In foregut fermenters, such as cattle and sheep, up to 50% of their energy may be obtained from microbial metabolites [92], including VFAs. In contrast, hindgut fermenters (such as pigs and chickens), in which most fermentation takes place in the cecum and large intestine, receive only 5–10% of energy demands from microbial fermentation products [93]. Although these differences seem to be important from a functional point of view, in ruminants or monogastrics, gastrointestinal microbiota composition is similarly central to improved animal production in both groups, and the impact of phytochemicals on these microbiota might be responsible for most of the positive effects observed. Many beneficial properties of plants are derived from their specific bioactive components, which are also synthesized as chemical protectants against microbial infection. The most important useful phytochemicals with antimicrobial activities can be divided into several categories, such as phenolics/polyphenols, terpenoids/essential oils, alkaloids, and lectins/polypeptides [94]. Some compounds among these categories are known to be important for improving animal production, as well as inducing an extensive number of health-promoting effects. Tannins (饲用单宁酸) and EOs are fed commercially to several domestic animal species and, as growth promoters, they modify the gut microbiota in different ways. Tannins (饲用单宁酸) are a complex group of polyphenolic compounds found in many plants species, functionally defined by their capacity to complex macromolecules (proteins and polysaccharides) and metal ions, which are commonly included in ruminant diets such as forage and sorghum. Tannins (饲用单宁酸) are chemically classified as hydrolysable or condensed based on their chemical structure, and are widely used to improve several aspects of animal husbandry. Some tannins (饲用单宁酸) are potent antimicrobials, acting, for example, by iron deprivation or interactions with vital proteins such as enzymes [95] or bacterial cell wall proteins [96], displaying either bactericidal or bacteriostatic activities [97]. Gram-positive bacteria are particularly sensitive to tannins (饲用单宁酸) [98]. In ruminants, tannins (饲用单宁酸) modify the digestive processes not only by binding dietary protein (rumen bypass), but also through modulation of rumen microbiota and improvement of the growth of certain bacterial populations [99]. The effects of tannins (饲用单宁酸) on rumen microbiota may vary depending on the molecular nature of these polyphenols [99, 100]. The understanding of in vivo interactions between rumen bacteria and sources of plant tannins (饲用单宁酸) are limited. Approximately 90% of total microbiota in the bovine rumen is composed by Firmicutes and Bacteroidetes, with large inter-individual variance in their relative abundance, with a strong inverse correlation between abundance of both phyla [101]. In steers fed with a high-starch diet, bacterial populations belonging to the Bacteroidetes were the most abundant in all animals (almost 50%) while Firmicutes accounted for ~40% of the total microbiota. However, this predominance was inverted when a blend of tannins (饲用单宁酸) were added to the feed, with a significantly higher percentage of Firmicutes and a reduction in Bacteroidetes. Accordingly, steers supplemented with tannins (饲用单宁酸) have a higher Firmicutes to Bacteroidetes (F/B) ratio in comparison with the control group [101]. Many studies have reported that F/B ratio increases when body mass index is increased, and F/B ratio is higher in obese than in lean animals [102,103,104]. The rational basis for the apparent relation between F/B ratio and increase in body weight is that Firmicutes are not as effective as Bacteroidetes at gathering energy from digesta for themselves, leaving more energy to be absorbed by the host. Diversity of rumen microbiota is one of the key features in ruminant animals, which confers upon cattle the ability to adapt to a wide range of dietary conditions [105]. Dietary quebracho and chestnut tannins (饲用单宁酸) diminish rumen richness but do not significantly affect the complexity of the bacterial communities (i.e. balance between the relative abundances of bacterial taxa). There is an increase in rumen microbiota richness but no change in Shannon’s diversity index after supplementation with a blend of polyphenols and EOs in dairy heifers fed a high-grain diet, supporting the idea that polyphenols can modulate bacterial