CAMPYLOBACTER AS A MAJOR FOODBORNE PATHOGEN: A REVIEW OF ITS CHARACTERISTICS, PATHOGENESIS, ANTIMICROBIAL RESISTANCE AND CONTROL

Campylobacter, mainly Campylobacter jejuni is viewed as one of the most well-known reasons of foodborne bacterial diarrheal sickness in people around the globe. The genus Campylobacter contains 39 species (spp.) and 16 sub spp. Campylobacter is microaerophilic, Gram negative, spiralshaped rod with characteristic cork screw motility. It is colonizing the digestive system of numerous wild and household animals and birds, particularly chickens. Intestinal colonization brings about transporter/carrier healthy animals. Consequently, the utilization of contaminated meat, especially chicken meat is the primary source of campylobacteriosis in humans and chickens are responsible for an expected 80% of human campylobacter infection. Interestingly, in contrast with the most recent published reviews that cover specific aspects of campylobacter/campylobacteriosis, this review targets the taxonomy, biological characteristics, identification and habitat of Campylobacter spp. Moreover, it discusses the pathogenesis, resistance to antimicrobial agents and public health significance of Campylobacter spp. Finally, it focuses on the phytochemicals as intervention strategies used to reduce Campylobacter spp.in poultry production.


INTRODUCTION
Attention to the public health significance of Campylobacter infection has advanced over a century. Campylobacteriosis of extraordinary general wellbeing significance is Campylobacter enteritis caused mainly by Campylobacter jejuni (C. jejuni) and Campylobacter coli (C. coli), but to a lesser extent ( For the consumer's safety, it is important to characterize the pathogenicity markers in strains that are recognized in food. C. jejuni has a few putative virulence genes, which have perceived to be liable for the pathogenicity expression Genotyping of Campylobacter spp. has been developed for studying the genetic variety and the link between the isolates from various origins to control human or animal health problems (Malakauskas et al. 2017). Chickens are recognized as the primary reservoir of thermotolerant Campylobacter spp. and they are the main source of human campylobacter infection. Therefore, intervention procedures for controlling Campylobacter in chickens have been created to diminish product contamination and subsequently the rate of Campylobacter diseases in human . With expanding the consumer requests for safe and natural products with negligible preservatives, important researches are being conducted to investigate the capability of natural antimicrobials for example, phytochemicals for controlling C. jejuni in chickens (Wagle et al. 2017a and Wagle et al. 2019). Thus, this review shed light on all important issues related to Campylobacter spp. including (i) the history, taxonomy and biological characteristics (ii) isolation, identification and natural habitat (iii) pathogenesis, virulence factors and resistance to antimicrobial agents and (iv) public health significance of Campylobacter spp. and (v) phytochemicals as intervention strategies used to reduce Campylobacter in poultry production.

HISTORICAL EMERGENCE OF CAMPYLOBACTER SPECIES
The genus Campylobacter comprises a huge and various group of bacteria. In 1886, Campylobacter was primary documented by Theodor Escherich which stated the appearance of nonculturable helical-shaped bacteria in smears of the mucosa of the large intestine related with diarrhea in children deceased of what he called "Cholera infantum". The primary isolation of campylobacters (a vibriolike bacterium) was made from the uterus of aborted sheep in 1906 (Kist, 1986). In 1912, a similar pathogen was isolated from fetus of aborted cow and called Vibrio fetus (Smith and Taylor, 1919). Fifteen years later, another vibrio pathogen was found in faeces of cattle suffering from diarrhea and later called Vibrio jejuni (Jones et al. 1931). In 1944, Vibrio coli was isolated from diarrheic pigs (Doyle, 1948). Campylobacter was considered as a cause of animal illness for over 40 years, except only in 1938 when Campylobacter spp. were incriminated in foodborne disease outbreak. A Vibrio jejuni like pathogen was detected in the blood of 13 victims of an outbreak due to the ingestion of contaminated milk and this outbreak caused acute diarrheal illness in 357 inmates in Illinois state institutions in the United States (Levy, 1946). In 1963, due to their specific characteristics for example low DNA base composition (low G+C content), microaerophilic development and nonfermentative metabolism, these microorganisms were moved into the recently made genus Campylobacter to recognize these bacteria from the Vibrio spp. (Sebald andVeron, 1963 andSilva et al. 2011). The genus's name means bended/ curved which derived from the Greek expression "kampyo's" (Keener et al. 2004 andSilva et al. 2018a). The first proper description of the genus Campylobacter was given by the American bacteriologist Elisabeth King, which was committed to find the proper techniques to isolate these bacteria from faeces because she believed that the prevalence of Campylobacter was more than the few reported cases (Butzler, 2004 and García-Sánchez et al. 2018).

