The Use of Plants as Phytobiotics: A New Challenge

Abstract

The search for bioactive compounds of natural origin, also called phytobiotics, has become a major challenge for industrialists, farmers, and scientists alike. Phytobiotics are compounds known for their anti-inflammatory, antioxidant, anti-carcinogenic, immunomodulatory, hypolipidemic, detoxifying, flavoring, and digestive-stimulating properties. These beneficial effects of phytobiotics depend on the part of the plant used (bark, leaves, stem, roots, fruit, flower, seeds) or their extract. Regarding their classification, there are several types of active compounds derived from plants, also grouped under the name of secondary metabolites such as tannins, polyphenols, terpenes, saponins, flavonoids, alkaloids, cyanides, and glycosides. Concerning their role, phytobiotics are used as feed additives to improve growth performance, nutritional status, and biochemical parameters of humans and animals. They can also be used ethno-medically for the prophylaxis and curative treatment of diseases such as diabetes, obesity, kidney stones, insomnia, gout, hemorrhoids, acne, and eye problems.

1. Introduction

Using antibiotic growth promoters (AGPs) in livestock has been banned in the European Union countries since 2006 [1]. These regulations were developed to limit the consequences associated with bacterial resistance to antibiotics, which constitute a risk to both animal and human health [2]. The emergence of bacterial resistance in farm animals such as poultry is linked to the continuous administration of antibiotics at levels between 5 and 50 ppm [3]. Moreover, some of these AGPs would be involved in the development of pathogenic bacteria due to the reduction of the commensal of the microbiota [4]. They can also be found in small concentrations in meat [5], or high concentrations in animal waste. On the other hand, it has been shown that the presence of antibiotic residues in waste used as agricultural fertilizers is harmful to the environment by altering the availability of soil nutrients due to changes in microflora and microfauna and leading to the development of AGP-resistant bacteria in the soil [6].

Faced with these findings, the use of alternatives to AGP in animal feed has developed since the end of the 1990s, marked by the development of a large number of these products. Among these, the most common are prebiotics (substrates for the growth of certain bacteria of the digestive microbiota and indigestible by the host animal), probiotics (living microorganisms), certain organic fatty acids and enzymes, and natural phytobiotics from plants [7].

Constituted of several molecules with various properties, phytobiotics are promising products. For example, it has been shown that the antibacterial activities of phytobiotics are associated with compounds of various kinds that act on microorganisms by targeting different mechanisms of their physiology essential to their survival and thus limiting the risk of resistance development [8]. The composition of active substances in phytobiotics depends considerably on certain factors such as the part of the plant used, the climate, the state of maturity of the plant at harvest, and the nature of the soil, ... [9]. Moreover, it has been shown that the antioxidant properties of natural plant-derived phytobiotics are mainly associated with their content of phenolic compounds whose actions are identical to synthetic phenolic antioxidants [10].

However, ignorance of the specific and efficient conditions of the use of phytobiotics could contribute to understanding their differences in effectiveness. On the other hand, the nature and number of compounds used, the genetics of the animals, the composition of feeds, and the rearing conditions used could also explain the wide variability in the results reported in the efficacy of phytobiotics as promoters of growth in animals [7]. Thus, from these observations and analyses, it appears that many phytobiotics are full of molecules with various properties and capable of improving the growth performance and health of animals and even humans. Thus, their actions must be studied and valued, hence the objective of this study.

2. Generalities on phytobiotics

2.1 Definition

Phytobiotics come from plants and can have positive effects on the growth and health of animals due to their antibacterial, anti-inflammatory, and antioxidant properties [11]. They have also been defined as non-nutritive compounds and are therefore distinguished from the nutrients found in plants, such as vitamins and minerals. Phytobiotics consist of products of plant origin such as herbs, oleoresins, and essential oils; They can be added to the diet of commercial animals to increase their productivity by improving their feeding properties, promoting the production performance of animals and improving the quality of products derived from these animals. In addition, [8] have classified phytobiotics according to their origin and transformation, on this basis we can have essential oils, oleoresins, spices, and herbs.