richness without disrupting the overall structure of the rumen microbiota population. Similarly, β-diversity analysis of rumen samples of steers fed with chestnut and quebracho showed no significant changes in bacterial diversity compared with the control group [101]. Low microbial richness in the rumen is closely linked to a higher feed efficiency in dairy cows [106]. The authors have suggested that lower richness in the rumen of efficient animals results in a simpler metabolic network, which leads to higher concentrations of specific metabolic components that are used to support the host’s energy requirements. Diversity analysis indicate that bacterial richness is lowered by tannins (饲用单宁酸), but the overall bacterial complexity of the rumen is not significantly affected by chestnut and quebracho tannins (饲用单宁酸) supplementation. Several studies have found an increase of rumen pH, decrease of ammonia concentration, and lower methane emissions after feed supplementation with several tannins (饲用单宁酸) including chestnut and quebracho, resulting in a reduction of protein degradation and therefore an improvement in nitrogen utilization in the rumen [107]. Tannins (饲用单宁酸) are considered as alternative agents to antibiotics, they improve animal health and productive performance while suppressing methanogenesis. These observations could be explained by changes in the microbiota in the rumen. Significant changes in the abundance of certain taxa have been detected in tannin-treated steers. Among Bacteroidetes, Prevotella was the most abundant genus, accounting for >40% of this phylum. The abundance of Prevotella was lower in tannin-supplemented animals than in the control group. In contrast, Clostridia was the predominant class, which accounted for >90% of total Firmicutes, and it was significantly enhanced in tannin-treated animals. Among Clostridia, Ruminococcaceae was the most abundant family and showed a significantly higher abundance in tannin-supplemented animals. Within the Ruminococcaceae, most of the sequences obtained in untreated animals belonged to unclassified members and the genus Ruminococcus, and both taxa were enhanced in tannin-treated steers. Other non-clostridial bacteria within the phylum Firmicutes were significantly altered by tannins (饲用单宁酸), including members of class Erysipelotrichi. Members of class Bacilli (Streptococcus and Lactobacillus) showed moderate increases in their abundance in tannin-treated animals. Genus Fibrobacter was significantly affected by tannins (饲用单宁酸), accounting for 0.10% of total microbiota in the control animals and only 0.005% in tannin-treated animals. Other minor fibrolytic bacteria were more abundant in tannin-treated steers, including the genus Blautia and member of the Eubacteriaceae genus Anaerofustis. Tannins (饲用单宁酸) remodel the bacterial ecosystem of the rumen, particularly the niche of fiber and starch degradation, and the methanogenic bacteria [108]. Treponema is also reduced by tannins (饲用单宁酸). Among Veillonellaceae members, Succiniclasticum, which specializes in fermenting succinate to propionate, doubles its levels in tannin-treated animals. Lipolytic genus Anaerovibrio is significantly enhanced by tannins (饲用单宁酸). Selenomonas is also increased in tannin-supplemented animals. Among ureolytic bacteria, Butyrivibrio is the most abundant and it is negatively affected by tannin treatment, as well as Treponema and Succinivibrio. Methanogens belonging to the phylum Euryarchaeota are less abundant in tannin-supplemented steers and their levels are inversely correlated with rumen pH. Methanosphaera is also reduced by tannins (饲用单宁酸). Current literature indicates that tannins (饲用单宁酸) can be supplemented to improve the sustainability of both dairy and beef cattle by reducing methane emissions and nitrogen excretion, and enhancing animal performance. In monogastrics, that is, broiler chickens, tannins (饲用单宁酸) obtained from several sources seem to improve growth performance and reduce the detrimental effects of pathogenic bacterial species such as C. perfringens [101]. The establishment of a stable microbiota is a complex process that is influenced by various factors, including genetic lineage, age, diet, use of growth promoter antibiotics, probiotics, litter composition, stress and disease [86, 109,110,111]. Therefore, any alteration in the intestinal microbiota may have functional consequences to the health of the host