcumin Regulates the JNK/NF-κ B/Akt signaling pathway, plays an anti-inflammatory and antioxidant effect, may alleviate liver damage and liver lipid metabolism disorders by increasing m 6 A RNA methylation. [155, 156] Green tea polyphenols mixture Inhibits NF-κB signaling and inhibit NLRP3 inflammasome activation. [167] Carvacrol Downregulates the expression of inflammatory cytokines by inhibiting the TLRs/NF-κB pathway.

[168]

Flavonoids Artemisia argyi flavonoids mixture Decreases the expression of NF-κB, IL-1β, and IL-6. [45] Quercetin Inhibits the activity of IκBα and NF-κB into the nucleus, reduces the expression of TNF-α and IL-1β.

[157]

Genistein Enhances the activity of monocytes and macrophages, increases the ratio of intestinal V/C. [154] Esters Ellagic Acid Antioxidant activity, inhibits AChE activity. [27] Sesame lignans

Reduces MCP-1, inflammatory cytokines TNF-α and IL-1β, prevents lipid peroxidation.

[165]

Alkaloids Berberine

Inhibits NF-κB signal transduction and the expression of inflammatory mediators, enhances the activity of antioxidant enzymes.

[158]

Crude extract Artemisia argyi aqueous extract mixture Inhibits the release of CORT and IL-2.

[40]

Overall, IS significantly impacts the host neuro-endocrine-immune axis and the braingut axis, which can result in hormone secretion disorders, cell apoptosis, intestinal flora disorders, intestinal barrier destruction, oxidative stress, and metabolic disorders, all of which can compromise the immune function and growth performance of livestock. Therefore, efficient and feasible control measures, such as providing good quality nutritious feed, reducing excessive stimulation of the immune system by organizing vaccine procedures at the appropriate time, and using selected plant extracts and potential new drugs for control, are required, as we are experiencing an upsurge of new infectious diseases in livestock.

Author Contributions: Conceptualization and writing, X.N.; writing-review and editing revision, Y.D.; investigation, conceptualization, writing-review and editing, S.C., visualization- Figures 1 and 2 , writing-review and editing, R.G.; writing-review and editing, supervision and project administration, X.J. All authors have read and agreed to the published version of the manuscript. 

The authors declare no conflict of interests.

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Betaine attenuates LPS-induced downregulation of Occludin and Claudin-1 and restores intestinal barrier function

Bacillus subtilis-fermented products ameliorate the growth performance and alter cecal microbiota community in broilers under lipopolysaccharide challenge

Porcine Milk Exosome MiRNAs Attenuate LPS-Induced Apoptosis through Inhibiting TLR4/NF-κB and p53 Pathways in Intestinal Epithelial Cells

Effects of rumen-protected Capsicum oleoresin on immune responses in dairy cows intravenously challenged with lipopolysaccharide

Network of hypothalamic neurons that control appetite

The Gut-Brain Axis, the Human Gut Microbiota and Their Integration in the Development of Obesity

Circulating leptin mediates lipopolysaccharide-induced anorexia and fever in rats

In vivo and in vitro evidence for the involvement of tumor necrosis factor-alpha in the induction of leptin by lipopolysaccharide

Leptin actions on food intake and body temperature are mediated by IL-1

Influence of peripheral lipopolysaccharide (LPS) on feed intake, body temperature and hypothalamic expression of neuropeptides involved in appetite regulation in broilers and layer chicks

A leptin-BDNF pathway regulating sympathetic innervation of adipose tissue

Glucagon-like peptide 1 receptor induced suppression of food intake, and body weight is mediated by central IL-1 and IL-6

Lipopolysaccharide increases resistin gene expression in vivo and in vitro

Bacterial lipopolysaccharide shifts fasted plasma ghrelin to postprandial levels in rats

From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation

The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis

Dietary high protein-induced diarrhea and intestinal inflammation by activation of NF-κB signaling in piglets

