ShapeShapeauthorShapechevroncrossShapeShapeShapeGrouphamburgerhomeGroupmagnifyShapeShapeShaperssShape
Sponsor message
Now new in the US - Dietary diformates Made in Germany Learn more

Alternatives to Antibiotics in Feed for Swine

by 5m Editor
1 June 2009, at 12:00am

A review of the potential and use of prebiotics, probiotics, bacteriophages and bacteriocins in feeds for pigs by Chad Stahl. Published in the April 2009 issue of North Carolina State's Swine News.

Using antibiotics in swine rations for growth promotion and/or disease prevention is exceptionally common in the United States. Over 87% of market pigs produced in the U.S. were reported to receive prophylactic antibiotics in their feed or water [1]. These antibiotics are used to help maintain solvency in a production system that has an extremely narrow profit margin. The prophylactic and growth-promotant use of antibiotics in animal agriculture has come under great scrutiny. Worldwide concern over this use of antibiotics and its contribution to the spread of antibiotic resistance has led to increased regulation over antibiotic use in animal agriculture [2-4], and will likely continue toward zero tolerance for prophylactic or growth-promoting antibiotic use in animals. Additionally, niche markets have begun to provide a higher value market for pork raised without antibiotics. Completely eliminating antimicrobial use in swine production would increase production costs by over $6 per pig [5]. Both traditional producers and those targeting these emerging niche markets must examine alternatives to conventional antibiotics in order to improve animal health and production efficiency. To this end, researchers have examined many technologies for their ability to maintain the healthy microflora of the swine gastrointestinal tract (GIT).

Growth-promotant and/or prophylactic antibiotics benefit pig health (and thereby production economy), at least partially, by altering GIT microflora. This microflora is exceptionally diverse due to the different micro-environmental conditions encountered along the GIT. Members of this flora can be viewed as either beneficial or detrimental for an animal’s health and performance. Microorganisms protect against pathogens and improve nutrient utilization. However, they also compete with the host for nutrients and produce toxins or detrimental compounds that can increase gut turnover and size by stimulating inflammatory responses. Growth and feed utilization improve with antibiotic usage, which has been demonstrated in all production animal species [6]. Research suggests that this effect occurs in several ways: (1) dampening of subclinical infections, (2) suppression of certain bacteria that compete with the host for nutrients, (3) enhancement of the host’s immune system, and (4) shifts in microbial populations [7]. Research into alternatives for conventional antibiotics in feed has focused on products that would have similar effects. The most promising current research areas include the use of prebiotics, probiotics, bacteriophages and bacteriocins.

Prebiotics

Prebiotics are nondigestible food ingredients that benefit the host by selectively stimulating the growth of beneficial bacteria in the colon [8]. Current views of prebiotics allow for including any compound designed to increase the growth of a particular bacteria or family of bacteria anywhere within the GIT. Most work has focused on carbohydrates that increase populations of beneficial bacteria, such as Bifidobacterium and Lactobacillus strains. This increase in beneficial bacteria may be caused by selectively feeding certain families of bacteria or by preventing the attachment of pathogenic or nonbeneficial bacteria. Many nondigestible oligosaccharides (NDO) have been examined as prebiotics with varying success: fructooligosacchardies (FOS), glucooligosacchardies (GluOS), galactooligosaccharides (GalOS), and other oligosaccharides. Wang and Gibson [9] demonstrated that Bifidobacteria will selectively ferment inulin, a FOS, over starch, fructose, and pectin. This finding led to studies demonstrating an increase in Bifidiobacteria with inulin-type FOS in continuous culture models [10, 11], and human studies [12-14]. Other oligosaccharides also have been shown to increase the abundance of beneficial bacteria, such as Bifidobacteria and Lactobacilli, in an animal’s GIT [15-17]. While an increase of these bacteria has been demonstrated with the use of several NDO, health benefits or improvements in growth performance of animals fed these products has not been clearly seen. Another concern for using prebiotics is how much their use would alter a diet’s nutrient density and how this could affect nutrient utilization by pigs.