and, therefore, productivity. The broiler chicken gastrointestinal tract is colonized by a dense community of microorganisms that is intimately connected to the global heath and development of the host. The cecum houses the highest microbial cell densities of the chicken gut and performs key process for birds such as the fermentation of cellulose, starch and other resistant polysaccharides [86]. A principal coordinate analysis (PCoA) based on unweighted UniFrac distances was conducted to determine any differentiation between sample clusters of tannin-treated versus antibiotic-growth-promoter-treated versus untreated birds. PCoA plots revealed that the samples corresponding to each dietary treatment shaped distinct series, suggesting that tannins (饲用单宁酸) differentially modulate cecal microbiota. High-throughput sequencing of 16S rRNA gene amplicons has been used to identify functional diversity [112] or variability [113] of the microbiome in the gut of broiler chickens. In most studies related to tannins (饲用单宁酸), cecal microbiota in chickens was dominated by Firmicutes and Bacteroidetes [114, 115], comprising >80% of the microbiota. The most abundant Bacteroidetes detected in cecal contents belonged to genus Bacteroides and an unclassified genus of the family Barnesiellaceae. Among the Firmicutes, order Clostridiales and family Ruminococcaceae were the most abundant taxa. The F/B ratio was significantly higher in tannin-fed animals than in the control or antibiotic growth promoter groups. Bacteroides is a Gram-negative genus that utilizes plant glycans as its main energy sources. Bacteroides is one of the main bacteria involved in producing short-chain fatty acids (SCFAs) [116], and plays an important role in breaking down complex molecules to simpler compounds that are essential for host growth [117]. SCFAs are absorbed by the host and used as an energy source but also have a variety of distinct physiological effects. SCFAs are saturated aliphatic organic acids that consist of 1–6 carbons of which acetate, propionate and butyrate are the most abundant (≥95%). Although Bacteroides generates acetate and propionate, its ability to produce butyrate has not been reported. Order Clostridiales are generally known as important contributors to short-chain fatty acid (SCFA) metabolism [86] because it contains a variety of bacterial families, among which Ruminococcaceae and Lachnospiraceae are capable of fermenting various substrates to butyrate. Feed tannin supplementation of chickens decreases the abundance of Bacteroides, which could reduce acetate and propionate production. However, it would be compensated by an increase in Clostridiales, particularly Ruminococcaceae, with a possible increase in butyrate production [96]. Concordantly, Masek et al. [118] have reported a global increase in SCFA production in poultry treated with tannic acid. Lactic acid bacteria, which are usually associated with enhanced gut health and productivity, are interesting. It was reported that cecal microbiota contained lower proportions of Lactobacillus in AGP-fed chickens, compared with chickens in tannin and control groups [119,120,121]. Lactic acid bacteria, especially Lactobacillus strains, have been considered as probiotic microorganisms because of their activities in reducing enteric diseases and maintaining poultry health [122,123,124]. The presence of Lactococcus spp. has been correlated with weight gain [125]. The inclusion of different AGPs in diet influences the diversity of gastrointestinal microbiota. These changes would probably be one of the most important driving forces resulting in efficiency improvement of animal production. Similarly, the existing information clearly shows a significant alteration in the relative abundance of specific bacterial populations by some phytochemicals in the gut of domestic animals (13). These phytochemicals added to feed are also connected with higher productivity parameters. Therefore, these natural compounds are able not only to improve animal health and welfare directly, but also to modulate gastrointestinal microbiota and increase the impact on health and production. We are just barely starting to understand the dynamics between the highly complex connection between environment, host and microbiota. More information is necessary to clarify how we can manipulate gastrointestinal microbiota to increase animal productivity under diverse productive settings.

