Research in Veterinary Science 137 (2021) 9–29

Contents lists available at ScienceDirect

Research in Veterinary Science

journal homepage: www.elsevier.com/locate/rvsc

Potential role of important nutraceuticals in poultry performance and

health - A comprehensive review
Mahmoud Alagawany a, *, Shaaban S. Elnesr b, Mayada R. Farag c, Mohamed E. Abd El-Hack a,
Rasha A. Barkat d, Amr A. Gabr e, Manar A. Foda f, Ahmed E. Noreldin g, Asmaa F. Khafaga h,
Karim El-Sabrout i, Hamada A.M. Elwan j, Ruchi Tiwari k, Mohd Iqbal Yatoo l,
Izabela Michalak m, Alessandro Di Cerbo n, *, Kuldeep Dhama o, *
a
Department of Poultry, Faculty of Agriculture, Zagazig University, Zagazig 44511, Egypt
b
Department of Poultry Production, Faculty of Agriculture, Fayoum University, Fayoum 63514, Egypt
c
Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt
d
Department of Physiology, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
e
Department of Physiology, Faculty of Veterinary Medicine, Cairo Unversity, Giza 1221, Egypt
f
Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
g
Department of Histology and Cytology, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
h
Department of Pathology, Faculty of Veterinary Medicine, Alexandria University, Edfina 22758, Egypt
i
Poultry production Department, Faculty of Agriculture, Alexandria University, Elshatby, Egypt
j
Animal and Poultry Production Department, Faculty of Agriculture, Minia University, 61519 El-Minya, Egypt
k
Department of Veterinary Microbiology and Immunology, College of Veterinary Sciences, Deen Dayal Upadhayay Pashu Chikitsa Vigyan Vishwavidyalay Evum Go-
Anusandhan Sansthan (DUVASU), Mathura 281001, India
l
Sher-E-Kashmir University of Agricultural Sciences and Technology of Kashmir, Shalimar, 190025 Srinagar, Jammu and Kashmir, India
m
Faculty of Chemistry, Department of Advanced Material Technologies, Wrocław University of Science and Technology, Wrocław 50-370, Poland
n
School of Biosciences and Veterinary Medicine, University of Camerino, Matelica, Italy
o
Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243 122, Uttar Pradesh, India

A R T I C L E I N F O A B S T R A C T

Keywords: Antibiotics use in poultry as a growth promoter leads to the propagation of antibiotic-resistant microorganisms
Nutraceuticals and incorporation of drug residues in foods; therefore, it has been restricted in different countries. There is a
Animal global trend to limit the use of antibiotics in the animal products. Prevention of the antibiotics use in the poultry
Poultry
diets led to the reduction in the growth performance. Consequently, there is a high demand for natural sub­
Health
Performance
stances that lead to the same growth enhancement and beneficially affect poultry health. These constituents play
Microbiota essential roles in regulating the normal physiological functions of animals including the protection from infec­
Immunity tious ailments. Nutraceuticals administration resulted beneficial in both infectious and noninfectious diseases.
Being the natural components of diet, they are compatible with it and do not pose risks associated with anti­
biotics or other drugs. Nutraceuticals are categorized as commercial additives obtained from natural products as
an alternative feed supplement for the improvement of animal welfare. This group includes enzymes, synbiotics,
phytobiotics, organic acids and polyunsaturated fatty acids. In the present review, the summary of various
bioactive ingredients that act as nutraceuticals and their mode of action in growth promotion and elevation of the
immune system has been presented.

1. Introduction DeFelice, who also specified that a nutraceutical could be either a food
or a part of it able to prevent and/or treat a diseases (Brower, 1998;
The term "nutraceutical" derives by the words "nutrition" and Kalra, 2003). The term has been always at the center of a worldwide
"pharmaceutical" that were firstly combined in 1989 by Stephen debate about its real definition and boundaries. Despite in 2016

* Corresponding authors.
E-mail addresses: [email protected] (M. Alagawany), [email protected] (A. Di Cerbo), [email protected] (K. Dhama).

https://doi.org/10.1016/j.rvsc.2021.04.009
Received 27 February 2021; Accepted 12 April 2021
Available online 20 April 2021
0034-5288/© 2021 Elsevier Ltd. All rights reserved.
M. Alagawany et al. Research in Veterinary Science 137 (2021) 9–29

Gonzalez-Suarez et al. confirmed the safety of nutraceuticals if 2013). In brief, microbiota in the intestine is critical for stabilizing the
consumed at dietary doses, the authors underlined their potential immune status and controlling the inflammatory response (Lan et al.,
toxicity at supra-dietary doses due to the presence of some substances 2005). For instance, short-chain fatty acids (SCFAs) which are created
with targeted activity at genomic level (Gonzalez-Suarez et al., 2016). In by the commensal bacteria, have an anti-inflammatory protective role as
2017, Lee compared nutraceuticals to functional foods, confirming the it prevents intestinal injury (Brestoff and Artis, 2013). Modulation of the
ability to exert health benefits but introducing the potential to reduce intestinal microbiota is possible with using nutraceuticals in the poultry
the risk of chronic diseases (Lee, 2017). diet, which is able to boost the propagation of useful bacteria and to
Notwithstanding the health-promoting activity and the lack of side suppress harmful bacteria (Adil and Magray, 2012). It is evident that
effects (Sachdeva et al., 2020), however, some authors raised the food items containing n-3 polyunsaturated fatty acids (PUFA) exert
concern about the difficulty to trace a clear boundary between nutrients, positive impact in boosting the immunity in broiler chickens (Al-Kha­
herbal products, pre- and probiotics, food additives, drugs, and nutra­ laifah et al., 2020; Lee et al., 2019).
ceuticals (Santini et al., 2018; Varzakas et al., 2018), remarking the
harmfulness of these latter if assumed by vulnerable subjects (old, very 1.1. Aim and searching criteria
young, chronically sick) without a medical control (Di Cerbo, Palmieri
et al., 2014, Télessy, 2019). This review aims to illustrate the different nutraceutical substances
By the years nutraceuticals gained importance in recent times in applied in poultry production to stabilize animal health, promote their
view of the increasing demand for improving production performance in development, and modulate their immunity. Also, the mechanism of
poultry birds and restriction or ban on use of antibiotics in feed sup­ induction of these effects is discussed. The current review discusses the
plements (Dhama et al., 2014a, 2014b; Di Cerbo et al., 2018; Filazi and potential role of nutraceuticals in improving the growth performance,
Yurdakok-Dikmen, 2019; Landoni and Albarellos, 2015; Mazzeranghi immune system and gut microbiota and public health of poultry. Addi­
et al., 2017; Yadav et al., 2016). Nutraceuticals should provide all the tionally, it covers the most popular aspects of nutraceuticals, applied as
necessary elements that support the health and productivity (Helal et al., a new strategy to diminish the use of antibiotic growth promoters (AGP)
2019; Yadav and Jha, 2019) and improved bioavailability and feed in the diets of poultry.
utilization efficiency enable better outcomes (Diaz-Sanchez et al., 2015; We searched Pubmed/Medline using the keywords “nutraceuticals”
Yadav and Jha, 2019). Increasing the efficacy of feed and promoting the and “poultry”. Selected papers from 1946 to 2020 were chosen on the
growth rate are essential outputs in poultry farming. Many elements basis of their content. Relevant articles that used such terms and were
should be considered to achieve this target, which includes quality of written in English language were included.
feed, the animals’ genetics, environmental conditions, and diseases
(Rinttilä and Apajalahti, 2013). Similar to other animals, the poultry’s 1.2. The utilization of antibiotics as growth promoters in poultry industry
digestive tract is their critical system for facilitating the feed-stuffs use
and intake and it also has significance regarding the environmental The discovery of antibiotics has been effective in controlling the
pathogen exposure (Yegani and Korver, 2008). Therefore, the functional infectious diseases and inducing nutritive efficiency (Engberg et al.,
disturbance of the digestive tract risks the animals’ health and perfor­ 2000). Antibiotics, whether synthetic or natural, produced by certain
mance as the feed absorption and digestion are disturbed. The small bacteria or by lower fungi, are used to prevent the spread of bacteria and
intestine is the major place for absorption of nutrients (Abdelnour et al., kill them. They are not efficacious against viral and fungal pathogen, but
2019). The intestinal mucosa plays a pivotal role as it boosts the nutri­ only treat infectious diseases caused by bacteria (Pacelli et al., 2020).
ents absorption and acts as a barrier between the host internal tissue and The antibiotics are widely used for human and animal treatment and
outside intestinal content thus serving as an immune defense mechanism prevention of infections (Di Cerbo et al., 2014; Iseppi et al., 2020a,
also (Rinttilä and Apajalahti, 2013). This mucosal function is deter­ 2020b; Palmieri et al., 2014; Panda et al., 2009).
mined by the balance between the mucosal layer, epithelial cells, im­ Scientific evidences, however, show that the widespread using of
mune cell and microbiota (Kogut, 2019). these components has contributed to an augmented problem of antibi­
Consequently, the disruption of this balance endangers the perfor­ otics resistance and the accumulation of antibiotics residues in food and
mance of animals (Schenk and Mueller, 2008; Yang et al., 2015). To the environment, which threatens animal and human health (Di Cerbo
maintain this prophylactic balance, doses of antimicrobials have been et al., 2020; Furtula et al., 2010; Tiwari et al., 2013).
used in poultry production for a long time (Landoni and Albarellos, Therefore, effective alternatives for controlling infectious diseases
2015). However, several countries have prohibited this usage as it leads and limiting the prevalence of resistant bacteria are increasingly
to the propagation of antibiotic-resistant microorganisms, detrimental required, but most significantly, maintaining the antibiotics as valuable
environmental effects and risks of consumer health (Apata, 2009). The means for the futurity (Gadde et al., 2017; Yadav et al., 2016).
reduction in animal performance and occurrence of particular poultry Over the past fifty years, the using of antibiotics in conjunction with
diseases have been observed after removing the antibiotics from the rigorous hygiene and biosecurity measures allowed poultry industry to
poultry diet (Huyghebaert et al., 2011). To fill this gap, a natural sub­ develop by avoiding the adverse effects of several avian ailments (Ber­
stance that preserves animal health and promotes the physiological mudez, 2013). Antibiotics are classified according to their mode of ac­
function was developed, and these substances were named “nutraceu­ tion, chemical family and bacteria species they work on. The poultry
tical” (Das et al., 2012). Besides their beneficial role in humans, nutra­ industry utilizes antibiotics to increase the production of meat through
ceuticals are also used in poultry to regulate the immune system and prevention of diseases, inducing growth rate and improving the feed
bacterial population, to modulate the morphology of intestine, as well as conversion (Di Cerbo et al., 2016a, 2016b; Lee et al., 2012). This is
to promote the growth rate (Sugiharto, 2016). primarily due to the gastrointestinal infection control and intestinal
It is known that the equilibrium between useful and pathogenic microbiota alteration (Singh et al., 2013). Antibiotics can decrease the
bacteria in the intestinal tract is essential for animal health as it de­ microbial load in the intestine, resulting in increased availability of
termines the morphology of the intestinal walls, and the immune re­ nutrients (Brisbin et al., 2008). In sub-therapeutic dosage, antibiotics
sponses are induced when this balance is disrupted (Choct, 2009). This were widely used as antibiotic feed additives (AFAs) in poultry ration
imbalance leads to an increase in energy consumption due to the in­ and animal feed and due to their unwarranted residual toxicity and/or
flammatory response to microbial infections (Kogut, 2013). However, developing drug resistance now researchers are finding new alternate
the inflammatory response is needed; it would be a risk for intestinal and feed additives like phytochemicals, phytosterols, phytosterol esters,
digestive function when it is not controlled (Brisbin et al., 2008). adjuvants, prebiotics and probiotics for commercial poultry production
Moreover, severe inflammation disrupts the body metabolism (Kogut, (Dhama et al., 2014a, 2014b; Kim et al., 2014; Mehdi et al., 2018; Suresh

