Challenges of a one-health approach to the development of alternatives to antibiotics

Antibiotic resistance is among the top five threats to humanity, with infectious disease expected to surpass cancer as the leading cause of death by 2050. Antibiotic resistance is a “One Health” issue with any anthropomorphic use of antimicrobials potentially promoting resistance. There is an urgent need to identify alternatives to antibiotics for use in livestock, before further restrictions in their use occur. Prudent use of existing antibiotics and emerging alternatives throughout the “One Health” continuum, coupled with disease prevention, are integral to sustaining human and animal health. By 2050, global infectious disease caused by antibiotic-resistant bacteria is projected to be responsible for 10 million human deaths per year—1.8 million more than cancer. Antibiotic resistance is a natural phenomenon, but the anthropomorphic use of antimicrobials has created heightened selective pressure that has led to an increased presence of antibiotic-resistant bacteria in agriculture, aquaculture, and hospital environments. Concerns over the emergence of antibiotic-resistant bacteria that threaten human health has prompted the retail and fast food sector to promote meat and milk produced from livestock that are raised “without the use of antibiotics.” Antibiotics have become an integral component of intensive livestock production and are used to treat (therapeutic use) and prevent (prophylactic, metaphylactic) infectious disease and promote growth (subtherapeutic). The growing restriction of antibiotic use in livestock production has promoted research into a plethora of potential alternatives. Some alternatives to antibiotics, such as plant secondary compounds (i.e., essential oils, tannins, saponins) and probiotics, have been used in human medicine for centuries, but have only recently been seriously considered for use in livestock and poultry. Over the last 70 yr, antibiotics largely replaced the use of these alternatives in most human societies and have been rapidly adopted for use in livestock and poultry production. Antibiotics are used to control bacterial infections in a range of environments and if resistance is to be reduced, antibiotic use must be curtailed and made more prudent throughout the “One Health” continuum. Such an outcome will require the integrative efforts of experts in human, livestock, and environmental health and the adoption of recommendations by stakeholders. Logically, studies on the ability of alternatives to reduce antibiotic resistance should also be structured from a “One Health” perspective using indicator bacteria, pathogens, and molecular techniques to document the extent to which they impact antibiotic resistance in humans, livestock, and the environment (Figure 1). Antimicrobial compounds in plants such as essential oils and condensed tannins (CT) as well as bacteriophages, vaccines, and probiotics are examples of a few of the alternatives that are being explored for use in livestock. However, antimicrobial activity of plant bioactives is often broad, inhibiting both commensal and pathogenic bacteria and reducing productivity. In contrast, the activity of bacteriophages is often too narrow, targeting only a subset of pathogenic bacteria. Compared with antibiotics, the mechanisms whereby these alternatives inhibit or kill bacteria are poorly defined, making therapeutic outcomes difficult to predict. Understanding the mode of actions of these alternatives is integral to using them in a manner that offsets the present reliance on the use of antibiotics to control infectious disease in livestock. Proposed approach to evaluating the impact of alternatives to antibiotics in livestock and poultry production on antibiotic resistance throughout the One Health Continuum. Indicator bacteria and samples for metagenomic analysis are collected from conventional and natural livestock and poultry production systems. Natural production systems limit the use of antibiotics and rely heavily on alternatives. Similar samples are collected from the surrounding environment, surface waters, sewage, hospital settings, and retail meat. Such a system should provide insight as to the degree that a reduction in the use of antibiotics in natural livestock production systems contributes to a reduction in antibiotic resistance throughout the One Health continuum. There are about 4,500-individual essential oils and numerous other bioactives that have been extracted from various plant components, including flowers, buds, seeds, leaves, twigs, bark, herbs, wood, fruits, and roots, with some sources used in human medicine since antiquity (Baby and George, 2009). The major constituents of essential oils include carvacrol, citronellol, geraniol, eugenol, and thymol (Perricone et al., 2015). Several essential oils have been shown to have antibacterial, antifungal, antiviral, and anti-inflammatory properties (Baby and George, 2009; de Cássia da Silveira e Sá et al., 2014; Chouhan et al., 2017). Constituents of essential oils seem to interact with bacterial cell membrane lipids and cause cell lysis. For example, terpinen-4-ol, α-terpineol, 8-cineole in tea tree oil caused the autolysis of Staphylococcus aureus and the formation of mesosomes (Carson et al., 2002), whereas cinnamaldehyde and carvacrol readily lysed Mycobacterium avium (Nowotarska et al., 2017). In addition to controlling pathogens, essentials oils have been investigated for their potential to improve the growth performance of livestock by increasing feed