Examples of commercial phytochemicals and their synergistic action with other feed additives

Tannins (饲用单宁酸) in animal husbandry

Tannins (饲用单宁酸) are present in many feeds such as fodder legumes, browse leaves and fruits. Although the structure of tannins (饲用单宁酸) are chemically diverse, they have one unifying property: tannins (饲用单宁酸) bind proteins. During the last 30 years, tannins (饲用单宁酸) have been successfully used in animal production to improve health and productivity, and several products based on blends of particular amounts of hydrolysable (predominantly chestnut) and condensed (mostly quebracho) tannins (饲用单宁酸) were developed to take advantage of the benefits of each tannin in livestock. These products are being used in many countries to improve quality and production of milk, meat and eggs. In poultry, a blend of tannins (饲用单宁酸) can be added to feed at a final concentration of 0.5–1 kg/tonne, both in pre-mix or directly into feed, to obtain several benefits including reduction of mortality rate, improvement of feed efficiency, weight gain and intestinal health, reduction of NE and foot-pad lesions, and increased feces consistency and litter quality of commercial settings. The selected blend of tannins (饲用单宁酸) added to the diet stabilizes and increases feed intake according to reduction of taste variation by changes in feed formulation [126], and reduces feed stress by improving the flavoring characteristics. The distinctive antispasmodic effects of tannins (饲用单宁酸) that modulate gut motility [127, 128], with strong antibacterial effects on several pathogenic bacterial species and viruses [97, 129], as well as their toxins [97], are used to prevent and control enteric diseases, including several diarrheal diseases [130] and NE [96]. Reduction of enteric diseases, intestinal motility and bacterial load, concurrently with an increase of feed digestibility, produces a reduction of humidity in the litter, affecting directly animal health and welfare. It has become obvious when foot-pad disorders are observed in commercial farms, dietary tannins (饲用单宁酸) reduced up to 50% of the animals with lesions, and up to 20% reduction of animals with the most severe lesions. These blend of tannins (饲用单宁酸) are also being used efficaciously to reduce the incidence of sub-clinical NE, and a slightly different blend is able to strongly reduce intestinal lesions in chickens on farms with a history of severe NE outbreaks. In experimental conditions, the tannin blend is able to reduce the most severe lesions as well as the number of animals with lesions. This result is also observed in commercial farms of different European, American and Asian countries where NE is a problem to different degrees. As an example, an integrated company in Brazil with a persistent history of sub-clinical NE started using the tannin product in 2015 and reduced the number of animals with lesions by 10%, improving productivity by almost 3% (Dr Joao Battista Lancini, personal communication). A comparative analysis of AGPs versus tannin blend use in feed was carried out in a commercial trial in Argentina over a period of 13 months (5 cycles) in a poultry farm of ~200 000 animals. The farm was divided into six barns under regular commercial feed; three were fed with AGPs in feed and three with 0.1% blend of tannins (饲用单宁酸) in feed but without AGPs. Greater improvements in intestinal health, microbiological quality and humidity of litters, mortality rate, undigested feed, foot-pad lesions, and weight gain were observed in the animals treated with tannins (饲用单宁酸) versus antibiotics. Analysis of the results showed a positive difference of almost 10 points for the Production Efficiency Factor for the blend of tannins (饲用单宁酸) against AGPs in feed, showing the benefits of using these blend of tannins (饲用单宁酸) during different weather conditions throughout the year [131]. Tannins (饲用单宁酸) added in feed to improve productivity in combination with other products, including EOs, organic acids, probiotics and AGPs, have been used frequently by different companies in several countries with significant positive results (Dr Javier Quintar and Dr Joao Battista Lancini, personal communication). In cattle, historically low doses of quebracho and chestnut tannins (饲用单宁酸) have been used in feed by many producers around the world to improve bypass protein from rumen degradation. Rumen bypass protein is one of the strategies to increase the amount of protein that enters abomasum and hence increases ruminant productivity. The reduction in protein degradation in the rumen may occur by the formation of a reversible tannin–protein complex in the rumen pH and/or the modulation of rumen microbiota. The addition of such tannins (饲用单宁酸) to a diet reduces the fermentability of protein nitrogen in the rumen [132]. Consequently, the flow of dietary amino acids into the duodenum of ruminants could be increased, as well as the total duodenal amino acid flow if ammonia nitrogen requirements for microbes could be met by supplementation of urea or ammonia salts. In addition, added tannins (饲用单宁酸) are also used to prevent acidosis and bloating [133], modulate rumen