MOLECULAR TAXONOMY OF CAMPYLOBACTER SPECIES
In 1960, several studies have reported that the gold standard technique for delineation of the bacterial spp. is the whole-genome DNA-DNA hybridization. In 1980, the bacterial phylogeny has been studied depending on the degree of the ribosomal genes' similarities. The bacterial classification schemes have been developed, revised and became more popular (Debruyne et al. 2008). In 1990, DNA sequencing became more common, therefore the molecular taxonomy researches and the molecular diagnosis of the bacteria including members of the genus Campylobacter have been increasingly used basing on the sequence similarity of 16S rRNA gene (Debruyne et al. 2008 andWhitehouse et al. 2018). The most common regions of DNA used for classification and differentiation of the bacteria such as Campylobacter spp. are the ribosomal genes, mainly 16S rRNA (Linton et al. 1996). However, because of similarity in Campylobacter spp. sequences; the 16S rRNA gene sequence cannot be used for differentiation of genetically related spp. including C. coli and C. jejuni (On, 2001). Since the past ten years, there was a considerable decline in DNA sequencing cost due to the advancement of many next-generation sequencing (NGS) techniques, which lead to the development of more robust phylogenetic trees by the whole-genome sequencing (WGS) utilization. Generally, for most of the published researches; the phylogenetic trees dependant on the 16S rRNA sequences correlate with the whole-genome spp. trees (Whitehouse et al. 2018).

Phenotypic and biochemical criteria of Campylobacter species
The members of genus Campylobacter are non-spore forming, small, slender, spirally curved Gram-negative bacilli. The size of a Campylobacter bacterium is 0.2-0.9 μm in width and 0.5 to 5.0 μm in length. Campylobacter could be present in chains or in pairs, showing up as gull-winged or S-shape appearance. The gull-wing gives them a darting motility. The motility of the genus Campylobacter is distinctively fast and darting in corkscrew appearance when seen by phasecontrast microscopy because of the existence of solitary unsheathed polar flagella at one or both ends of the bacterial cell. Among every single known spp., C. gracilis is the only nonmotile spp., while C. showae shows up as straight bacilli due to the appearance of numerous flagella (Goni et al. 2017 andSilva et al. 2018a). Campylobacter spp. are successful foodborne bacteria and they require complex growth requirements which make them quite fastidious microorganisms (Bhunia, 2018). Campylobacters are mainly microaerophilic and they need limited oxygen, but these bacteria can be killed by normal atmospheric levels of oxygen (approximately 20%). These criteria lead to difficult diagnosis of campylobacteriosis cases (Hu and Kopecko, 2018

Physiology of Campylobacter species
Campylobacter spp. can be killed by high temperatures reached in frying, cooking and pasteurization, but they can survive in sun-sheltered moist environment at 4°C (Llarena, 2015 andLlarena et al. 2015). Moreover, these bacteria can survive for many weeks at 4°C in water, but they survive at temperatures more than 15°C for only a few days. Campylobacters can survive at −20°C for 2-5 months, but they can suffer from a great fall in the number of viable bacteria due to thawing and freezing. Some spp. of the genus Campylobacter can survive in uncooked, salted meat if the primary contamination level due to their ability to survive at 4°C for several weeks in 2% sodium chloride solution (Hu and Kopecko, 2018). Campylobacters don't have gene for cold shock protein, so they can't survive at temperatures below 30°C. Additionally, they cannot survive in water activity below 0.987 (Facciolà et al. 2017). In spite of the disappearance of cold shock gene in C. jejuni isolates, these bacteria can survive and form biofilms at 13°C with the largest surface area in comparison with those formed at 42°, 37° and 20°C (Micciche et al. 2019). Campylobacter spp. are more liable to be affected with stress conditions including radiation, disinfectants, acidity, freezing, heat, desiccation and drying than other pathogenic foodborne bacteria. This finding suggests that Campylobacter spp. are survived better in vivo than in vitro (Silva et al. 2018a). Some C. jejuni can survive under extreme environmental and aerobic conditions due to biofilm production, which facilitate its spread in the environment of food production and antimicrobial resistance (Platts-mills and Kosek, 2014 and Silva et al. 2018b). Under prolonged cultivation and during stress conditions, Campylobacter become increasingly difficult to be cultured and the cells become coccoid. These bacteria can enter a viable but nonculturable (VBNC) form. Pre-enrichment as well as microaerobic growth condition and adding oxygen-quenching agents to the growth media such as charcoal and hemin can improve the recovery Campylobacter spp. (Hu and Kopecko, 2018).