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et al., 2018; Yadav et al., 2016). In this regards, one study conducted positive effect on the functioning of other vital organs. They are
over 240-day old broiler chickens concluded that the incorporation of recognized as alternative natural feed additives, safe to use (Slizewska
Lactobacillus acidophilus as a feed additive in the diet of broiler chickens et al., 2020). Through the presence of pharmacological and biological
at the concentration of 106 CFU/g of basal diet was capable of improving activities, nutraceuticals impede drug resistance to antibiotics and often
blood biochemical parameters, histological morphology of intestine and provide synergistic effects (Maass et al., 2005). Recently, Sachdeva et al.
gut health of broiler chickens and hence Lactobacillus acidophilus was revealed that nutraceuticals are getting interested because of their
proposed as a promising alternative to antibiotic growth promoters nutritional and therapeutic benefits over the medicine with no side ef­
(Biswas et al., 2018). Antibiotics also adversely affect immunity of birds fects (Sachdeva et al., 2020).
(Schokker et al., 2017; Yadav and Jha, 2019). Due to prospective dietary and therapeutic impacts, nutraceuticals
Further than the several useful advantages of antibiotics, there is a have recently obtained a significant interest (Nasri et al., 2014). Appli­
risk of developing antibacterial resistance and transferring the antibiotic cability in the infectious and non-infectious diseases including lifestyle
resistance genes from animals to humans. For this reason, a much- diseases of humans amounts to their popularity in recent times and the
needed is alternative to antibiotics. Therefore, this current review is rising demand (Chanda et al., 2019). The nutraceutical industry
focused on addressing nutraceuticals as a new alternative for improving amounts to over 250 billion dollars annually, and the nutraceuticals
poultry performance and enhancing the immune response in poultry used in animal diseases are more common than in human owing to their
farming. low cost and safety (Gupta et al., 2019). Nutraceuticals have broad uses
in poultry nutrition and production. It is important to add that using a
1.3. Nutraceuticals definitions new generation of feed additives, including nutraceuticals in poultry
feeding, it is possible to obtain poultry products (e.g., eggs, meat)
Nowadays, decrease in the use of antibiotics in animal farms and enriched with biologically active compounds, like polyunsaturated fatty
looking for safer and healthier alternatives is a global trend. The sen­ acids, microelements, vitamins (Alagawany et al., 2019a, 2019b, Dhama
tence “Let food be thy medicine and medicine be thy food” was proposed et al., 2014a, 2014b, Lee et al., 2019, Michalak et al., 2020, Yadav et al.,
by Hippocrates long back around 2500 years ago and the concept sug­ 2016). Biofortified food can be consumed as part of the daily diet (nu­
gested that balanced food itself is a remedy in correcting many health traceutical food) and egg material can be also used for the production of
ailments. However with the passage of time various attractive terms as new biopreparations or a new generation of nutraceuticals (Trziszka,
functional foods, nutraceuticals, superfoods, direct fed microbials came Różański and Polanowski 2013). Eggs active compounds (e.g., lyso­
into picture serving the same role of promoting health through food and zyme, yolkin, cystatin, phospholipids for example ovolecithin have
dietary supplements (Junaid et al., 2018). The concept of functional significant nutraceutical properties such as antioxidant, antimicrobial
food was introduced nearly 1980s in Japan and such dietary components antiallergenic, antiatherogenic and cardioprotective (Laudadio, Lor­
were designated as Food for Specified Health Use (FOSHU). More than usso, Lastella, Dhama, Karthik, Tiwari, Gazi Mahabubul and Tufarelli
300 food items have been given the status of FOSHU in Japan. The 2015, Trziszka, Różański and Polanowski 2013). These products can be
nutraceutical can be defined as natural substances such as milk products, used for the treatment of various civilization diseases, such as cancers,
organic acids, and fruits added to food to provide medicinal or health heart and cardiovascular diseases, hypercholesterolemia, neuro­
benefits for living organisms, including the treatment/prevention of a generative disorders (e.g., Alzheimer’s disease) etc (Trziszka, Różański
disease (Brower, 1998). Nutraceuticals, in general, are natural compo­ and Polanowski 2013).
nents (pharmaceuticals) which play roles in altering and sustaining
normal physiological actions that benefit the healthy host (Das et al., 1.4. Gut microbiota, defense system and performance of poultry
2012). It means that nutraceuticals beside they are nutritional products,
they have also medicinal effects and physiological benefits. Nutraceut­ Nutraceuticals, such as organic acids, prebiotics, exogenous enzymes
icals are health enhancing products that improve mental and physical and probiotics, are used as alternatives to antibiotics with the intestinal
activities of the body, minimize risk factors of disease (Helal et al., microbiota modulating effects (Dhama et al., 2008; Dhama et al., 2014a,
2019). There is a confusion, that still exists among several researchers 2014b; Yadav et al., 2016; Yadav and Jha, 2019). Such nutraceuticals
whether to consider them as an additive or food supplement. Actually, can help protect the host from infectious diseases (Cencic and Ching­
nutraceuticals differ from other dietary supplements in several aspects waru, 2010), and improve the gut microbiota, immune functions, and
such as their capacity for ameliorating the well-being and health of promote growth in poultry (Sugiharto, 2016). They modulate gut
animal without leaving any residues in meat consumed by human. microbiota that helps in improving improve nutrient digestion, ab­
Therefore, it seems to locate nutraceuticals somewhere between drugs sorption, metabolism, and overall health and growth performance of
and food nutrients and hence considered as hybrid of drug and food poultry(Yadav and Jha, 2019). They have antigastritis and gut protec­
(Helal et al., 2019). tive roles (Sangiovanni et al., 2018). Rinttilä and Apajalahti reported
There are different systems of classification being followed in that the commensal gut microbiota seems to play vital roles in directing
nutraceuticals (Chanda et al., 2019). They may be based on food the inner structure and morphology development, modulating the im­
availability, mechanism of action and chemical nature. Traditional and mune responses, guarding against luminous pathogens, and facilitating
nontraditional food items have been used as nutraceuticals under food- the absorption and use of nutrients (Rinttilä and Apajalahti, 2013). So,
based category when the traditional nutraceuticals include chemical that means that intestinal mucosa plays crucial roles in the digestion and
constituents (nutrients, herbals, and phytochemicals), probiotic organ­ gastrointestinal tract (GIT) development. Nutraceuticals have proven
isms and nutraceutical enzymes and the nontraditional ones include beneficial in modulating gut environment thereby elaborating the
fortified and recombinant nutraceuticals. Based on mechanism of action digestive and absorptive role to metabolic and immunological functions
they are antimicrobial, anti-inflammatory and antioxidant which reflect that are vital for growth, development, health and productivity of
their therapeutic importance. Classification can also be based on poultry (Adedokun and Olojede, 2018). Commensal gut microbiota has
chemical nature of nutraceuticals be it primary metabolite or secondary been known to be essential inductors for the maturation and develop­
metabolite source. However detailed description of individual nutra­ ment of both innate defense mechanisms and chicken adaptive immune
ceutical with respect to poultry will help in better understanding response (Brisbin et al., 2008). The gut microbiota plays decisive roles in
importance in poultry health and production. the manipulation of epithelial proliferation of gut, synthesis of vitamins
A vast number of nutraceuticals are used in the form of probiotics, and host energy metabolism. In poultry, GIT accommodates a sophisti­
prebiotics or synbiotics (combination of probiotics and prebiotics) to cated and dynamic microbiome primarily consists of bacteria and a low
improve the intestinal health in animals, and they also seem to have a level of fungi, protozoa, bacteriophages, yeast, and viruses. These

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microbes extensively react with the host and consumed feeds. Every part probiotics), herbal products (spices, herbs, polyphenols), to genetically
of GIT has a different microbe population, each niche (Yadav and Jha, modified foods, and they could improve the gut microbiota, immune-
2019). Often in the chicken, the influence on intestinal health may come response, and enhance growth performance in poultry (Das et al.,
from the microbial imbalance in the gut (Abudabos et al., 2018; Olnood 2012; Sugiharto, 2016).
et al., 2015). It is commonly recognized that the appropriate microbial The growing interest in medicinal plants is due to their properties
balance between the number of harmful and favorable bacteria in GIT that can contribute to enhancing the final product quality of poultry
(favorable bacteria are about 85% of total bacteria) is pivotal for the (Alagawany et al., 2019a, 2019b; Dhama et al., 2015; Dhama et al.,
host (Choct, 2009). The bacterial imbalance is compounded by the 2014a, 2014b; Vinus et al., 2018). Herbs and plant oils have been used
elimination of antibiotics from the feed. In agreement, Kabir revealed normally in poultry feed to maintain their health and enhance the pro­
that the balance of gut microbiota is vital for enhancing the maximum ductive performance due to their active constituents content that have
chicken’s growth performance and healthy gut (Lutful Kabir, 2009). medicinal impacts such as anti-inflammatory, antioxidant and antibac­
However, the gut microbial population can be changed by dietary terial, and exert affirmative impacts on the physiological processes
means, in combination with the growing beneficial bacteria in the (Alagawany et al., 2019a, 2019b; Dhama et al., 2015; Dhama et al.,
chicken intestine (Adil and Magray, 2012). Humphrey and Klasing 2014a, 2014b; Khafaga et al., 2019; Reda et al., 2020; Vinus et al.,
found that the microbiota change can impact the gut wall morphology 2018). Some reports showed that hen’s feed conversion rate and egg
and elicit immune reactions that in turn can influence the energy ex­ production were improved with the addition of cinnamon or rosemary
penses and chicken’s development (Hussein et al., 2020). Changes in essential oils in the diets (Ding et al., 2017; Şimşek et al., 2015).
chickens’ intestinal microbiota can affect their immunity and health. To understand the influence of these essential oils, there are two
However, several factors may influence the change in the gut microbiota acceptable mechanisms. The first mechanism is considering by the
of chicken, including the presence of antibiotics in the diet, the exposure boosting digestive enzyme secretion, and the second is dealing with the
to pathogens and housing condition (Lee et al., 2012). ecosystem stabilization of intestinal microflora, which leads to enhance
Nutraceuticals are comprised of fortified nutrients besides the reg­ the utilization of food and decreasing the exposure to growth-depressing
ular vitamins, minerals in the diet and when consumed in recommended disorders that could be correlated to the digestion and metabolism
dosage along with diet, nutraceuticals/ functional foods claim various processes (Bento et al., 2013; Kurekci et al., 2014; O’Bryan et al., 2015).
health benefits (Hasler, 2002). Providing the birds with nutraceuticals Additionally, some broiler studies have documented affirmative in­
can perform several activities in the animal body, such as anti- fluences of essential oils on the digestive enzyme secretion of pancreas
inflammatory, antimicrobial, sedative, adaptogenic, immunomodula­ and the gut mucosal (Jamroz et al., 2006; Jang et al., 2007), and these
tory, antioxidative and free radical scavenging with various pharma­ impacts have been established through enhancing nutrient digestibility
cological impacts (Attiq et al., 2018; Dhama et al., 2014a, 2014b; Gupta, (Abdelnour et al., 2019; Amad et al., 2011).
2016). Das et al. reported that nutraceuticals could range from isolated
nutrients (vitamins, minerals, amino and fatty acids), dietary supple­
ments (prebiotics, organic acids, antioxidants, enzyme, synbiotics,

Fig 1. The mode of action of non-starch polysaccharide-degrading enzyme (NSPase) and phytase

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M. Alagawany et al. Research in Veterinary Science 137 (2021) 9–29

