Alternatives to the Use of Antibiotics in Animal Production

Abstract

There is a growing demand for livestock products and by-products due to an increase in the human population globally. Farmers utilize feed additives and antibiotics to enhance growth and alleviate diseases to meet this increasing demand for meat and meat products. Although antibiotic use as growth promoters (AGPs) in the livestock industry has brought about a positive increase in production, the industry has also been negatively affected by the development of bacteria resistant to antibiotics and the presence of chemical residues in meat and excreta. Due to this, concerns have risen as this poses a health risk. Resistant bacteria can be transmitted to humans by consuming meat from antibiotic-fed animals or environmental spread from animal wastes. Therefore, action is required to curb this issue because it is estimated that the annual losses in GDP and death toll globally could increase because of the continuous use of antibiotics in livestock production. Hence, this review aims to examine natural alternatives that have the potential to replace antibiotics for food safety, health, and environmental reasons. These could bring a satisfactory impact on nutrient absorption for growth together with health-stimulating virtues.

1. Introduction

The use of antibiotics in livestock production started as early as 1928 by Alexander Fleming, where their use was to fight against diseases in humans. An increase in the demand for meat and poultry in the latter years led to research studies being conducted [1]. It was then discovered that the continuous administration of antibiotics in small amounts in livestock diets was essential to alleviate diseases and improve growth. This led to antibiotics being used as growth promoters (AGPs) in livestock diets [2]. Antibiotics promote growth by inhibiting pathogenic bacteria growth, preventing the development of growth-suppressing metabolites, reducing the inflammation of the gut wall, and improving microorganisms in the gut. This enables optimal performance of animals through efficient utilization of nutrients. The positive influence of antibiotics led to their approval by the Food and Drug Administration of the United States of America to be used as growth promoters in animal diets [3]. Antibiotic use increased in the following years because of the growing global demand for meat and meat products [1].

However, antibiotic resistance in animals started when farmers were allowed to use antibiotics even without a veterinary prescription, leading to continuous overdose or abuse sub-therapeutically by zealous farmers. This resulted in certain bacterial death, and those that remain develop resistant genes [4, 5]. They develop several means of surviving the selection pressures brought about by antibiotics, such as antibiotic molecule deactivation by enzymes, efflux pumps, and the development of cell wall and ribosomal modification to protect cellular targets against antibiotics. When they contact these animals or consume meat from antibiotic-fed animals, these resistant bacteria are also transferred to human beings. According to Letchumanan et al. [6] and Low et al. [1], food safety remains under threat because of the high incidents of antibiotic resistance.

About 50–80% of the antibiotics produced are available for livestock production in developing countries, and these have the highest rates of resistance genes that can be passed on to human beings [7]. Therefore, action is required to address antibiotic resistance because it is estimated that the death toll could rise to 10 million by 2050 from 2.8 million in 2019, and losses on the annual GDP by 3.8% globally [1].

Similarly, an increase in cases of antimicrobial resistance associated with health risks resulted in the banning of antibiotics as growth promoters in livestock in 2006 by the European Union (EU) [4]. Although antibiotics for growth promotion were prohibited, they are still being used upon regulation on disease treatment. Regulations were put in place by the Food and Drug Administration of the United States of America to limit antibiotic use as growth promoters in 2014. However, not much has been done regarding this issue in some developed countries and many developing countries where there is still unregulated use of antibiotics as growth promoters.

The total removal of antibiotics in animal production is implausible, as it affects the livestock industry negatively. It is pivotal to search for naturally occurring, available, low cost and effective growth promoters as substitutes to AGPs in livestock diets, particularly in territories in which antibiotics were banned. Hence, researchers in recent times have been working increasingly on natural alternatives that could replace the use of antibiotics in livestock production for food safety, health, and environmental reasons [8]. Antibiotic alternatives are natural, organic ingredients that could be utilized as feed additives, resulting in promoting growth and the animal’s health, primarily exerting their influence on the gastrointestinal tract [9]. Such natural antibiotic alternatives include prebiotics, probiotics, organic acids, photobiotic products (medicinal plants and products), exogenous enzymes, phage therapy, fossil shell flour, antimicrobial peptides, and bacteriocins [10, 11, 12]. They have attracted substantial recognition as additives in livestock production because of their satisfactory impacts on the absorption of nutrients and health-stimulating virtues [13].