2.2 Characteristics of phytobiotics

One of the most important criteria to take into account when choosing phytobiotics in animal husbandry is their general acceptability by the animals because if the organoleptic properties are not met, it is difficult for these phytobiotics to be accepted by the animals. In addition, among the biological activities of phytobiotics, some have a particular interest in making phytobiotics act on animal growth performance, antibacterial properties, stimulating digestion, anti-inflammatory, and antioxidant properties. Taking the latter case, the antioxidant properties of phytobiotics supplemented in feed could also improve the oxidative status of animals, which could have a positive impact on both animal health and the quality of their meat [12]. These functions can be performed by different families of compounds such as phenolic compounds, alkaloids, and terpenoids [13, 14].

By using phytobiotics in animal feed, the cost must not lead to an excessive increase in the price of the feed. Hence the importance of using by-products of other productions as the source of phytobiotics [7].

The ability of animals to perceive phytobiotics with odorous properties during feeding depends on the animal species, the molecule, and the portion of food considered which will prepare the digestive tract for intake, by stimulating digestive secretions and gastric motility [15, 16]. Thus, odorous compounds can therefore promote efficient digestion and so, improve the growth performance of animals.

2.3 Active ingredients of phytobiotics: plant secondary metabolites

Secondary metabolites are a group of various molecules involved in the adaptation of plants to their external environment. Indeed, there are more than 24,000 secondary metabolite structures involved in many mechanisms such as defense against herbivores and pathogens, regulation of symbiosis, control of seed germination, and chemical inhibition of competing plant species. Thus, secondary metabolites are integral to the interactions of species in plant and animal communities and the adaptation of plants to their environment. Some of the major plant secondary metabolites or phytochemicals found in plants include saponins, tannins, protease inhibitors, lectins, alkaloids, non-protein amino acids, and cyanogenic glycosides [17].

Many criteria have to be considered for the classification of secondary metabolites including chemical structure, composition, solubility, and the biosynthetic pathway. According to [18], they can be grouped based on their composition by the presence or not of nitrogen (Table 1).

Types of secondary metabolites	Estimated number of structures
Nitrogen-containing metabolites
Alkaloids	21,000
Lectins, peptides, and polypeptides	2000
Non-protein amino acids	700
Alkylamids	150
Amines	100
Glucosinolates	100
Cyanogenic glycosides	60
Metabolites without nitrogen
Monoterpenes (C10)	2500
Sesquiterpenes (C15)	5000
Diterpenes (C20)	2500
Triterpenes, steroids, saponins (C30, C27)	5000
Tetraterpenes (C40)	500
Flavonoids, anthocyanins, catechins, tannins	5000
Phenylpropanoids, coumarin, lignans, lignin	2000
Polyacetylenes, fatty acids, waxes	1500
Polyketides	750

Table 1.

Plant secondary metabolites based on the presence or not of nitrogen [18].

However, one of the most widely used criteria in the classification of secondary metabolites is the biosynthetic pathway where secondary metabolites of the plant could be grouped into three major groups namely: terpenes, alkaloids, and phenolic compounds [19].

2.3.1 Terpenes

In plants, terpenes constitute the largest group of secondary metabolites (SM) to which more than 40,000 different molecules are attributed. Structurally, they are unsaponifiable lipids since fatty acids are not involved in their formation. Since the basic structural unit that forms terpenes is isoprene, they are also known as isoprenoids. They can be classified based on their number of isoprene units (Table 2). For instance, hemiterpenes are the simplest class of terpenes, with a single isoprene unit and five carbons in its structure. Isoprene the best-known hemiterpene is a volatile product that results from photosynthetically active tissues. With two groups of isoprene, we have monoterpenes, sesquiterpenes with three units, diterpenes with four units, triterpenes with six units, tetraterpenes with eight units, and polyterpenes with more than 10 units [20]. Terpenes can be found in different plant parts such as flowers and fruits. These include lemon, ginger, mint, and eucalyptus. They act as defense molecules, toxic compounds, and food deterrents for insects. In some plants, terpenes function as a disperser by attracting pollinators [21].