1.5. Exogenous enzymes performance and zinc utilization of white pekin ducks (Attia et al.,
2019). The mode of action of non-starch polysaccharide-degrading
Historically enzymes are considered to be non-toxic and not of safety enzyme (NSPase) and phytase is illustrated in Figure 1.
concern for consumers since they are naturally present in ingredients
used to make food. However, food enzymes produced industrially by 1.6. Probiotics
extraction from plant and animal tissues, or by fermentation of micro­
organisms, are assessed for safety. Exogenous enzymes have been Nutraceuticals or functional foods (probiotics) improve host health
employed for improving feed utilization, growth performance, nutrient by altering nutritional, immunological and physiological parameters
digestibility, meat quality and physio-biochemical status of poultry within the body of host and in the form of probiotic strains they help in
birds (Attia et al., 2019; Kumanda et al., 2019). The nutritional signif­ setting a balance in gut microflora (Al-Khalaifah, 2018, Cencic and
icance of exogenous enzymes in feed use efficiency and promoting the Chingwaru, 2010, Dhama et al., 2008, Di Cerbo and Palmieri, 2015,
growth is well known in poultry sector (Alagawany et al., 2018b). They Junaid et al., 2018). At present, safety data is available for some tradi­
help in reducing anti-nutritional compounds such as fiber and tional starter micro-organisms and also certain probiotic strains that
condensed tannins, increase feed intake, improve feed conversion effi­ have been commercially available for several years. In most cases, the
ciency, body weight gain, meat quality and European production index safety of novel strains has been deduced mainly from the common
(EPI) (Attia et al., 2019; Kumanda et al., 2019). Exogenous enzymes occurrence of the species either in foods or as normal commensals in the
originate either from bacteria such as Streptococcus faecium, Lactobacillus human gut. It is recommended to use probiotics to avoid diseases and
acidophilus and Bacillus subtilis, fungi as Aspergillus oryzae and Tricho­ maintain health despite their complex mechanism of action, which is
derma longibrachiatum or yeast as Saccharomyces cerevisiae (Slominski, strongly influenced by their location in the gastro-intestinal tract, the
2011). Some are produced from plants or animals, but the microbial integrity of the intestinal mucosa and transit time within the gut
enzymes are preferred (Chanda et al., 2019). Different digestive en­ (Huyghebaert et al., 2011). Probiotic preparations include: lactic acid
zymes, including amylase, xylanase, β-glucanase, etc., have been pro­ bacteria (LAB) (Lactobacillus plantarum, Lactobacillus helveticus, Lacto­
vided to animals (Adeola and Cowieson, 2011). The enzyme activity is bacillus bulgaricus, Lactobacillus lactis, Lactobacillus. casei, Lactobacillus
affected by different factors such as the feed ingredients, moisture, acidophilus, Lactobacillus salivarius), Bifidobacterium spp., Enterococcus
temperature, intestinal pH, age and species of animal (Yang et al., 2008). faecalis, Enterococcus faecium, Streptococcus thermophilus, Bacillus, Ped­
Digestion and absorption of a raw material as corn and soya is iococcus and yeast such as Saccharomyces cerevisiae and Candida spp. (Al-
complicated as it contains polysaccharides and protease inhibitors, so Khalaifah, 2018; Khaksefidi and Rahimi, 2005; Lutful Kabir, 2009).
the addition of exogenous enzyme facilitates their digestion (Costa et al., Metabolites in yeast culture of Saccharomyces cerevisiae (such as pro-
2008). Exogenous enzymes compensate for the deficiency of an endog­ vitamins and micronutrients which comprise growth factors) can stim­
enous enzyme that is important in the digestion of the anti-nutritional ulate bacterial growth in the digestive tract and optimize the feed intake
factors (Sugiharto, 2016). The addition of enzymes is essential in of poultry (Sun et al., 2019).
poultry rather than in animals due to short gut and lack of microbial Probiotics, which usually are not affected by the microflora activity
flora. Glucanase and cellulase are important in the digestion of barley of digestive system, are essential promote weight gain, regulate feed
and cellulose, respectively (Slominski, 2011). intake, digestion, immune response, decrease mortality rate; conse­
The increase in SCFAs such as lactic or organic acid and decrease in quently, they are primarily used in poultry feeding (Al-Khalaifah, 2018;
ammonia is attributed to the addition of xylanase to the feed (Adeola Alagawany et al., 2018a; Armut and Filazi, 2012; Markowiak and Sli­
and Cowieson, 2011). Poultry fed diets supplied with xylanase demon­ zewska, 2018). Being resistant against different pH values and organic
strated increase in Lactobacillus and Bifidobacteria in the caecal content. acids, probiotics grow fast and organize gut immunity cells cling to in­
On the contrary, it led to decreased bacterial counts of Salmonella and testinal cells without affecting intestinal tissue or its permeability. It is
Coliform (Nian et al., 2011). Other investigations indicated no changes in necessary for probiotics to demonstrate inhibition and resistance to the
the number of Lactobacilli (Yang et al., 2008). “Gallazyme” composed of intestinal colonization by pathogenic bacteria to decrease the frequency
protease, Bacillus subtilis (8,000 units/g), xylanase, Trichoderma long­ and duration of diseases (Alagawany et al., 2018a; Dhama et al., 2011).
ibrachiatum (600 units/g), amylase and Bacillus amyloliquofaciens (800 Despite the usefulness of probiotics to the host’s digestive, immune
units/g) was used with corn distiller’s dried grains with soluble (DDGS) system, and metabolism (Russo et al., 2016), they may become
to examine the effect on blood metabolites, egg nutrients, egg quality responsible for toxins production and consequent intercurrent affections
and performance of laying hens (from 22 to 42 weeks of age). DDGS was development as well as for the spread of antibiotic resistance genes in
used as a suitable replacement of soya bean (SBM). The same experiment pathogen bacteria (Courvalin, 2006)(Bach et al., 2018)
was done without enzyme cocktail. It was shown that using an enzyme The main impact of probiotics is as follows: (1) protection of healthy
mixture in DDGS-based diet may promote egg quality and feed effi­ intestinal microflora against pathogenic bacteria through competing
ciency, as well as decrease ammonia and increase calcium in the blood. and antagonistic effects, (2) adjusting the digestion by controlling feed
It is advised to replace SBM by DDGS in the diet (up to 500 g/kg) (Abd intake, absorption after the disintegration of organic substance, (3)
El-Hack et al., 2018). It was reported that the supplementation of alteration of metabolism by raising digestive system activities, bacterial
exogenous proteases to broiler diet boosted weight gain by 7.3%, and activity, and decrease ammonia production, (4) promotion of immunity
this result confirmed the usefulness of exogenous enzyme (Cowieson through raising antibiotics, macrophage, and cytokine secretion, (5)
et al., 2019). prevention of bacterial toxin production besides, control protozoa and
Using the enzyme in the poultry feed increases intestinal viscosity by coccidiosis by altering water quality (Alagawany et al., 2018a; Aziz
improving digestibility and metabolism of nutrients. Besides, the Mousavi et al., 2018; Brisbin et al., 2010; Dhama et al., 2017; Dhama
enzyme can replace antibiotics and can prevent the development and et al., 2011; Khaksefidi and Rahimi, 2005; Lan et al., 2005; Lutful Kabir,
colonization of hurtful microorganisms in the gut (Kum and Sekkin, 2009). Nowadays, it is recommended to use commercial products of
2012). Lowering of pH level below 4 is vital to make the effect of the different probiotic combinations to stimulate the effectiveness of pro­
exogenous enzyme (Solis-Cruz et al., 2019), and the use of enzyme biotic although we should take into account that each bacterial strain
mixture is preferred to avoid the anti-nutritive effects of feed compo­ used for the probiotic purpose is specific for unique host type or kind of
nents (Adeola and Cowieson, 2011). The supplementation of phytase in disease (Musa et al., 2009).
poultry feed may improve the feed utilization, performance, nutrient We should put also into consideration that microorganisms (Mos) of
digestibility and energy availability (Abd El-Hack et al., 2016). Phytase probiotic products do not affect all types of diseases, thus, to fully
along with zinc supplementation in diet has improved growth benefit from particular strain of disease, suitable dose must be known

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M. Alagawany et al. Research in Veterinary Science 137 (2021) 9–29

Fig 2. The favorable actions of probiotics in poultry

(generally 109 CFU/kg feed for poultry) besides, risks and harmful effect better option as growth promoters in poultry production (Ferdous et al.,
on metabolic activity can be obtained because of an adjuvant that hold 2019). CloStat® was found to protect poultry against Staphylococcus
probiotic (Mikelsaar, 2011). The reason for the unsteady bacterial aureus, Escherichia coli, Salmonella Typhimurium and Clostridium per­
population when adding a single probiotic is unknown. So, the complex fringens (Aljumaah et al., 2020).
microbial combination is added to promote the natural bacterial popu­ Anti-aflatoxigenic effect of indigenously characterized probiotic
lation and overcome competitive pathogens (Alagawany et al., 2018a). lactobacilli against Aspergillus flavus has been reported (Azeem et al.,
It is known that this aspect is useful in animals as a prominent drop in 2019). It helps in reducing activity and content of aflatoxins in feed
intestinal salmonella count resulted when a mixture of commensal which are a common poultry feed contaminant. In one study, 300 one
aerobic bacteria was added to those animals (Markowiak and Slizewska, day old Hy-line layer chicks were provided with Bacillus subtilis and
2018). Antibiotic resistance of probiotic that is transported to intestinal Enterococcus faecium as dietary supplementation till the period of 10
bacteria is significantly discussed among industrial institutions and au­ weeks of age, to see their health modulating effects on performance,
thorities, which started publishing reports in this regard (Nawaz et al., physiological and immunological response. Findings of the study
2011). favourably showed a considerable increase in total body weight gain
Khoobani et al. performed an experiment to examine the effect of including comparatively higher weight of carcass, proventriculus, small
chicory (Chicorium intybus L.) powder and probiotic blend (PrimaLac®) intestine, heart, liver, spleen, kidney, thymus and bursa of Fabricius.
in the form of natural feed additives on the performance of broiler Also blood parameters, such as serum glucose, calcium, phosphorus, red
chickens (Khoobani et al., 2019). For this reason, a total number of 225 blood cell (RBCs) count, white blood cells (WBCs) count, haemoglobin
one day old Ross 308 broilers were fed with different diet combinations. concentration, haematocrit values and triiodothyronine hormone were
The results showed a significant increase in the body weight gain indi­ also enhanced along with significant drop in concentrations of serum
cating favourable growth and performance traits, reduction in blood alkaline phosphatase (ALP), aspartate transaminase (AST), alanine
triglycerides and low density lipoprotein (LDL) with a rise in high transaminase (ALT), uric acid, triglycerides and cholesterol, suggesting
density lipoprotein (HDL) and a balanced gut microbiota including ileal an important role of B. subtilis and E. faecium used as feed additives
microflora in broiler chickens. A comparative study in broilers fed with (Hatab et al., 2016). Increase in body weight gain, a significant decrease
different additives like antibiotic (Renamycin 100®), phytobiotic, in feed conversion ratio, as well as improved blood and immunological
(Galibiotic®), probiotic (Bio-Top®) and combination of Probiotic and (serum immunoglobulin A and G) indices were observed in 336 Arbor
phytobiotic showed that feeding probiotic improved the growth per­ Acres broilers fed with yeast culture of Saccharomyces cerevisiae rich in
formance of broilers. Hence, it was concluded that probiotics can be a effective compounds such as fructose, glycine, galactose, inositol and

