Herbal Plants as New Immuno-stimulator in Poultry Industry: A Review
The aim of this study was to review research currently being carried out on the herbal plants and phytogenics that have been shown to modulate the immune system and special attention is given to the use of herbal plants on poultry herbal feed supplement. The uses of herbal plants as health promoters are gaining increasing attention in both consumer and scientific circles. Although, there are few studies which have revealed the mechanism of action of the immunostimulatory compounds of herbal plants but the exact molecular mechanisms of some herbs are not already known. There are several possible explanations for immunomodulation mechanisms of herbal plants and their derivatives that have been put forward. Our attempt here would be to look more closely at the herbal plants mechanisms involved, including from the immunomodulation point of view, and relationships between structures and activities.
Received: July 30, 2011;
Accepted: October 28, 2011;
Published: December 24, 2011
The immune system provides protection against infectious diseases that are
caused by various microorganisms including viruses, bacteria genetic, pathogenic
fungi and parasites. Unfortunately, over the years in poultry industry, most
of the selection emphasis has been on the improvement of growth performance,
and these changes have been shown to be negatively associated with immunological
parameters of poultry and animals (Emmerson, 1997).
Havenstein et al. (1994) showed that over a period
of 35 years, a modern commercial broiler strain hatched in calendar year 1991
gained 3.9 times more body weight compared to a randombred control line developed
in 1957. Whiles, control strain from 1957 performed significantly better in
antibody response (total, IgM and IgG) against Sheep Red Blood Cells (SRBC)
compared with the 1991 commercial broiler strain (Havenstein
et al., 1994). It has also been showed that genotypes with higher
body weight give poor antibody response to Sheep Red Blood Cells (SRBC) than
lower body weight line of broilers (Miller et al.,
1992; Qureshi and Havenstein, 1994; Rao
et al., 1999). On the other hand, National Research Council (NRC)
recommendation for feeding regimes are usually based on the needs of healthy
birds under ideal management, but birds in commercial systems are normally exposed
to different kinds of stresses and diseases. However, in many cases it is not
known whether the requirement values that maximize productivity in healthy,
unchallenged birds are optimal for immunocompetence and disease resistance.
Animal feeding studies indicate that changes in components of the immune system
are sensitive to dietary amino acid intake (Defa et al.,
It has been reported that chicks fed deficient amino acid had suboptimal interleukin
production during immunologic stress (Klasing and Barnes,
1988). Rama-Rao et al. (2003) showed that
methionine levels lower than 0.50% in broiler diet generates a poorer immune
cell response as compared to higher concentrations. Bhargava
et al. (1971) showed that increasing of threonine level more than
NRC requirements increased serum antibody titres in chickens infected with the
Newcastle disease virus. In poultry production, it is very important to improve
immunity so as to prevent infectious diseases. Minimizing immunosuppression
and its impact is also an important strategy for success in the broiler industry.
However, strategies to control immunosuppression are largely based on vaccination
programs for poultry and management to minimize stress during rearing (Fussell,
1998). Utilization of immunostimulants is one solution to improve the immunity
of animals and to decrease their susceptibility to infectious diseases (Liu,
1999). Relationship between nutrition and the immune system has been the
centre of attention in scientific communities in last decade. The use of plant
products as immunostimulants has a traditional history. Modern herb research
and new understanding of the immune system have explained many mechanisms by
which these herbs work. Unfortunately, there are a small number of studies which
have revealed the mechanism of action of the immunostimulatory compounds of
herbal plants. An understanding of the mechanisms through which phytochemical
influences the immune system is necessary to appreciate the use of herbal plant
as immunostimulator and veterinary medicinal products.
Immune system: The primary role of the immune system is to recognise
foreign or non-self organisms or substances that have managed to enter the body
and to initiate and manage the appropriate physiological responses to neutralise
or eliminate them. The immune system uses a variety of mechanisms to achieve
this goal, including inactivation of biological agents, lysis (rupture) of foreign
cells, agglutination (clumping) or precipitation of molecules or cells and phagocytosis
(engulfing and inactivating) of foreign agents (Roitt, 1997).
The immune response has two ways of dealing with foreign pathogens. The B-lymphocytes
synthesize specific antibodies called immunoglobulins. This is known as humoral
immunity (Sproul et al., 2000). The other system
involves T-lymphocytes, which regulate the synthesis of antibodies as well as
direct killer cell activity and the inflammatory response of delayed type hypersensitivity.