NATURAL HABITAT OF CAMPYLOBACTER SPECIES
Campylobacter spp. are commonly found in the gut of different domestic animals for example, swine, sheep, cattle, cats and dogs and also the poultry caecum. Avian spp. especially, poultry has become the most well-known reservoir of Campylobacter spp. as a result of their high body temperature and they are responsible for an expected 80% of human Campylobacter infection (Silva et al. 2011;Epps et al. 2013 andWhiley et al. 2013). Thus, the gut mucosa of mammals and birds are considered the ideal site of bacterial multiplication and serve as a natural reservoir of Campylobacter spp. Campylobacter is a ubiquitous microorganism, which means that it can be found nearly everywhere as a commensal microorganism in the intestinal tract of different animals from the red kangaroos and Antarctic macaroni penguins to common housefly (Llarena, 2015). Thermotolerant Campylobacter spp. (C. lari, C. jejuni and C. coli) are linked to the chicken intestine and to illness due to contaminated food, but in relation to the public health importance C. jejuni is believed to be the predominant spp. Lamb, beef, pork and poultry meat and its products may become contaminated with Campylobacter spp. during slaughtering and its subsequent steps, because the microorganism found in the intestinal tract of infected animal can spread to their viscera, meat cuts and carcasses. In the chicken processing line, the stages with the highest contamination levels for are evisceration, plucking, defeathering, and scalding because of the meat exposure to the gut contents. Moreover, keeping the evisceration room temperature lower than 15ºC can minimize the risk of contamination with these bacteria ( Moreover, cross-contamination with Campylobacter spp. can occur in the postmarketing stages at home and in public areas like restaurants and retails usually through consumers processing and handling of contaminated raw chicken and its products. Thoroughly cooking of chickens before consumption can destruct the microorganism cell. On the other hand, raw chickens and ready-to-eat food crosscontamination can happen as a result of bad hygienic practices of consumers such as cleaning raw chicken with water, which can lead to the contamination of kitchen utensils and other ready-to-eat food (FSA, 2012). Additionally, defrosting and storing chickens without hygienic precautions may increase the cross-contamination between foods by contact with dripping water from the defrosted meat ( Interestingly, unpasteurized milk is another potential vehicle for human campylobacteriosis, due to the bad hygienic practices during milking which can result in milk fecal contamination. The Campylobacter incidence in dairy cow may be seasonal with a summer peak, while human Campylobacter infection outbreaks because of the contaminated milk consumption increases in the spring and fall (Elangro et al. 2012 and Mungai et al. 2015). However, the Campylobacter transmission through contaminated raw fruit and vegetables is uncommon, it may be significant. Vegetables and fruits may get contaminated with Campylobacter spp. during distribution, packaging, processing, harvesting and production. Possible sources of contamination include dust, contact with infected animals, improper hygienic practices of the utensils, equipment and handlers, inadequately composted or natural manure, faeces, contaminated irrigation water and the survival or presence of the bacteria in the soil

