INTERNATIONAL JOURNAL OF VETERINARY AND ANIMAL MEDICINE (ISSN:2517-7362)

Inflammation is a complex but defensive biological response of living tissue to infection that can be triggered by exogenous injury and infectious agents such as bacteria and viruses. Inflammation is part of the innate immune response acting as the first line of defense against pathogens and disease. The inflammatory response acts as a doubleedged sword because if inflammation persists or augments, it may switch from a defensive mechanism to a detrimental process, therefore, modulating the inflammatory response using therapeutic interventions is important for animal health and well being and for longterm food security. Recent studies have reported that plant-derived bioactive compounds are precursors for numerous anti-microbial and anti-parasitic medicines. The antibiotic activities may be attributed to some bioactive compounds such as polyphenols, flavonoids, terpenes, tannins, terpenoids, vitamin C, essential oils, and carotenoids. The ban on the use of synthetic antibiotics and inconsistent efficacy of non-steroidal anti-inflammatory drugs as NSAID have elevated the need for alternative drugs, particularly, those which are derived from plant-based bioactive compounds. Such substances can be used as supplements in animal food to boost the immune system particularly, for domestic ruminants, which are the main source for milk and meat for humans. During the past recent years, plant-based bioactive substances were studied intensively along with their anti-inflammatory and other therapeutic effects, both in-vivo and in-vitro. Modulating the inflammatory response using plant-based bioactive compounds is important for understanding the anti-inflammatory pathways that stimulate the innate immune response to pathogens or injury. The present study is a literature review that focuses on the applications of plant-derived bioactive substances and their effects on the immune responses of goats, sheep, and cows.

Inflammation; Ruminants; Innate immunity; Cytokines; Plant bioactive compounds

Ruminants are a group of mammals characterized by having four-chambered stomachs. To obtain nutrients from plant-based food, they can ferment them in a specialized chamber called rumen through microbial actions aiding in digestion. Cattle, sheep and goats which are the three ruminants globally consumed as sources of animal protein, contribute substantially to the economy. Inflammatory diseases cause significant losses to the livestock industry with public health and economic consequences.

There is a close nexus between healthy animals, innate immunity, and the inflammatory response. Since inflammation is the harbinger of upcoming disease, addressing the cause of inflammation and modulating it is essential for animal health and productivity. Inflammation is a complex but defensive biological response of living tissue to infection triggered by exogenous injury and baleful stimuli due to pathogens [1]. The innate immune system is the first line of a host defense mechanism that is responsible for the fast pathogen recognition and activation of the pro-inflammatory response. The effective immune response requires proper crosstalk between pro- and anti-inflammatory cytokines because their strong interaction not only governs local inflammatory reactions but also generates systemic effects through blood circulation [2]. Being a vital part of both innate and acquired immunity, inflammation orchestrates the body’s immune system responses through leukocytes, chemokines, and cytokines signaling to reconcile homeostasis. Pattern recognition receptors (PRR) such as Toll-like receptors (TLRs) are the ones that sense the invading microbes or traumatized cells and activate the local and systemic immune response that, in turn, stimulates four cardinal signs of inflammation which are redness, hotness, swelling & pain in the affected area.The redness of tissues is caused by the momentary vasoconstriction due to the injury following by vasodilatation to facilitate the infiltration of more fluids, cytokines, macrophages, and proteins to the affected area, heat results from enhanced blood flow, swelling, and pain. The heat is raised in the injured area due to the increased blood flow, while tissue swelling is due to the leaking of fluid from blood vessels to the affected tissue, consequently swelling causes pain due to the sensation and stimulation of the nerves in the area [3,4]. In particular, invasion of pathogenic microbes incites an intricate process that promotes the production and release of pro-inflammatory cytokines, which are hormone-like polypeptides such as tumor necrosis factor (TNF-α), interferons (IFN-γ), and interleukins (IL-6) [5]. The augmented level of pro-inflammatory cytokines in blood evokes a number of systemic changes in the body such as fever, reduced appetite, gastric function, plasma iron, and zinc levels, which stimulate the activity of lymphocytes and neutrophils with subsequent phagocyte mobilization and acute-phase proteins, altered metabolism of carbohydrates, lipids and proteins cumulatively called as acute phase response (APR) [2]. Activated mononuclear cells release monocytes and macrophages that primarily synthesize TNF-α, and IL-1β to act against bacterial pathogens while in the case of viral infection, IFN-γ is released from T-cells. Sustained inflammation is associated with oxidative damage due to the release of radicals by leukocytes and can result in deleterious effects on the host. Interlinked signaling events in cells and their consequences result in symptoms of inflammation that cannot be overlooked because if the condition of inflammation persists or augments, it may switch from a defensive mechanism to a detrimental process [3].