Other oligosaccharides that may maintain gut health by preventing the attachment of pathogenic bacteria have also been examined. Research has shown that Mannan oligosaccharides (MOS) can bind potentially pathogenic Gram negative bacteria, such as E. coli and Salmonella spp., in vitro [18-20]. In intestinal cell culture work, Naughton et al. [21]demonstrated that both mannose and FOS decreased E. coli binding in the jejunum. They suggested that this effect was due either to inhibiting the bacteria’s ability to bind to the mucosa or to changes in intestinal morphology due to increased short-chain fatty acid production by commensal organisms. Other work has also suggested that these nondigestible oligosaccharides may benefit pigs by modulating their immune response [21-24]. However, current research does not support that these compounds alone could replace traditional antibiotics in pig diets . Many reports about the potential benefits MOS present conflicts. Mathew et al. [25] showed a reduction in E. coli K88 colonization in young pigs fed MOS, while White et al. [20] saw a decrease in total fecal coliforms but not in the colonization of E. coli K88. Studies on the effect of MOS on immune function conducted by Davis et al. [20, 22-24] also show the inconsistency of a beneficial response. The effects of MOS on growth rate and feed efficiency are equally inconclusive [20, 26, 27].

Probiotics

Probiotics are live microbes fed to benefit the host animal by improving its intestinal microbial balance [28]. They could be used to obtain the same benefits as prebiotics, but more directly. Rather than feeding a compound that will selectively increase beneficial flora in the GIT, the beneficial bacteria are fed directly. Probiotics can exert beneficial effects through either competitive or noncompetitive means. Competitive means include direct competition for resources (nutrients and attachment sites) with pathogens or less-beneficial bacteria, as well as the production of compounds that provide other flora with an advantage over nonbeneficial organisms. Modulation of immune response, enhancement of mucosal repair, and anti-mutagenic/carcinogenic effects are all considered noncompetitive means.

The GIT is a highly competitive environment for its microbial inhabitants, and a healthy microbial population can help to prevent infection by pathogenic bacteria [28]. This effect has been described as “competitive exclusion” [29]or as a “barrier effect” [30]. Probiotic bacteria have been shown to bind to/persist in the intestinal tract and prevent the binding of pathogens [31-34]. Lee et al. [35] demonstrated that probiotic lactobacilli strains can both prevent the attachment of pathogens to intestinal cells and displace those that have attached. In addition, many probiotic bacteria produce volatile fatty acids that can be toxic to pathogenic or nonbeneficial bacteria. Additionally, some of these bacteria produce antimicrobial compounds (traditional antibiotics as well as bacteriocins) as a means of “chemical warfare” in their competition for resources with other bacteria that occupy similar niches in the GIT [36]. Several bacteriocin-producing bacterial strains, with inhibitory activity against a broad spectra of bacteria, have been isolated from the GITs of healthy pigs [37-39].

Research suggests that probiotics also are beneficial to animals through means other than bacterial competition. Feeding of probiotic yeasts caused changes in neurochemistry and morphology of the small intestine [40, 41]. Bai et al. [42]demonstrated that probiotics affect the immune function of intestinal epithelium. Interleukin-8 secretion, stimulated by pro-inflammatory cytokines, was suppressed by co-incubation of either Bifidobacteria or Lactobacillus with intestinal epithelium cells. The work of Davis et al. [22-24] suggests other immune modulation effects of probiotics. However, feeding Bifidobacteria to pigs has been shown not to influence cell-mediated or humoral immune response [43].