2. Antibiotics alternatives

2.1 Phytogenic compounds

Phytogenic compounds are based on bioactive compounds derived from plants, and many such plant products can be broadly classified as essential oils, herbs, and spices [14]. Examples include lavender, green tea, cinnamon, garlic, pepper, oregano, rosemary, sage [15], and ginger [16]. Some of these plants contain secondary metabolites such as saponins, tannins, alkaloids, and flavonoids that could play the role of antibiotics in the body of animals.

Tannin-containing plants such as chestnut, Acacia karroo, and Grape pomace [17, 18] help alter rumen fermentation and mitigate disease-causing bacteria in the animal. Similarly, the presence of tannin in the diet reduces methane emissions from the rumen, thereby increasing the energy available for growth and production. Orlandi et al. [19] reported that 2–5% of tannins in livestock diets are highly beneficial to the development and health of the animal and for environmental safety against greenhouse gas. The mode of action of tannins includes protein binding, which affects the growth of bacteria in the rumen and fermentation. They reduce the amount of protein available for bacteria, thereby reducing nitrogen excretion and decreasing bloating and internal parasites [20]. Nawab et al. [18] noted that tannins could improve the production status, gut health, and immune status and reduce methane emission, which leads to improvement in the animal’s overall performance. On the other hand, Saponins are involved in binding sterols, causing cell destruction and microorganism damage [15].

Other photogenic compounds that are often used as natural feed additives in animal diets are essential oils. These compounds are naturally extracted from plants and used in the cosmetic and fragrance industries and recently in livestock production [17]. They are extracted from leaves, stems, flowers, roots, seeds, and barks. Essential oils constitute compounds that are involved in the elimination of pathogenic bacteria in the rumen. Examples of essential oils used as feed additives in animal diets are rosemary oil, coriander oil, eucalyptus oil, garlic oil, cinnamon oil and clove bud oil [21]. Essential oils destroy gram-positive and gram-negative bacteria’s cell membranes, making them ineffective in the animal’s body. Since essential oils exhibit a lipophilic characteristic [22], they also have substances that weaken fungi, protozoa, and viruses through coagulating cytoplasmic contents [23]. According to Zhu et al. [22], supplementing broiler diets with essential oils and oregano or saponins improves growth performance and immunity by removing pathogens. Since essential oils constitute various components, bacteria have fewer chances to develop resistance than when fed antibiotics. In ruminants, essential oils improve immunity, decrease ammonia and methane production, and improve rumen fermentation, rumen microbes, and volatile fatty acid production. In monogastric animals, essential oils increase feed intake, growth performance, egg production, immunity, nutrient digestion, and utilization [21].

Herbs such as wormwood, also known as Tethwan, are natural herbs with a peculiar scent and various medicinal impacts. According to Beigh et al. [24], tethwan and oregano in livestock diets can enhance feed intake, the animal’s ability to utilize nutrients efficiently, and rumen fermentation. However, there is a need to investigate further the mode of action, effect on microbial populations, and these compounds’ ability to be utilized to provide a better understanding [3] since there is limited knowledge on how they function in the gastrointestinal tract of the animal.

3. Probiotics and prebiotics

Humans have been consuming them as natural constituents in diets or fermented foods for a long time. Probiotics are live microorganisms added to livestock diets to assist in enhancing microbial balance in the intestines by suppressing pathogenic bacteria [13]. The commonly used probiotics are Lactobacillus, Streptococcus, Lactococcus, Bacillus, Enterococcus faecalis [25], and Bifidobacterium species [3]. Various Bacillus species are formulated in probiotic supplements as they are stable to heat and can withstand low pH conditions in the stomach. To improve variety and compliance, there is a need to introduce probiotics that are cheap commercially, have a long shelf life, are stable in the feed and can withstand the process of heat pelletization [25]. Honan et al. [17] deduced that probiotics could reduce methane emission production because of their effect on the rumen microbiome or metabolites. According to Abd El-Hack et al. [15], probiotics do not have any side effects on animals. They are specific to targeted strains of bacteria and resistant to acid and bile.