14
M. Alagawany et al. Research in Veterinary Science 137 (2021) 9–29

sucrose (Sun et al., 2019). microflora. Favourable effects have been also observed on the intestinal
Researchers studied the effect of dietary administration of zinc morphology, content of microflora; feed conversion efficiency, growth
bacitracin as antibiotic growth promoter (AGP), multi-strain probiotic characteristics, structure and quality of broiler meat and immune status
preparation in combination with vitamins and minerals and commercial of broiler birds (Shanmugasundaram et al., 2019b).
preparation of probiotic Bacillus subtilis on the haematological parame­ Prebiotic structure and metabolism are highly distinct. The osmotic
ters and gut microbiota over a total of 240 one day old Indonesian effect of prebiotics appears where they are not fermented. However,
indigenous crossbred chickens for the time period of ten weeks. Results when bacteria are fermented, a limited number of them is selectively
concluded that multi-strain probiotic preparation along with vitamins activated. After that, reduction of the nitrogen production rate so, in­
and minerals had better immune enhancing properties as compared to crease in SCFAs formation, lowering the efficiency of reductase enzyme
other groups (Sugiharto et al., 2018). The favorable actions of probiotics and adjustment of the immune system is observed. Consequently, pre­
in poultry are summarized in Figure 2. biotics increase gas production and fecal weight, evade constipation,
Researchers examined the effect of bile salt, pH and the addition of adjust gut habitat, somewhat decrease pH level in the colon, the ratio of
synbiotics on the survival of probiotics like Lactobacillus reuteri, Ped­ active carrier protein is increased, and toxic ratio, mutagenic residues,
iococcus acidilactici, Bifidobacterium animalis and Enterococcus faecium in bile acid, carcinogenic enzymes are reduced (Roberfroid et al., 2010).
the intestinal tracts of broiler birds. In vitro experiments suggested that Besides their positive impact, by variation in quantity and application
1.0% bile salt in the medium enhanced the growth of Lactobacillus reuteri periods, a different result can be obtained. For example, the use of large
and Pediococcus acidilactici, while 0.5% concentration of bile salt was prebiotics doses causes intestinal swelling, excessive gas fermentation,
optimum for the sufficient growth of Bifidobacterium animalis and and diarrhea. In brief, since they do not significantly affect pathogens as
Enterococcus faecium. Besides, in ovo studies showed that when probiotic an antibiotic, its disposal can be a negative side regarding prebiotic
is supplemented as a synbiotic, the colonization and survival ability of (Kum and Sekkin, 2012).
different probiotic get altered in different sections of duodenum, Prebiotics stimulate the host immune system and also improving the
jejunum and ileum of intestine, which could be confirmed by real-time colonization of beneficial bacteria, reducing the pathogenic bacterial
PCR (Siwek et al., 2018). load by competitive exclusion thereby reducing the death of poultry
(Alloui et al., 2013). The pathogen is compressed in the high intestinal
1.7. Prebiotics acidity of SCFAs produced by prebiotics, and an animal’s defense
response is improved due to the fast removal of the pathogen from the
Prebiotics are the degraded products produced by microbial action intestine (Kim et al., 2011). Promotion of the indirect mechanism of the
on nutrients in gut. They feed microbiota and their degradation products immune system by interaction with immune cells and prebiotics leads to
are short chain fatty acids that can be absorbed in blood and hence the stimulation of beneficial MOs colonization in these places in the
prebiotics have not only local gut-oriented action but also affect other intestine (Janardhana et al., 2009). No change in the feed consumption
organs (Davani-Davari et al., 2019; Fernández et al., 2016). Prebiotics and efficiency and the death rate was obtained after the application of
modulate diet fiber composition, the effect on gut flora, and have ad­ prebiotic separately (FOs and MOs) when compared to control, but live
vantageous physiological action on the colon and throughout the body weights were increased (Kim et al., 2011), in opposition to other studies
and decrease different probable risks of pathogens (Ezzat Abd El-Hack that reported no increase in live weights after prebiotic addition (Biggs
et al., 2016; Micciche et al., 2018; Ricke, 2018), especially food-borne et al., 2007; Janardhana et al., 2009).
pathogens such as Salmonella and Campylobacter (Micciche et al., These differences explain the different types of prebiotic used in each
2018). When prebiotics are fermented by gastrointestinal bacteria, study. As inulin and FOs increase the growth of Bifidobacteria that have
generated short chain fatty acids are believed to be a primary inhibitory the same binding sites of the pathogen, so they prevent the existence of
mechanism against pathogens (Ricke, 2018). pathogen bacteria (Salmonella, E. coli) in the host’sintestine. Moreover,
The activity of gut bacteria should be selectively motivated by pre­ it has been found that the intestinal epithelium barrier feature is regu­
biotic without being affected by gastric activity, hydrolytic enzyme, lated by prebiotic. As a result, the energy was provided to large bowel
intestinal digestion even by the meager rate (Kolida and Gibson, 2011). cells and antibiotic related diarrhea was stopped. Prebiotics increase
Prebiotics differ from probiotics, which are non-living ingredients that nitrogen extraction from bowel, so that relieves kidney load, decreases
are not used by the host cells and most efficient are utilized in the colon, low density lipoprotein and triglyceride level and augments immuno­
while probiotic acts in the small intestines (Kum and Sekkin, 2012). globulins in the immune system. Thus, they can modulate immunity to
Fructooligosaccharides (FOs) including inulin, galactooligosaccharides enhance product quality (low egg cholesterol), and regulate intestinal
(GOS), soya-oligosaccharides (SOS), xylo-oligosaccharides (XOS), microbiota and decrease pathogenicity of MOs (Roberfroid et al., 2010).
pyrodextrins, isomalto-oligosaccharides (IMO), lactulose, oligofructose However, Solis-Cruz et al. clarified that the efficiency of prebiotics de­
etc., have been used recently by poultry sector (Huyghebaert et al., pends on many factors, for instance the type of additions, dosage, con­
2011; Kim et al., 2011; Micciche et al., 2018; Ricke, 2018). tents of the diet, environmental condition and animal type, displaying
Prebiotics of natural origin include legumes, fruits, and cereals. variable influences on poultry species (Solis-Cruz et al., 2019). Thus, it is
Nevertheless, nowadays there is an overwhelming use of synthesized essential to determine conditions that prebiotics are efficacious and
types (Markowiak and Slizewska, 2018). Probiotics and prebiotics are clarify their mechanisms and actions, to ensure their practical use.
supplemented to the poultry diet in order to prevent intestinal diseases
(Dhama et al., 2008; Dhama et al., 2011; Elgeddawy et al., 2020). Both, 1.8. Synbiotics
probiotics and prebiotics have the same mechanism in the modification
of gut microbiota (Huyghebaert et al., 2011). In commercial systems of Synbiotics are referred as nutritional supplements combining pro­
chick raising and rearing, during the perinatal period due to various biotics and prebiotics (Alloui et al., 2013; Mansour Hamed and Hassan,
operations over hatched chicks like vaccination and transportation, the 2013). Synergistic effects are observed in the case of combination of
microbial profile of chicks gets altered what affects the development of beneficial probiotic species and prebiotic carbohydrates (Aziz Mousavi
gastrointestinal microflora and innate immunity, Therefore, in ovo et al., 2018; Markowiak and Slizewska, 2018). For example, Śliżewska
stimulation of chicken microflora offers a better approach in establish­ et al. examined the effect of synbiotics that contained Lactobacillus and
ing intestinal microflora. For this reason, embryonated chicken eggs are Saccharomyces cerevisiae (probiotic) and inulin (prebiotic) (Slizewska
inoculated with prebiotics, probiotics or synbiotic on day 12, so that et al., 2020). These preparations stimulated the growth and develop­
after crossing outer and inner shell membranes they can enter into the ment of intestinal microorganisms (Lactobacillus and Bifidobacterium)
embryonic gut in order to stimulate the establishment of internal and reduced the count of potential pathogens (E. coli and Clostridium).

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M. Alagawany et al. Research in Veterinary Science 137 (2021) 9–29

Fig 3. The role of organic acid additives in supporting gut health

Shanmugasundaram et al. found that supplementation of synbiotic synbiotics included avilamycin, live probiotic (Bacillus subtilis), natural
composed of Lactobacillus reuteri, Bifidobacterium animalis, Enterococcus phytobiotic compounds (sanguinarine and protopine), and spore pro­
faecium, Pediococcus acidilactici and fructooligosaccharide decreased biotic strain (Bacillus subtilis).
colonization of Salmonella in the intestine and carcass contamination in
broiler birds (Shanmugasundaram et al., 2019a). Recently synbiotic
(Lactobacillus spp., Saccharomyces cerevisiae and inulin) use in poultry 1.9. Organic acids
broilers, increased lactic acid, short chain fatty acids and beneficial
bacterial population, while decreased branched chain fatty acids and Organic acids are of animal and plant origin. Microbial fermentation
pathogenic population in the intestine (Slizewska et al., 2020). The of carbohydrates in the cecum of poultry is another source of organic
following increased feed conversion ratio warranted the use of syn­ acids (Huyghebaert et al., 2011). Different organic acids with various
biotics as feed additives in broiler chicken production. chemical and physical properties can be used by addition to water and
Similarly, another recent study showed that under heat stress con­ food, whether used alone or in combination. However, their combina­
dition, synbiotic supplementation to broilers reduced the harmful tion is more beneficial (Menconi et al., 2014). The use of the organic
changes caused by heat stress, which was evident in the reduction of acids is not expected to pose a risk to consumer, considering that these
HSP70 levels in liver and hypothalamus of synbiotic treated groups than acids are rapidly metabolized with very low deposition, if any, in edible
control (Jiang et al., 2020). Two synbiotics namely Lactobacillus sali­ tissues of poultry. Considering the body of evidence available, the use of
varius with galactooligosaccarides (GOS) and Lactobacillus plantarum organic acids in animal nutrition at the maximum proposed levels will
with raffinose family oligosaccharides when tested in broilers showed not affect exposure of consumers to residues or metabolites of concern
that Lactobacillus salivarius with GOS had better beneficial effect like via food from treated animals. Owing to the unlikelihood of exposure, no
reducing the pathogen load in gut thus this combination of synbiotic can risk to users upon inhalation of the organic acids is expected; the organic
be used for better production of broilers (Dunislawska et al., 2017). A acids are not a skin sensitizer, but may be a skin/ eye irritant. The
synbiotic mix namely Lactobacillus rhamnosus HN001 and Pediococcus proposed use of the organic acids does not pose environmental risks. In
acidilactici MA18/5M and Agave tequilana fructans when feed to poultry, European Union countries, organic acids and their salts (such as formic
there was reduction in Salmonella Typhimurium and Clostridium per­ and propionic acid) are used as food preservatives. The antimicrobial
fringens load in the intestine. Thus, synbiotics reduces pathogenic bac­ effect is obtained from organic acid with short-chain such as simple
terial load in the intestine of poultry (Villagran-de la Mora et al., 2019). monocarboxylic acids, carboxylic acids with hydroxyl and carboxylic
A combination of antibiotic, probiotic and phytobiotic-supplemented acids with double bonds (Shahidi et al., 2014). Weak acidic activity and
diets has ameliorated deteriorative effects of Clostridium perfringens dissociation are the characteristics of organic acids. Some of them are in
infection in broiler chicken and improved the performance, intestinal the form of sodium, potassium or calcium salts.
health, carcass traits, and meat quality (Hussein et al., 2020). These Therefore, many benefits are obtained as they are more soluble in
water, odorless, less corrosive and less volatile than acids during food

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M. Alagawany et al. Research in Veterinary Science 137 (2021) 9–29