Like the research into prebiotic intervention strategies, current research provides conflicting data for the purported benefits of using probiotics in swine diets. While several studies have shown reduced incidences of diarrhea and mortality of young pigs with probiotic treatment [44-46], other work has shown that several probiotics could not prevent E. coli induced diarrhea or mortality [47]. Even the ability of probiotic cultures to alter the GIT microbial population is not always reported [48]. The possible reasons for these discrepancies in probiotic efficacy are too numerous to discuss here. The concept of feeding specific beneficial organisms or supplying them directly to the diet to maintain gut and animal health is sound. However, our current knowledge of the diversity and interactions among the GIT flora is too rudimentary to use these organisms to replace antibiotic use in pigs. Most of our understanding of the bacterial community in the GIT has been obtained via culture-based methods. These methods only provide information on bacteria that are readily cultivated, and therefore may give a biased view. The recent use of molecular methods to examine the diversity of the intestinal microflora has shown that approximately 60% of the total bacterial community cannot be cultured in the lab [49, 50]. Sequencing of the 16S ribosomal DNA isolated from bacteria obtained from the colonic mucosa of pigs show that most of these organisms are not closely related to known organisms [49]. Our limited knowledge of these organisms and their ecological relevance in the homeostasis of the intestinal ecosystem seriously limits our ability to improve the health of animals via probiotics or prebiotics.

While our current understanding of microbial homeostasis in the GIT limits our ability to design pre- or probiotic strategies to replace conventional antibiotics in animal agriculture, other potentially more useful alternatives have been discovered from studying the gut’s microbial ecology. Bacteriophages as well as bacteriocins produced by native flora can have a profound impact on GIT microflora. These strategies are more similar to conventional antibiotics than “biotic” strategies because they are designed to kill specific types of bacteria rather than manage the entire microbial community. Although both hold promise as alternatives to conventional antibiotics, much more work is needed before we can implement their use.

Bacteriophages

Bacteriophages are viruses that infect bacteria, and can disrupt bacterial metabolism and cause lysis. Prior to the commercialization and widespread use of antibiotics in human medicine, bacteriophage therapy was extensively examined for use in human medicine [51]. Questionable efficacies, coupled with the availability of antibiotics, moved research away from bacteriophage therapy. Recently, however, concerns about antibiotic resistance, as well as demonstrated efficacy in animal models, have renewed interest in bacteriophage research. Bacteriophages are attractive alternatives to conventional antibiotics due to their high specificity, mode of bacterial lysis, and safety. The high specificity of bacteriophages would allow for effective treatment/removal of specific pathogens or nonbeneficial bacteria from the gut without affecting the beneficial or benign bacteria. Bacteriophage use could offer the benefits of traditional antibiotic usage without increasing the risk of offsetting the normal GIT flora. This high specificity is, however, also a major drawback to using bacteriophages as an alternative to conventional antibiotics in swine. Researchers recently examined four different bacteriophages for efficacy against a broad range of pathogenic E. coli strains [52]. Each phage caused lysis to several of the E. coli strains; however, no phage was effective against all of the strains in a given class (enteropathogenic or enterotoxigenic), and 64% of these isolates were resistant to all four phages. This high specificity can be a serious disadvantage when looking for an alternative to conventional broad-spectrum antibiotics because the pathogens would need to be identified prior to treatment. This would severely limit the ability to use bacteriophage as a prophalactic or growth-promotant. Although the potential benefits and drawbacks of bacteriophages specificity pose concerns for their success as antibiotic alternatives, they have been shown effective in treating experimentally induced E. coli diarrhea in young pigs [53]. Although more work is needed to elucidate the behavior of bacteriophage in the gut, this technology has great potential.

Bacteriocins

Bacteriocins are antimicrobial proteins produced by bacteria with efficacy against similar types of bacteria. These proteins have several characteristics that make them desirable alternatives to conventional antibiotics. They have a narrow spectrum of activity, so, like bacteriophages, they could be used to target specific pathogenic or nonbeneficial bacteria without affecting the normal native flora. There is also no risk of residues in the meat or milk of animals receiving bacteriocins in feed because they are proteins and will not be absorbed intact. Also, they will likely be degraded during transit through the GIT and will, therefore, pose no environmental safety concerns. Bacteriocins also do not closely resemble traditional antibiotics important to human medicine, and have a history of safe use in food (i.e., Nisin). For these reasons and the current regulatory milieu, developing a bacteriocin-based antibiotic alternative for use in swine could be highly beneficial.

