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Current Protein and Peptide Science, 2016, 17, 785-796 ISSN: 1389-2037 eISSN: 1875-5550

The Signal Pathway of Antibiotic Alternatives on Intestinal Microbiota and Immune Function

Volume 17, Number 8, 2016

Impact Factor: 2.441

BENTHAM SCIENCE

Ji Wanga, , Meng Hana, , Guolong Zhangb, Shiyan Qiaoa, Defa Lia,* and Xi Maa,c,* #

#

a

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State Key Lab of Animal Nutrition, China Agricultural University, No 2. Yuanmingyuan West Road, Beijing, 100193, China; bDepartment of Animal Science, Oklahoma State University, Stillwater, Oklahoma, 74078, USA; cDepartment of Internal Medicine, Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9113, USA Abstract: Antibiotics are one of the most important discoveries in the 20th century and have been widely used for treating animal diseases in the 21st century. However, antibiotic resistance among bacterial pathogens and widespread concerns regarding their use in animals has received great attention all over the world. Great attention has focused on scientific breakthroughs of the alternatives to antibiotics. Various materials such as enzymes, prebiotics, probiotics, minerals, antimicrobial peptides, acidifiers, plants and plant extracts have been tested as possible antibiotics alternatives. Owing to their effects on intestinal microbiota and immune function, research efforts have been conducted on the application of these feed supplements. This review highlights promising research results about the alternatives to antibiotics in animal husbandry that are expected to beneficially limit the adverse effects of antibiotics and ensure the safety of animal-derived foods and the environment.

Keywords: Animal husbandry, antibiotic alternatives, application, immune function, microbiota, regulation pathway. Received: November 05, 2015

Revised: January 03, 2016

Current Protein & Peptide Science

1. INTRODUCTION

It is an effective way to use antibiotics allowing the development of intensive and large-scale livestock production [1]. However, increasing concern has been expressed about the adverse impact of feeding antibiotics to livestock for both human and animal health has been expressed. Antibiotic use could lead to drug resistance in pathogens of significance to human by transferring resistance from non-pathogenic bacteria to pathogenic bacteria through a variety of mobilized genetic elements [2]. Considering the possible contribution of in-feed antibiotics to the development of antibioticresistant bacterial strains [3], the European Union banned infeed antibiotics in livestock diets in January 2006. Several other countries are considering a similar ban [4]. To maintain animal health and performance without using antibiotics, a great many projects have been carried out. It has been reported recently that a new antibiotic called teixobactin kills pathogens without detectable resistance [5]. Instead of developing new antibiotics, antibiotic alternatives could also be an efficient way to maintain animal production while avoiding the growth of antibiotic resistant bacteria [6]. Close relationship exists between mammalian host and the microbes residing in the gastrointestinal tract (GIT) during the evolutionary journey [7]. By promoting supply, di*Address correspondence to this author at the State Key Lab of Animal Nutrition, China Agricultural University, Beijing, 100193, China; Tel: +8610-62733588; Fax: +8610-62733688; E-mails: [email protected] or [email protected], and [email protected] # Ji Wang and Meng Han contributed equally to this work.

1875-5550/16 $58.00+.00

Accepted: January 11, 2016

gestion and absorption of nutrients, preventing pathogen colonization and maintaining normal mucosal immunity, the commensal microflora in the GIT strongly influences the nutrition and health of the host. To some degree, intestinal microbiotas are now considered to be an essential organ placed within a host organ [8]. This review is focused on current developments pertaining to some possible antibiotic alternatives including enzymes, prebiotics, probiotics, minerals, antimicrobial peptides (AMPs), acidifiers, plants and plant extracts. Focusing on intestinal microbiota and immune function, the regulation pathways of the antibiotic alternatives will be reviewed and discussed in this paper. 2. CATEGORY DESCRIPTION OF ANTIBIOTIC ALTERNATIVES The effects of the antibiotic alternatives include growth promotion and immune regulation. Some of these have already been studied extensively in humans and animals. 2.1. Growth Promoter

It is well known that there are various gastrointestinal enzymes beneficial to feed digestion in pigs. Nevertheless, weaned piglets could not produce enough enzymes, neither could adult pigs fed with complex carbohydrates. Addition of exogenous enzymes to the feed might be a useful way to increase digestibility. Some reports reveal that supplementation of enzymes can improve feed quality, increase digestibility of existing nutrients and reduce nutrient contents in waste [9]. These effects are connected with the increased © 2016 Bentham Science Publishers

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amounts of nutrients released from the diet that can be absorbed from the GIT [10]. Probiotics, beneficial bacteria colonizing the host digestive system, could increase the natural microflora, prevent colonization of pathogenic organisms, thus leading to optimal usage of the feed [11]. It has shown that probiotic supplementation in animal feeds could improve growth rate, food utilization, milk or egg production and reduce the risk of resistance to infectious disease [12].

Most of the available studies related to antimicrobials found in scientific literature involve plants and their extracts [25-27]. Plants and their bioactive components are very diverse and their potential properties to enhance pig health and immunity has been scarcely evaluated in vivo [28]. Some of the bioactive antimicrobial chemical forms derived from plants include phenolic acids, quinones, flavonoids, tannins and alkaloids [29]. The plants have been extracted and concentrated for use in animal nutrition for their aromatic value as flavouring agents in feeds and also for their antioxidant and antimicrobial properties against pathogenic and spoilage microbes, as well as their nutritional and pharmaceutical properties [30].

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Prebiotics are defined as a nondigestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon. Various types of oligosaccharides, including inulin, fructooligosaccharides and galactooligosaccharides are commonly considered as prebiotics [13]. Prebiotics are considered to potentially reduce enteric disease in poultry [14], and increase levels of immunoglobulins in the serum of pigs. When prebiotics and probiotics are used in combination, it is known as synbiotics.