ISOLATION AND IDENTIFICATION OF CAMPYLOBACTER SPECIES
No standard culture technique for Campylobacter spp. isolation is present and techniques used vary between research facilities. Campylobacter multiply more gradually than the other microbial flora in the intestine and need low oxygen levels. Therefore, it is hard to be isolated without utilizing selective media. Additionally, enrichment techniques are important for food, environmental specimens and old stool specimens where the quantity of Campylobacter is low. However, an enrichment step is not typical essential for clinical samples ( The most well-known selective agar utilized for isolation of Campylobacter is modified charcoal cefoperazone deoxycholate agar (mCCDA). The petri dishes are incubated at 42°C/37°C for 2 days in anaerobic jars with gas-generating sachets, envelopes or Campy packs to maintain microaerobic condition comprising of 10% CO2, 5% O2 and 85% N2 (Levin, 2007 andHu andKopecko, 2018). The colonies of Campylobacter are typically gray, flat, irregular, and spreading in freshly prepared media. Selective culture is a fast, modest, and efficient technique for distinguishing C. jejuni and C. coli. After that, colonies suspected to be Campylobacter are cultured onto blood agar plates and the isolates are distinguished by motility, biochemical techniques and Gram's stain (Galate and Bangde, 2015 and Hu and Kopecko, 2018). Hippurate hydrolysis test is the most common conventional characterization procedure, which is utilized for distinguishing C. coli from C. jejuni, but this technique may produce false negative results (Van Dyke et al. 2010). A few replacement and quick techniques have been documented for distinguishing Campylobacter spp. Polymerase chain reaction (PCR) is the best strategy for confirmation of Campylobacter spp. because the phenotypic responses are frequently atypical and hard to be read (Galate and Bangde, 2015). Many studies reported the Campylobacter spp. detection by the use of culturebased techniques; however, these techniques have minimal bacterial recovery rates and they possibly underestimate the Campylobacter count in a given specimen, due to Campylobacter requirements for fastidious and complex growth condition. Biochemical techniques rely upon biochemical pathways and their interruption can cause false results and product failure. These outcomes give false

PATHOGENESIS AND VIRULENCE FACTORS OF CAMPYLOBACTER SPECIES
Campylobacter has a complex and not completely known mechanisms for survival to conquer the host barriers and to cause sicknesses in humans, interestingly studies on pathogenesis of Campylobacter are usually made with C. jejuni (Silva et al. 2018a). The dosage for Campylobacter infection is believed to be 350-10,000 cells and the infective dose is frequently correlated to the attack intensity. Campylobacter infections are most common in immunocompromised, elder people and children (Epps et al. 2013;Bolton, 2015 andBhunia, 2018). After the consumption of contaminated water or food, Campylobacter needs to go through the gastric acid barrier of the stomach and the highly alkaline secretions from the bile duct in the upper small intestine (Hu and Kopecko, 2018). Interruption of the gastric acid barrier permits the pathogenic microflora like Campylobacter to survive and flourish. Thus, people with diminished gastric acidity such as those accepting antacid and inhibitors of proton pump can be at a high risk of campylobacteriosis (Same and Tamma, 2018). Severe inflammation and cell damage are well established when Campylobacter attacks the distal ileum and colon epithelial cells after its arrival to the lower gastrointestinal tract; though in chickens, the cecum is the essential colonization site for Campylobacter (Meade et al. 2009). In developed countries, C. jejuni causes an invasive, inflammatory disease. However; in developing countries, Campylobacter causes a non-inflammatory watery diarrheal disease (Hu and Kopecko, 2018). It is believed that host colonization, adhesion and invasion by Campylobacter needs chemotaxis and motility. Iron acquisition, resistance to gastric acids and bile salts and oxidative stress defense are important for growth and survival. Bacterial toxins mediate inflammatory responses and tissue damage (Galate and Bangde, 2015). Many putative survival and virulence factors are believed to be significant for pathogenesis and induction of gastroenteritis by Campylobacter spp. The molecular mechanism of Campylobacter infection is believed to be affected by the epidemiological and clinical features of the disease. Several genes have been identified as significant keys for the expression of pathogenicity. The cadF (adhesin gene), flaA (flagellin A gene), dnaJ, and racR are pathogenic genes involved in colonization and adherence; iamA (invasion-associated gene A), virB11 (virulence plasmid) and ciaB are pathogenic genes responsible for invasion; cgtB and wlaN (β-1,3-galactosyltransferases) are pathogenic genes involved in lipopolysaccharide production and cdtC, cdtB and cdtA, (cytolethal distending toxins C, B, and A) are pathogenic virulence genes significant for the cytotoxin production expression (