While a great deal is known about the characteristics of many bacteriocins [36, 54, 55], little research has examined the use of these proteins as antibiotic alternatives in swine feed. With the exception of Nisin, the use of bacteriocins as antibiotic alternatives for animals has been extremely limited. The value of bacteriocins in food and food fermentations has been clearly demonstrated [56-58], but examining these proteins in animal diets has not been examined, likely due to the costs associated with their production. Bacteriocin use in animal feed has been indirectly examined with the use of probiotics. As a cost-effective means of supplying bacteriocins, many bacteriocin-producing bacteria have been examined as probiotics [37-39, 59]. Unfortunately, probiotic strategies have a great deal of limitations, as discussed earlier, independent of bacteriocin production. Also, the conditions under which bacteriocin production is induced in vitro may not occur in the GIT.

Colicins, a class of bacteriocins produced by and effective against, E. coli and closely related species [60], hold particular promise as alternatives to conventional antibiotics in pig diets. Colicins are effective against many pathogenic E. coli strains, including those responsible for post-weaning diarrhea and edema disease in pigs [61-64]. We have recently demonstrated that dietary inclusion of Colicin E1 is highly effective in preventing post-weaning diarrhea caused by F18+ E. coli [65]. We are now conducting research to make dietary supplementation of colicins a cost-effective antibiotic alternative for commercial pig production.

Conclusion

With current concerns about antibiotic use in animal agriculture and its contribution to antibiotic resistance in humans, it is almost a foregone conclusion that the use of prophylactic or growth-promotant antibiotics will be banned from animal agriculture. The size of the potential market, as well as the estimated costs of a complete ban on antibiotic use in swine production, make the research and development of alternatives to conventional antibiotics a high priority. Several approaches have been discussed here, but others were omitted due to lack of available research information or severe impracticality/cost-effectiveness. These methods may one day serve as alternatives to conventional antibiotics, but their efficacy and implementation are not likely in the near future.

The four alternative therapies discussed can be divided into two categories, ecological and bacteriocidal. The ecological strategies (pre- and probiotics) could be very successful and cost-effective; however, our current knowledge of the GIT ecosystem is too rudimentary for these to be implemented successfully. Moreover, the differences in microbial populations between animals complicate the use of these therapies. As our understanding of GIT microbial ecology and microbial/host interactions expands, these methods may prove very effective. Currently, they are not effective strategies to replace conventional antibiotics.

Both bacteriocidal therapies (bacteriophage and bacteriocin) seem to be more likely alternatives to conventional antibiotics in the near future. With our current knowledge of bacteriocins, these seem the best immediate alternative to conventional antibiotics. While producing and purifying these proteins has been cost prohibitive in the past, advances in recombinant protein expression and genetic engineering could make these proteins feasible for cost-effective use in swine feed in the near future.