Contributions of microbes in vertebrate gastrointestinal tract to production and conservation of nutrients

Effects of feeding fermented Ginkgo biloba leaves on small intestinal morphology, absorption, and immunomodulation of early lipopolysaccharide-challenged chicks

Glutamate alleviates intestinal injury, maintains mTOR and suppresses TLR4 and NOD signaling pathways in weanling pigs challenged with lipopolysaccharide

N-Acetylcysteine improves intestinal function in lipopolysaccharides-challenged piglets through multiple signaling pathways

Thymol Improves Barrier Function and Attenuates Inflammatory Responses in Porcine Intestinal Epithelial Cells during Lipopolysaccharide (LPS)-Induced Inflammation

Chronic social stress in pigs impairs intestinal barrier and nutrient transporter function, and alters neuro-immune mediator and receptor expression

Effect of zinc supplementation on growth performance, intestinal development, and intestinal barrier function in Pekin ducks with lipopolysaccharide challenge

Dietary protocatechuic acid ameliorates inflammation and up-regulates intestinal tight junction proteins by modulating gut microbiota in LPS-challenged piglets

Holly polyphenols alleviate intestinal inflammation and alter microbiota composition in lipopolysaccharide-challenged pigs

Lentinan modulates intestinal microbiota and enhances barrier integrity in a piglet model challenged with lipopolysaccharide

Gut Immunity and Microbiota Dysbiosis Are Associated with Altered Bile Acid Metabolism in LPS-Challenged Piglets

Maternal stevioside supplementation ameliorates intestinal mucosal damage and modulates gut microbiota in chicken offspring challenged with lipopolysaccharide

Intravenous lipopolysaccharide challenge alters ruminal bacterial microbiota and disrupts ruminal metabolism in dairy cattle

LPS challenge increased intestinal permeability, disrupted mitochondrial function and triggered mitophagy of piglets

Effects of dietary glycyl-glutamine on growth performance, small intestinal integrity, and immune responses of weaning piglets challenged with lipopolysaccharide

Effects of glucocorticoids on the gene expression of nutrient transporters in different rabbit intestinal segments

Regulation of metabolism and growth during immune challenge: An overview of cytokine function

Growth and Development Symposium: Endotoxin, inflammation, and intestinal function in livestock

Inhibition of growth by pro-inflammatory cytokines: An integrated view

High dietary energy content increases inflammatory markers after lipopolysaccharide challenge in meat ducks

Dietary soy isoflavone attenuated growth performance and intestinal barrier functions in weaned piglets challenged with lipopolysaccharide

Do different vaccination regimes affect the growth performance, immune status, carcase characteristics and meat quality of broilers?

Nutritional aspects of leukocytic cytokines

The influence of age and repeated lipopolysaccharide administration on body temperature and the concentration of interleukin-6 and IgM antibodies against lipopolysaccharide in broiler chickens

Fever and the thermal regulation of immunity: The immune system feels the heat

Molecular mechanisms of growth depression in broiler chickens (Gallus Gallus domesticus) mediated by immune stress: A hepatic proteome study

Leukocytic Cytokines Regulate Growth Rate and Composition Following Activation of the Immune System

Effects of ND vaccination combined LPS on growth performance, antioxidant performance and lipid metabolism of broiler

High frequency vaccination-induced immune stress reduces bone strength with the involvement of activated osteoclastogenesis in layer pullets

Determinants of broiler chicken meat quality and factors affecting them: A review

The relationship of raw broiler breast meat color and pH to cooked meat color and pH

Glucose requirements of an activated immune system in lactating Holstein cows

Effect of level of chronic immune system activation on the lactational performance of sows

Effects of dietary phosphorous supplementation on laying performance, egg quality, bone health and immune responses of laying hens challenged with Escherichia coli lipopolysaccharide

Introduction to poultry vaccines and immunity

The use of vaccination in poultry production

Hatchery Vaccination Against Poultry Viral Diseases: Potential Mechanisms and Limitations