Infection and injury may result in an APR initiated primarily by tissue macrophages or blood monocytes. Pro-inflammatory cytokines may trigger the production of acute-phase proteins in the liver and their release in the blood in an effort to neutralize any pathological change, which may trigger the acute inflammation signs. For example, pro-inflammatory cytokines TNF-α, IL-6, and IL-1 can counteract endotoxin and restore homeostasis [6]. In response to cytokines, several signal cascades are propagated, causing cortisol secretion and, eventually the release of some acute-phase proteins such as serum amyloid A (SAA), C-reactive proteins, fibrinogen and haptoglobin by the liver. C-reactive protein and SAA are used in medical laboratories to identify tissue injury and the stage of inflammation, which helps in the prognosis and determination of treatment options [7]. The APR is crucial in regulating defense mechanisms including initiation of the defense process, immune cell production, metabolic changes, and fever to combat pathogens [8].

Inflammation can be categorized into acute and chronic inflammation depending on its severity and the nature of injury and pathogen causing the inflammation. Acute inflammations are prominent and rapid mainly governed by neutrophils and may cause injury to the tissues. On the other hand, chronic inflammation can cause severe injury to the tissues and is often mediated by lymphocytes, monocytes/ macrophages and may involve neutrophils. The onset of chronic inflammation is indeed a gradual process over a protracted period;thus, the symptoms are less conspicuous [7]. 

In domestic ruminants, is the major cause of mastitis, which impacts greatly on milk production, and neutrophils play a central role in the inflammatory response associated with E. coli mediated mastitis [10,11]. In particular, TLRs upon binding with LPS, a major inflammatory inducerstimulates innate immunity responses, and this process is accompanied by LPS-binding proteins (LBP) and a cluster of differentiation antigen 14 (CD14) [12]. TLRs recognize a variety of conspicuous microbial patterns including LPS, flagellin, viral RNA (double-stranded), and CpG (unmethylated) motifs [13]. Besides immune and inflammatory responses, cell proliferation and differentiation invariably depend on the transcription of nuclear factor κB (NF-κB) which is found to be inactive in cell cytoplasm with its inhibitory κB (IκB) counterparts. The NF-κB signaling pathway is being triggered by LPS and various receptors such as TLRs, tumor necrosis factor receptor (TNF-R), and interleukin 1 receptor (IL1R), which in turn initiates phosphorylation of inactive NF-κB-I-κB. Later, activated NF-κB is released, enters the nucleus, and binds with its promoter to upregulate the transcription of proinflammatory cytokines including interleukin 1-beta (IL-1β), IL-6, IL-8, and hormone-like polypeptide tumor necrosis factor-alpha (TNF-α) [14]. Several pieces of research articles also supported the implication of LPS in the propagation of inflammatory responses.

Demonstrated that bacterial pathogens like M. haemolytica infected cattle [15] demonstrated high levels of tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β), and interferon-γ (IFN-γ), [16] also reported a rising level of TNF-α, IL-1β, and IFN-γ upon LPS intravenous administration. In lactating dairy cows, [13] showed that digestive tract derived LPS stimulates inflammatory gene expression and obstructs casein synthesis.