References

  1. USDA, Reference of Swine Health and Management, 2000. 2001, National Animal Health Monitoring System: Fort Collins, CO.
  2. FDA, Guidance for Industry #78. 1999, CVM/FDA/DHHS.
  3. FDA, Guidance for Industry #152. 2003, CVM/FDA/DHHS.
  4. WHO. WHO Global Principles for the Containment of Antimicrobial Resistance in Animals Intended for Food. 2000. Geneva, Switzerland: WHO/CDS/CSR/APH.
  5. Hayes, Dermot, and James, Economic impact of a ban on the use of over-the-counter anitibiotics in U.S. swine rations. 1999, Iowa State University: Ames, IA. p. 25-27.
  6. Hays, V.W.. Adv-meat-res, 1991. 7: p. 299-320.
  7. McEwen, S.A. and P.J. Fedorka-Cray. Clin Infect Dis, 2002. 34 Suppl 3: p. S93-S106.
  8. Gibson, G.R. and M.B. Roberfroid. J Nutr, 1995. 125(6): p. 1401-12.
  9. Wang, X. and G.R. Gibson. J Appl Bacteriol, 1993. 75(4): p. 373-80.
  10. McBain, A.J. and G.T. Macfarlane. Scand J Gastroenterol Suppl, 1997. 222: p. 32-40.
  11. Hopkins, M.J. and G.T. Macfarlane. Appl Environ Microbiol, 2003. 69(4): p. 1920-7.
  12. Gibson, G.R., et al. Gastroenterology, 1995. 108(4): p. 975-82.
  13. Kleessen, B., et al. Am J Clin Nutr, 1997. 65(5): p. 1397-402.
  14. Buddington, R.K., et al. Am J Clin Nutr, 1996. 63(5): p. 709-16.
  15. Oli, M.W., B.W. Petschow, and R.K. Buddington. Dig Dis Sci, 1998. 43(1): p. 138-47.
  16. Butel, M.J., A.J. Waligora-Dupriet, and O. Szylit. Br J Nutr, 2002. 87 Suppl 2: p. S213-9.
  17. Smiricky-Tjardes, M.R., et al. J Anim Sci, 2003. 81(10): p. 2535-45.
  18. Mirelman, D., G. Altmann, and Y. Eshdat. J Clin Microbiol, 1980. 11(4): p. 328-31.
  19. Spring, P., et al. Poult Sci, 2000. 79(2): p. 205-11.
  20. White, L.A., et al. J Anim Sci, 2002. 80(10): p. 2619-28.
  21. Naughton, P.J., L.L. Mikkelsen, and B.B. Jensen. Appl Environ Microbiol, 2001. 67(8): p. 3391-5.
  22. Davis, M.E., et al. J Anim Sci, 2004. 82(2): p. 581-7.
  23. Davis, M.E., et al. J Anim Sci, 2002. 80(11): p. 2887-94.
  24. Davis, M.E., et al. J. Anim. Sci., 2004. 82: p. 1882-1891.
  25. Mathew, A.G., et al. J Anim Sci, 1993. 71(6): p. 1503-9.
  26. LeMieux, F.M., et al. J. Anim Sci, 2003. 81(10): p. 2482-7.
  27. Burkey, T.E., et al. J Anim Sci, 2004. 82(2): p. 397-404.
  28. Fuller, R.. J Appl Bacteriol, 1989. 66(5): p. 365-78.
  29. Lloyd, A.B., R.B. Cumming, and R.D. Kent. Aust Vet J, 1977. 53(2): p. 82-7.
  30. Fedorka-Cray, P.J., et al. J Food Prot, 1999. 62(12): p. 1376-80.
  31. Jin, L.Z., R.R. Marquardt, and X. Zhao. Appl Environ Microbiol, 2000. 66(10): p. 4200-4.
  32. Styriak, I., et al., Lett Appl Microbiol, 2003. 37(4): p. 329-33.
  33. Gardiner, G.E., et al. Appl Environ Microbiol, 2004. 70(4): p. 1895-906.
  34. Kos, B., et al. J Appl Microbiol, 2003. 94(6): p. 981-7.
  35. Lee, Y.K., et al.. Appl Environ Microbiol, 2004. 70(2): p. 670-4.
  36. Riley, M.A. and J.E. Wertz. Annu Rev Microbiol, 2002. 56: p. 117-37.