Class	Number of isoprene units	Number of carbon atoms in the structure	Examples	Usages	Isolated from
Hemiterpene	1	5	Isovaleramide	Anticonvulsant	Valeriana povonii
Monoterpenes	2	10	Geraniol	Fragrance material	Palmarose oil
Sesquiterpenes	3	15	Farnesol	Source of perfume	Citrus aurantium
Diterpenes	4	20	Vitamin E	Antioxidant	Corylus avellana L.
Triterpenes	6	30	Squalene	UV protector	Olive oil
Tetraterpenes	8	40	Carotene	Antioxidant	Rhodotorula glutinis
Polyterpenes	>9	>40	Rubber	Restorative material (endodontics)	Palaquium gutta

Table 2.

Classes of terpenes according to the number of isoprene units [17].

2.3.2 Alkaloids

Like terpenes, alkaloids represent an important group of secondary metabolites comprising molecules primarily derived from vascular plants. It is noted that plants most often produce a complex mixture of alkaloids where a main constituent is mainly found. However, even if in a given plant their structures are slightly different, the origin of their synthesis is common [22]. The number of alkaloids varies significantly between plants and parts of the same plant, we can also see the case where a plant does not contain any at all. Also, just like plants, they can be found in beings such as animals, fungi, and bacteria [23]. From a structural point of view, a nitrogen atom is generally found in alkaloids, and from a functional point of view, they are compounds that can be toxic and they commonly respond to precipitation reactions [24]. According to their biosynthetic origin, alkaloids are classified as true alkaloids, protoalkaloids, and pseudoalkaloids [25]. Although the presence of alkaloids is not vital to the plant, studies indicate that because of their deterrent ability and toxicity, they play a defensive role in the plant against insects and herbivores. While some alkaloids serve to protect the plant against certain predators (animals or microorganisms), others are used to fight other plant species in their habitat [26]. On the functional level, alkaloids have important physiological and toxicological properties exerted mainly at the level of the central nervous system (Table 3). Approximately 15,000 alkaloids have been isolated from plants to date. However, it is important to note that there is still a large amount of these compounds that have not been isolated from unidentified or no recorded higher plant species. Thus, from these observations and given the important medicinal, pharmacological, and therapeutic properties of alkaloids, more efforts must be made in the study of these compounds [27].

Class	Name	Biological properties	Plant family
True alkaloids	Atropine	Anticholinergic drug.	Solanaceae
	Nicotine	A potent poison that at low doses is stimulating.	Solanaceae
	Morphine	Narcotic and anesthetic properties.	Papaveraceae
Protoalkaloids	Mescaline	Hallucinogen.	Cactaceae
	Hordenine	Stimulant of the central nervous system.	Cactaceae
	Ephedrine	Sympathetic nervous system stimulant.	Ephedraceae
Pseudoalkaloids	Aconitine	Highly poisonous.	Ranunculaceae
	Theobromine	Stimulating the central nervous system.	Malvaceae
	Coniine	Highly poisonous.	Apiaceae; Sarraceniaceae

Table 3.

Some biologically relevant plant-derived alkaloids [17].

2.3.3 Phenolic compounds

The biosynthesis of phenolic compounds in plants is done from the two aromatic amino acids namely phenylalanine and tyrosine via the shikimic acid pathway. These compounds can have a simple or complex structure and the hydroxyl group (OH) of the aromatic ring is responsible for their antioxidant activity. Thus, polyhydrophenolics are those that contain more than two hydroxyl groups and phenolic compounds are those that contain more than one phenolic fraction [28]. Chemically, phenolic compounds are a very diverse group of secondary metabolites with phenol, the simplest representative of this class [29]. In the classification of phenolic compounds, one of the criteria to be considered is the number of carbon atoms present in the molecule, which makes it possible to have simple phenols, acid phenols, acetophenones, phenylacetic acids, hydroxycinnamic, coumarins, flavonoids, biflavonyls, benzophenones, xanthones, stilbenes, quinones, and betacyanins. In addition, compounds such as tannins, neolignans, lignans, and phlobaphenes can also be classified in the group of phenolic compounds (Table 4). Functionally, phenolic compounds can act as antioxidants [30], and they can also act as plant growth inhibitors [31]. Seeds can accumulate high numbers of phenols that act as filters so that oxygen does not reach the embryo and inhibit its germination [32]. In addition, phenolic compounds are responsible for the coloration and smell of fruits and thus make them appetizing for animals [33]. Plants also defend themselves against the attack of pathogens by synthesizing phytoalexins that are toxic to microorganisms and their presence prevents infections. Phenols also protect plants by generating bitter flavors or textures that are unpleasant for herbivores [34].