Tutida et al. [26] stated that the probiotics used in swine research studies vary and bring about variable effects, especially when administered under different conditions. Hence it is essential to consider the animal’s age, feeding, and method of handling to aid in choosing the probiotic to add to the diet. Probiotics improve the overall health of the animals by colonizing the intestines, removing pathogenic microorganisms, releasing metabolites, and boosting the immune system [14]. However, the limitation of probiotic use is the risk of spreading and transferring genes resistant to antibiotics, as probiotics are directly involved with disease-causing bacteria in the gut.

Prebiotics are indigestible carbohydrates (oligosaccharides, fructans, pectin) that aid in the growth of beneficial bacteria in the intestines [13]. Thereby improving the overall performance of the animal [14, 26]. They are involved in eliminating pathogens such as E. coli and Salmonella and preventing cancer in the colon. Shehata et al. [25], observed that prebiotics could improve poultry’s immune system, leading to faster disease clearance, decreased pathogenic bacteria such as streptococcus and staphylococcus, and improved intestinal morphology. Specific prebiotics have been known to enhance butyrate production in the rumen by providing a favorable environment for the growth of bacteria responsible for butyrate production [3].

When probiotics are used together with prebiotics, they are regarded as synbiotics. This combination promotes the growth and function of beneficial bacteria in the gastrointestinal tract [27]. Hence, it is beneficial to include synbiotics in livestock diets as the combined effect produces better output than including either. Since the aim is to improve livestock production by replacing antibiotics with these substances, combining them would benefit the animals and reduce their use.

4. Phage therapy

Bacteriophages are bacteria-infecting viruses with high specificity to target organisms [1]. They were first discovered during the early 1900s, and their use increased in the following years. However, increased use and benefits of antibiotics led to a decline in phage therapy use. Recent cases of antibiotic resistance and chemical residues in livestock brought about by antibiotics as growth promoters have caused researchers to gain interest in phage therapy. Phage therapy could be useful as an alternative to antibiotics to curb antibiotic resistance in livestock [28]. This is because phages are specific and can multiply when they detect an infection. Phages also can evolve and are cheaper, unlike antibiotics [1, 7]. Bacteriophages aid in growth promotion and coccidiosis prevention by eliminating pathogens in animal production.

Łusiak-Szelachowska et al. [29] pointed out that a combination of antibiotics and phage therapy could significantly reduce pathogenic microorganisms such as Staphylococcus aureus than utilizing one in livestock diets. The phage-antibiotic combination could result in increased production of phages and cell elongation by antibiotics. This could reduce the use of antibiotics and their concentration, thereby decreasing the rate of antibiotic resistance.

5. Organic acids

Organic acids are carboxylic acids with the general structure R-COOH [30]. For a couple of years, they have been used in the poultry industry as a substitute for antibiotics [31]. Their ability to function efficiently lies in the targeted bacteria or fungi, chemical composition, molecular weight, and form [4]. Organic acids interfere with bacterial growth and cause death by entering the bacteria’s cell membrane, leading to a reduced pH in the alkaline environment of the bacteria, thereby altering their mode of function [5]. Organic acids enter gram-negative bacteria cell walls and release H⁺ ions which reduce the pH and interfere with replication and protein synthesis in the cytoplasm of the pathogen [30]. Kiarie et al. [32], suggested that organic acids are useful as feed additives for weaned piglets. Organic acids such as benzoic acid reduce the presence of pathogens such as E. coli, promote digestion of nutrients, and improve gut health in swine. Piglets fed with a diet containing benzoic acids had been reported to have better overall performance in the first 3 weeks after weaning compared with those fed diets fortified with antibiotics as growth promoters. Table 1 shows the effects of various organic acids, their blends, and recommended inclusion levels as discovered in research studies.