preparation, in other words, quickly processed (Huyghebaert et al., animal feed on animal and human health. Phytobiotics are classified
2011). Excessive use of organic acids in poultry feeding is due to (1) according to their processing features and source into: (1) plants which
antimicrobial effect, (2) intestinal regulation, (3) good effect on health, include nonpermanent blooming and non-woody plants, (2) spices
nutrition, performance and egg quality (Khan and Iqbal, 2016). Dis­ which are plants with a dense odor or flavor that are supplemented to
solved in water improve bowel microflora, feed digestion and growth, food (3) essential oil particularly volatile lipophilic component and (4)
and decrease the diseases in the stomach (Mansour Hamed and Hassan, oleoresins which are extracted from spices (Gheisar et al., 2015; Huy­
2013). ghebaert et al., 2011; Windisch et al., 2008; Yang et al., 2009). For
Administration of organic acid and its salts or combination increases production of phytobiotic products, leaves, flowers, roots and whole
crypt depth and villus height in the small intestine of broiler chicken plants can be used (Grashorn, 2010). There is a huge interest in phyto­
(Adil et al., 2010; Kum et al., 2010; Paul et al., 2007). Rise of villus biotics and phytochemicals derived from herbs due to their numerous
height causes bowel epithelium strong natural barrier against toxic advantages such as easy availability, low cost, lack of the threat of
substances and pathogenic bacteria. So, the colonization of pathogen antibiotic resistance etc (Dhama et al., 2015; Mahima et al., 2012;
decreases, digestion and absorption of the nutrient increases due to the Tiwari et al., 2018; Yadav et al., 2016).
addition of organic acid and its salt (Iji and Tivey, 1998). Moreover, the The main secondary ingredients of phytobiotics involve: essential
reduction in LAB number in ileum and cecum, decreases Enterobacteri­ oils, e.g., terpenes, carvacrol; bitterns are reported for thyme and sage
aceae and Salmonella, increases body weight and feed efficiency are a (carnesol); hot stuffs, e.g., capsaicin, peperin; colorants, e.g., xantho­
result of the addition of organic acid to the feed of broiler chicken (Adil phylls (lutein, zeaxanthin, β-carotene and lycopene); phenolic com­
et al., 2010). Organic acid reduces Salmonella and E. coli in the intestine pounds, e.g., chicoric acid, flavonoids (Dhama et al., 2015; Grashorn,
and are better than polypeptide structures as a growth factor (Hassan 2010; Tiwari et al., 2018; Wald, 2003). Largely, alkaloids, glycosides,
et al., 2010). Organic acids to enter the cytoplasm of bacteria freely and phenols and terpenoids are the active constituents of phytobiotics
come from the antimicrobial rely on their dissociated form, pKa values, (Huyghebaert et al., 2011). The chemical structure of phytobiotics
and hydrophobicity (Van Immerseel et al., 2006). Acids, when enter the active component varies in relation to several factors such as: harvesting
bacterial wall, stop the bacteria activities as a result of their hydro­ season, geographical sources, and used plant part (leaves, pulp, etc.)
phobicity (Huyghebaert et al., 2011). Microflora, as lactic acid affects (Windisch et al., 2008). Some studies have proven the antimicrobial,
bacteria, formic and propionic acids affect yeast and fungi, while sorbic antioxidant, anti-inflammatory, immunomodulatory and growth pro­
and fumaric acids affect fungi only (Kum et al., 2010). Organic acid motion effect of phytobiotics (Dhama et al., 2018; Dhama et al., 2015;
decreases the number of Coliforms, while Clostridium is not impaired Mahima et al., 2012; Rahal et al., 2014; Tiwari et al., 2018; Yadav et al.,
(Paul et al., 2007). 2016). Therefore, they are known to have a wide range of activities of in
Herbal oil-covered sodium butyrate is more successful than uncov­ poultry nutrition such as stimulation of feed intake probably due to
ered one because Salmonella settlement in both the digestive tract and improved diet palatability, nutrient digestibility, growth promotion
liver was reduced by using the covered compounds (Fernandez-Rubio (improved weight gain and feed conversion ratio), improved gut
et al., 2009). Sodium butyrate covered by herbal oils is more constant microflora, antimicrobial potential, coccidiostatic, immunostimulating
against acidic pH (Mansour Hamed and Hassan, 2013). and anthelmintic effects, meat safety and quality (Dhama et al., 2015;
A short-chain fatty acid influenced the lower digestive tract, so it is Gheisar et al., 2015; Grashorn, 2010; Yadav et al., 2016). Moreover, due
absorbed in the upper GIT (Fernandez-Rubio et al., 2009). Microen­ to antioxidative properties of phytobiotics, the stability of animal feed is
capsulation (protective lipid matrix) of a short-chain fatty acid allows it improved, as well as animal’s products quality and storage time increase
to reach the whole digestive tract (Van Immerseel et al., 2006). Organic (Gheisar et al., 2015).
acids in an encapsulated form increase beneficial microflora in poultry, In commercial poultry nutrition, several plant seeds or extracts are
while harmful one is reduced (Liu et al., 2017). Acid sensitive bacteria used singly or in combination as feed additives – the most popular are:
are affected dramatically by butyrate (Kwon and Ricke, 1998). Sodium alfalfa (Medicago sativa L.), bergamot oil (Cannabis sativa), black cumin
butyrate as a bactericidal and a stimulant of intestinal epithelium (Nigella sativa), clove (Syzygium aromaticum (L.), cumin (Cuminum cym­
development supports advancement of the poultry industry by produc­ inum L.), chilli (Capsicum annum), cinnamon (Cinnamomum zeylanicum
ing a bird with good intestinal health (Elnesr et al., 2019). Conversely, Nees), garlic (Allium sativum L.), grap e (Vitis vinifera L.) seed, honey­
Araujo et al. concluded that the use of organic acids (butyric acid (1%), suckle (Lonicera japonica), oregano (Origanum vulgare), purple cone­
acetic acid (7%) and lactic acid (40%), 8 kg/ton with or without (1 × 109 flower (Echinacea purpurea), pumpkin (Cucurbita pepo L.), rosemary
CFU/g) probiotic (Bacillus amyloliquefaciens), does not display any sig­ (Rosmarinus officinalis), sage (Salvia officinalis), thyme (Thymus vulgaris),
nificant impacts on economic viability and broiler performance (Araujo turmeric (Curcuma longa L.), wild mint (Mentha longifolia L.), and others
et al., 2019). Organic acids pass through bacterial cell walls and leads to (Abd El-Hack et al., 2016; Alagawany et al., 2017; Alagawany et al.,
anion accumulation that begins to decrease pH levels, which destroy 2015; Dhama et al., 2015; Grashorn, 2010; Hojati et al., 2014).
most intracellular structures and biological processes, decrease ATP, and Supplementation of soybean isoflavones (10~20 mg/kg SI) has
illustrated as a bactericide or bacteriostatic, but the bacteria had resis­ improved growth performance, immune function, and viral protein 5
tance to acids not affected anymore (Patten and Waldroup, 1988). The mRNA expression in broiler chickens challenged with infectious bursal
role of organic acid additives in supporting gut health is illustrated in disease virus (Azzam et al., 2019). The supplementation of a phytogenic
Figure 3. mixture (quillaja, anise, and thyme) in the diet at a level of 0.075%
promoted body weight and feed efficiency of meat-type duck and broiler
1.10. Phytobiotics and phytochemicals chickens (Gheisar et al., 2015; Gheisar and Kim, 2018). In these studies,
it was shown that phytobiotics boosted feed flavor, increased their
Phytobiotics are natural active compounds obtained from several consumption in return, and also stimulated secretion of digestion en­
herbal sources for instance spices and plants (plant extracts) and are also zymes and antimicrobial activity, causing an increase in the growth
termed as botanicals or phytogenics (Grashorn, 2010; Tiwari et al., performance of poultry. In other investigations, the phytobiotics addi­
2018; Windisch et al., 2008). On the basis of protocols developed else­ tion into laying hen or broiler diet led to a significant decrease in feed
where in EFSA for the assessment of botanicals extracts/components consumption (Maass et al., 2005; Roth-Maier et al., 2005). The inclusion
used as food/food supplements, the FEEDAP Panel was able to propose of essential oils into birds diet inhibited pathogen adhesion and pro­
the approach to botanicals eventually incorporated into Commission moted bacterial balance in the intestinal tract (Brenes and Roura, 2010),
Regulation (EC) No 429/2008. Generally, there is little information and increased intestinal mucosal secretion (Jamroz et al., 2006), as well
about the possible negative effects of the phytochemical addition to as an increase in pancreatic amylase maltase and trypsin activities (Jang

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M. Alagawany et al. Research in Veterinary Science 137 (2021) 9–29

et al., 2007). Essentials oils like thymol, carvacrol, and cinnamaldehyde performance in chicken (Oni et al., 2018). Comparative study with
were found to reduce the Campylobacter load in poultry intestine oyster mushroom extract, garlic extract, ginger extract revealed that
(Micciche et al., 2019). Lipiński et al. demonstrated that herbal formula ginger extract in drinking water improved growth performance in tur­
composed of Achyranthes aspera, Andrographis paniculata, Aphanamixis keys (Olaifa et al., 2019).
polystachya, Azadirachta indica, Boerhavia diffusa, Citrullus colocynthis, Another feature of phytobiotics is antioxidant property that attracts a
Eclipta alba, Fumaria indica, Ichnocarpus frutescens, Phyllanthus emblica, lot of attention. Significant antioxidant effects were observed in extracts
P. niruri, Sida cordifolia, Solanum nigrum, Tephrosia purpurea, Terminalia of Labiatae plants (thyme, oregano and rosemary) (Brenes and Roura,
chebula, T. arjuna, Tinospora cordifolia, with confirmed growth- 2010). This influence was confirmed in meat-type ducks fed on thyme as
promoting and liver protective effects, had a beneficial effect on the an additive in the diet (Gheisar et al., 2015) and in broilers after the
growth performance of broiler chicken (body weight, average daily gain, addition of sweet wormwood (Artemisia annua) to their diet (Cherian
feed conversion ratio and the proportion of heart relative to total carcass et al., 2013). These phytobiotics improved lipid metabolism regulation
weight) (Lipinski et al., 2019). Phytobiotics have not only beneficial as they elevated the levels of particular antioxidant enzymes (superoxide
impact on the breeding efficiency and health status of poultry, but can dismutase (SOD) and glutathione peroxidase (GSH-Px) (Franz et al.,
also increase the nutritional value of poultry products. As it was shown 2010). Other studies revealed that plants for instance Coriander Anise,
in the work of Al-Yasiry et al. supplementation of resins from Boswellia Curcuma and Ginger; spices for instance chili (Capsicum frutescens), red
serrata tree to the diet of Ross 308 chickens increased the content of pepper (Capsicum annuum L.) and black pepper (Piper nigrum); and an­
calcium and phosphorus in muscles (Al-Yasiry et al., 2017). Boswellic thocyanins like some fruits, and flavonoids rich-plants with like green
acid, which is the main component of this resin due to antibacterial and tea (Camellia sinensis) have antioxidant activities (Nakatani, 2000; Wei
immunostimulatory properties, stabilizes the intestinal microbiota. and Shibamoto, 2007; Yatao et al., 2018). Due to the sharp taste and
Many investigations have studied the antimicrobial impacts of phy­ odor of these plants, which is related to their active constituents, their
tobiotics (Burt, 2004; Panghal et al., 2011; Si et al., 2006). Most of them use as feed additives is limited. Other authors argue that phytobiotics
have revealed that phenolic components, for instance, citronellal, ge­ like antibiotic accelerated development in broilers (Abd El-Ghany and
raniol, phenylpropane, limonene, carvacrol and thymol, are the most Ismail, 2014; Diaz-Sanchez et al., 2015). Nm et al. found that turmeric
efficacious antimicrobials. The arrangement of phytobiotics hydroxyl used as a natural feed supplement enhanced broiler chicken growth
and alkyl groups is an essential factor in the antimicrobial impact (Yang performance, antioxidant activity and antimicrobial responses (Nm
et al., 2015). For instance, certain terpenes (for example thymol and et al., 2018). However, other authors reported that black cumin and
carvacrol) have similar antimicrobial actions; nevertheless, their impact thyme did not affect the growth of broilers. These differences between
against Gram-positive or negative bacteria depends on the settlement studies are due to the dose and type of phytobiotics used in the diets (Al-
position of functional groups in their molecular structure (Salehi et al., Mufarrej, 2014; Karimi et al., 2010).
2018). A comparative study in broilers using antibiotics, probiotics In an experiment, nutrigenomic evaluation of commercially avail­
(Bacillus subtilis) and phytobiotics (sanguinarine and protopine) either able garlic (Allium sativum) powder and holy basil (Ocimum sanctum) leaf
singly or in combination showed that probiotic and phytobiotics com­ powder supplementation in poultry ration was performed for period of
bination could protect birds from necrotic enteritis caused by Clostridium six weeks over 280 day old Ven Cobb broilers. The aim of this research
perfringens. Similarly, the carcass characters improved in group that was to assess their effect on growth performance and immune status in
received combination of probiotic and phytobiotics (Hussein et al., broilers. Blood was collected after 6 weeks post-trial and through real-
2020). time polymerase chain reaction expression of m-RNA of toll-like re­
The most well-known phytobiotics are obtained from Labiatae plant ceptors viz. TLR 2, TLR 4 and TLR 7 was detected in the blood samples of
family (oregano, sage and thyme). Disruption of the bacterial membrane broilers. Growth parameters showed improvement in body weight gain,
by adhesion of hydrophobic essential oils leads to ionic imbalance (Burt, feed conversion efficiency and immune parameters expressed enhanced
2004). Moreover, antimicrobial effects were observed in several non- T-cell mediated immune response and support the use of garlic and holy
phenolic constituents extracted from bloodroot (Sanguinaria cana­ basil leaf powder in poultry diet to boost the birds performance and for
densis) and limonene (Burt, 2004; Newton et al., 2002). Particularly, the disease prevention (Sheoran et al., 2017). In another study, the combi­
impact of essential oils against Clostridium perfringens and E. coli has been nation of garlic with fenugreek and black pepper powder has also
presented in broilers (Jamroz et al., 2006; Mitsch et al., 2004), and the showed promising results in improving growth characteristics, lipid
effect of particular phytobiotics confirmed against Eimeria (Oviedo- profile and production traits in broilers (Issa and Abo Omar, 2012;
Rondon et al., 2006). Also, phytobiotics improved carcass-microbial Kirubakaran et al., 2016). Garlic is known for its antibacterial, antiviral,
hygiene. For instance, the helpful influence on the microbial load of antioxidant, immunostimulatory, properties and literature proposed its
whole live bacteria or specific pathogens in broiler carcass has observed use in poultry diet as a supplement. Due to the presence of compounds
after the supplementation of oregano essential oil to the diet at a level of like polyphenols, saponins, fructans, organosulfur compounds and
0.1% (Akşit et al., 2006). However, informations are relatively limited in fructo-oligosaccharides, allium has shown lipid and cholesterol reducing
presenting phytobiotics as a stable for promoting carcass hygiene. A effects also and can be helpful in maintaining the gut microbial ho­
study showed that clove leaves and nutmeg fruit leaves as phytobiotics meostasis (Kothari et al., 2019; Poojary et al., 2017; Putnik et al., 2019;
in broilers were found to be safe and effective alternative for antibiotic Ramirez et al., 2017).
use as growth promoters (Sapsuha et al., 2019). Phytobiotics (combi­
nation of Zingiber officinale and Glycyrrhiza glabra, Withania somnifera, 1.11. Phytosterol
Camellia sinensis, Nigella sativa) and organic acids were found to improve
health and blood parameters in broilers. Thus, combination of organic Phytosterols (PS) are natural steroid components derived from
acids and phytobiotics can be used as an alternative to antibiotics (Gilani plants, required for stabilization of various biological plasma membrane
et al., 2018). Commercial phytobiotic formulations Poultvita, VitaG and of plant cells, acting as precursor to various bioactive molecules like
HerbaS in combination with maize, wheat, soybean meal were found to steroidal saponins, steroidal glycoalkaloids, phytoecdysteroids, and
improve growth performances in broilers (Yashoda et al., 2019). Gali­ brassinosteroids (Moreau et al., 2018). Phytosterols generally include
biotic was found to improve growth performance, carcass quality, β-sitosterol, stigmasterol, campesterol, and brassicasterol. Recent in­
improved gut health and lower FCR in broilers (Ripon et al., 2019). vestigations have studied the impact of PS application on livestock
Similarly, extracts of Echinacea pallida improved hematological param­ production (Elkin and Lorenz, 2009; Hu et al., 2017; Liu et al., 2010).
eters in poultry (Chudak et al., 2019). Mixture of garlic, ginger and Nevertheless, their mode of action and physiological function is difficult
chaya leaf improved hematological, biochemical and growth to decipher due to their mixed compositions. The European Commission