Infection by viral pathogens activatescytokine gene expression. Cattle infected with the bovine respiratory syncytial virus (BRSV) showed high IL-6 and IFN-γ levels while infection with bovine viral diarrhea virus (BVDV) raised levels of TNF-α, IL-1β, as well as IL-6 [17]. However, cattle infected with both viral and bacterial infection demonstrated noticeably increased TNF-α, IL-6, IFN-γ except IL-1β [15]. Variation in innate immunity has been observed [18]. The TLR and cytokine responses of susceptible and resistant varieties of goats and water buffalo to pestes des petits ruminant virus (PPRV) was observed differently. Naturally, PPRV susceptible goats showed a weak immune response with high viral loads and poor TLRs expression. On the other hand PPRV resistant breeds, where synthetic TLRs agonists mediated peripheral blood mononuclear cells stimulation showed a remarkably higher level of pro-inflammatory cytokines including IFN- γ with the mitigated expression of immunosuppressive cytokine IL-10. The difference in immune response was attributed to higher IFN- γ and TLR-7 response in resistant variety that restricted PPRV replication.

Long-term intake of grain-enriched diets by ruminants leads to subacute ruminal acidosis (SARA) which may cause a number of malfunctions including increased intestinal permeability, alteration in microflora, metabolic disorders, lowering of ruminal pH to 5.8, reduction of cellulolytic bacteria with subsequent increase in starch-fermenting and lactic acid-producing bacteria [20]. It has been reported that low pH in rumen causes the lysis of gramnegative bacteria, and the effect of acidosis on the free ruminal lipopolysaccharides content (LPS) is strong evidence of inflammation [21]. After the onset of local inflammation in the ruminal epithelium, LPS passes through epithelial barrier reaching into the blood, and there it causes systemic inflammation by activating pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin IL-1β and IL-6. The release of IL-8 release further deploys various adaptor molecules leading to the transcriptional factor activation of NFκB [22,23]. The initiation of inflammatory signals simultaneously affectsbody tissues in terms of energy and lipid metabolism.

Also, systemic inflammation at organ level increases acute phase proteins secretion (serum amyloid A, haptoglobin), fever, elevated cortisol level. The crucial role of serum amyloid A is to bind endotoxin and nullify its effect in the blood, whereas haptoglobin binds with free plasma hemoglobin, thereby preventing iron availability to bacteria required for their growth and multiplication. The most prominent consequences of SARA are the malfunctioning of the cellular junction and cellular adhesion that leads to redundant infiltration of pathogens/toxins into blood from the lumen. However, systemic inflammation is a defensive mechanism to restore homeostasis, although inflammation for a protracted period can disrupt energy and lipid metabolism, immune inhibition, and disease susceptibility [6].

The most common PRR are TLRs that are located in different bovine granulosa cells, oviductal epithelial cells, and epithelial and stromal cells of the endometrium [24]. Upon recognition of MAMPs or DAMPs by the receptors on the abovementioned cells starts gushes of signaling events (NF-κB or MAPkinase) that, in turn, activates proinflammatory mediators (IL-1, IL-8, TNF-α). As a result, it leads to vasodilation, tissue healing, reactive oxygen species generation, and infiltration of macrophage and neutrophil to aid phagocytosis. Besides, several metabolites, peptides with antimicrobial properties,and apoptosis suppressing factors have also be released [3,25,26].

To ascertain the exact reason, the studies which were conducted with mastectomized cows have found that neither gestation nor calving was responsible for the prolonged pro-inflammatory stage. However, it was found that lactation and metabolic changes during the transition period were the real culprits [28]. The studies have also shown that there is a close nexus between metabolic disorders and the responsiveness of immune cells. The skewed dietary shifts in transition cows may also lead to systemic inflammation. Moreover, during the transition period, monocytes are noticed to be highly receptive to inflammatory stimulants, which in turn provoke more production of inflammatory cytokines, which is followed by systemic inflammation and altered liver metabolism. The elevated ketone levels in blood, hypocalcemia, and non-esterified fatty acid concentration greatly affect the immune cells to the pathogenic signals which result in mitigated immune function.