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Acidifiers are compounds with acidic properties, including citric, formic, acetic, propionic and lactic acid. Usually based on carriers, acidifiers may not react with the effective constituent in feed [15], which could result in positive effects on performance in weaned piglets. These effects are generally related to increased gastric acidity, antimicrobial activity, reduced coliform populations and improved feed digestibility [16]. In addition, response to mixed acids is generally better than single acid usage due to dissociation properties of these acids at various locations in digestive tract of pigs and their synergistic action [17]. 2.2. Immune Modulator

Clays minerals, including montmorillonite, illite, kaolinite, clinoptilolite, zinc and copper [18], are used as enhancers of the nutritive value of diets and immune modulators in monogastric animals [19]. Containing molecules of silicon, aluminum and oxygen, clay minerals are stratified formed by a net of tetrahedral and octahedral layers. The layers can be interconnected by a system of hydrogen bonds or a group of cations [20]. Adding clay minerals to feeds can improve nutrient digestibility, promote feed efficiency and protect the intestinal mucosa [21].

AMPs are small molecules with a molecular mass of 1 to 5 kDa [22]. Elements improving the interaction with negatively charged membranes are contained in the structure. The mode of action involves the cell membranes of target organisms [23]. AMPs are classified into two categories, nonribosomally synthesized AMPs and ribosomally synthesized AMPs, according to the peptide synthesis mechanism [1]. The non-ribosomal AMPs are mainly produced by bacteria. Ribosomally synthesized AMPs can be further classified according to the sources of the peptides, such as mammals, amphibians, insects, plants, bacteria, and viruses [24]. The positive charges of AMPs can form electrostatic adsorption with negatively charged phospholipid structures on the bacterial cell membranes resulting in structural damage of the membranes [1].

3. REGULATION PATHWAYS 3.1. Regulation of Intestinal Microbiota There is a concentration gradient with numbers and diversities increasing from proximal to distal in the GIT microbiome. For example, the stomach and proximal small intestine in pigs contain relatively low numbers of bacteria (103–105 bacteria/g or mL of contents), with the dominant bacteria of Lactobacillus spp. and Streptococcus spp. To the contrary, the distal intestine harbours a more diverse and numerically greater population (108 bacteria/g or mL of contents) of bacteria [31]. In broiler chickens, analysis of 16S rDNA gene sequences revealed thirteen, eleven, fourteen, twelve, nine and fifty-one operational taxonomic units in the crop, gizzard, duodenum, jejunum, ileum and caecum, respectively [32]. However, there are many specific bacterial pathogens also inhabiting in the GIT. They generally cause diseases when the gut ecosystem is disturbed in some manner [33]. In the post-weaning period in pigs, numbers of pathogenic Escherichia coli proliferate to exceed those of other bacterial populations, resulting in clinical disease [31]. Therefore, it is important to consider the complexity of the intestinal microenvironment where a network of interactions exists among the microorganisms of the resident microbiota associated with the gut and nutrients [34]. 3.2. Improving Inhibitory Effects and Suppressing Harmful Microorganisms Varied from strain to strain, the modes of action of probiotic strains are multifactorial. In general, probiotics exert their beneficial effects through enhancement of host resistance to bacterial colonization and/or direct inhibition of pathogens thereby reducing the incidence and duration of gastroenteritis. Probiotic strains have inhibited pathogenic bacteria both in vitro and in vivo through several different mechanisms, including production of directly inhibitory compounds (e.g. bacteriocins), reduction of luminal pH through short-chain fatty acid (SCFA) production (which could themselves be directly inhibitory to certain pathogens), competition for nutrients and adhesion sites on the gut wall, modulation of the immune response and regulating colonocyte gene expression (e.g. mucin) [35]. Beneficial intestinal microflora can protect the host from intestinal pathogens, termed a barrier effect or competitive exclusion [2], which refers to the process in which epithelial associated or bound microorganisms preclude contact between pathogens and host epithelial cells [36]. In broiler nutrition, the gut micro-

The Signal Pathway of Antibiotic Alternatives on Intestinal Microbiota

flora changes during the growth of the birds. Bacteria with type-1 fimbriae will bind to mannose-based receptors in the intestine. Furthermore, it has been demonstrated that mannanoligosaccharides act as a receptor analogue to prevent harmful bacteria possessing type-1 fimbriae from attaching to the gut wall, thereby helping birds to maintain a healthy gut [37].

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both bacteriostatic and bactericidal. Non-ionized organic acids can penetrate the bacterial cells and disrupt the normal physiology of the bacteria [45]. Bacteria are penetrated and the undissociated organic acids dissociate to H+ and anions (A-), a process that reduces the internal pH of the bacteria. This process restricts the growth of pH sensitive Coliforms, Clostridia and Listeria because of non-tolerance of a broad range of internal pH in the bacteria and external stomach pH (Fig. 1), while non-pH sensitive bacteria like Lactobacilli and Bifidibacterium spp. can tolerate it. In addition, microbial metabolism is dependent on enzyme activity, which is depressed at a lower pH. To redress the balance, the cell is forced to use energy to expel protons across the membrane via the H +-ATPase pump to restore the cytoplasmic pH to normal. Exposure to an organic acid over a period can be sufficient to kill the cell [46]. According to Bearson et al. [47], a correlation exists between the response of enterobacteria to acid stress and pathogenecity. Synergistic effects of natural antioxidant compounds from E. hirta and acidifier could exert oxidative stability and might increase the polyunsaturated fatty acids (PUFA) in plasma, thereby protecting PUFA from oxidative rancidity. PUFA omega-6 fatty acids are the metabolic precursor of eicosanoids. Eicosanoids are a group of biologically important lipids which include prostaglandins, thromboxanes, lipoxins and leukotrienes. These lipids play an important role in immunity, inflammation and blood clotting.