18
M. Alagawany et al. Research in Veterinary Science 137 (2021) 9–29

sought an update on the safety of phytosterols from the EFSA. The EFSA is studied based on gas chromatography or mass spectrometry for
review noted that the phytosterol esters can be used safely to provide an detailed analysis of phytosterols (Moreau et al., 2018).
“additional” cholesterol-lowering effect in cases of hyper­
cholesterolaemic. Since the 1950s, PS is known to reduce blood 1.12. Omega 3, 6 and 9 fatty acids
cholesterol levels through inhibiting cholesterol biosynthesis and ab­
sorption (Fernandez et al., 2002). Being fat-soluble in nature, phytos­ The two essential types of polyunsaturated fatty acids (PUFAs) are
terols lower the cholesterol absorption in the body leading to decreased omega-6 (n-6) and omega-3 (n-3) fatty acids, which are obtained only
level of LDL-cholesterol and total cholesterol; hence consumption of from the feed. So, they have been categorized as “essential fatty acids”.
phytosterols prevents the risk of cardiovascular diseases (Ortega et al., Arachidonic and linolenic acids are omega-6 fatty acids. Omega-3 fatty
2006). Recently, Dumolt et al. has suggested that PS may have acids include docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA)
triglyceride-lowering agents, although PS has been illustrated to inter­ and α-linolenic acid. Omega-6 (present in sunflower, soybean, palm, and
fere with cholesterol and might be triglyceride absorption within the rapeseed oils) and omega-3 (present in plant and fish oils and nuts) fatty
intestine (Dumolt and Rideout, 2017). In addition to the cholesterol acids are important constituents of cellular membranes (Alagawany
lowering activity, PS has different effects such as anticancer, growth et al., 2019b; Alagawany et al., 2015), whereas omega-9 fatty acids are
regulators, anti-inflammatory and immune modulator (Xie et al., 2015). present in animal fat and olive oil and are not essential (Alagawany
In 2008, due to affirmative impacts of phytosterols on animal growth et al., 2015). The EFSA concluded that the Omega 3, 6 and 9 fatty acids
and performance, the Ministry of Agriculture of China Poultry Science play important roles in blood pressure, blood clotting, and inflamma­
Association had approved PS as functional feed supplements for tion, which are emerging risk factors for cardiovascular disease. Also, it
growing-finishing pigs and poultry. Because of PS protein synthesis in­ reported that a cause and effect relationship has been established be­
duction and elevated disease resistance effect, several studies have tween the consumption of EPA and DHA and maintenance of normal
presented that dietary addition of PS could promote meat quality or/and cardiac function. Generally, polyunsaturated fatty acids play essential
enhance the growth rate of broilers (Naji et al., 2013). Recently, PS as roles in the improvement of growth, productive performance, immune
antioxidants has been studied thoroughly in both in vitro (Vivancos and responses and anti-oxidative properties, egg quality and nutritional
Moreno, 2005; Yoshida and Niki, 2003) and in vivo (Panda et al., 2009) value of eggs, meat quality, mineral metabolism (including bone for­
studies. Interestingly, these investigations have stated that PS acts as a mation, growth and development), fertility rates and semen quality
radical scavenger and stimulates antioxidant enzymes (SOD and GSH- (Alagawany et al., 2019b; Lee et al., 2019).
Px), whereas reducing the accumulation of malondialdehyde, which is Researchers investigated the effect of pomegranate seed oil and
a lipid peroxidation-end product. grape seed oil on the nutritive value of poultry meat in regards to the
The most abundant type of phytosterol is β-sitosterol which is level of rumenic acid (cis-9, trans-11 conjugated linoleic acid CLA), n-3
naturally common in plant products and is similar in chemical structure and n-6 fatty acids deposition in selected tissues of chickens. The ob­
to cholesterol (Cheng et al., 2019). Both clinical and in vitro studies have tained results suggested that pomegranate seed oil is an important
affirmed that β-sitosterol induce cholesterol lowering (Cicero et al., valuable feed supplement in poultry diet with meat quality enhancing
2002; Hwang et al., 2008; Kim et al., 2014), anticancer (Rajavel et al., properties (Bialek et al., 2018). Studies suggested that soybean oil, high
2018), and anti-inflammatory effects (Kim et al., 2014; Lampronti et al., in oleic acid incorporated into the diet of laying hens helped in depo­
2017). Besides, β-sitosterol boosted antioxidant enzymatic and nonen­ sition of unsaturated n-3 polyunsaturated fatty acids in the egg yolk
zymatic systems of macrophages (Vivancos and Moreno, 2005), phorbol (Elkin et al., 2018). In the work of Michalak et al. extract from microalga
ester stimulated free radicals scavenging capacity of macrophages Spirulina platensis obtained by supercritical fluid extraction added to the
(Moreno, 2003), and reduced oxidative damage in thymocyte exposed to drinking water of laying hens increased the content of γ-linolenic acid
irradiation (Li et al., 2007). In vivo studies on rats presented that 1,2- (GLA, 18:3, n-6), eicosadienoic acid (20:2, n–6), eicosatrienoic acid
dimethylhydrazine- and streptozotocin-induced oxidative damage was (ETE, 20:3, n–3) and docosapentaenoic acid (DPA, 22:5, n–3) in egg
diminished by β-sitosterol (Baskar et al., 2012; Gupta, 2016). Further­ yolks (Michalak et al., 2020). Świątkiewicz et al. also showed that algal
more, β-sitosterol could efficiently eliminate the depletion of gluta­ oil increased the content of eicosapentaenoic acid (EPA, 20:5, n-3) and
thione and reducing antioxidant enzymes (GSH-Px and SOD) in rats docosahexaenoic acid (DHA, 22:6, n-3) in yolks of ISA Brown hens,
intestine stimulated by 1,2-dimethylhydrazine (Baskar et al., 2012). without negative effect on egg performance, but boiled eggs had inferior
Cheng et al. showed that β-sitosterol supplemented at the level of 80 mg/ flavor and taste (Świątkiewicz et al., 2020). Kalakuntla et al. found that
kg to the diet of broiler chicken, improved their growth performance and traditionally used in poultry feeding sunflower oil can be replaced by n-3
quality of the breast muscle meat due to enhanced oxidative status and rich soybean oil, mustard oil, linseed oil or fish oil. When added to the
mitochondrial biogenesis in the breast muscle (Cheng et al., 2019). broiler chicken diet in the dose 2-3%, it enriched meat with n-3 fatty
Phytosterols, including β-sitosterol improve meat quality by increasing acids without affecting the birds performance and sensory attributes of
the antioxidant status (total antioxidant capacity, glutathione, and meat (Kalakuntla et al., 2017).
catalase) of broiler chickens (Naji et al., 2013). According to Sioen et al., omega-3 fatty acid as a feed additive has
In literature, there are many examples showing positive effect of favorable impacts associated with physiological actions (Sioen et al.,
phytosterols on poultry growth and development. Experiments per­ 2006). Moreover, the modern diet contains a low level of PUFAs,
formed over 256 one day old male Partridge Shank chicks confirmed particularly omega-3 fatty acids content. Therefore, the ratio of omega-
that supplementation of 40 mg/kg of phytosterols in the diet improved 6:omega-3 fatty acids is high and should approach the recommended
antioxidant level, growth performance and meat quality of Partridge value < 5 (Gallardo et al., 2012). This high ratio is a critical reason in the
Shank chickens as it caused significant increase in level of serum pathogenesis of numerous ailments (inflammatory or autoimmune dis­
glutathione peroxidase (GSH-Px) activity, hepatic GSH-Px and hepatic eases and cancer). Using omega-3 fatty acids in the feed reduced this
superoxide dismutase activity (Zhao et al., 2019). Studies showed also ratio (Kalakuntla et al., 2017; Simopoulos, 2004). The addition of flax-
positive effects of dietary supplementation of phytosterol esters to the seed oil (Lopez-Ferrer et al., 2001), fish by-products (Lopez-Ferrer
broiler hens as it supported the muscle development in embryo and et al., 2001), canola oil (Gallardo et al., 2012) to the poultry diet has
growth of hatched chick and broiler offspring (Wang et al., 2020). Fer­ promoted omega-3 fatty acids levels in their meat (mainly α-linolenic
guson et al. used curcumin as phytosterol therapy and found that cur­ acid). Gallardo et al. (2012) found also that canola oil (15% addition to
cumin has a complementary cholesterol-lowering effect. Furthermore, the diet) increased also the content of omega-9 (oleic acid) and
there were no observable side influences in the previous literature decreased the content of omega-6 (linoleic acid) fatty acids in meat, fat
(Ferguson et al., 2018). Sterolomics is new area where sterol lipidomics and plasma in broiler chickens and suggested that fatty acid composition

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M. Alagawany et al. Research in Veterinary Science 137 (2021) 9–29

Table 1
The role of nutraceuticals in improving the physiological functions and health status
Items Doses Origin Mechanism of action Main findings References

Antibiotic growth 55 mg/kg of penicillin. Natural or synthetic, Gastro-intestinal infection control Improve meat production by (Brisbin et al.,
promoters 20 mg zinc bacitracin. produced by certain and intestinal microbiota increasing feed conversion, 2008)
60 mg salinomycin bacteria or by lower fungi. alteration. promoting growth rate and (Engberg et al.,
200 mg/kg virginiamycin Reduce the microbial load in the preventing diseases. 2000)
intestine, resulting in increased (Khodambashi
availability of nutrients for the Emami et al. 2012,
host. Singh et al., 2013)
(Schokker et al.,
2017; Yadav and
Jha, 2019).
Exogenous DDGS up to 500 g/kg diet. Bacteria such as Bacillus The enzyme activity is affected by Digestion and absorption of (Slominski, 2011)
enzymes 1.0 g/kg xylanase subtilis, Lactobacillus different factors as the raw material as corn and soya. (Costa et al., 2008)
acidophilus and Streptococcus temperature, moisture, feed Compensate deficiency of the (Sugiharto, 2016)
faecium. ingredient, age and species of the endogenous enzyme that is (Yang et al.,
Fungi as Trichoderma animal, and chiefly pH level of the important in digestion of anti- 2008).
longibrachiatum and intestinal channel. nutritional factor. (Abd El-Hack
Aspergillus oryzae. Glucanase and cellulase are et al., 2018)
Yeast as Saccharomyces important in digestion of (Attia et al., 2019;
cerevisiae barely and cellulose Kumanda et al.,
respectively. 2019).
Using enzyme mixture in
DDGS-based diets may
promote feed efficiency and
egg quality, as well as decrease
blood ammonia and increase
blood calcium.
Probiotics Lactobacillus at 75 mg/kg LAB (Lactobacillus Resistant against different pH Protection of normal intestinal (Kabir 2009)
feed. bulgaricus, L. acidophilus, L. values and organic acid so, microflora against pathogenic (Armut and Filazi,
Lactobacillus acidophilu casei, L.helveticus, L. lactis, L. probiotic grow fast and organize bacteria through competing 2012)
Lactobacillus casei, salivarius, L. plantarum). gut immunity cells cling to and antagonistic effects. (Brisbin et al.,
Bifidobacterium bifidum, Streptococcus thermophilu, intestinal cells without affecting Adjust digestion by controlling 2010)
Aspergillusoryzae, Enterococcus faecium, E. intestinal tissue or its feed intake, absorption after (Khaksefidi and
Streptococcus faecium and faecalis, and Bifidobacterium permeability. disintegration of organic Rahimi, 2005)
Torulopsis sp. and was fed at sp. substance. (Siwek et al.,
100 mg/kg diet Alter metabolism by raising 2018)
digestive system activities, (Yadav and Jha,
bacterial activity and decrease 2019)
ammonia production.
Promote immunity through
raising antibiotic, macrophage
and cytokine secretion.
Prevent bacterial toxin
production besides, control
protozoa and coccidiosis by
altering water quality.
Prebiotics 0.25% FOS and 0.05% MOS. Natural origin includes Tthe same mechanism in Prebiotic increase gas (Alloui et al.,
legumes, fruits and cereals. modification of gut microbiota as production and fecal weight, 2013)
But there is an probiotic but most efficient in evade constipation, adjust gut (Markowiak and
overwhelming use colon while probiotic act in small habitat, somewhat decrease pH Śliżewska 2018)
nowadays of synthesized intestines. level in colon, the ratio of (Roberfroid et al.,
types. active carrier protein is 2010(
increased and toxic ratio, (Kim et al., 2011)
mutagenic residues, bile acid, (Davani-Davari
carcinogenic enzymes are et al., 2019)
reduced.
Pathogen is compressed in the
high intestinal acidity of SCFAs
produced by prebiotics and
animal’s defense response is
improved due to fast removal
of pathogen from intestine.
Prebiotic increase nitrogen
extraction from bowel so that
relieve kidney load, decrease
LDL and serum triglyceride
from liver and increase IGA in
immune system. Consequently,
they are able to 1- increase
conversion rate 2- modulate
immunity to enhance product
quality for example, decrease
cholesterol level in egg 3-regu­
late intestinal microbiota and
decrease pathogensity of MOs
(continued on next page)