The continuous use of antibiotics has been practicing for the treatment of LPS induced mastitis that reflects putative risks of antibiotic resistance and their potential residues in milk that eventually goes to human through the food chain [35]. After the ban on several antibiotics, the use of non-steroidal anti-inflammatory (NSAID) has emerged as an alternative treatment, but they were found not very promising. To treat early lactation inflammation, acommercial NSAID drug sodium salicylate was used on 78 cows including control for the first seven days of lactation [36]. With average outcome at the beginning, the oldest cohort treated with salicylate yielded 21% more milk over the whole lactation and 30% more milk fat than parity matched control as lactation progressed. However, salicylate treatment outcome in primiparous cows was not promising because of low milk yield that might be attributed to the difference in response to inflammatory signals or baseline inflammatory status [37,38]. The whole-lactation productivity of multiparous cows was ascertained on 153 cows. Cows were assigned to postpartum treatment with two drugs, one with sodium salicylate forthree days and second with meloxicam for one day compared to the control group [38]. Despite the short treatment duration of the drug, there was a fruitful effect of either salicylate or meloxicam on milk production (10% hike) compared to control. Butyrate (volatile fatty acids) and its salts (sodium butyrate) have been claimed to diminish inflammatory responses by reducing the NF-κB signaling pathwayand LPS mediated cytokine expression. In dairy goats, sodium butyrate administration improves inflammation, which was caused by a high concentrate fed diet by downregulation of proinflammatory cytokines (IL-6, IL-1β, TNF-α) in rumen epithelium [39]. These results witnesses that the effect of NSAID has not been consistent.

Genetics contributes substantially to an animal’s innate immunity by plant bioactive substances and modulate gene expression through activating the innate and adaptive immune response. It can underpin alternate control strategies to target gene-specific modulation to curb inflammation either by stimulating inflammation so that there is rapid pathogen elimination or can dampen inflammation to reduce oxidative damage. Galectins, (gal) carbohydrate-binding proteins have demonstrated to modulate innate immunityin goats and cows. Galectin acts as PRR; thus, it can identify PAMPs by binding microorganism-specific glycan of micro organisms and begin host immune responsesby modulating host cells such as neutrophils, macrophages, eosinophils, mast, and dendritic cells remarkably [42,43]. Parity and periparturient period is the time when fertility, milk production, and inflammation in dairy cows, sheep, and goats are affected terribly. Hence, most of the studies on ruminants are performed during the periparturient period so that therapeutic targets such as galectins can be tapped [44]. Moreover, in periparturient goats and sheep, galectins have been found to regulate innate and adaptive immunity to combat immune suppression during the periparturient stage, which is highly susceptible to diseases [45]. In particular, gal-8 exhibited bovine neutrophil activation and migration through superoxide production as a potential therapeutic to reduce inflammation [8,46,47]. Adjei-Fremah et al. [48,49] reported that polyphenols extract from cowpeas can bind and regulate gene expressions of galectins in bovine inflammatory diseases. Besides, several plant extracts such as Curcuma longa, Echinacea angustifolia, and Butea frondosa have been used on sheep neutrophil to evaluate their anti-inflammatory and apoptotic modulation properties [41].

As an alternative non-chemical approach, [50] studied the effect of probiotics on lactating Holstein-Friesian cows and found that the lymphocytes count significantly increased with a percent decrease in neutrophil count in the treatment group. Probiotics serve as the non-pathogen associated molecular pattern; as a result, it promotes growth and rumen function in cows [51]. Moreover, probiotic treatment impacted three pathways remarkably, such as inflammatory response, TLR, and wingless signaling pathways.  