Motility
Motility is significant for Campylobacter to avoid harsh environmental conditions and genes associated with motility are mostly upregulated under stressful environments. The motility of bacteria needs flagella and a chemosensory system, which guides the flagella movement according to the surrounding gut environment. So, flagella are significant pathogenic factors that are required for the movement of the bacterium towards the epithelium surface, colonization, adhesion and invasion of the host epithelial cells. Campylobacter has characteristic helical shaped polar flagella at both or one end of the bacterial cell, which is responsible for the corkscrew torque impulsive motion in the viscid mucus, which allow the Campylobacter to go to its colonization site in the internal intestinal mucosa (Bhunia, 2018

Chemotaxis
Chemotaxis is a normal reaction of the motile bacteria to be driven towards chemoattractants by the use of chemosensors. The chemosensors are two structures: methyl-accepting chemotaxis proteins (MCPs) and signal transduction pathway, which depends on histidine kinase and consists of chemotaxis proteins such as CheZ, CheY, CheW, CheR, CheB and CheA (Bhunia, 2018). The flagellar proteins are regulated by chemosensing proteins, which regulate the bacterium directional movement that drive the bacteria to move towards the favorable environmental conditions and avoid unfavorable ones (Rowe and Madden, 2014). Campylobacter motility towards glycoproteins and mucins on the surface of the mucus membrane can favor the intestinal colonization of Campylobacter. Moreover, there is other chemoattractant such as succinate, lactate, malate, formate, serine, pyruvate, glutamate, cysteine, asparagine, aspartate, αketoglutarate, acceptors and donors of electrons, other metabolic substrates and amino acids (

Adhesion
After bacteria have passed the mucosal layer, they bind to the gut epithelial cells. Adhesion to the epithelial cells is a complex mechanism, where adhesions on the microorganism cell surface attach to the receptors of the host cells resulting in specific and irreversible binding. This cellular adherence of the gut is prior to colonization and essential for Campylobacter resistance to the intestinal expulsion and peristalsis (Ganan et al. 2012 and Silva et al. 2018a). Many adhesion proteins of Campylobacter spp. that present on the bacterial cell surface have been identified. CadF protein (37 kDa) is a protein presents on the outer membrane of Campylobacter, it regulates the adhesion of the bacterial cell by attaching to fibronectin, which is an extracellular glycoprotein present in the intestinal tract. This reaction stimulates a signaling pathway, which result in the activation of the Cdc42 and GTPases Rac1 that stimulate the bacterial cell to internalize through actin-mediated induced phagocytosis. Many researches have showed that mutation in this protein can prevent Campylobacter colonization Moreover, there are three Cia proteins; CiaI, which has a fundamental role in Campylobacter survival inside host cell, CiaC that is essential for maximal invasion of INT-407 cells and CiaB that is important for target cells adherence. In the recent years, a 4 th protein, CiaD has been showed to have a key role in the host cells invasion (Samuelson et al. 2013). Additionally, mutation in CiaB protein results in reduction of the invasion ability through minimizing the adherence and the possible invasion. Moreover, there are other proteins including FspA, VirK, HtrA (a chaperone protein), CeuE, IamA (invasion-associated protein A) and FlaC, which also play a role in the invasion of host cell, but the mechanisms are not fully known yet (Bolton, 2015 and García-Sánchez et al. 2018). Moreover, some Campylobacter isolates have a plasmid with high molecular weight, pVir, which has been reported to be correlated to bloody diarrhea. pVir has been reported to have vital role in the invasion of host cell and it is encoded by virB11 gene (Same and Tamma, 2018).

Toxin production
After the internalization, Campylobacter enters a vacuole or a membrane-bound structure to escape the host immune system and survive inside the epithelial cell for long period of time until the conditions become favorable for cytotoxic response induction (Rowe and Madden, 2014). Campylobacter secretes many toxins and the main toxin is the cytolethal distending toxin (CDT), which encoded by a three gene operon (cdtABC). The CDT composed of three toxins with identical molecular weight, CdtB (29 kDa), CdtC (21 kDa) and CdtA (30 kDa). So, it is named a tripartite "AB2" toxin, where CdtB toxic subunit is the enzymatically active one, while the CdtC and CdtA comprise the "B2" subunit that have a role in binding to the receptor of the cell membrane and the CdtB internalization (Bolton, 2015 andBhunia, 2018). The CdtB subunit is internalized in the nucleus after its translocation in cytoplasm of the host cell (Silva et al. 2018a). Additionally, CdtB has a nuclease activity, which stimulates damage of DNA through double strand breaking. This will result in stopping the cycle of the cell, mainly in the mitosis G2/M transition stage, which affect the cell division and lead to distension of the cell and apoptotic cell death (Koolman et al. 2016 and García-Sánchez et al. 2018). The CDT is believed to cease the crypt cells maturation into effective villous epithelial cells; so, it stops the intestinal absorption for a short time and causes diarrhea. CDT is trypsin-sensitive and affected by heating (70 °C for 30 min). Moreover, Campylobacter have other toxins like hepatotoxin, pore-forming hemolysin, a shiga-like toxin, which disrupt the protein production and choleralike enterotoxin that activates cAMP (Bhunia, 2018).