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M. Alagawany et al. Research in Veterinary Science 137 (2021) 9–29

Table 1 (continued )
Items Doses Origin Mechanism of action Main findings References

• Organic acids 3% butyric acid, 3% fumaric Plant and animal origin. Organic acids pass through Antimicrobial effect. (Huyghebaert
acid, 3% lactic acid. Also, microbial bacterial cell wall lead to anion Intestinal regulation. et al., 2011)
0.92 g/kg of an additive with fermentation of accumulation that begin to Good effect on health, )Shahidi et al.,
free sodium butyrate. carbohydrates in cecum of decrease pH levels which cause nutrition, performance and egg 2014(
poultry is another source of destruction of most intracellular quality (Khan and Iqbal,
organic acid. structures and biological process, Administration of organic acid 2016).
decrease ATP and illustrated as and its salts or combination )Rodríguez-
bactericide or bacteriostatic but increase crypt depth, villus Lecompte et al.
the bacteria had resistance to height in small intestine of 2012(
acids are not affected anymore. broiler chicken. (Hamed and
Organic acids in water improve Hassan 2013)
bowel microflora, feed (Fernandez-Rubio
digestion and growth and et al., 2009)
decrease that the diseases in (Liu et al., 2017)
the stomach.
• Phytobotics and Feeding broiler chickens Natural active compounds Disruption of the bacterial Addition of a phytogenic (Windisch et al.,
phytochemicals with diet containing 0.075% that obtained from various membrane by adhesion of mixture to meat-type duck feed 2008)
of phytogenic blend herbal sources such as hydrophobic essential oils to ionic and broiler chickens at a ratio (Huyghebaert
75 g/kg of feed; containing plants and spices as imbalance. of 0.075% promoted body et al., 2011).
thymol and vanillin. terpenoids, phenols, Phytobiotics improved lipid weight and feed efficiency. (Burt, 2004)
glycosides, alkaloids. metabolism regulation as they elevation in trypsin, maltase, )Franz et al., 2010
elevated the levels of particular and pancreatic amylase (
antioxidant enzymes such as activities of broilers )Jamroz et al.,
glutathione peroxidase (GSH-Px) Increased intestinal mucosal 2006(
and superoxide dismutase (SOD). secretion. (Mohammadi
The addition of phytogenic Gheisar and Kim,
blend led to 3.9% and 3.4% 2018)
improvement in BWG and FCR.
• Phytosterol 40 mg/kg PS. Natural steroid compounds PS could act as radical scavenger PS have reduced blood (Hu et al., 2017)
The β-sitosterol dietary that derived from plant, and and stimulate antioxidant cholesterol levels through (Naji et al., 2013)
supplementation at the level generally include enzymes such as SOD and GSH-Px, inhibiting cholesterol (Fernandez et al.,
of 80 mg/kg is recommended β-sitosterol, stigmasterol, whereas reduce the accumulation absorption and biosynthesis. In 2002)
in broilers. campesterol, and of malondialdehyde which is end addition to the cholesterol- (Xinmei et al.
brassicasterol. product lipid peroxidation-end lowering effect, PS has 2015)
product. Moreover, βsitosterol it different effects such as growth (Baskar et al.,
could efficiently eliminate regulator, anti-inflammatory, 2012)
depletion of glutathione (GSH) anticancer, and immune (Kim et al., 2014)
and reduction antioxidant modulator. (Rajavel et al.,
enzymes including SOD and GSH- β-sitosterol induce cholesterol- 2018)
Px in rats intestine stimulated by lowering (Lampronti et al.,
1,2-dimethylhydrazine Anticancer and anti- 2017)
inflammatory effects (Suresh et al.,
β-sitosterol boosted 2018; Kim and
antioxidant enzymatic and Lillehoj, 2019)
nonenzymatic systems of
macrophages phorbol ester has
stimulated free radicals
scavenging capacity of
macrophages.
Omega 3, 6 and 9 Supplementations of 10% T- Polyunsaturated fatty acids Oomega-3 as feed additive has Increases were observed in (Alagawany et al.,
fatty acids 3 enriched PUFAs. (PUFAs) which is only beneficial effects related to spleen weights, antibody titers, 2015)
acquired from diet. physiological functions. interleukin-2, and interferon-γ (Maroufyan et al.,
Moreover, modern diet contains concentrations in broilers fed 2012)
low level of the PUFAs on a tuna oil, sunflower oil, and (Lopez-Ferrer
particularly omega-3 fatty acid palm oil combination (omega-3 et al., 2001)
ions content. Therefore, the sources). In the result the (Kankaanpää et al.
omega-6: omega-3 fatty acid ratio immune responses of these 2001)
is high. This high ratio is a critical broilers were promoted (Alagawany et al.
factor in the pathogenesis of Conjugated linoleic acid is 2019c)
various diseases: cancer and another PUFAs type which (Lee et al., 2019;
inflammatory and autoimmune enhances immune responses in Al-Khalaifah et al.,
diseases. Adding omega-3 fatty chickens. Particularly, it 2020)
acids to the diet, reducing the enlarges immune tissues such
ratio of omega-6: omega-3. as thymus and bursa in
chickens and accelerates T
lymphocyte proliferation while
increasing antibody
production.
Omega-3 has an antimicrobial
effect in an in vitro condition.

is better represented by fat tissue than muscle tissue. (Ponte et al., 2008). It is well known that corn oil and fish oil are omega-
Nevertheless, these products stimulate meat lipid oxidation, which 6 and 3 main sources in poultry. Corn oil reduced the immune response,
leads to a decrease in the flavor (Bou et al., 2001). According to Ponte but fish oil elevated it (Yang and Guo, 2006). Also, increases were
et al., free-range chickens feed on greenplants have a high body weight observed in spleen weights, concentrations of interferon-γ, interleukin-2

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M. Alagawany et al. Research in Veterinary Science 137 (2021) 9–29

Table 2
Advantages and disadvantages of nutraceuticals
Item Advantages Disadvantages

Exogenous enzymes Improving digestibility and metabolism of nutrients replace antibiotics and Lowering of pH level below 4 is vital to make the effect of the exogenous, (
can prevent the development and colonization of hurtful microorganisms in Solis-Cruz et al., 2019).
the gut (Attia et al., 2019; Kumanda et al., 2019).
Phytase in poultry feed may improve the feed utilization, performance,
nutrient digestibility and energy availability.
Using an enzyme mixture in DDGS-based diet may promote egg quality and
feed efficiency, as well as decrease ammonia and increase calcium in the
blood.
Facilitates corn and soya digestion (Costa et al., 2008).
Probiotics Protection of healthy intestinal microflora against pathogenic bacteria. Influence gene expression during different phases of production (Bach et al.,
Adjusting the digestion by controlling feed intake. 2018).
Alteration of metabolism by raising digestive system activities, bacterial We should take into account that each bacterial strain used for the probiotic
activity, and decrease ammonia production. purpose is specific for unique host type or kind of disease (Musa et al., 2009).
Promotion of immunity. Risks and harmful effect on metabolic activity can be obtained (Mikelsaar,
Prevention of bacterial toxin production (Alagawany et al. 2018, Aziz 2011)
Mousavi et al., 2018, Brisbin et al., 2010, Dhama et al., 2017, Dhama et al.,
2011, Khaksefidi and Rahimi, 2005, Lan et al., 2005, Lutful Kabir, 2009).
Compared to antibiotic: probiotics can be a better option as growth
promoters in poultry production (Ferdous et al., 2019).
Anti-aflatoxigenic effect (Azeem et al., 2019).
Increase in body weight gain, a significant decrease in feed conversion ratio (
Sun et al., 2019).
Prebiotics Decrease pathogens (Ezzat Abd El-Hack et al., 2016, Micciche et al., 2018, Increase gas production and fecal weight (Roberfroid et al., 2010).
Ricke, 2018). Large doses causes intestinal swelling, excessive gas fermentation, and
Prevent intestinal diseases (Dhama et al., 2008; Dhama et al., 2011; diarrhea (Kum and Sekkin, 2012).
Elgeddawy et al., 2020). Other studies presented no increase in live weights (Solis-Cruz et al., 2019).
Evade constipation, adjust gut habitat (Roberfroid, Gibson, Hoyles,
McCartney, Rastall, Rowland, Wolvers, Watzl, Szajewska, Stahl, Guarner,
Respondek, Whelan, Coxam, Davicco, Leotoing, Wittrant, Delzenne, Cani,
Neyrinck and Meheust 2010).
Synbiotics Growth and development of intestinal microorganisms and reduction of the
count of potential pathogens.
Decreased colonization of Salmonella in the intestine and carcass
contamination in broiler birds.
Decreased branched chain fatty acids and pathogenic population in the
intestine (Slizewska et al., 2020).
In broilers reduced the harmful changes caused by heat stress (Jiang et al.,
2020).
Organic acids Antimicrobial effect. Bacteria had resistance to acids not affected anymore (Patten and Waldroup,
Intestinal regulation, good effect on health, nutrition, performance and egg 1988).
quality (Khan and Iqbal, 2016). Araujo et al. (2019) found nonsignificant effect on economic viability and
Improve bowel microflora, feed digestion and growth, and decrease the broiler performance.
diseases in the stomach (Mansour Hamed and Hassan, 2013).
Phytobiotics and Low cost, lack of antibiotic resistance. -
phytochemicals Safe and effective alternative for antibiotic use as growth promoters (
Sapsuha et al., 2019).
Improve growth performance, carcass quality, improved gut health and
lower FCR in broilers (Ripon et al., 2019).
Phytosterol Reduce blood cholesterol levels through inhibiting cholesterol biosynthesis -
and absorption (Fernandez et al., 2002)

Promote meat quality or/and enhance the growth rate of broilers (Naji et al.,
2013)

PS acts as a radical scavenger and stimulates antioxidant enzymes (SOD and

GSH-Px), whereas reducing the accumulation of malondialdehyde, which is
a lipid peroxidation-end product.