microbiome to improve feed utilization [130], and reduce methane emissions [134] and nitrogen excretion [135]. A particular tannin mix added in feed was able to reduce liver abscesses in beef cattle by >80% [136]. Supplementation of tannin also reduced fecal moisture, resulting in better fecal consistency. According to Rivera-Mendez et al. [137], the addition of up to 0.2% of a blend of tannin to steers during the feedlot finishing phase increased average daily gain by 6.5%. Body weight in young animals was improved up to 7% in commercial conditions before the breeding period [107, 138]. Similarly, DM intake tended to increase with level of tannin. Tannin supplementation increased gain efficiency (5.5%) and dietary net energy (3.2%). These results have been also observed in commercial feedlot finishing settings. The analysis of 15 different trials in North America between 2010 and 2013 using tannins (饲用单宁酸) at 0.25%, with or without antibiotics or ionophores in feed, showed an average daily gain of 9.2% and gain efficiency of 5.07% compared to non-tannin controls [139, 140]. Similar results have been observed in feedlots in other parts of the world, including large beef producers in Brazil [141, 142] and Argentina [136]. In conclusion, the addition of low-dose tannins (饲用单宁酸) to ruminant diets in intensive fattening is an available tool to increase nutrient use efficiency, improving daily weight gain and feed conversion, through different metabolic mechanisms. The estimated level of animal feed supplemented with tannins (饲用单宁酸) produced in the world in 2016 was 15 000 000 tonnes, reflecting the acceptance of tannins (饲用单宁酸) as an important tool in animal husbandry. The available scientific information about mechanism of action, the observed animal response and the accumulated experience in the use of tannins (饲用单宁酸) as feed additive confirms that tannins (饲用单宁酸) are a valuable alternative to complement or replace the use of AGPs in industrial livestock production.

Synergistic action of phytochemicals with other feed additive antibiotic alternatives for commercial products

Designing an antibiotic alternative to address several components of gut health may work better than using a single approach to reduce negative consequences of gut damage caused by complex etiologies such as those that cause diseases such as NE. C. perfringens produces several exotoxins, including α-toxin and NE toxin B (NetB), that disrupt the intestinal epithelium, causing necrotizing lesions that constitute the characteristic sign of NE [21, 143]. For complex disease like NE, it takes a multi-faceted approach to decrease the effects of disease on gut health. For example, a commercial product Varium^® was designed to improve barrier function by removing pathogens by agglutination, removing biotoxins via adsorption, priming immune development, and providing energy to the enterocytes [144]. Varium^® has been tested in vitro for its ability to bind biotoxins of pathogenic bacteria (i.e. C. perfringens and E. coli) such as α-toxin, NetB toxin, lipopolysaccharide, heat-labile toxin and Shiga-like type 2 toxin. The binding of these toxins was dose dependent, with the exception of NetB toxin, which was bound 100% across the doses tested. Two large broiler trials have been conducted to test the hypothesis that CaMM, or its blends with other materials (e.g. fermentable fibers, organic acids, and/or phytonutrients) could improve gut health and decrease the negative effects of avian NE. The two trials evaluated CaMM-based dietary products on growth performance, clinical signs, immunopathology, and cytokine responses of young broilers using disease challenge models with avian NE [144]. When tested in unchallenged birds, Varium exerted an effect similar to an in-feed AGP on body weight, feed intake, and FCR. Chickens fed a diet supplemented with CaMM plus a fermentable fiber and an organic acid showed increased body weight gain, reduced gut lesions, and increased serum antibody levels to C. perfringens α-toxin and NetB toxin compared with chickens fed the basal diet alone. Levels of transcripts for inflammatory cytokines such as IL-1β, IL-6, inducible NO synthase, and TNFSF15 were significantly altered in the intestine and spleen of CaMM-supplemented chickens compared with unsupplemented controls [144]. In Trial 2, Cobb/Cobb chickens were fed an unsupplemented diet or a diet supplemented with CaMM; each with a fermentable fiber and an organic acid, and co-infected with E. maxima and C. perfringens under subclinical infection conditions to elicit NE. Compared with unsupplemented controls, broilers fed with CaMM plus a fermentable fiber and an organic acid showed increased body weight gain, reduced FCR, mortality, and intestinal lesions, compared with chickens fed an unsupplemented diet. Based on both broiler trials, it is recommended that dietary supplementation of CaMM or CaMM plus a fermentable fiber and an organic acid is useful to decrease negative effects of avian NE in the field. Future studies are needed to characterize further the CaMM-regulated physiological and immunological mechanisms that are activated in response to avian NE.

