Investigation Of The Effectiveness Of Non-Antimicrobial Compounds Against Brachyspira Hyodysenteriae, Lawsonia Intracellularis, And Salmonella Enterica Serovar Typhimurium

Abstract

Brachyspira hyodysenteriae, Lawsonia intracellularis, and Salmonella enterica serovar Typhimurium are the causative agent of swine dysentery (SD), proliferative enteropathy (PE), and salmonellosis in pigs, respectively. SD is characterized by mucohemorrhagic diarrhea in grower and finisher pigs (Alvarez-Ordóñez et al., 2013). There is no efficient vaccine available for SD, and antibiotics are the only approach to prevent, control, and treat it in swine herds. In 2013, it was estimated that SD adds US$11.70-$17.50 for each diseased pig that reaches market weight (McKean and Burrough, 2013). In 2015, the World Organization for Animal Health (OIE) identified B. hyodysenteriae and L. intracellularis as agents for which high or moderately high amounts of antibiotic was still used for treatment, and could benefit from novel preventative approaches (World Organization for Animal Health, 2015). Disease caused by L. intracellularis in pigs is characterized as two syndromes: porcine intestinal adenomatosis (PIA) and proliferative hemorrhagic enteropathy (PHE) (Vannucci and Gebhart, 2014). PIA is observed after weaning and clinical manifestations are anorexia, diarrhea, and poor growth performance (Roberts et al., 1980). PHE mainly affects finisher pigs, gilts, and boars, resulting in mucosal thickening in the ileum, the classic hose-pipe gut lesion (Vannucci and Gebhart, 2014). In 1996, an Australian study suggested that PE costs in additional AUD$ 0.80-$7.57 per affected pig (Holyoake et al., 1996). Salmonellosis is an One Health issue. In the United States of America (USA), Salmonella infection was the second most common cause of foodborne illness in 2018 (CDC, 2018). In pigs, S. Typhimurium infection is associated with watery diarrhea and enterocolitis during the grower-finisher phases (Patterson et al., 2016). Each pig diseased with Salmonella was estimated to cost an additional €1.55 to producers, due to the impact in daily weight gain and costs with antimicrobial therapy (Gavin et al., 2018).The three diarrheal diseases described above significantly impact the pork industry due to sub-optimal performance of pigs while affecting animal welfare. Treatment, control, and eradication of these infections still rely on the use of antimicrobial agents (Alsop, 2005; Hampson et al., 2019; Wattanaphansak et al., 2019). However, the misuse of antimicrobial drugs raised concerns associated with the identification of multi-drug resistant bacterial strains. In 2020, the World Health Organization (WHO) considered antimicrobial resistance (AMR) one of the top 10 global public health threats facing humanity (World Health Organization, 2020). AMR affects our ability to control and treat bacterial infections in humans and animals. According to the 2019 Antibiotic Resistance Threats Report from the USA CDC, more than 2.8 million antibiotic-resistant infections occur in the USA yearly, and more than 35,000 people die as a result of these infections (CDC, 2019). Furthermore, AMR infections impacts the economy through death, disability, and cost of hospital stays and medicine (World Health Organization, 2020). As a measure to minimize this problem, the use of antimicrobials is now strictly regulated in several countries. In the European Union (EU), for example, the use of antibiotics as a growth promoter was prohibited in January 2006 (Castanon, 2007). Brazil has restricted the use of colistin, tylosin, lincomycin, and tiamulin (Diário Oficial da União, 2016, 2020; Skov and Monnet, 2016). Additionally to AMR concerns, the use of antimicrobials in animal production may lead to residues in meat products. Carbadox, for example, a drug used to treat enteric infection in pigs, results in carcinogenic residues in pork. Therefore, its use was banned from use in food animals by the EU and Canada (Mathew et al., 2007), whereas the USA is studying proposed proposal to remove it from the market (U.S. Food & Drug Administration, 2016; U.S. Food and Drug Administration, 2020). In light of the decrease in bacterial susceptibility to antimicrobials and the increasingly stringent regulations, the livestock industry is actively seeking for novel alternatives to aid in control and to treat intestinal infections. Prebiotics, organic acids, and phytogenics are some optional tools that have been applied in swine production up to now (Thacker, 2013; Lillehoj et al., 2018). Enzyme inhibitors, although still not used in swine medicine, are potential tools yet to be investigated. Overall, this thesis work aimed to investigate the effectiveness of novel compounds to mitigate the diseases caused by B. hyodysenteriae, L. intracellularis, and S. Typhimurium in vitro.