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The majority of AMPs are amphiphilic, leading to the germicidal effects through permeating the membranes of a pathogen. The electrostatic interaction between the cationic peptide and the negatively charged membrane of bacteria is probably due to the presence of its amphiphilic properties [38]. The mode of action of the bioactive peptides is believed to trigger disintegration (damaging and puncturing) of cell membranes of organisms. In its action against gram-negative bacteria, the peptide can move across the outer membrane, and then pass the layer of peptidoglycan, and cross the inner membrane into the cytoplasm of the bacterial cell [39]. There are several mechanisms of peptide penetration across the cytoplasmatic membrane. One of them is called barrel-stave, based on the growing of peptides in the form of barrels, of which the hydrophilic inner surface creates a gap for AMPs to penetrate [40]. Another is named connecting channels, when peptides combine with the cytoplasmic membrane and create clusters, which penetrate into the interior of the cell by creating gaps [41]. It should be noted that cathelicidins, beyond the mechanisms of membrane binding, can also activate extracellular factors inducing autolysing phospholipase A2 [42].

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PR-39, a proline-arginine-rich antibacterial peptide, was originally isolated from the porcine small intestine and subsequently localized in neutrophils. It is reported that PR-39 enters cells without membrane lysis, and after a short lag is capable of killing bacteria by inhibiting bacterial mRNA translation and DNA synthesis [38]. PR-39 modulates production of proteoglycans in wound healing, promoting leukocyte chemotaxis, interacting with sarcoma homology 3 domains of different proteins, and inhibiting superoxide production by neutrophils [38]. Increased expressions of PR-39 and protegrins in porcine bone marrow progenitor cells have been observed following cell activation with bacteria or purified lipopolysaccharides [43]. Prophenin-1 (PF-1) was isolated from pig leukocytes. Three perfect and three nearly perfect repeats of a decamer, FPPPNFPGPR were found in prophenin-1 N-terminal. Prophenin-2 (PF-2), with 97 amino acid residues, stored in secondary granules of neutrophils, is expressed in immature myeloid cells. Both peptides show more activity in vitro against E. coli than against Listeria monocytogenes [44]. AMP-P5 (P5-60) and apramycin show potential in reducing harmful microflora such as faecal and intestinal Coliforms and caecal Clostridium spp. in weanling pigs. In brief, AMPs beneficially affect the host animal by improving its intestinal microbial balance and creating gut microecological conditions that suppress harmful microorganisms such as Clostridium and Coliforms and by favouring beneficial microorganisms such as Lactobacillus and Bifidobacterium.

Acid-intolerant bacterial species such as E. coli, Salmonella and Campylobacter could be reduced by organic acids, altering the gastrointestinal microflora. Organic acids are

Fig. (1). Undissociated acid get dissociated to H+ and anions (A-) penetrating the microbial cell membrane. This action further reduces the internal pH of the bacteria checking the growth of pH sensitive Coliforms, Clostridia, Listeria because these bacteria cannot tolerate the broad range of internal pH in the bacteria and external stomach pH.

Plant compounds produce different antimicrobial actions through variations of structure and chemical composition [48]. Plant-derived compounds is structural diverse, and the structural configuration could lead to antimicrobial action against microorganisms. There are great structural variations in phenolic compounds, which are one of the most diverse groups of secondary metabolites. The hydroxyl groups in phenolic compounds are thought to cause inhibitory action [49] as these groups can interact with the cell membrane of bacteria to disrupt membrane structures and cause the leak-

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and this is associated with increased abundance and activity of specific bacteria communities such as Lactobacilli [66]. Recent studies have shown that if the use of enzymes is to replace prophylactic antibiotics, the target must be to enrich the ileum and cecum with Clostridium cluster XIVa species and E. coli while depressing the numbers of Lactobacillus spp. [67]. It has also been studied how enzyme supplementation influenced the distribution of organic acids in the ileum, indicating a shift in dominating bacteria, which could be an effective means for promoting gut health in piglets [68]. Beneficial effects of prebiotics are thought to be mediated predominantly through their selective stimulation of the proliferation and activities of bacteria associated with a healthy gut, such as Bifidobacteria, Lactobacilli and Eubacteria. Prebiotics increase the populations of Bifidobacteria and Lactobacillus in the gut of young pigs [69]. Moreover, among prebiotics, mannanoligosaccharides have the confirmed regulatory effect on the desirable microflora in the intestinal tract in different species of livestock. This is connected with the ability of mannanoligosaccharides to bind with mannose-binding proteins presenting on the cell surface of some strains of bacteria. Thereby a host is prevented from colonization mainly by interfering with binding of microorganism to carbohydrate residues on the epithelial cell surface [70]. In ileum, the inclusion of chicory roots (Cichoriumintybus L.) was found to associate with increases in lactic acid concentrations in the digesta and the relative abundance of lactic acid bacteria. In the colon, the inclusion of chicory forage was associated with the relative abundance of butyrate-producing bacteria and colonic acetate concentration [71].

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age of cellular components [50]. Essential oils (EO) and aromatic plants are known to exert antibacterial, antifungal and antiviral activity in experiments in vitro [51]. Comparable in vivo studies found inhibiting affects against pathogens such as C. perfringens, E. coli or Eimeria species. The controlled pathogen load also contributes to healthy microbial metabolites, improved intestinal integrity and protection against enteric disease [52, 53]. Potential negative effects induced by EO on healthy intestinal bacteria should also get attention. In an in vivo anti-bacterial study, Thapa et al. [54] found that the beneficial commensal Faecalibacterium prausnitzii was sensitive to EO at similar or even lower concentrations than the pathogens.