Antibiotic alternatives: industry perspective

In general, there is a lack of consensus on what is meant by the phrase “antibiotic alternatives”. AGP use is a common practice that has been around for >65 years in modern livestock production that to this day has no consensus about its mechanism of action. Yet, most of the technologies discussed here have proposed or known mechanisms of action that involve inhibition, alteration or killing of one or more bacteria. In general, it appears that most people equate the phrase with something not termed an antibiotic that can be substituted for low level feeding of broad-spectrum antibiotics used to promote growth in livestock. The reason there is a need for alternatives to AGP is the recognition that the practice can lead to development of infective bacteria that are resistant to many of the current antibiotics available to human medicine. The rising incidence of superbugs globally and the rising human deaths from multiple drug-resistant bacteria have alerted WHO, CDC and UN to release strict action plans on reducing the use of antibiotics in animal production. Regardless of which side of the argument over whether AGP use in animals is contributing to the problem of resistant bacteria in humans you are on, the sociopolitical momentum has created a marketing opportunity for selling meat from animals claimed to have never received antibiotics during production. This in turn creates a market for products that can provide the benefit of AGPs but not be antibiotics used in human medicine, or sometimes any antibiotic at all. The alternative to antibiotics market is growing rapidly and attracting interest from companies and organizations of all sizes and capabilities. This is evident from the need for a meeting such as this and the plethora of products marketed, with or without credible data, to be alternatives to AGPs. Although the banning of AGPs has accelerated over the last few years, the search for alternatives started in earnest following the ban in the EU of avoparcin in 1997. The most important development in the search for credible alternatives is the increasing understanding in both human and veterinary medicine that the gastrointestinal tract is more than a nutrient-absorbing organ, but in fact is fundamental to health and development of humans and animals. The scientific advancement in our understanding of the importance of the gut environment and its barrier function in health provide a way to develop products that can deliver the benefits of AGPs without causing an increase in the emergence of antibiotic-resistant bacteria. This can be accomplished by using multiple technologies to maintain or strengthen gut barrier function. Scientific principles should be applied to the development of products such that they provide reliable positive benefits to the target animals. In a recent survey, more than 70% of animal feed companies showed interest in willingness to use some kind of feed additive as antibiotic alternatives. However, there are still many challenges remaining with the most consistent concerns being consistency, safety and solid scientific proof. This is not surprising when you consider most of the popular alternative products marketed today modify the microbiota in some way to enrich beneficial bacteria. We are just learning what the desirable microbiota is and how it works in given animal, and we have even less knowledge of the variations between different animals and the normal daily and lifetime changes in different ecosystem. So, it is likely that a product that can deliver consistent results will need to incorporate two or more components that have complimentary and/or synergistic mechanisms of action. In addition to the microbiota, it will be necessary to understand clearly what impact the product has on the gut barrier which comprises the mucus layer, endothelial cells and attendant immunological cells and structures associated with the gut wall. This is a relatively new field of research and as time goes on, the industry, through application of good science, will learn more. This will be both in the basic understanding of the gut environment, including the microbiota and the dynamic function of the gut barrier, and how to manipulate these structures in individuals, but as part of a population. Because it is new and there are many unknowns, regulation of these products poses a challenge in different regions of the world. What constitutes acceptable efficacy and what types of claims can be supported are largely unknown. However, there is little doubt that use of the FDA drug approval process is not a viable option today. Perhaps as science defines ways to measure and test efficacy in a consistent manner across several mechanisms of action, a regulatory pathway can be established. There will need to be tolerance and flexibility in the approval process for these products or the market will be flooded by products with no proof of efficacy or safety. At a minimum, these products should have scientific proof of efficacy in the target species for which they are marketed. In vitro tests are insufficient to provide confidence that a product will work in an animal, let alone provide consistent value across a population of animals.