Anticancer (Rajavel et al., 2018), and anti-inflammatory effects (Kim et al.,

2014; Lampronti et al., 2017). Besides, β-sitosterol boosted antioxidant
enzymatic and nonenzymatic systems of macrophages (Vivancos and
Moreno, 2005)

Supported the muscle development in embryo and growth of hatched chick

and broiler offspring (Wang et al., 2020).
Omega 3, 6 and 9 Roles in the improvement of growth, productive performance, immune Stimulate meat lipid oxidation, which leads to a decrease in the flavor (Bou
fatty acids responses and anti-oxidative properties, egg quality and nutritional value of et al., 2001)
eggs, meat quality, mineral metabolism (including bone formation, growth
and development), fertility rates and semen quality (Alagawany et al. 2019, Ameliorated immune responses notably reduced phagocytosis and
Lee et al., 2019) lymphocyte proliferation was observed in broiler chicken after the dietary
addition of omega-3 (Al-Khalifa et al., 2012).
Helped in deposition of unsaturated n-3 polyunsaturated fatty acids in the
egg yolk (Elkin et al., 2018)
It is reported that omega-3 fatty acids and fish oil is well tolerated and is
(continued on next page)

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M. Alagawany et al. Research in Veterinary Science 137 (2021) 9–29

Table 2 (continued )
Item Advantages Disadvantages

Fatty acids have a strong impact on the component cells of immune system, little toxic when taken at a dose level of 1000-2000 mg/day. But in case of
lymphocytes proliferation was enhanced, natural killer (NK) cell activity was patients taking anticoagulants (like warfarin), they may intensify
triggered in splenocytes, fatty acid composition was improved throughout anticoagulations and increase hemorrhage (Gross et al. 2017).
the tissues mainly in spleen, thymus, blood and plasma in the body.
Researchers used fish oil, linseed oil, echium oil and algal biomass as source Simultaneous consumption of fish liver oils which also contain vitamin A
of n-3 fatty acids (Al-Khalaifah et al., 2020). and multivitamin supplements could result in hypervitaminosis A (Buckley
et al. 2004).
Bioactive peptides Antioxidant effect(Aslam et al., 2020). -
Improving growth in poultry (Abdollahi et al., 2017; Osho et al., 2019).
Enhance intestinal morphology (Salavati et al., 2020).
Significant delay in the lipid oxidation of breast meat and enhanced shelf
stability of broiler breast meat (Aslam et al., 2020)

Protected broilers from coccidia induced changes in the intestines like

improved jejunal villi height thus improving the growth of the poultry (
Abdollahi et al., 2017, Osho et al., 2019).

and antibody titers in broilers fed on omega-3 sources (a palm oil, significant delay in the lipid oxidation of breast meat and enhanced shelf
sunflower oil and tuna oil combination). stability of broiler breast meat (Aslam et al., 2020). Soybean bioactive
As a result, the immune responses of these broilers were promoted peptide protected broilers from coccidia induced changes in the in­
(Maroufyan et al., 2012). Experiments performed over 340 one day old testines like improved jejunal villi height thus improving the growth of
Ross-308 male broilers to assess the effect of n-3 polyunsaturated fatty the poultry (Abdollahi et al., 2017; Osho et al., 2019). Similarly, Sesame
acids on the immune response of broiler chickens, revealed that n-3 fatty meal bioactive peptide was also found to reduce E. coli in gut, improved
acids have a strong impact on the component cells of immune system, gut microbiota, intestinal morphology and also general health of poultry
lymphocytes proliferation was enhanced, natural killer (NK) cell activity (Salavati et al., 2020). Other bioactive peptides like Canola also had
was triggered in splenocytes, fatty acid composition was improved good results in improving the poultry health (Karimzadeh et al., 2016).
throughout the tissues mainly in spleen, thymus, blood and plasma in Supplementation of bioactive peptides derived from sesame meal
the body. Researchers used fish oil, linseed oil, echium oil and algal (BPSM) (50-150 mg/kg) has produced better on the productive perfor­
biomass as source of n-3 fatty acids (Al-Khalaifah et al., 2020). mance, internal organs, gut microbial population, and intestinal
In contrast, ameliorated immune responses notably reduced phago­ morphology in broiler chickens compared to mannan-oligosaccharides
cytosis and lymphocyte proliferation was observed in broiler chicken (MOS) (prebiotic) (2 g/kg) and avilamycin (antibiotic) (10 mg/kg)
after the dietary addition of omega-3 (Al-Khalifa et al., 2012). Conju­ (Salavati et al., 2020). In addition to bioactive peptides amino acids also
gated linoleic acid (CLA) is another PUFA type which enhances the affect growth and development of poultry birds. L-Carnitine and excess
immune response in chicken (Zhang et al., 2005). Particularly, it en­ lysine-methionine supplementation has improved growth performance,
larges immune tissues in chickens (such as bursa and thymus) and in­ carcass characteristics, and immunity markers of broiler chicken
creases antibody production, as well as accelerates T lymphocyte (Ghoreyshi et al., 2019). The EFSA approves the use of amino acids as
proliferation. These investigations propose that this response highly feed additives and there is no harm to the consumer or the user as long as
varies according to several factors: the type of essential fatty acid, bio­ they are used in the permissible levels.
logical differences (breed, age and gender), diet composition, and the Advances in biotechnology, nanotechnology, immunology,
ratio of omega-6:omega-3 in the feed (He et al., 2007). Sources of such biochemistry, pharmacology, pharmaceuticals and biomedicine need to
fatty acids may have beneficial role in bone or joint related ailments as be exploited to their full potential for designing novel feed formulations
reported in other animal species (Manfredi et al., 2018). and delivery systems for obtaining optimum usages and benefits of
Furthermore, omega-3 has a bacterial activity in an in vitro condi­ nutraceuticals in poultry production and health as well as for obtaining
tions (Kankaanpaa et al., 2001). Conversely, some studies on the chicken functional foods and designer foods for human consumption to safe­
gut claim that CLA and omega-3 have a limited impact on general in­ guard from various health issues (Aklakur et al., 2016; Alagawany et al.,
testinal microbiota (Chanuwat et al., 2011). Despite, some studies 2015; Gangadoo et al., 2016; Helal et al., 2019; Kuldeep et al., 2014;
confirmed that dietary addition of CLA or omega-3 (EPA and DHA) was McClements, 2012; Prasad et al., 2018; Saeed et al., 2019).
able to boost poultry growth rate (Chanuwat et al., 2011; Roy et al.,
2008), other studies argued that these barely affect the growth perfor­ 2. Conclusion and future prospects
mance (Cho et al., 2013; Zhang et al., 2005). In this line, the feed
composition, PUFAs sources and types and animal biological variations Nutraceuticals are the similar natural components of the dietary
can elucidate these arguable results. nutrients as already present in the poultry ration. Besides having
nutritional importance, they also have health promoting beneficial ef­
fects. They modulate physiological and immunological processes of the
1.13. Bioactive peptides poultry birds being the biochemical constituents of the various pathways
involved in growth, development, immunity and health of the birds
Bioactive peptides are organic compounds made of amino acids that (Table 1). They do not pose the problem of antibiotic resistance and drug
are linked by covalent bonds namely amides/ peptide bonds (Hou et al., residues unlike the antibiotics. Hence, the demand for using an alter­
2017; Sánchez and Vázquez, 2017). Bioactive peptides obtained from native natural feed additive such as nutraceuticals is essential, especially
fish waste have shown antioxidant potential on breast meat of broilers. A after preventing the use of antibiotics in poultry sector as a growth
total of 180 broiler birds were kept in 6 groups, 30 birds in each and factor. Nutraceuticals are of various types however the present review
were supplemented with bioactive peptides in concentration of 0, 50, provides a detailed description of exogenous enzymes, probiotics, pre­
100, 150, 200, and 250 mg/kg feed for six weeks, after which they were biotics, organic acids, phytobiotics and phytochemicals, phytosterol,
slaughtered and total phenolic contents (TPC), DPPH• scavenging ac­ omega 3, 6 and 9 fatty acids to elucidate their importance as nutra­
tivity, ferric reducing antioxidant activity and lipid oxidation assay were ceuticals in promoting production performance and health of poultry
conducted to assess the antioxidant potential and results suggested a

23
M. Alagawany et al. Research in Veterinary Science 137 (2021) 9–29

birds. Their enzymatic, digestive, immunoregulatory, anti- Alagawany, M., Abd El-Hack, M.E., Farag, M.R., Sachan, S., Karthik, K., Dhama, K.,
2018a. The use of probiotics as eco-friendly alternatives for antibiotics in poultry
inflammatory, antioxidant, antimicrobial, hormonal, gut microflora
nutrition. Environ. Sci. Pollut. Res. Int. 25, 10611–10618 (Epub 2018/03/14).
regulatory roles have been described in addition to their nutritional Alagawany, M., Elnesr, S.S., Farag, M.R., 2018b. The role of exogenous enzymes in
importance. Currently, nutraceuticals are applied for boosting the promoting growth and improving nutrient digestibility in poultry. Iran. J. Vet. Res.
poultry growth rate, prevent disease and as immunity modulators. 19, 157–164 (Epub 2018/10/24).
Alagawany, M., Elnesr, S.S., Farag, M.R., 2019a. Use of liquorice (Glycyrrhiza glabra) in
Conversely, applying nutraceuticals for disease treatment has yet to be poultry nutrition: Global impacts on performance, carcass and meat quality. World’s.
verified. Nutraceuticals can be used for covering the gap between the Poultry Sci. J. 75, 293–304 (Epub 2019/04/01).
increase of the world’s population and the production of high quality Alagawany, M., Elnesr, S.S., Farag, M.R., Abd El-Hack, M.E., Khafaga, A.F., Taha, A.E.,
Tiwari, R., Yatoo, M.I., Bhatt, P., Khurana, S.K., et al., 2019b. Omega-3 and omega-6
and low-cost animal feed. Advantages and disadvantages of nutraceu­ fatty acids in poultry nutrition: effect on production performance and health.
tical s are illustrated in Table 2. However, further large-scale studies are Animals (Basel) 9 (Epub 2019/08/21).
required in order to use nutraceuticals commercially in poultry Aljumaah, M.R., Alkhulaifi, M.M., Abudabos, A.M., 2020. In vitro antibacterial efficacy
of non-antibiotic growth promoters in poultry industry. J. Poult. Sci. 57, 45–54
production. (Epub 2020/03/17).
Al-Khalaifah, H.S., 2018. Benefits of probiotics and/or prebiotics for antibiotic-reduced
poultry. Poult. Sci. 97 (1), 3807–3815 (Epub 2018/08/31).
Author contributions Al-Khalaifah, H., Al-Nasser, A., Givens, D.I., Rymer, C., Yaqoob, P., 2020. Comparison of
different dietary sources of n-3 polyunsaturated fatty acids on immune response in
MA, SSE, MRF, MEA and KD conceptualized the manuscript. MA, broiler chickens. Heliyon 6, e03326 (Epub 2020/02/14).
Al-Khalifa, H., Givens, D.I., Rymer, C., Yaqoob, P., 2012. Effect of n-3 fatty acids on
SSE, MRF, MEA, RAB, AAG, MAF, AEN, AFK, KES and KD retrieved and
immune function in broiler chickens. Poult. Sci. 91, 74–88 (Epub 2011/12/21).
analyzed the data from various multi-omics sources to obtain the Alloui, M.N., Szczurek, W., Świątkiewicz, S., 2013. The Usefulness of Prebiotics and
necessary statistics. MA, SSE, MRF, MEA, HAME, RT, and MIY prepared Probiotics in Modern Poultry Nutrition: a Review / Przydatność prebiotyków i
the figures and tables. MA, SSE, MRF, MEA, RAB, AAG, MAF, AEN, AFK, probiotyków w nowoczesnym żywieniu drobiu – przegląd. Annals of. Anim. Sci. 13
(17).
KES, HAME, RT, MIY, IM, ADC and KD wrote the manuscript. All authors Al-Mufarrej, S.I., 2014. Immune-responsiveness and performance of broiler chickens fed
contributed to the article and approved the submitted version. black cumin (Nigella Sativa L.) powder. J. Saudi Soc. Agric. Sci. 13, 75–80.
Al-Yasiry, A.R.M., Kiczorowska, B., Samolinska, W., 2017. Effect of boswellia serrata
resin supplementation on basic chemical and mineral element composition in the
muscles and liver of broiler chickens. Biol. Trace Elem. Res. 179, 294–303 (Epub
Declaration of Competing Interest 2017/02/18).
Amad, A.A., Manner, K., Wendler, K.R., Neumann, K., Zentek, J., 2011. Effects of a
phytogenic feed additive on growth performance and ileal nutrient digestibility in
The authors declare that the review was conducted in the absence of broiler chickens. Poult. Sci. 90, 2811–2816 (Epub 2011/11/15).
any commercial or financial relationships that could be construed as a Apata, D.F., 2009. Antibiotic resistance in poultry. Int. J. Poult. Sci. 8, 404–408.
potential conflict of interest. Araujo, R., Polycarpo, G., Barbieri, A., Silva, K., Ventura, G., Polycarpo, V., 2019.
Performance and economic viability of broiler chickens fed with probiotic and
organic acids in an attempt to replace growth-promoting antibiotics. Braz. J. Poultry
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