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3.3. Producing Specific Products of Metabolism

Not only do the exogenous enzymes influence the absorption of nutrients but the actions of these enzymes also produce nutrients for specific populations of beneficial bacteria [55]. Their use has a direct impact on the microfloral populations [56]. Enzymes might influence the intestinal microbiota through two main mechanisms, including reducing the undigested substrates and creating short-chain oligosaccharides from non-starch polysaccharides (NSP) with potential prebiotic effects. It has been proposed of how phytate binds to protein and reduces its digestibility. An acidic pH, a binary protein-phytate complex may form where phytate can bind to the α -NH2 groups and side chains of the basic amino acids arginine, histidine and lysine [57]. Indeed, in recent digestive tract simulation studies, Yu et al. [58] demonstrated that degradation of phytate to lower-level esters dramatically increases the solubility of soya and casein proteins. Anti-nutritive effects of phytic acid lead to reduced ideal digestibility of dietary protein and increased endogenous secretions [59]. It is therefore plausible that phytic acid destruction through supplemental phytase would reduce endogenous losses and increase protein digestibility, thus limit protein supply to the hindgut and exert microbiota changes. Limpkins et al. [60] showed that phytase reduces intestinal 5AC mucin mRNA abundance in broiler chickens. Because Clostridium thrives on mucin, a reduction in mucin levels could correspond to a reduction in C. perfringens and the occurrence of necrotic enteritis [61]. In pigs, Rostagno et al. [62] observed that the addition of alkaline phosphatase to a phosphorous-deficient diet (80% requirement) reduces the ileal digesta count of Enterococci, whereas the addition of alkaline phosphatase to a diet adequate in phosphorus reduced Coliforms, aerobes and anaerobes. Previous reports showed that supplemental carbohydrases reduced caecal counts of Campylobacterjejuni in broilers and Brachyspiraintermedia in the laying hen [63]. Clearly, these enzymes alter the caecum ecology leading to the changes of microbiota. Moreover, it has been hypothesized that supplementing swine diets with enzymes to digest soluble NSP will minimize intestinal microbial load which in turn will increase nutrient availability to the host and minimize proliferation of pathogenic bacteria [64]. Enzyme-free diets containing soluble NSP-rich cereals have been shown to induce lymphocyte infiltration in the gut wall and induce apoptosis of epithelial cells much more than cereals such as maize that have low levels of soluble NSP [65]. Numerous reports from pig research indicated that supplemental NSPases increase SCFA

Addition of clay minerals in feeds could lead to immobilization of anti-nutritional components [72], reduce the number of pathogenic microorganisms and depress the activity of bacterial enzymes in the small intestinal digesta [73], prevent irritation and damage, and improve the morphological characteristics of the mucosa [74]. As for montmorillonite, incremental cetylpyridinium - montmorillonite (CP-Mt) inclusion in the diet decreases E. coli and Streptococcussuis in the jejunal and colonic contents. The cetylpyridinium (CP)exchanged clay enhanced hydrophobicity and affinity for pathogenic bacteria. The possible mechanisms for the antibacterial activity involved the adsorption of the bacteria and immobilization on the surface of the organo clay [75]. It has been reported that CP-Mt supplementation could increase intestinal mucosa diamine oxidase (DAO) while reducing plasma DAO, indicating CP-Mt feeding could improve barrier function and alleviate weaned diarrhea. Reported effects of dietary supplementation with zinc oxide include increased gene expression of AMPs in the small intestine [76], positive effects on the stability and diversity of the microbiota particularly with respect to Coliforms, increased insulin-like growth factor-I and insulin-like growth factor-II expression in the small intestinal mucosa [77], bactericidal effects, and reductions in electrolyte secretion from enterocytes [78]. Zinc can decrease the toxic effects of the metabolites of some microorganisms such as Staphylococcus aureus, Salmonellatyphi and Aeromonas hydrophylia. Højberg et al. [79] suggested that reduced fermentation of digestible nutrients in the proximal part of the GIT might render more energy available for the host animal and contribute to the

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and pathogens [86]. Tight junctions (TJ), a network of proteins consisted of transmembrane protein complexes and the cytosolic proteins ZO, plays a crucial role in maintaining gut barrier function, therefore the expression levels of ZO-1 and occludin, the key proteins of TJ, are consistently associated with barrier function [87]. Addition of ZnO has been demonstrated reducing intestinal permeability by increasing the expression of the TJ proteins ZO-1 and occludin in weaned piglets [88], but once the ZnO amount in the small intestine exceeds a certain level, TJ proteins will be impaired, resulting in dysfunction of the intestinal mucosal immune barrier. It has also been studied that 3000 ppm Zn (ZnO) can enhance the mRNA expression of Insulin-like growth factor-1 (IGF-1) in the mucosa of weaned piglets [89]. Both highdose ZnO and low-dose coated ZnO could enhance the mRNA expression levels of IGF-1 in the mucosa, while the improvements in small intestinal morphology by feeding coated ZnO may be just partly attributed to an enhancement of IGF-1 expression in the GIT [90]. Meanwhile, Weyenbergh et al. [91] reported that increased Cu levels inhibited in vitro IFN-γ production.

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growth-promoting effect of high levels of dietary ZnO. Copper-montmorillonite (Cu-MMT) has been demonstrated to rupture the bacterial cell membrane and inhibit the tricarboxylic acid cycle pathway of the bacterial respiration metabolism [80]. Copper supplementation impacted the prevalence and quantity of the various tetracycline, ceftiofur and copper resistance genes. Supplementation of copper may favor expansion of certain genes, perhaps at the expense of other gene targets, especially during the treatment period. Copper supplementation in swine production is also associated with lowered blaCMY-2 gene copies, without being associated with increased pcoD gene quantity. Copper supplementation is an alternative to antibiotics in swine production and the actual role of pcoD as copper resistant determinant in the gut microbial community of pigs should be further elucidated.