palatability. However, their antibacterial activity is often less pronounced in vivo than in vitro, possibly due to the inactivation by other feed ingredients and to their poor absorption (Si et al., 2006). Some have proposed that essential oils be protected from degradation in the upper digestive tract in order to promote their passage to the lower tract. Diets supplemented with encapsulated carvacrol or citral at either 250 or 650 μg/g reduced the prevalence and severity of necrotic enteritis associated with Clostridium perfringens in chickens (Liu et al., 2016; Yanga et al., 2016). Adverse effects have also been observed when essential oils are included in poultry diets. For example, even though cinnamaldehyde and eugenol decreased colonization of the broiler gut by Salmonella enteritidis, birds exhibited reduced growth (Kollanoor-Johny et al., 2012). Similarly, Patraa and Yu (2012) reported that essential oils from clove, eucalyptus, garlic, oregano, and peppermint decreased methane and ammonia production as well as the abundance and diversity of archaea in ruminal laboratory batch cultures, but others found adverse effects on feed digestion and fermentation in cattle. In general, these additives have shown promise in laboratory studies, but have frequently failed to deliver similar responses when included in the diets of livestock. American cranberry (Vaccinium macrocarpon), wild-blueberry (Vaccinium angustifolium), and highbush blueberry (Vaccinium corymbosum) are important commercial fruits in the United States and Canada (Figure 2). They are rich sources of bioactives including polyphenolics (Harrison et al., 2013). The ability of polyphenolics to alter the diversity of the intestinal microbiome has been well documented (Cardona et al., 2013). The commensal bacteria, Bifidobacterium and Lactobacillus have been shown to ferment cranberry xyloglucans to produce formate which may aide these bacteria in colonizing the human gut (Özcan et al., 2017). Cranberry extracts were found to be nearly as effective as trimethoprim, with less adverse effects when used to treat urinary tract infections in women (McMurdo et al., 2009). (A) American cranberry (Vaccinium macrocarpon), (B) wild-blueberry (Vaccinium angustifolium), and (C) highbush blueberry (Vaccinium corymbosum) are all sources of bioactives with the potential to be used as alternatives to antibiotics. Photo taken by Dr. M. S. Diarra. Few studies have assessed the potential of these berry polyphenolics to serve as alternatives to antibiotics in livestock. Inclusion of a commercial cranberry juice powder in the feed of broilers did not improve feed intake or gain (Leusink et al., 2010). Cranberry juice has been found to contain at least 19 phenolic compounds, with quercetin, vanillic acid, and protocatechuic acid shown to enhance immune function in poultry (Islam et al., 2017). Considering that the pomace remaining after juice extraction also contains these polyphenolics, the use of this by-product is likely a more economical alternative to antibiotics. Berry pomaces can be a good source of nutrients and other functionally important molecules including vitamins, minerals, and polyphenolics (Ross et al., 2017). A polyphenol rich bioactive fraction from cranberry pomace exhibited high antibacterial activity against a number of multidrug-resistant bacteria including methicillin resistant Staphylococcus aureus (Diarra et al., 2013). Feeding turkeys a diet containing 5% pomace from strawberries resulted in no differences in the final body weights or meat yield as compared to birds fed a conventional diet (Juskiewicz et al., 2017). However, the strawberry pomace did increase the α-linolenic acid level in breast meat. Coddensa et al. (2017) showed that spray-dried cranberry powder reduced the intensity and duration of shedding in piglets challenged with F18+ E. coli. The potential and modes of action whereby berry products may modulate gut microbiota in food animals has recently been reviewed (Das et al., 2017). Key research gaps include the effects of processing on the stability and bioavailability of bioactives in these sources (Das et al., 2017). Despite the lack of information on the toxicity of these sources for livestock, cranberry extract powder has been approved for human use by the European Food Safety Authority (EFSA, 2017). Condensed tannin (CT) are naturally occurring plant secondary compounds that are oligomeric or polymeric flavonoids consisting of flavan-3-ol units that include catechin, epicatechin, gallocatechin, and epigallocatechin with molecular weights ranging from 1,000 to 20,000 Da (Figure 3). They protect the plant against invasion by pathogens and attack by insects and herbivory, mainly through their ability to form complexes with proteins, polysaccharides, and minerals. CT possess anti-bacterial, anti-parasitic, anti-oxidant, and immunomodulation activities and have been used as herbal medicines for centuries. In the last few decades, researchers have demonstrated that CT potentially be used as natural alternatives to antibiotics et al., CT activity against than bacteria and However, some CT also activity against bacteria such as et al., 2013). of of of of and the formation of complexes with cell membrane are a few of the mechanisms whereby CT inhibit or kill bacteria. polyphenolics can also enhance the and effects of or CT to livestock on gut health and and have been reviewed et al., et al., in the effects of CT are to their in and in various plants and plant et al., 2017). 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