Organic acid	Recommended inclusion rate (%)	Effect/s	Reference
Citric acid	0.5	Enhanced feed intake, growth, carcass yield	[4]
Combination of caproic, caprylic, fumaric, citric, and malic acids	0.2	Enhanced average daily feed intake, and growth rate, eliminated pathogenic microorganisms in swine.	[26]
Synergistic blend	—	Improved digestibility and absorption in poultry.	[30]

Table 1.

Organic acids, recommended inclusion rates, and effects.

Supplementing diets with short-chain fatty acids and medium-chain fatty acids improves disease protection, performance, and digestion rate and prevent the growth of pathogenic bacteria respectively in poultry and pigs [5]. This suggests that organic acids have the potential to be used as alternatives in livestock production [3]. However, there is inconsistency in research studies on the potential and effects of combinations of organic acids in animal production. These inconsistencies could be associated with variations in the composition and incorporation levels, feed type, environment, and breed [30]. Hence more research is essential.

6. Enzymes

Enzymes are proteins in nature, and they are regarded as biological catalysts that aid in speeding up the rate of chemical reactions [15]. They improve gut health in broilers and result in improved performance [22]. The nutritional value of the feed improves when diets are supplemented with enzymes. This results in improved feed efficiency, utilization, and decreased nutrients excreted. They are grouped into different classes based on the source and the substrates they act upon [15]. Adding exogenous enzymes to poultry diets enhances digestibility and utilization, reducing the quantity of nutrients excreted. Including exogenous enzymes in livestock diets also aid in lowering feed cost by providing a more significant return on investment [33].

Inclusion of the enzyme phytase in animal diets aids in the digestion of phytate to inositol ad inorganic phosphate. This is usually done because the phosphorus from cereal grains cannot be digested by poultry without phytase addition. The addition of phytase in poultry diets is economical because it efficiently utilizes phosphorus, which is regarded as the most expensive mineral in poultry production [15]. It is essential to include fiber and starch digesting enzymes in poultry diets as they assist in digesting non-starch polysaccharides. Xylanase and β-glucanase addition to poultry diets improve feed conversion ratio, digestibility, growth performance, and nutrient utilization and reduce wet litter [34]. The inclusion of enzymes in livestock diets is of great benefit not only to the animal through improved health, nutrient utilization, and growth but to the farmer also through reduced cost and increased returns.

7. Fossil shell flour

It is made from fossilized remains of diatoms, which are minute single-celled organisms found in seas, lakes, and soils [35, 36]. Fossil shell flour, also known as Diatomaceous Earth (DE), is regarded as a substance with multiple purposes and has the potential to be utilized as a substitute for antibiotics in livestock production. Anand et al. [37] stated that fossil shell flour is abundantly available and cheap than chemical-based feed additives. It is an anti-caking agent; it averts the formation of clumps in animal feed. This results in increased surface area of the feed that comes in contact with microbes and enzymes during digestion, leading to increased nutrient availability and utilization [38]. Fossil shell flour improves the animal’s well-being as it has over 14 minerals, including calcium, phosphorus, potassium, magnesium, copper, zinc, and iron silica. These are usually not available abundantly in most feed crops [39]. It also aids in reducing parasite load due to its sharp edges (that are seen with a scientific microscope), which can harm bacterial cell membrane surfaces, thereby causing dehydration and eventually leading to death [35].

Table 2 shows different inclusion levels of Fossil shell flour among other species and its effects discovered by researchers. Wikoff et al. [43] found that 2% inclusion of red lack diatomaceous earth (a naturally occurring blend of diatomaceous earth and calcium bentonite) in livestock diets does not pose a health risk to human beings. This signifies that fossil shell flour has the potential to be utilized in livestock diets as a substitute for antibiotics. Further studies need to be conducted to validate the safety of Fossil shell flour and the maximum inclusion rate based on each livestock species.