Skeleton structure	Class	Characteristics	Examples	Isolated from
C6	Simple phenolics.	Substituted phenols.	Hydroquinone	Bearberry plant
C6 – C1	Phenolics acids and related compounds.	A carboxyl group substituted on a phenol.	Galli acid	Banana
C6 – C2	Acetophenones and phenylacetic acids.	Are rarely found in nature.	2-hydroxyacet-ophenone	cocoa, coffee.
C6 – C3	Cinnamic acids, cinnamyl aldehydes, cinnamyl alcohols.	Are commonly found in plants as esters of quinic acids, shikimic acid, and tartaric acid or as sugar esters.	Sinapoyl choline	Seeds of Arabidopsis thaliana
C6 – C3	Coumarins, isocoumarins, and chromones.	They possess an oxygen heterocycle as part of the C3-unit.	Umbelliferone	Rutaceae and Apiaceae (Umbelliferae) families.
C6-C3-C6 (C15) Flavonoids	Chalcones, aurones, dihydrochalcones.	Two benzene rings are linked together by a group of three carbons.	Butein	Dahlia and Coreopsis
	Flavones	Contain a ketone group, and an unsaturated C-C bond.	Kaempferol	Green leafy vegetables (spinach and kale), and herbs (dill, chives, and tarragon).
	Flavanones	Contain a ketone group.	Naringenin	Orange
	Flavanonols	Occur in association with tannins.	Taxifolin	onions, tamarind seeds.
	Anthocyanidins	The heterocycle is a pyrilium kation.	Cyanidin	Pomegranate, red cabbage, grapes.
	Anthocyanins	Are water-soluble glycosides of anthocyanidins.	Peonidin	Raw cranberries
C30	Biflavonyls	Are dimers of flavones or methylated derivatives.	Ginkgetin	Ginko biloba L.
C6-C1-C6	Benzophenones	Are aromatic ketones.	Benzophenones	Clusiaceae (Guttiferae)
	Xanthones	Are yellow pigments in flowers.	Xanthone	Mangosteen
C6-C2-C6	Stilbenes	Two benzene rings are linked together by a group of two carbons.	Resveratrol	Strawberry
C6, C10, C14	Quinones	Oxidizing agents	2,6-dimethoxy benzoquinone	Rauvolfia vomitoria, Tibouchina pulchra.
C18	Betacyanins	Are red pigments and contain nitrogen.	Betanidin	Cacti, carnations, amaranths, ice plants, beets.

Table 4.

Classes of phenolic compounds according to the number of carbons [17].

2.4 Good practice in the use of plant secondary metabolites

When studying secondary metabolites derived from plants, several steps must be taken into consideration, namely: extraction from plant sources, phytochemical screening of extracts for qualitative determination of metabolites present, purification of individual components and the elaboration of their chemical structures; the study of their biological activity (in vivo or in vitro assays), and the study of their toxicity or cytotoxicity on organisms or cells. However, to avoid possible chemical damage, the freshness of the plant samples must be maintained. Thus, the interval between the harvesting of plant species and the start of extraction should not exceed 3 hours, because due to the fragility of plant tissue, it deteriorates faster than dry tissue [35]. In addition, the most commonly found plant-drying processes are air-drying, microwave-drying, oven-drying, and lyophilization. But each of these methods has advantages and disadvantages that must be considered before their use [36, 37]. Another important point to consider during pre-treatment is the particle size of the plant material. Indeed, the smaller the particle size, the higher the contact area between the plant material and the solvent and, therefore, the more efficient the extraction of chemicals [38]. The various studies that exist on the effectiveness of these compounds are only at the laboratory level, which is why it is still necessary to explore and evaluate their effectiveness at the greenhouse and field levels.