This system is known as cell-mediated immunity (Radoja et
al., 2006). The T-cells are further divided into helper lymphocytes
(Th) and cytotoxic cells (Tc), also known as suppressor cells. When the T-cells
encounter a foreign pathogen (antigen) they further secrete a number of communication
molecules called lymphokines, cytokines, interleukins or interferons (Abbas
et al., 1996; Abbas et al., 2007). These
factors further elaborate and direct the immune response to a specific antigen.
The whole process is a symphony of many co-factors, which are orchestrated into
a sophisticated immune response.
Plant immune system and secondary metabolites: Herbal plants and their
effects on immune system are shown in Table 1. Plants, unlike
mammals, lack mobile defender cells and a somatic adaptive immune system. Instead,
they rely on the innate immunity of each cell and on systemic signals emanating
from infection sites (Dangl and Jones, 2001; Ausubel,
2005; Chisholm et al., 2006). This type of
defence response is due to the presence of a large, diverse array of organic
compounds that appear to have no direct function in growth and development (Jones
and Dang, 2006). These substances are known as secondary metabolites, secondary
products, or natural products.
Secondary metabolites have no generally recognized, direct roles in the processes
of photosynthesis, respiration, solute transport, translocation, protein synthesis,
nutrient assimilation, differentiation, or the formation of carbohydrates, proteins
and lipids. Secondary metabolites also differ from primary metabolites (amino
acids, nucleotides, sugars, acyl and lipids) in having a restricted distribution
in the plant kingdom. That is, particular secondary metabolites are often found
in only one plant species or related group of species, whereas primary metabolites
are found throughout the plant kingdom. Also, they are often generated only
during a specific developmental period of the plant. Many such compounds occur
in nature as anti-feedant and anti-infectant chemicals, and are found effective
against microbes. Flavonoids and hydroxylated phenols, for example, are naturally
synthesized by plants in response to infection (Dixon et
al., 1983). Flavones and flavanones, being bitter, also have natural
anti-feedant effects. Alkaloids are the most common plant metabolites (Levin
and York, 1978). An alkaloid derivative, nicotine, for example, has been
shown to have insecticidal activities (George et al.,
2000). Quinine, another alkaloid isolated from the bark of the South American
Cinchona tree in, 1817 was the first effective anti-malarial drug (Mita
et al., 2009). More recently, many secondary metabolites have been
suggested to have Immuno-modulation properties in animals (Table
1) (Hashemi and Davoodi, 2011).
Herbal plants as growth and health promoters: Results of research on
phytobiotics as growth and health promoters in poultry are not completely consistent
(Hashemi and Davoodi, 2010). Some authors state significant
positive effects on broiler performance (Ertas et al.,
2005; Cross et al., 2007; Peric
et al., 2008; Hashemi et al., 2009a,
2009b), whereas another group of researchers established
no significant effects on performance (Cross et al.,
2007; Ocak et al., 2008). Assumption is that
differences in results are consequences of numerous factors such as: type and
part of plant used and their physical properties, harvest time, phytogenic additive
preparation method, herbal extraction methods and compatibility with other food
components (Hashemi et al., 2008a: Yang
et al., 2009). Although, quality of chickens, health condition, environment
management and production facility can also be considered as another parameters
that positive effect of phytobiotics cannot always be confirmed. One of the
Main mechanisms by which herbal plants exert helpful effects on animals' growth
and health is immunostimulatory properties (Yang et al.,
2009; Hashemi and Davoodi, 2010, 2011).
Herbal plants and their drivities effects on animal immune system:
can be difined as the changes in stimulating and suppressing of the indicators
of cellular, humoral and non-specific defense mechanism. Typically, immune system
is held in homeostatic balance between immunestimulation and immunesuppression.