Iron acquisition
The capability of Campylobacter to take iron from transferrin in the host serum and lactoferrin from the mucosa is significant for pathogenesis and persistence of Campylobacter in the host cells and the effective colonization of the intestinal mucosa including many receptors on the cell membrane, regulators and transporter proteins (Hermans et al. 2011;Bolton, 2015 andBhunia, 2018). Campylobacter cannot produce siderophores, but it uses enterochelin, ferrichrome and siderophores secreated by other microorganisms to obtain iron. Thus, Campylobacter will have a competitive advantage taking into account the several genes involved in regulation of iron acquisition and homeostasis despite its small DNA. Moreover, there are two important regulator proteins for iron uptakes include PerR (peroxide stress regulator) and fur (ferric uptake regulator)

Carbohydrate structures
Four various categories of carbohydrate structures like N-and O-linked glycans, capsular polysaccharides (CPS) and LOS can be established on the Campylobacter cell surface. The LOS molecule is a significant virulence factor associated with the immunological symptoms. It is composed of lipid A and a core oligosaccharide and it has been related to various activities such as protection from killing by complement-mediated, invasion, host cell adhesion and immune evasion. Adding a sialyl group to the LOS molecule will maximize the invasive ability and minimize the Campylobacter strains immunogenicity

Regulation of virulence genes
Colonization and thermotolerance in the intestinal tract are regulated by regulatory system composed two components including a response regulator (RR) and a histidine kinase (HPK) sensor. The RR is phosphorylated by HPK and responsible for the regulation of the expression of RacR, CheY and other proteins those are important for thermotolerance at 37°-42°C and colonization. Moreover, the acquisition of iron is regulated by PerR and Fur proteins. Additionally, the flaA regulon, which have a key role in synthesis of Campylobacter flagella, is regulated by a signal transduction system composed of two components (FlgS/FlgR) (Bhunia, 2018).

Campylobacter survival in stress environment
The foodborne microorganisms are exposed to stressful environment both inside and outside of the host organism. The expression of stress response mechanisms by the foodborne pathogens has a significant role in their persistence in different habitat (Silva et al. 2018a). Unlike other foodborne pathogens, Campylobacter doesn't possess several adaptive responses to stressful environment. These bacteria do not have the rpoS gene, which is a sigma factor in the stationary stage that encodes for the RpoS (sigma 38) global regulator that is associated with virulence genes and the transcription of stress response (Silva et al. 2018a). However, Campylobacter have few adaptive responses for reactive oxygen spp., acid tolerance and heat shock that permit them to persist in the stressful environmental conditions (Bolton, 2015 and Dasti et al. 2010). Despite lack of many stress response mechanisms, fastidious growth requirements and its sensibility to environmental stressors, these bacteria can cause a public health hazard due to its persistence in the food chain (Silva et al. 2018a).