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3.4. Enhancement of Immune Function

The microbiota is an important constituent of the intestine’s defense barrier because it induces and maintains specific immune responses and hyporesponsiveness to antigens. Furthermore, it is known that certain bacterial species in the GIT can liberate low molecular weight peptides that trigger the immune system [81]. Such tolerance induction and antigenic stimulus matures the gastrointestinal associated lymphatic tissue, such that it is ready to produce IgA in response to an antigenic stimulus (i.e. in the presence of E. coli toxin). Therefore, the immune system plays an important role in protecting piglets against pathogenic infection [82]. 3.4.1. Nonspecific Immunity

It has been studied that transgenic probiotic can significantly decrease intestinal inflammation in murine acute colitis, along with increased frequencies of Foxp3+ Tregs and decreased macrophage inflammatory protein-1α/β. While, colon transepithelial resistance and barrier function were significantly improved in pigs receiving the transgenic probiotic and post-weaning colon inflammation was reduced. Supplementation of the diet of weaner pigs with Bifidobacterium lactis HN019 resulted in greater cellular immune responses such as phagocytosis and lymphoproliferative responses, and a higher GIT pathogen-specific antibody titre. Bifidobacterium animalis MB5 and Lactobacillus rhamnosus GG protected cultured intestinal Caco-2 cells from the inflammation-associated responses, such as chemokine and cytokine gene expressions, in response to Enterotoxigenic Escherichia coli (ETEC) by inhibiting neutrophil transmigration and preventing ETEC-induced expression of tumor necrosis factor (TNF)-α and interleukin (IL)-lb. A recent study described a Bifidobacterium lactis HN019 strain that can enhance nonspecific immune function, namely leucocyte (lymphocytes and phagocytes) proliferation, enhanced phagocyte production and proinflammatory cytokine production [83]. Several studies have shown that feeding B. lactis HN019 resulted in an increase of peripheral blood leucocytes and natural killer cells that were active in tumour killing and viral destruction [84, 85]. Clay minerals are reported to have effects on nonspecific immunity. One of the major functions for the small-intestinal epithelium is serving as a barrier against noxious antigens

AMPs could confer protection against a variety of pathogens and function as potent immune regulators altering host gene expression, thereby inducing chemokine production, inhibiting lipopolysaccharide (LPS) or hyaluronan induced pro-inflammatory cytokine production, modulating the responses of dendritic cells or T cells of the adaptive immune response [92]. Thus, AMPs set up a bridge between nonspecific and specific immunity (Fig. 2). Another function of AMPs is that they directly recruit leukocytes or induce the expression of chemokine or cytokines including IL-8, CCL2 and IFN-α, thereby indirectly promoting recruitment of cells. Subsequently, defensins hBD3 and 4 are chemotactic for monocytes and macrophages [93], and hBD2 has chemoattractant activity for mast cells [94]. In addition to direct chemotactic activity, AMPs can exert indirect chemotactic activity by stimulating chemokine and cytokine secretion from a variety of cell types through receptor-dependent mechanisms [95]. hBD3 can induce expression of the costimulatory molecules CD80, CD86 and CD40 by interaction with TLRs1 and 2 on monocytes and dendritic cells resulting in MyD88 signaling, leading to IL-1 receptorassociated kinase-1 phosphorylation [96]. LL37 promotes IL-1-induced production of cytokines and chemokines such as MCP-1 and MCP-3 in peripheral blood monocytes (PBMC). Despite different structures, β -defensins and cathelicidin show similar effects on the activation of the ERK mitogenactivated protein kinase (MAPK) pathway to induce inflammatory cytokine production in epithelial cells [97]. The activation of ERK1/2 led to the activation of the downstream transcription factor, Elk-1, resulting in the secretion of Elk-1-controlled IL-18, which activated T, B and NK cells to produce high levels of IFN-g and increased IgE production in CD4+ T cells [98]. Many in vitro experiments show anti-inflammatory activity of plant extracts (PE) [99]. Dung et al. [100] concluded that the EO of the C. operculatus buds had potential antiinflammatory effects due to inhibition of TNF-α and IL-1β expression and secretion from LPS-induced RAW 264.7 cells. Lee et al. [101] demonstrated that eugenol, tea tree oil and garlic extract can inhibit the secretion of both TNF-α and

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Fig. (2). Multiple functions of antimicrobial peptides (AMPs) in host defense. AMPs induce a variety of responses in host innate immune cells such as monocytes, macrophages. They alter gene expression of host cells, induce production of chemokines and cytokines, promote leukocyte recruitment to the site of infection, influence cell differentiation and activation and block or activate TLR signaling. The outcome of the selective immunomodulation by AMPs results in innate immune responses, leading to protection against infection, selective control of inflammation and initiation of adaptive immune responses. Abbreviations: LPS, lipopolysaccharide; TLR, Toll-like receptor.