A review of combined immunization: Current research situation and its promising future

A comparison of different vaccination schemes used in sheep combining inactivated bluetongue vaccines against serotypes 4 and 8

Evaluation of the efficacy of a trivalent vaccine mixture against a triple challenge with Mycoplasma hyopneumoniae, PCV2, and PRRSV and the efficacy comparison of the respective monovalent vaccines against a single challenge

Efficacy of combined vaccination against Mycoplasma hyopneumoniae and porcine reproductive and respiratory syndrome virus in dually infected pigs

Evaluation of vaccination against infectious laryngotracheitis (ILT) with recombinant herpesvirus of turkey (rHVT-LT) and chicken embryo origin (CEO) vaccines applied alone or in combination

Impact of Housing Environment on the Immune System in Chickens: A

Effects of stocking density on growth performance, feather growth, intestinal development, and serum parameters of geese

Immune Function and Micronutrient Requirements Change over the Life Course

Dietary arginine supplementation alleviates intestinal mucosal disruption induced by Escherichia coli lipopolysaccharide in weaned pigs

Dietary Supplementation with α-Ketoglutarate Activates mTOR Signaling and Enhances Energy Status in Skeletal Muscle of Lipopolysaccharide-Challenged Piglets

Dietary supplementation with glutamate precursor α-ketoglutarate attenuates lipopolysaccharide-induced liver injury in young pigs

Dietary L-theanine alleviated lipopolysaccharide-induced immunological stress in yellow-feathered broilers

Influences of dietary methionine and cysteine on metabolic responses to immunological stress by Escherichia coli lipopolysaccharide injection, and mitogenic response in broiler chickens

Protective effects of N-acetylcysteine on intestinal functions of piglets challenged with lipopolysaccharide

Dietary N-acetylcysteine supplementation alleviates liver injury in lipopolysaccharide-challenged piglets

Dietary supplementation of glycine modulates inflammatory response indicators in broiler chickens

Effects of supplemental glutamine on growth performance, plasma parameters and LPS-induced immune response of weaned barrows after castration

Dietary supplementation of aspartate enhances intestinal integrity and energy status in weanling piglets after lipopolysaccharide challenge

Asparagine attenuates intestinal injury, improves energy status and inhibits AMP-activated protein kinase signalling pathways in weaned piglets challenged with Escherichia coli lipopolysaccharide

Effects of dietary conjugated linoleic acid supplementation on performance and immune function of weaned pigs

Vitamin E and omega-3 fatty acids independently attenuate plasma concentrations of proinflammatory cytokines and prostaglandin E3 in Escherichia coli lipopolysaccharide-challenged growing-finishing pigs

Parenteral Fish-Oil Containing Lipid Emulsions Limit Initial Lipopolysaccharide-Induced Host Immune Responses in Preterm Pigs

Dietary fish oil alters specific and inflammatory immune responses in chicks

Effects of altering the ratio of dietary n-6 to n-3 fatty acids on performance and inflammatory responses to a lipopolysaccharide challenge in lactating Holstein cows

Vitamin C alleviates LPS-induced cognitive impairment in mice by suppressing neuroinflammation and oxidative stress

Supplemental vitamin C and yeast cell wall beta-glucan as growth enhancers in newborn pigs and as immunomodulators after an endotoxin challenge after weaning

Effects of dietary vitamin E on immunological stress of layers and their offspring

Effects of different levels of vitamin E on growth performance and immune responses of broilers under heat stress

Vitamin A inhibits the action of LPS on the intestinal epithelial barrier function and tight junction proteins

Magnesium sulfate attenuates lipopolysaccharidesinduced acute lung injury in mice

Magnesium sulfate provides neuroprotection in lipopolysaccharide-activated primary microglia by inhibiting NF-κB pathway

Effect of immunological stress to neuroendocrine and gene expression in different swine breeds