RESISTANCE OF CAMPYLOBACTER SPECIES TO ANTIMICROBIAL AGENTS
Bacterial resistances are mainly caused because of the aimless utilization of the antibiotic agents in human disease treatment as well as its exaggerated use in animal production (Silva et al. 2018a). Recently, the emergence of antimicrobial resistance in C. coli and C. jejuni originating from food of animal origin has become a critical public health problem worldwide (EFSA, 2017). Campylobacteriosis is characterized by a self-limited diarrhea; in this way, antimicrobial therapy is not usually recommended. But antimicrobial therapy is required in case of serious infection, which may be systemic or prolonged. Campylobacter is a zoonotic pathogen; subsequently, Campylobacter resistant strains will cause serious problems because the most well-known antimicrobial agents would be useless against campylobacteriosis (Bhunia, 2018).
Campylobacter is a commensal bacterium in the intestine of different domestic animals and this led to their exposure to several classes of antimicrobial agents. Between these antimicrobial agents, quinolones as enrofloxacin or ciprofloxacin is believed to be associated with causing high resistance rates in food products and farms; so, the US Food and Drug Administration (FDA) has restricted fluoroquinolones utilization in USA chicken industry as a growth supplement (Bhunia, 2018 and Same and Tamma, 2018). Additionally, the natural competence and hypervariable genomic structure of Campylobacter lead to an extensive genomic diversity which may be another cause of antibiotic resistances . Four main methods are implicated in Campylobacter resistance to antibiotics including (i) production of enzymes that modify or inactivate antimicrobial agents (e.g., β-lactamase), (ii) changing the antibiotic recipient and/or its expression (e.g., 23S rRNA or gyrA genes mutations), (iii) antimicrobial efflux pumps which actively eject the antimicrobial agents from the cell (e.g., multidrug efflux pumps, CmeABC), and (iv) minimize the antimicrobial permeability, so the antimicrobial cannot reach its target due to unique membrane structures (i.e., the major outer membrane porin expression or MOMP) (

Multidrug efflux pump system
The Campylobacter multidrug efflux (CME) pump usually mediates Campylobacter resistance to heavy metals, bile salts and a wide range of other antibiotics. So, it is an active method for these agents to be pumped extracellulary, consequently avoiding their accumulation inside the bacterial cell, which essential for the bacterial cell death (Kurinčič et al. 2012). The CME pump is encoded by the cmeABC operon that is composed of a periplasmic fusion protein; CmeB a protein on the outer membrane, CmeC an efflux transporter on the inner membrane that belongs to the superfamily of resistancenodulation-cell division and CmeA that bridges CmeC and CmeB

Quinolones
The European Food Safety Authority (EFSA) stated that Norway and Denmark are the only European state members, which have very high ciprofloxacin resistance levels. Five member states stated increased trends in C. jejuni fluoroquinolone resistance. Moreover, 11 out of 17 member states countries showed high levels of C. coli ciprofloxacin resistance (80-100%) with 2 reporting countries have increased trends during the period from 2013-2015 (EFSA, 2017). According to the high level of fluoroquinolones acquired resistance, they should not be used for treatment of patients suffering from campylobacteriosis (EFSA, 2017). Thus, other antimicrobial agent has been required for treatment of human campylobacteriosis such as macrolides (azithromycin and/or erythromycin) and probably soon fluoroquinolones may become disused. Several researches have showed a correlation between the increased resistance of Campylobacter isolates among chicken and human and the fluoroquinolone use in poultry industry

Aminoglycosides
Aminoglycosides antimicrobial agents include streptomycin, tobramycin, neomycin, amikacin, kanamycin and gentamicin. There are two mechanisms for aminoglycosides to maintain their antimicrobial activities: (i) proofreading interference which lead to dysfunctional proteins due to using wrong amino acids and (ii) interference with the early peptide chain translocation from the ribosomal A site to the P site, which result in its premature end (Iovine, 2013 and Yao et al.

2017).
Campylobacter jejuni aminoglycoside resistance is mainly occurred through aminoglycoside-changing enzymes (Sat, aacA AadE, AphD and AphA) that are encoded by plasmids genes. Moreover, the efflux pump system contribution is not fully understood yet (Iovine, 2013 and García-Sánchez et al. 2018). The first report of Campylobacter resistance to aminoglycosides was in C. coli and has been mediated by a 3′-aminoglycoside phosphotransferase that is encoded by the aphA-3 gene. Moreover, other genes have also been identified in Campylobacter spp. such as genes conferring to kanamycin resistance (aphA-7 and aphA-1), streptothricin resistance (sat) and streptomycin resistance (aadE)