IL-1β. In addition, a high concentration of nitric oxide (NO), produced mainly by macrophages through the activity of nitric oxide synthase (NOS), is associated with inflammatory diseases. Cinnamaldehyde and eugenol were reported to have the ability to suppress the NO release and suppress the inducible NOS expression in LPS-treated murine macrophages [99]. In addition to several chemokines, such as IL-8, interferon -induced protein 10 kDa (IP-10), and monokine induced by γ-interferon secreted by intestinal epithelial cell can be inhibited by aliicin, a kind of PE derived from garlic, which mediates the inflammatory response by recruitment of various circulating leukocytes into the flamed tissue [102] Althogh the modes of action for the anti-inflammatory activity of PE are still not clear, it is suggested that these effects are mediated by blocking the nuclear factor NF-κB pathway, a key regulator of genes involved in immune responses. In resting cells, NF-κB exists in an inactive state in the cytoplasm, complexed with an inhibitory protein, called I-κB. IκB undergoes phosphorylation and degradation upon activation, and NF-κB is translocated into the nucleus, where it binds to DNA and activates transcription of various genes, including TNF-α and IL-1β. Several studies have revealed that curcumin could block cytokine-induced NF-κB DNA binding activity, I-κBα degradation, I-κBserine 32 phosphorylation, and IκB kinase (IKK) activity, all of which play a role in the upstream NF-κB signaling pathway. Another report demonstrates the blockage of p50 and p65 translocation, phosphorylation of ERK 1/2 and p38 kinase, and degradation of I-κBα by cinnamaldehyde and eugenol [103]. 3.4.2. Specific Immunity

Many studies have demonstrated that Bacillus subtilis can grow and sporulate in the gut, and they can promote the development of gut associated lymphoid tissues (GALT).

Thus, feeding B. subtilis could have beneficial effects in strengthening the immune system and perhaps priming it for an adaptive immune response. A study in mice reveals that B. subtilis could promote active lymphocyte proliferation within the Peyer's patches, accompanied by a remarkable increase in the expression of several cytokines, while the vegetative cells of B. subtilis up-regulate the expression of TLR2 and TLR4z [104]. Moreover, there is a distinct tendency that intestinal intraepithelial T-cell subpopulations, cytokine mRNA levels, and macrophage function increase after feeding diets supplemented with B. subtilis spores. Feeding of young broiler chickens with B. subtilis-based DFM also enhanced NO production and phagocytosis of peripheral blood derived macrophages. Determined the ratios of PBMC subsets and measured proliferative responses and cytokine production of PBMCs, blood samples of probiotictreated piglets showed a significantly lower frequency of CD8high/CD3+ T cells and CD8low/CD3+ T cells and a significant higher CD4+/CD8+ ratio. IL-4 and IFN-γ production of polyclonally stimulated PBMCs was higher on average in the probiotic group [105]. AMPs have diverse and complementary effects on cellular inflammatory responses that are beyond the stimulation of chemotaxis. In particular, mammalian AMPs have a crucial role in regulation of TLR-dependent inflammatory responses. In dendritic cells, cathelicidins inhibit TLR4- but not TLR2-mediated induction of dendritic cell maturation and cytokine release, and this inhibition is associated with an alteration of cell membrane function and structure by cathelicidin [106]. A similar effect of cathelicidin was also observed in macrophages for another TLR4 ligand, small hyaluronan (HA), which is released following injury and is an endogenous ligand for TLR4 and CD44. Cathelicidin inhibits HA induced MIP-2 release from mouse bone-marrow-

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trient allocation towards growth rather than immune defense. Investigations conducted under practical conditions of largescale animal production have shown better responses to EO treatment than more recent studies conducted undercontrolled experimental conditions with a higher level of hygiene [112]. This might be explained by a lower pathogen pressure in the intestine and an improved immune status. Supplementing EOs has been reported to improve the immune status of piglets after weaning, as indicated by an increase in lymphocyte proliferation rate, phagocyte’s rate, as well as in IgG, IgA, IgM, C3 and C4 serum levels [113]. The absorbed component might initiate an immune response indicated by changes in blood immunological parameters while the unabsorbed component may contribute to relief from intestinal immune defense stress. However, the precise mechanisms through which EOs function are not clear and further investigations are necessary.

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derived macrophages by interfering with membrane binding events mediated by HA in a CD44-dependent manner, but independent of G-protein coupled receptor or epidermal growth factor (EGF) receptor signaling [107]. Both observations provide evidence that cathelicidin can act to inhibit TLR4. In contrast to models in which AMPs have been proposed to act directly on the receptor, these results indicate that the membrane active peptide influences the local membrane environment of the receptor and thus alters its activation state. Genomic approaches showed that LL37 significantly inhibits the expression of specific proinflammatory genes upregulated by NF-κB in the presence of LPS, including NF-κB1 (p105/p50) and TNF-α induced protein 2 (TNFAIP2), whereas LL37 does not inhibit LPS-induced genes antagonizing inflammation, like TNF-α-induced protein 3 (TNFAIP3) and the NFκB inhibitor, NF-κBIA or certain chemokine genes that are classically considered proinflammatory [108]. Collectively, all these observations indicate that AMPs have an important role in regulating and balancing inflammatory responses to microbes. Although central questions regarding the mechanisms of the immunomodulatory effects of AMPs are yet to be clarified, the overall capacity of AMPs to influence multiple steps in host cell activation leads to the conclusion that some AMPs are not only involved in suppressing uncontrolled microbial growth but that they also modify inflammation.