In ruminants, to cure nonspecific postpartum inflammation, specific pharmaceutical drugs have not yet been approved with dosage. On the other hand, due to the possible threat of antibiotic resistance against microbial agentsas well as its putative risk to access the human body through the food chain, the use of antibiotics is banned on livestock. In addition, the efficacy of NSAIDs administration on inflammation remained inconsistent. With some handful of positive effects including mastitis [52] and pregnancy rate at embryo transfer [53], most of the treatments exhibit the moderate or negative effect of NSAIDs on reproduction. During artificial insemination, the drug did not ameliorate the pregnancy rate [54] and insemination success rate at mid-luteal phase. Also, treatment before ovulation was baleful as the drug mitigated ovulation and follicular cyst formation [55]. Besides, studies on immunomodulation are at a novice stage and need in-depth study to implement on ruminants.

Moreover, after heavy restriction on the use of antibiotics as feed additives by European legislature (2003) and new Veterinary Feed Directives by United States (2017) on the use of medicated feed, numerous research programs have gained momentum towards phytochemicals based therapy to augment immune functionality of livestock [19,57]. Since then, plant bioactive enriched compounds were thoroughly investigated and justified the scope of alternative feed ingredients in the form of herbs, spices and plant extract to boost ruminant’s immune health by exhibiting the immense potential to exert the same anti-inflammatory potency as a commercial drug without side effects.

The phenolic compounds and polyphenols are abundantly found in all plants. In the past few decades, these chemopreventive agents have received enormous attention because of their supreme antiinflammatory, antioxidant properties, and other biological roles on animal’s health [60]. Chemically, phenolics are the compound that owns an aromatic ring having one hydroxyl group, while polyphenols can have one or more aromatic rings with many hydroxyl groups [13]. These plant secondary metabolites are produced as a plants’ defense mechanism against pathogens, as a result, have been explored for a variety of applications in animals including sheep, cows, and goats [61]. Alpha-tocopherol (vitamin E) is a known antioxidant that neutralizes ROS production and consequently obstructs the progression of inflammation. A study was found that the plasma concentration of α-tocopherol in cows was very low that indirectly associated with transition cow disorders [62]. Administration of α-tocopherol not only modulates inflammation by decreasing inflammatory cytokine production in transition cows but also ameliorates clinical mastitis, retained placenta, and liver function. [63,64] investigated the efficacy of polyphenol from cowpea in bovine blood and reported that it upregulated the expression of antiinflammatory cytokine IL-10. In addition, cowpea polyphenols also mitigated the Wnt signalingpathway, which has been implicated in inflammation [65]. Crude polyphenols extract from Cherokee tomato significantly suppressed the transcription of cox-2 gene expression, thereby reducing inflammation and modulated innate immunity in cows [66].

It has been monitored that during mastitis, TLR4-located receptors at mammary epithelial cells and resident leukocytes identify LPS, there by activating NF-κB mediated inflammatory response. [70,71] evaluated the effect of baicalein (flavones) and morin (flavonol) respectively on bovine mammary epithelial cells in in vitro studies and found mitigated action of NF-κB and mitogenactivated protein kinase. In particular, the phosphorylation of I κB and p65 were greatly suppressed by flavonoids, which in turn reduces NF-κB activation.

In addition, [71,72] reported that mRNA expression of proinflammatory cytokines was greatly diminished when the cells were treated with flavonoids. Also, heifers treated with flavonoid essential oil had reduced neutrophil blood concentration, LPS binding protein, and serum amyloid A than control heifer [73] suggesting that flavonoid-rich diets can ameliorate rumen fermentation and minimize the risk of acidosis. Administration of concentrate feed pellets containing fermented green tea probiotics, illite, and licorice to beef cattle from birth to post-weaning (60 days) did not modify leukocyte count [74]. Another piece of in vitro study on calves fed pomegranate extract demonstrated that blood mononuclear cells produced more IFN-γ and IL-4. Ovalbumin vaccine challenged calves fed pomegranate extract produced high anti-ovalbumin IgG compared to control [75].