Nutrition is a critical determinant of immune response
s and malnutrition the most
common cause of immunodeficiency worldwide (Kirk, 1997
). Of the micronutrients, zinc (Cardoso
et al., 2006
), selenium (Da Silva et al.,
), copper (Hosseini et al., 2011
A (Dalloul et al., 2002
), vitamin C
et al., 2010
), vitamin E (Erf et al., 1998
Cardoso et al., 2006
and Ruiz-Feria, 2006
) and B-6 (Blalock et al.,
) have important influences on immune response
s. Natural products and
natural product derivatives has a traditional history as immunostimulants. Emerging
evidence indicates that herbal plants exert their beneficial effects on animal
immune system mostly by plant secondary metabolites (Hashemi
et al., 2008b
). The immunostimulating activities of many of these components
have been most widely studied in mouse, chicken and human cell lines (Shan
et al., 1999
; Cao and Lin, 2003
and Zhang, 2004
). These pharmacological effects are extensive ranging. For
example, Ginsing with its steroidal saponine, has immune-stimulating properties
including cytokine production (IL-2, IL6, TNF-α and INF-γ), macrophage
activation and lymphocyte activity (Tan and Vanitha, 2004
Conversely, flavonoids and terpenes from Ginko biloba
can mediate production
and inflammatory cytokines (Li, 2000
). Saponins have ability
to stimulate the cell-mediated immune system, as well as to enhance antibody production
(Oda et al., 2000
). Saponins reportedly induced
production of cytokines such as interleukins and interferons (Jie
et al., 1984
; Kensil, 1996
). Meyer saponins
(Jie et al., 1984
), Quillaja saponins (Maharaj
et al. 1986
) and the butanol extract of Lonicera japonica
et al., 1998
) and de-acylated saponin-1 administered on the nasal mucosa
(Recchia et al., 1995
), all stimulated the immune
responses in vivo
. The immunostimulants activity of saponins was thought
to be associated to branched sugar chains or aldehyde groups (Bomford
et al., 1992
) or to an acyl residue bearing the aglycone (Kensil,
). As against the stimulatory effects on specific immunity components,
saponins have also been shown to be capable to put a stop to some non-specic immune
reactions such as inflammation (De Oliveira et al.,
; Haridas et al., 2001
) and monocyte proliferation
(Delmas et al., 2000
; Yui et
). Herbal plant polysaccharides, also has been extensively studied
for immunomodulatory effects (Nair et al., 2004
; Chen et al., 2010
Qiu and Cui (2008)
reported that the polysaccharides obtained
from four Chinese herbs, Astragalus root, Isatis root, Achyranthes root and Chinese
Yam, considerably improved the antibody titer in vaccinated chicken. Beta-sitosterol
and its glycoside are sterol molecules and a mixture of them showed that to have
profound immune modulating activities. This phytosterol complex seems to target
specific T-helper lymphocytes, the TH1 and TH2 cells, helping normalize their
functioning, resulting in improved T-lymphocyte and natural killer cell activity
(Bouic and Lamprecht, 1999
). Furthermore, it has also
been reported that Chinese herbs can stimulate the development of immune organs,
such as the thymus and spleen (Gao and Wu, 1994
) as well
as increase antibody production.
Although, there are a small number of studies which have revealed the mechanism
of action of the immunostimulatory compounds of herbal plants but the exact
molecular mechanisms of some herbs are not already known. There are several
possible explanations for immunomodulation mechanisms of herbal plants and their
derivatives that have been put forward. Our attempt here would be to look more
closely at the herbal plants mechanisms involved, including from the immunomodulation
point of view and relationships between structures and activities. Although,
more research on this topic needs to be undertaken before the association between
herbal plant and immune systems is more clearly understood.
Heat-shock proteins: One recent area of research in immunity may explain
the action of phytogenics to protect against pathogens is production of Heat-Shock
Proteins (HSPs) in cells. Heat-shock proteins are produced in abundance within
the cell in response to various stressors. proteins are an evolutionary conserved
family of proteins whose expression increases in response to a variety of different
metabolic insults. Despite their designation, most of the HSPs are constitutively
expressed and perform essential functions (Ellis, 1990;
Lee and Tsai, 2005; Bukau et
Under stressful conditions such as heat shock, pH shift or hypoxia, increased
expression of HSPs protect the cell by assists in protein transport into mitochondria
and the endoplasmic reticulum, protects proteins under stress, stabilizes proteins
prior to complete folding, giving the cell time to repair or re-synthesize damaged
proteins and transports across membranes and proteolysis (Zulkifli
et al., 2002; Zulkifli et al., 2003;
Bukau and Horwich, 1998; Bergner,
2005). Cell stressors that induce heat shock proteins are shown in Table
Heat shock proteins greatly enhance the efficiency of intracellular protein
manufacture and transport and may enhance immunity against pathogens by improving
immune surveillance of infected cells (Bergner, 2005).
A number of herbs or their derivatives have been showed to induce or to facilitate
HSP responses are listed below and such herbs may strengthen the systemic response
to antigens. All have been traditionally use as tonics, adaptogens, or immuno-modulators.
They include: Allium savitum (Sumioka et al.,
2001) Curcuma longa (Dunsmore et al.,
2001; Batth et al., 2001), Schisandra
chinensis (Chiu et al., 2004) Glycyrrhiza
spp. (Yan et al., 2004), Paeonia spp. (Yan
et al., 2004), and the Chinese medicinal herbs Panax notoginseng
(Yao and Li, 2002), Platycodon grandiflorum (Lee
et al., 2004) and Saussurea lappa (Matsuda
et al., 2003), Zingiber zerumbet (Hashemi,
2010) and Zingiber officinale (Hashemi, 2010).