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Recent evidence has revealed that certain phytochemicals, such as cinnamaldehyde and curcumin, inhibit pattern recognition receptor (PRR) activation by targeting the receptor itself or the specific downstream signaling molecules. These results suggest the possibility that PRR-mediated inflammation and the consequent risk of damaging disease conditions can be suppressed by particular food supplements containing anti-inflammatory phytonutrients. It has been shown that PRR-mediated proinflammation by certain phytonutrients could be modulated by the diets. For example, the activation of TLR4 by interfering with cysteine residue mediated receptor dimerization could be inhibited by curcumin, helenalin, and cinnamaldehyde with αβ-unsaturated carbonyl groups, or sulforaphane with an isothiocyanate group. Curcumin and helenalin could also inhibit NOD2 activation by interfering with NOD2 dimerization. On the contrary, resveratrol specifically inhibits TLR3 and TLR4 signaling by targeting TANK binding kinase 1 and receptor interacting protein (RIP1) in Toll/IL-1 receptor domain-containing adaptor inducing the IFN-β (TRIF) complex. Collectively, PRR and downstream signaling components are the molecular targets for certain dietary disease prevention strategies. Using the techniques of quantitative real time-PCR and gut tissue morphology, EO and avilamycin have been reported to significantly decrease the expression of the transcriptional factor NF-κB, the apoptotic marker TNF-α and the size of Peyer’s patches in the intestine of weaned pigs, the proliferation marker cyclin D1 in the colon, mesenteric lymph nodes and spleen [109]. Reduced numbers of intraepithelial lymphocytes in the jejunum and reduced B lymphocytes in mesenteric lymphnodes were also observed by Manzanilla et al. [110] and Nofrairas et al. [111]. This might serve as direct evidence for a lower need for immune defense activity in the gut due to the antimicrobial action of EOs. The relieved intestinal immune defense stress may partly contribute to nu-

3.5. Interaction Between Microbiota and Immune Function

Studies with germ-free animals reveal that the microbiota contributes to the development of GALT and promotes mucosal barrier function. Peyer patches in germ-free mice are less active and contain smaller germinal zones than those in conventionally raised mice. In mice that are deficient in pattern recognition receptors, maturation of ileal and colonic isolated lymphoid follicles is incomplete. These observations indicate that the microbiota through an innate detection system could induce the generation of the intestinal lymohoid tissues. Moreover, microbiota can enhance the unspecific immunity through production of AMPs and the regulation of mucous secretion. Production of AMPs REGIIIγ and REGIIIβ is demonstrated to be damaged in mice lacking myeloid differentiation factor 88, leading to the increased susceptibility of mice to infection by enteric pathogens. In addition, mucosal barrier function can be enhanced by the microbiota through the production of metabolic by-products. SCFAs, such as acetate, propionate, and butyrate, are byproducts of fermentation of dietary fiber by colonic bacteria. Bifidobacteria inhibit the translocation of the E. coli O157:H7 Shiga toxin from the gut lumen to the blood through the production of acetate. Butyrate also reduces Tcell-mediated immune reaction via modulating antigenpresenting cell function. SCFAs bind the GPR43 and SCFAGPR43 interactions profoundly affect inflammatory responses. Some effects of probiotics may also indicate how the agents may displace other organisms and evaluate in inflammatory bowel disase. It has been reported that Lactobacillus and a Bifidobacterium produces a striking and parallel reduction in inflammation in the colon and cecum and in the production of the pro-inflammatory cytokines TNF-α, IFN-γ and IL-12, yet levels of the anti-inflammatory cytokine TGFβ remain unchanged [114]. Similar effects have been studied for the probiotic cocktail VSL#3. These anti-inflammatory effects could be transmitted by bacterial DNA alone [115]. 4. APPLICATIONS There is a general belief that consumers would prefer to purchase meat from animals treated with natural agents rather than antibiotics, hormones, or other chemicals. In the future, there will likely be advantages for farmers who pro-

792 Current Protein and Peptide Science, 2016, Vol. 17, No. 8

Table 1.

Wang et al.

Benefits and Risks/Use Limitations of Antibiotic Alternatives.

Benefit

Risk/use limitation

Reference

Enzymes

High purity; extensive source; low pollution

Animal responses not entirely predictable; unstability; relatively high cost

[10, 117]

Probiotics

Able to survive to gastric juice and bile salts; an adequate dose is enough to have beneficial effects

Often not meeting the expected standards; questionable viability of the efficacy; occurrence of antibiotic resistance genes (mutations in indigenous genes; acquisition of an exogenous resistance determinant from another bacterium by horizontal gene transfer)

[11, 118]

Clay minerals

Extensive source; great exploitation potentiality

Environmental pollution; odor characteristics

[19, 121]

Antimicrobial peptides

High biological activity; thermostability

Too costly; to be modified chemically to make them more resistant to proteolysis in animals; hemolytic activity; changes in bacterial cell surface and blockage of the AMP access to their targets by affecting its binding and/or its penetration into the cells

[22, 122]

Acidifiers

Already wide applications; protect feed from mildew

Acidic resistance; variety singleness

[16, 124]

Plants and plant extracts

Simple composition; explicit effects

Organoleptic properties of food; natural antimicrobials' solubility in complex food matrices; unstability; resource restriction

[30, 127]

Pe N rs ot on fo al rD U is se tri O bu n tio ly n

Category

actively stop antibiotic use for growth purposes [116]. The benefits and risks of the antibiotic alternatives can be shown in Table 1. 4.1. Enzymes

An increase in the use of enzymes in both poultry and pig diets will be seen in the future. The dose-response effect of enzymes is usually quadratic with decreasing positive responses at doses higher than the optimum. However, unlike feed additives derived from plants, high doses do not generally have a negative effect on production [117].