In addition to the abovementioned bioactive compounds, there are thousands of other compounds that plants can synthesize such as saponins, lectins, polypeptides, polyamines, glucosides, and omega-3 fatty acids which exhibited potential roles as antiinflammatory agents. Table 2 shows the effect of anti-inflammatory bioactive compounds from plants and their therapeutic potential on ruminants. In dairy cattle, the synergistic activity of green tea and Curcuma extract in milk were investigated during the transition that resulted in augmented milk yield (4.5L/day), reduced liver lipids, and plasma NEFA concentration after calving [82]. The less responsive immune system was noticed in cows when treated with omega-3 sources [83]. On the other hand, [84] fed fresh cows with whole flaxseed containing omega-3 fatty acids that outweighed omega-6 fatty acids by enhancing greater phagocytic activity of circulating leukocytes and plasma glucose with decreased plasma ketones. The plant extracts, rich in w3-polyunsaturated fatty acids (PUFA), linoleic acid, and antioxidants, such as Se, vitamin C, vitamin E, b-carotene, and polyphenols reported modulating various transcriptional factors like NF-kB and PPARa that in turn governs inflammation affecting genes [85].

[86] studied the efficacy of garlic (Allium sativum, L), eucalypt (Eucalyptus globulus), and Gnaphalium conoideum extract in Holstein cows suffering from acute endometritis. Among all three garlic extract effectively worked against endometritis followed by eucalypt. Also, garlic extracts remarkably alleviated gastrointestinal infections caused by Coccidia in adult female Boar goats [87]. In sheep, β-sitosterol mitigated high grain diet-induced inflammatory response and improved ruminal fermentation and microbiota by obstructing the attachment of LPS to TLR4 in the NF-κB pathways thereby reducing (TNF)-α, IL-1β and IL-6 levels [23].

The bioactivity for anti-inflammatory effects of spice principles - curcumin, eugenol, linalool, zingerone, capsaicin, cuminaldehyde, and piperinewas studied and found highly effective (15-52%) in inhibition of carrageenan-induced inflammation in rats, [88,89]. Some researchers claim that the rich terpenoids and flavonoids contents in spices can subdue the synthesis of arachidonate metabolite and, eventually, the synthesis of prostaglandins that are considered to be potent inflammatory mediators. In addition, terpenoids and flavonoids also inhibit the secretion of lysosomal enzymes, for example, hyaluronidase, elastase, and collagenase enzymes by macrophage [90,91]. Some other herbs and spices are also enlisted, such as anis, licorice, marigold, and chamomile, whose anti-inflammatory perspective can be explored [92].

A growing number of researches on anti-inflammatory effects of plant-based bioactive compounds reflect that this field showed the immense potential to curb inflammation and boost the immune system without side effects. However, the amount of studies undertaken so far is inadequate to tap vast plant-based bioactive compounds that bear analogous attributes. Inflammation may play a vital role in the development of transition disorders and metabolic diseases. Therefore, research on plant-based bioactivesfor diseases/ metabolic disorders in combination with targeting immunomodulation could be a novel and wise approach to fight inflammation. Essential oil-based bioactives such as eugenol and cinnamaldehyde showed promising results to fight inflammation; hence they have tremendous potential to be used in immunomodulatory effects in ruminants. Also, targeting neutrophils using galectins can worth noting to explore its prospects as anti-inflammatory tools.Therefore, in-depth studies on the abovementioned aspects warrant to harvest the full efficacy of plantbased bioactives against inflammation and its allied complications.

The authors are grateful to the National Institute of Food and Agriculture Evans Allen funds:

‘MOLECULAR SIGNATURES AND REGULATORY CHECKPOINTS

FOR ANIMAL HEALTH’ Project NO. NC. X 320-5-19-120.1 for funding the postdoctoral Scientist. Special thanks also go to the Members of the Laboratory for Animal Genomic Diversity and Biotechnology (LAGenDB) at North Carolina A&T State University for assisting with edits.

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