Toll-like receptors: Until recently it was assumed that the non-specific
side of the immune system, characterized by tissue macrophages, dendritic cells
and complement system has been viewed as the poor-cousin of the specific immunity
produced by the humoral and cell-mediated systems. It was thought that non-specific
immunity was primarily a local immune response and that the specific immunity,
characterized by B-Cell and T-Cells must be directly activated to elicit a systemic
response. Recent discoveries in the field of immunology showed that TLRs has
main function in immune system. TLRs are a class of proteins that play a key
role in the innate immune system. They are single, membrane-spanning, non-catalytic
receptors that recognize structurally conserved molecules derived from microbes.
Once these microbes have breached physical barriers such as the skin or intestinal
tract mucosa, they are recognized by TLRs which activate immune cell responses.
Recent discoveries in the area of TLRs in macrophages and dendritic cells has
shown that different TLRs recognizing different Pathogen-associated Molecular
Patterns (PAMPs) (Underhill and Ozinskym, 2002) and
these non-specific defense cells can also initiate a systemic response by previously
unknown pathways (Bergner, 2005).
Research shows that some polysaccharides from medicinal plants can trigger
the expression and activity of the some TLR and plants containing polysaccharides
may assist in the initiation of system wide enhanced immune surveillance. Plants
or plant-derived polysaccharides which have been shown to initiate or enhance
TLR response and immune activation are: Ganoderma lucidum (Shao
et al., 2004a), Astragalus membranaceus (Shao
et al., 2004b), Panax ginseng (Nakaya
et al., 2004; Pugh et al., 2005) Panax
quinquefolius, Echinacea angustifolia and purpurea (Pugh
et al., 2005), Acanthopanax senticosus (Han et
al., 2003), Platycodon grandiflorum (Yoon et
al., 2003), Tinospora cordifolia (Nair et
al., 2006) and Cordyceps sinensis (Chen et
It should be noted that polysaccharides are insoluble in alcohol, and are not present in tinctures with greater than about 35% alcohol. These plants must be taken as powders, infusions, or decoctions for these effects on TLR to occur.
TH-1/TH-2 Balance: The T-Helper (TH) cells are like the quarterbacks
of the specific immune system, and they coordinate the escalation of both the
humoral (antibody) and cell-mediated responses (Bergner,
2005). Proliferating helper T cells that develop into effector T cells differentiate
into two major subtypes of cells known as Th1 and Th2 cells. The major differences
between Th1 and Th2 are shown in Table 3. Th1 cells producing
INF-γ, IL-2 and TNF-β are involved in the regulation of cellular immunity.
On the other hand, Th2 cells producing IL-4, IL-5 and IL-6 are important in
humoral immunity. The composition of the TH pool of cells may become unbalanced,
favoring one side of the immune equation over the other.
|| Major differences between Th1 and Th2 function
|INF-γ: Iinterferon-gamma; TNF-β: Tumor necrosis
factor-beta and IL: Interleukin
Several nutrients and hormones measurably influence Th1/Th2 balance, including
plant sterols/sterolins, melatonin, probiotics, progesterone, minerals such
as selenium, zinc and some long chain fatty acid like Eicosapentaenoic Acid
(EPA) and Docosahexaenoic Acid (DHA) (Kidd, 2003). Herbal
medicines may be used to help restore the TH1/TH2 balance, but evidence for
consistent effects on either system is scarce and it is difficult to predict
clinical effects from the suggestive in vitro and in vivo evidence
that exists. The five herbal medicines with some evidence of being to restore
balance in a TH-2 dominant system are Allium sativum, Astragalus membranaceus,
Ganoderma lucidum, Grifola frondosa and Panax ginseng (Bergner,
The global for poultry production experienced leaps and bounces over the past fifty years to accommodate rising demand. On the other hand, popular demand and scientific interest for organic poultry production, particularly feeding with medicinal botanicals, has increased considerably in recent years. Previous studies have clearly established the fact that herbal plants and their derivatives have potential as immunomodulators. Both, the innate and adaptive components of the immune system are stimulated by phytogenics. However, the studies have overly relied on in vitro data and there is rare use of animal subjects in the research. Moreover, most studies have used herbal extracts rather than the purified compounds. Therefore, there is still suspicion concerning the efficacy and optimum dosage of herbal plants and their derivatives as immunostimulators. Hence, more research is required for scientific validation of herbal plants as potent animal immunostimulators.
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