Effect of copper on antioxidant ability and nutrient metabolism in broiler chickens stimulated by lipopolysaccharides

Influence of Mushroom Polysaccharide, Nano-Copper, Copper Loaded Chitosan, and Lysozyme on Intestinal Barrier and Immunity of LPS-mediated Yellow-Feathered Chickens

Practical aspects of the use of probiotics in pig production: A review

Dietary inclusion of multispecies probiotics to reduce the severity of post-weaning diarrhea caused by Escherichia coli F18(+) in pigs

Dietary Bacillus subtilis-based direct-fed microbials alleviate LPS-induced intestinal immunological stress and improve intestinal barrier gene expression in commercial broiler chickens

Dietary Supplementation with Lactobacillus casei Alleviates Lipopolysaccharide-Induced Liver Injury in a Porcine Model

Supplementation of a Lactobacillus acidophilus fermentation product can attenuate the acute phase response following a lipopolysaccharide challenge in weaned pigs

Lactobacillus delbrueckii Protected Intestinal Integrity, Alleviated Intestinal Oxidative Damage, and Activated Toll-Like Receptor-Bruton's Tyrosine Kinase-Nuclear Factor Erythroid 2-Related Factor 2 Pathway in Weaned Piglets Challenged with Lipopolysaccharide

Effects of Clostridium butyricum and Enterococcus faecalis on growth performance, intestinal structure, and inflammation in lipopolysaccharide-challenged weaned piglets

Modulation of hypoxia-inducible factor-1α/cyclo-oxygenase-2 pathway associated with attenuation of intestinal mucosa inflammatory damage by Acanthopanax senticosus polysaccharides in lipopolysaccharide-challenged piglets

Effects of Acanthopanax senticosus Polysaccharide Supplementation on Growth Performance, Immunity, Blood Parameters and Expression of Pro-inflammatory Cytokines Genes in Challenged Weaned Piglets

Individual and combined effects of genistein and hesperidin on immunity and intestinal morphometry in lipopolysacharide-challenged broiler chickens

Dietary Supplementation of the Antioxidant Curcumin Halts Systemic LPS-Induced Neuroinflammation-Associated Neurodegeneration and Memory/Synaptic Impairment via the JNK/NF-κB/Akt Signaling Pathway in Adult Rats

Curcumin Attenuates Lipopolysaccharide-Induced Hepatic Lipid Metabolism Disorder by Modification of m(6) A RNA Methylation in Piglets

The therapeutic potential and mechanisms of action of quercetin in relation to lipopolysaccharide-induced sepsis in vitro and in vivo

Effects of berberine on the growth performance, antioxidative capacity and immune response to lipopolysaccharide challenge in broilers

Maternal supplementation of seaweed-derived polysaccharides improves intestinal health and immune status of suckling piglets

Artemisia ordosica Polysaccharide Alleviated Lipopolysaccharide-induced Oxidative Stress of Broilers via Nrf2/Keap1 and TLR4/NF-κB Pathway

Effects of Glycyrrhiza polysaccharide in diet on growth performance, serum antioxidant capacity, and biochemistry of broilers

Dietary Stevioside Supplementation Alleviates Lipopolysaccharide-Induced Intestinal Mucosal Damage through Anti-Inflammatory and Antioxidant Effects in Broiler Chickens

Salidroside attenuates lipopolysaccharide (LPS) induced serum cytokines and depressive-like behavior in mice

Influence of procyanidin supplementation on the immune responses of broilers challenged with lipopolysaccharide

In vivo modulation of LPS induced leukotrienes generation and oxidative stress by sesame lignans

Sesamol supplementation prevents systemic inflammation-induced memory impairment and amyloidogenesis via inhibition of nuclear factor kappaB

Green tea polyphenols prevent lipopolysaccharide-induced inflammatory liver injury in mice by inhibiting NLRP3 inflammasome activation

Effect of carvacrol essential oils on immune response and inflammation-related genes expression in broilers challenged by lipopolysaccharide