3. Properties of some plants as phytobiotics in livestock

Phytobiotics are used in poultry, but also in other rent, particularly in pigs and ruminants. The introduction of phytobiotics in animal feed was carried out by combining observations from “traditional” herbal medicine particularly important in certain regions of the world (China, Africa, South America), and rational phytotherapy based on scientific observations [7]. Over the past two decades, studies have shown that phytobiotics exert multiple effects such as anti-inflammatory, antimicrobial, antioxidant, and metabolic effects [39]. Phytobiotics are known to promote growth and improve meat and egg quality in poultry production [40]. Due to the gradual and continuous elimination of growth-promoting antibiotics due to biological resistance effects observed in animal production, the use of phytobiotics has expanded in animal husbandry to improve the growth performance of animals [41].

3.1 Antibacterial properties of phytobiotics

Medicinal herbs are used as a treatment for human diseases. The whole plant or part of the plant (leaves, roots, stem, flower, and fruits) is subjected to the extraction process for the derivation of the bioactive compound [42]. The inhibitory effect of bacterial growth has been demonstrated for many phytobiotics, and the intensity of their effect depends on both the target bacteria, the phytobiotics, and the dose used [7]. Indeed, several bioactive compounds from plants and fungi have demonstrated significant stimulatory properties of useful bacteria such as lactobacilli and bifidobacteria without however promoting the growth of pathogenic bacteria. Thus, the stimulation of these beneficial bacteria would contribute to the balance of the intestinal microflora and provide optimal conditions for effective protection against pathogenic microorganisms and an intact immune system in animals. In addition, in monogastric animals like pigs, spice-derived phytobiotics have been shown to stimulate appetite and endogenous enzyme secretion and exert coccidio-static or anthelmintic antimicrobial activities [43]. Researchers found that leaves of rosemary (Rosmarinus officinalis) at a concentration of 10 g/kg enhanced the immune system of Nile tilapia and increased their disease resistance against Aeromonas hydrophila [44]. In addition, many studies have revealed the potential of medicinal herbs for aquaculture uses; thus, researchers have developed new and improved approaches for antibacterial discoveries from plants. According to the literature, many medicinal herbs were reported to demonstrate antibacterial properties against A. hydrophila. For instance, Murraya koenigii, Pandanus odoratissimus, Colocasia esculenta, and Euphorbia hirta inhibited the growth of A. hydrophila. These medicinal herbs (Table 5) contain bioactive compounds, such as carbazole alkaloids, phenolic compounds, polypeptides, and alkaloids, that were responsible for antibacterial activities [45].

Compound’s family	Sub-family	Mechanism of action
Protein derivatives	Sulfur derivatives	Formation of ion channels in membranes via the formation of disulphide bridges.
	Lectins	Competitive inhibition of bacterial adhesion to their polysaccharide receptors.
	Alkaloids	Intersperse DNA.
Terpenes, terpenoids, and Saponins.	Terpenes, terpenoids.	Permeabilization of bacterial membranes.
	Saponins	Permeabilization of bacterial membranes.
Phenolic compounds	Simple phenols and phenolic acids.	Formation of complexes with many proteins, destruction of bacterial membranes, unavailability of certain substrates for bacteria.
	Quinones	Inactivation of membrane proteins.
	Flavones, flavanols, and flavonoids.	Binding to adhesins, binding to cell walls, inactivation of enzymes.
	Tannins	Binding to different proteins: adhesins, enzymes, substrate, cell wall, membrane. Formation of complexes with minerals.

Table 5.

Families of molecules with antibacterial activity and mechanisms of action (adapted from [7]).

3.2 Antioxidant properties of phytobiotics

An antioxidant is any organic (or inorganic compound) presents at low concentrations compared with those of an oxidizable substrate, significantly delaying or preventing oxidation of that substrate [46]. The health benefits of the ingestion of phytobiotics are attributed to their antioxidant activity which has also been assessed from plant extracts. This activity is mainly associated with the presence of active compounds such as polyphenols. However, flavonoids would mainly act as buffers by capturing free radicals and transforming them into less reactive flavin radicals because their structure has delocalized electrons. On the other hand, quercetin can chelate transition metal ions such as iron or copper, thus preventing the synthesis of reactive oxygen species or free radicals [47]. Also, caffeic, chlorogenic, sinapic, ferulic, and p-coumaric acids have antioxidant activity by the inhibition of oxidation of lipids and the elimination of reactive oxygen species, these effects are important to the plant defense [48]. According to [49], some polyphenolic compounds exhibit antioxidant effects through a variety of mechanisms that are regulated by antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase, rather than the single mode of action of typical synthetic antioxidants (Table 6). In addition, the antioxidant activity of phytobiotics, especially phenolic acids, and flavonoids, is predominantly determined by the structure and electron delocalization over an aromatic nucleus [50].