Recommended inclusion rate	Species	Effect/s	Reference
2000 mg/kg	Broilers	Improved lymphoid organs, reduced aflatoxin availability	[40]
2%	Layers	Reduction in parasitic load increased body weight gain and egg production.	[38]
Up to 2%	Layers	Improved egg quality	[36]
2%	West African Dwarf ewes	Weight retention during lactation, improved feed intake, twin survival.	[41]
4%	Dohne Merino weathers	Improved weight gain, nutrient digestibility, overall performance	[35]
40 g FSF/kg	Dohne Merino rams	Reduced heat stress and improved growth performance	[42]

Table 2.

Research studies of FSF effects and recommended inclusion rates.

8. Antimicrobial peptides (AMPs)

These are structurally heterogeneous cationic, amphiphilic peptides expressed by most multicellular organisms as part of their innate immune system [2]. Most of the antimicrobial peptides are derived from the cleavage of proteins during the replacement of proteins by protease enzymes [44]. They assist in fighting against disease-causing microorganisms in every animal, and approximately 5000 antimicrobial peptides have been discovered to date. Targets for antimicrobial peptides differ because of their nature; they can target gram-negative, gram-positive fungi, or viruses. This leads to different modes of action against pathogenic organisms. Some of them destroy the plasma membrane of the cell, which alters the proper functioning of the bacteria; others affect DNA, protein, and cell wall formation.

It is unlikely for bacteria to develop resistance against antimicrobial peptides because they break down the cell membrane of the bacteria’s cell through non-specific disturbance of lipid bilayers. Antibiotics are regarded as bacteriostatic, but antimicrobial peptides are considered bactericidal and advantageous over antibiotics [45]. The typical families of antimicrobial peptides in livestock are cathelicidins and defensins. They are proteins involved with the innate immune system, proteolytically active, and in the animal’s immune response to prevent and eliminate infections [44]. However, there is little knowledge on clinically antimicrobial peptides, mode of action, and availability. Hence, more research studies need to be conducted to understand AMPs in animal production better.

9. Bacteriocin

Another group of antimicrobial peptides (AMPs) is Bacteriocins. They are regarded as proteins or peptides produced by bacteria that exhibit repressive actions against numerous bacteria. They are produced in the late log growth phase and at the beginning of the stationary phase, unlike antibiotics, which are a product of secondary metabolism [46]. Schulze et al. [2] reported that bacteriocins are small bactericidal or bacteriostatic peptides synthesized by bacteria that play a regulatory role in bacterial ecosystems. They emit strains of bacteria that aid in preventing the growth of pathogens.

Bacteriocins are effective antibiotics and preservatives in the food and pharmaceutical industries. According to Murugaiyan et al. [28], bacteriocins are stable to heat and are less toxic. Hence they have the potential to replace or be used as a substitute for antibiotics. Bacteriocins also reshape the microbiota by killing the targeted pathogenic bacteria without harming the surrounding microorganisms, making them advantageous over antibiotics [47]. However, inconsistencies in research are the barrier to providing proper and complete knowledge, function, and potential of bacteriocins as a substitute for antibiotics in livestock production.

10. Summary

Organic acids, phytogenic compounds, antimicrobial peptides, phage therapy, bacteriocins, fossil shell flour, enzymes, probiotics, and prebiotics can bring success, profits, and the possibility of replacing antibiotics in livestock. As they can enhance growth, alleviate diseases, and improve production. However, it should be noted that none of these antibiotic alternatives is more efficient at a large-scale farming level. They can compensate for the total exclusion of antibiotics in livestock diets to a certain extent. Hence the researcher recommends that blending these alternatives can be a possibility to improve production and ensure more returns to farmers in place of antibiotics. Utilizing these natural alternatives in place of antibiotics is beneficial for food safety, health, and environmental reasons. They could bring a satisfactory impact on nutrient absorption for growth together with health-stimulating virtues.