Animal responses to feed enzyme additives are not entirely predictable, mostly due to the differences of the enzyme type, the amount of enzyme applied, the presence of enzyme activities, the diet composition and animal variation. In addition, the stability and activity of feed enzymes depend mainly on the process used for their production. In addition, the relatively high cost of enzymes is another important drawback [117]. 4.2. Probiotics Probiotics have been used throughout human history. The use of probiotics is seen as a rapidly expanding market, estimated to be over $20 billion within the next 5-10 years. Most research has used monostrain or multistrain probiotic microbes of the same species or genus [118]. The health effects of probiotics are genera, species, and strain specific, and the use of multistrain and multispecies probiotics might be more effective than monostrain probiotics. However, commercial probiotics often do not meet the expected standards and the viability of the efficacy of these strains remains questionable. Some reports highlighted another major issue in relation to the application of probiotics where there is an occurrence of

antibiotic resistance genes, especially those encoded by plasmids which can be transferred between organisms. Probiotics are able to survive to gastric juice and bile salts and thus an adequate dose is necessary to have beneficial effects. The most known characteristics of probiotics are the following: a capacity to adhere to intestinal mucosa and to inhibit pathogen adhesion, ability to transiently colonise and proliferate in the intestine, prevention of some intestinal diseases as well as the ability of probiotics to protect the intestinal cells against pathogens and avoid inflammatory processes [119]. 4.3. Clay Minerals

In recent years, montmorillonite has been studied as controlled-release carrier for drug molecules and for gene delivery [120]. Montmorillonite intercalated by drug molecules has attracted great interest from researchers since it exhibits novel physical and chemical properties. Drugmontmorillonite interactions and applications of montmorillonite to carry out specific functions such as delaying and/or targeting drug release, improving drug dissolution, increasing drug stability, and modifying drug delivery patterns were studied [121]. The addition of high levels of copper and zinc resulted in low digestibility and absorption, which caused the increase of this mineral excretion in feces and poses an environmental problem. Copper supplementation improves odor characteristics of swine waste. One undred ad twenty-five ppm of dietary copper, regardless of source, may provide an effective environmental alternative to 250 ppm copper as copper sulfate in weanling pig diets. If the problems of environmental pollution and oder characteristics of swine waste can be solved, the swine production may increase. A reduction of high dose supplementation of heavy metals, such as zinc, has been recommended by the European

The Signal Pathway of Antibiotic Alternatives on Intestinal Microbiota

Community. Mineral elements remain a valid alternative to in-feed antibiotics and that it may exert a protective effect even at moderate doses. Considering the various mechanisms of action of mineral elements, a low dose of metal supplementation could be able to induce beneficial effects in piglets, as proven by a wider array of health status parameters than those used up to now. This may contribute to reduce environmental pollution by high doses of metal in Nature [119]. 4.4. Antimicrobial Peptieds

793

4.6. Plants and Plant Extracts Plants and plant extracts could be also used as natural antimicrobial additives. The use of natural compounds in combination with other natural preservatives or with other technologies could produce synergistic effects against foodborne pathogens because the higher concentration may negatively impact the organoleptic properties of food. The antimicrobial compounds have been directly applied either in the form of a powder or a liquid. In addition, the solubility of natural antimicrobials in complex food matrices is another limitation. The by-products could be of great benefit from economic and environmental perspectives as sources of low cost natural antimicrobials. The waste produced by the processing industry could be incorporated into antimicrobial packaging or utilized as edible antimicrobial films [127].

Pe N rs ot on fo al rD U is se tri O bu n tio ly n

If chemical synthesis turns out to be costly for large-scale production of certain AMPs, biological production with microorganisms, tissue cultures, or in transgenic animals will be attempted. Transgenic plants could be used for production of peptides and perhaps for some applications, the peptidecontaining plant material could be added to animal feed. The prospects for such an approach are currently rather uncertain because important economic and ecological issues need to be resolved. However, in anticipation of the development of plants expressing traits of medicinal interest, the Food and Drug Administration has initiated the process of developing guidelines. Perhaps, the peptides have to be modified chemically to make them more resistant to proteolysis in animals or their administration might have to include encapsulation methods that protect the peptides from immediate attack. Both strategies would add to the costs of antimicrobial peptide treatment.

Current Protein and Peptide Science, 2016, Vol. 17, No. 8

Potentially for peptides that influence intestinal microbiota in the same way as currently used antibiotics, smaller amounts will be required than feed applications, and enzymatic degradation would also be of less concern [122]. It has also been shown that peptides have strong hemolytic activity, which is generally correlated with high hydrophobicity, high amphipathicity, and high helicity. As a matter of fact, AMPs are not used in their original structure. In order to reduce their hemolytic effect in animal husbandry, it is always used analog peptides or derivatives of the original AMPs that could be created by amino acid alterations [123]. 4.5. Acidifiers

Dietary acidifiers have been broadly applied worldwide in diets of livestocks in order to replace antibiotic growth promoters [124]. Acidifying additives can be used in feed or incorporated in drinking water, which improves its quality. In substitution of antibiotics, the use of different additives in combination could be an approach to achieve better performance [125]. The variation of pig response to acid supplementation depends on type, level of the acid, composition of the diet, age and health status of the animals, alkalizing effects of feed ingredients and mineral supplement such as calcium sources.

Generally, dietary addition of organic acids may help to increase the control of microorganisms in the stomach and, afterwards, in the intestine. However, some caution is required for the use of acidifiers, since there are indications of development of acidic resistance [126].

However, major disadvantages of plant extracts lie in the fact that their composition is unstable. Therefore, it is necessary to select effective plant extracts, standardize them and investigate a potential synergistic benefit deriving from their combination. CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS The review was mainly conceived and designed by XM. Literature was collected and analyzed by JW and MH. The manuscript was mainly written by JW and MH and edited by GLZ, SYQ, DFL and XM. XM resourced the project. All the authors contributed to, read and approved the final manuscript. The financial support from the National Natural Science Foundation of P. R. China (31272448, 31472101 and 31528018), the National Basic Research Program of China (973 Program, 2013CB117301), Beijing Nova Program (xx2013055), the 111 Project B16044 and National Department Public Benefit Research Foundation (201403047) are gratefully acknowledged. REFERENCES [1] [2]

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