Conclusions and future directions

Increasing concerns about the increase of superbugs and limited development of new drugs for livestock and humans necessitates the timely development of alternatives to AGPs. With increasing availability of many different categories of antibiotic alternatives in the market for animal agriculture with various claims and efficacy, the industry needs to understand the mode of action associated with different types of antibiotic alternatives and the kind of synergy that can be offered by the combinations of different antibiotic alternatives, especially for prevention and treatment of complex diseases such as necrotic enteritis. Furthermore, the definition of the phrase antibiotic alternatives should be better defined, although this terminology is now an accepted term to refer to non-antibiotic substances that can be substituted for low-level feeding of broad-spectrum antibiotics that promote growth in livestock. Antibiotic alternatives will be mainly used to replace AGPs whose primary function is to decrease microbial populations and promote growth via many different modes of action that may include alteration and/or inhibition of microbial growth, decrease of inflammation, enhancement of innate immunity, reduction of oxidative stress, and improvement of gut integrity. Increasing marketing opportunity for selling animal meat products claimed to have never received an antibiotic (antibiotic-free, ABF; no antibiotics ever, NAE) has created a market for products that can provide the benefit of AGPs without using antibiotics that are used therapeutically in human medicine. The most important development in the search for credible alternatives to AGPs is the new understanding in both humans and veterinary animals that animals including humans are “superorganisms” that contain trillions of bacteria, with more than thousands of species, and that the gastrointestinal tract is an intelligent sensory organ that not only absorbs nutrients, but also communicates with the largest neuroendocrine system in the body. This new scientific knowledge in our understanding of the importance of the gut environment and barrier function in health should guide finding a future solution to develop novel products that can deliver the benefits of AGPs without causing an increase in the emergence of resistance. For example, when we consider using phytochemicals as antibiotic alternatives, we need to consider: (1) dose for immune versus bacteriostatic/cidal effect in target animals; (2) variations in active compound in plants and plant-derived products; (3) unexplored concurrent effects of phytochemicals (antiviral and antineoplastic); (4) target organs/tissues affected by phytochemicals; (5) safety of phytochemical residues in humans; and (6) the long-term effect of using phytochemicals in animals on developing resistance. Since using phytochemicals as antibiotic alternatives in agricultural animals is a relatively new field of research, regulation of these products poses a challenge. There is a timely need to provide increased public funding for mechanistic research for phytochemicals that include standard measurements to define the efficacy in a consistent manner across several regulatory pathways, to prevent false claims and yet have flexibility in the approval process for proof of efficacy or safety for commercialization. Owing to the rise in consumer demand for livestock products from ABF production systems, scientists, regulatory agencies and commercial partners need to work together to develop effective antibiotic alternatives to improve performance and maintain optimal health of food animals. Using optimal combinations of various alternatives coupled with good management and husbandry practices will be the key to maximizing performance and maintaining animal productivity, while we move forward with the ultimate goal of reducing antibiotic use in the animal industry. Further research is needed regarding understanding their mechanism of action, identifying means to standardize the effects, improving delivery methods (e.g. microencapsulation) for site-targeted delivery, and increasing their in vivo efficacy in farm settings.