Phenolic compounds	Pathological condition	Mechanism of actions
Catechins	Neurodegenerative diseases.	Enhance activity of SOD and catalase.
Ferulic acid	Diabetes, colon cancer.	Decrease lipid peroxidation and enhance the level of glutathione and antioxidant enzymes.
Quercetin, Procyanidins.	Oxidative stress in human astrocytoma U373 MG cell line.	Enhance the activity of antioxidant enzymes and expression of proteins.
Ellagic acid	Oxidative stress induced by oxidized lipids.	Enhance the activity of GSH and antioxidant enzymes.

Table 6.

Antioxidant properties of some phenolic compounds (adapted from [49]).

According to their mechanism of action, there are primary antioxidants and secondary antioxidants. Primary antioxidants can neutralize free radicals by two mechanisms, either by the transfer of a hydrogen atom (most often labile hydrogen) (Figure 1) or by the transfer of a single electron (Figure 2). Primary antioxidants are very effective and are most often needed in small quantities and their high catalytic property is one of the reasons for their diversity in nature. Phenolic compounds are an example of these antioxidants and during their mechanism, they can be regenerated by resonance [49].

Figure 1.

The reaction of gallic acid with free radicals and its stabilization of gallic acid-free radical [49].

Figure 2.

Mechanism of single-electron abstraction reaction (SET) [49].

Secondary antioxidants can be distinguished by their mechanism of action. For example, ethylenediaminetetraacetic acid (EDTA) and citric acid can act as chelators of pro-oxidant metal ions (Fe²⁺ and Cu²⁺). β-carotene can neutralize reactive species like singlet oxygen. Secondary antioxidants usually neutralize a free radical and are therefore easily depleted. Metal chelation can directly inhibit Fe⁺³ reduction, consequently reducing the formation of reactive OH-free radicals of the Fenton reaction [51] (Figure 3). The metal chelation depends on the reduction potential of the phenolic compounds; however, chelation is subject to certain conditions such as the metal ions do not attach to proteins or other chelator molecules.

Figure 3.

Mechanism of metal chelation of phenolic antioxidants. (a) Coordination of Fe²⁺ by polyphenols and subsequent electron transfer reaction in the presence of oxygen-generating the Fe²⁺-polyphenol complex; (b) coordination of Fe³⁺ by polyphenols, subsequent iron reduction and semiquinone formation, and reduction of Fe³⁺ to form a quinone species and Fe²⁺. R = H, OH [51].

More recently, a third class has been included called tertiary antioxidants. These antioxidants repair damaged biomolecules such as DNA or proteins. However, very little is known about their role in foods [49].

3.3 Growth performance properties of phytobiotics

Because of the increased risk of occurrence of antimicrobial resistance due to antibiotic growth promoters (AGPs), the use of phytobiotics as an alternative to AGPs has been extended to farm animals for improving their intestinal status and subsequently promoting growth [52]. So, numerous studies have reported the growth-promoting effects of phytobiotics in chickens, but their precise mechanism of action is yet to be elucidated [53]. However, a few reviews have suggested the possible mechanisms by which phytobiotics lead to health benefits and growth promotion [54, 55]. According to [56], the effect of phytochemicals on growth performance elevation may associate with their antioxidant capacity or anti-inflammatory activity. Indeed, some natural phytochemicals represent a promising non-antibiotic tool for better intestinal health, nutrient digestibility, and general health status, thus leading to increase growth performance. In addition, it has been shown that supplementation with Broussonetia papyrifera leaf extract can increase the growth performance and antioxidant capacity of weaned piglets [57]. Supplementing rations with Camellia sinensis powders could be a good alternative to enhance the growth performance, carcass characteristics, and blood lipid profile of broilers [58]. However, regarding the biological activities of phytochemicals, 04 mechanisms (Figure 4) supporting the observations of physiological changes in animals (growth performance, carcass characteristics, and meat quality) have been proposed, namely: 1) Improvement of food status and consumption animal feed; 2) Modulator of ruminal fermentation; 3) Improved digestion and absorption of nutrients; and 4) Source of direct and indirect anabolic activity on target tissues [55].