  37. Du Toit, M., et al. Journal of Applied Microbiology`, 2000. 88: p. 482-494.
  38. Robredo, B. and C. Torres. J Clin Microbiol, 2000. 38(10): p. 3908-9.
  39. Rodriguez, E., et al. Lett Appl Microbiol, 2003. 37(3): p. 259-63.
  40. Kamm, K., et al. Neurogastroenterol Motil, 2004. 16(1): p. 53-60.
  41. Baum, B., et al. Z Gastroenterol, 2002. 40(5): p. 277-84.
  42. Bai, A.P., et al. World J Gastroenterol, 2004. 10(3): p. 455-7.
  43. Apgar, G.A., et al. J Anim Sci, 1993. 71(8): p. 2173-9.
  44. Shu, Q., F. Qu, and H.S. Gill. J Pediatr Gastroenterol Nutr, 2001. 33(2): p. 171-7.
  45. Kyriakis, S.C., et al. Res Vet Sci, 1999. 67(3): p. 223-8.
  46. Abe, F., N. Ishibashi, and S. Shimamura. J Dairy Sci, 1995. 78(12): p. 2838-46.
  47. De Cupere, F., et al. Zentralbl Veterinarmed B, 1992. 39(4): p. 277-84.
  48. Mathew, A.G., et al. J Anim Sci, 1998. 76(8): p. 2138-45.
  49. Pryde, S.E., et al. Appl Environ Microbiol, 1999. 65(12): p. 5372-7.
  50. Tannock, G.W., et al. Appl Environ Microbiol, 2000. 66(6): p. 2578-88.
  51. Sulakvelidze, A., Z. Alavidze, and J.G. Morris Jr.. Antimicrob Agents Chemother, 2001. 45(3): p. 649-59.
  52. Chibani-Chennoufi, S., et al. Antimicrob Agents Chemother, 2004. 48(7): p. 2558-69.
  53. Smith, H.W. and M.B. Huggins. J Gen Microbiol, 1983. 129 (Pt 8): p. 2659-75.
  54. Moll, G.N., W.N. Konings, and A.J. Driessen. Antonie Van Leeuwenhoek, 1999. 76(1-4): p. 185-98.
  55. Jack, R.W., J.R. Tagg, and B. Ray. Microbiol Rev, 1995. 59(2): p. 171-200.
  56. Lewus, C.B., A. Kaiser, and T.J. Montville. Appl Environ Microbiol, 1991. 57(6): p. 1683-8.
  57. Barefoot, S.F. and C.G. Nettles. J Dairy Sci, 1993. 76(8): p. 2366-79.
  58. O’Sullivan, L., R.P. Ross, and C. Hill. Biochimie, 2002. 84(5-6): p. 593-604.
  59. Ganzle, M.G., et al. Int J Food Microbiol, 1999. 48(1): p. 21-35.
  60. Fredericq, P. Annu Rev Microbiol, 1957. 11: p. 7-22.
  61. Jordi, B.J., et al. SFEMS Microbiol Lett, 2001. 204(2): p. 329-34.
  62. Murinda, S.E., R.F. Roberts, and R.A. Wilson. Appl Environ Microbiol, 1996. 62(9): p. 3196-202.
  63. Schamberger, G.P. and F. Diez-Gonzalez. J Food Prot, 2002. 65(9): p. 1381-7.
  64. Stahl, C.H., T.R. Callaway, L.M. Lincoln, S.M. Lonergan, and K.J. Genovese.. Antimicrob Agents Chemother, 2004. 48(8): p. 3119-21.
  65. Cutler, S.A., S.M. Lonergan, N. Cornick, A.K. Johnson, and C.H. Stahl.. Antimicrob Agents Chemother, 2007. 51(11): p. 3830-35.

July 2009

Sponsored content
Our Formi products fulfil tomorrow’s requirements today.

Formi NDF and the 3rd Generation acidifier Formi 3G have been formulated to replace the need for in-feed antibiotics, by ensuring a strong antibacterial impact against Gram negative and Gram positive bacteria.

The Formi product line, based on Addcon’s patented diformate technology ensures optimal efficiency, highest growth rates and maximum safety, which are key requirements in animal production worldwide – and are now available in the USA.

Learn more