Macrolides
European food safety authority (EFSA) studies reported that Campylobacter resistance to macrolides has been increased in the last years and it is found usually at high levels in several European Union members. Historically, the incidence of C. jejuni macrolides resistance has been low, but there are many methods for Campylobacter to acquire macrolides resistance (EFSA, 2017). Campylobacter has four main mechanisms for macrolides resistances including: (i) efflux by CmeABC efflux pump and possibly others, (ii) methylation of the ribosome encoded by ermB gene, (iii) ribosomal proteins target mutations and (iv) mutation in the 23S rRNA gene (Bolinger and Kathariou, 2017). The ribosomal methylation pathway has been reported recently in one avian C. coli isolate in Spain. This was the first report about the Campylobacter ermB gene in Europe. This isolate had an elevated level of erythromycin resistance (MIC1024 mg/L) and the ermB gene was detected among a multidrug resistance island having five genes for antibiotic resistance. Additionally, this isolate was gentamicin susceptible, but it was resistant to streptomycin, tetracyclines, Campylobacter has another method for macrolide resistance includes an alteration in the permeability of the cell membrane mediated by the expression of the MOMP that is encoded by porA gene. Porins are proteins in the external membrane of Gram-negative microorganisms, which made pores across the membrane that permit the hydrophilic molecules passive diffusion like several antimicrobial agents. The MOMP make a small pore, which is selective for positively charged ion, in C. coli and C. jejuni this result in minimizing the passage of most antimicrobial agents with a negative charge or those which have a molecular weight more than 360 kDa (Iovine, 2013 and Silva et al. 2018a).

β-lactams
β-lactams resistance in Campylobacter spp. is usually mediated by β-lactamases enzymes, which breakdown the β-lactams structure. Additionally, some Campylobacter strains have other mechanisms for β-lactams resistance such as cation-selective MOMP and efflux pump system ( In developing countries, campylobacteriosis is hyperendemic and the Campylobacter infection is symptomatic and occurs almost exclusively and repeatedly in young children and infants. Subsequent infections can be asymptomatic, which make the symptomatic infection rare in adults or older children (Same and Tamma, 2018). Campylobacteriosis is usually sporadic, but there were many reported outbreaks.

PHYTOCHEMICALS AS INTERVENTION STRATEGIES USED TO REDUCE CAMPYLOBACTER SPECIES IN POULTRY PRODUCTION
Chickens are believed to be answerable for up to 80% of human Campylobacter infection. Therefore, intervention procedures have been developed for controlling Campylobacter in chickens at the farm level to minimize the products contamination and accordingly the incidence of human campylobacteriosis (Upadhyay et al. 2019). Since ancient times, phytochemicals have been utilized as food supplements, enhancers of flavor and natural preservatives in numerous cultures. Most of phytochemicals are produced in plants as secondary metabolites due to the interactions between plants and their surrounding environment. The phytochemicals do not participate with any principle metabolic procedures in plants, but they possibly increase the immunity and capacity of these plants to persist in stressful environment and pathogenic infection (Upadhyay et al. 2017). Several phytochemicals possess important antimicrobial activities including betaresorcylic acid (from Brazilian berries and wood), eugenol (from clove oil), trans-cinnamaldehyde (from cinnamon bark), caprylic acid (from coconut oil as medium-chain fatty acid), thymol and carvacrol (from oregano oil) ( Recently, a great expansion in the consumer preference towards natural products has been reported. Therefore, several scientists concentrated on utilizing products from plant origin as an alteration to antimicrobial agents in food from animal origin. Several phytochemicals have an antimicrobial efficacy by disrupting the bacterial cell wall and membrane integrity, which may cause a leakage of cellular contents and cell death (

CONCLUSION
Campylobacter spp., mainly C. jejuni have become the leading cause of bacterial foodborne enteritis worldwide. Human Campylobacter infection is caused by the consumption of contaminated poultry meat and meat products. Over the last decade, many researches have been applied to study the biology, antimicrobial resistance, pathogenicity, virulence and epidemiology of Campylobacter spp. to found the ideal control strategies of these bacteria and thus reduce Campylobacter infection in humans. However, the lack of surveillance programs in developing countries making it difficult to control campylobacteriosis; therefore, efforts to survey and control these bacteria should be increased worldwide. There are various methods to control these pathogens, but recent researches prefer the use of phytochemicals such as beta resorcylic acid and eugenol due to their antimicrobial properties and their ability to down regulate the expression of several virulence genes, which lead to minimizing C. jejuni attachment and invasion to the epithelial cells in the gastro intestinal tract.