Figure 4.

The classification proposed and several examples of phytochemicals used as growth promoters’ additives [55].

3.4 Immune-activating properties of phytobiotics

By preventing and controlling infectious diseases in the animal population, phytobiotics derived from plants can be used as alternative products to minimize the need for antibiotics. For instance, the immune-activating properties of medicinal plants such as Carthamus tinctorius, Taraxacum officinale, and Brassica juncea, have been evaluated in vitro using avian lymphocytes and macrophages, and all their extracts stimulate innate immunity, inhibit tumor cell growth, and exert antioxidant effects in poultry [59]. In addition, cinnamaldehyde a constituent of cinnamon (Cinnamomum cassia) stimulated primary chicken spleen lymphocyte proliferation in vitro and activated macrophages to produce high nitric oxide (NO) [60]. Phytochemicals also exert their action through immunomodulatory effects such as the increased proliferation of immune cells, modulation of cytokines, and increased antibody titters [54]. In addition, it has been revealed that curcumin inhibits TLR4 (Toll-like receptors) and NOD (nucleotide-binding oligomerization) which are two primary targets of phytobiotics [61]. Two garlic metabolites namely propyl thiosulfinate (PTS) and propyl thiosulfinate oxide (PTSO) have been used in poultry feeding, and results revealed that supplementation of 10 mg/kg PTS/PTSO increased body weight gain and serum antibody titters against profilin, an immunogenic protein of Eimeria, and decreased fecal oocyst-excretion-in Eimeria acervuline-challenged chickens compared with chickens receiving a control diet. Also, adding PTS/PTSO in the broiler’s diet, altered many genes related to innate immunity such as TLR3, TLR5, and NF-κB, and down-regulated expression of a cytokine such as IL-10 compared with the control diet [62]. Also, the combination of multiple phytochemicals exerts synergistic effects to reduce the negative consequences of enteric infections. A study revealed that the association of Curcuma/Capsicum/Lentinus-fed birds increased the levels of transcripts for IL-1β, IL-6, IL-15, and IFN-γ in gut lymphocytes compared with those fed the standard, Curcuma or Capsicum/Lentinus diet [63]. It can be observed that phytobiotics improve the intestinal inflammatory status and barrier functions, possibly via the inhibition of TLRs and subsequent activation of NF-κB, the activation of the xenobiotics detoxifying system, the reduction in pathogenic bacteria, and the Nrf2 pathway. This improvement in intestinal function subsequently prevents the translocation of pathogens and harmful constituents such as lipopolysaccharide (LPS) into the circulatory system and the induction of systemic inflammation via excess secretion of cytokines and glucocorticoids. The HPA (hypothalamic-pituitary-adrenal) axis controls glucocorticoid secretion, and excessive and long-term glucocorticoid secretion disrupts the protective function of the gut barrier and the gut microbiota [64]. These disturbances accelerate the production of cytokines, which in turn stimulate the HPA axis to secrete glucocorticoids. Thus, a vicious circle is initiated, which generates inflammatory and metabolic deregulations (Figure 5).

Figure 5.

Possible mechanisms of the mode of action in the beneficial effect of phytobiotics [53].

4. Conclusion

Increasing concerns about the increase of superbugs and limited development of new drugs for livestock necessitates the timely development of alternatives to antibiotic growth promoters. So, the trend in the use of phytobiotics in animal feed has increased during the last two decades. The health benefits and growth-promoting effects of phytobiotics may be dependent on several mechanisms based on their various biological activities. Also, many studies have been done using phytobiotics in livestock production. They have shown particularly the antimicrobial, antioxidant, anti-inflammatory, and growth-promoting effects of phytobiotics. The antioxidative function of phytobiotics can positively affect the stability of animal feed and increase animal products’ quality and storage time. However, due to the contradictions in published results, further research and investigations are still necessary to elucidate various aspects such as the nutritional’s aspect of phytobiotics.

Conflict of interest

The authors declare no conflict of interest.