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November 21, 2018
Achieving a complicated dream: Mass production of antibiotic-free meat and fish versus scientific reality
AGPs made inexpensive protein possible while creating a serious human health problem. Deconstructing the metabolic pathways by which antibiotics boost productivity and replacing them with natural alternatives is far easier said than done.
By Eric J. Brooks
An eFeedLink Hot Topic

Once a fringe topic, antibiotic-free meat is now mainstream and in demand by better educated, upmarket consumers. Coincidentally, both livestock producers and their distribution partners have signaled a strong willingness to have their meat perceived as healthy, ecologically friendly and sustainable.
Alongside leading US and European supermarkets, fast food chains including McDonald's, Subway, Chipotle, Panera, Starbucks, Burger King and Chick-fil-A have all committed themselves to serving antibiotic-free chicken, red meat or promise to do so within a few years.
These new private sector initiatives are all following the lead of Sweden's ban on antibiotic growth promoters (AGPs) in 1986, a similar law passed by the European Union in 2006 and similar (but more flexible) restrictions that have come into effect in Japan and South Korea. America's FDA is phasing out the use of antibiotics critical to human medicine –but its integrators are already ahead of the curve.
Tyson, Perdue and other large integrators began researching and planning AGP free meat production in the early 2010s, several years before the FDA began tightening its regulations. Like their European counterparts, they and other large US integrators both now produce antibiotic-free chicken meat and eggs.
On the other hand, outside Europe, red meat production still depends on AGPs. In America, Australia and some parts of Asia, antibiotic free red meat is only supplied by small, upscale niche farmers. They rely on premium retail prices to offset their relatively high production costs. Even with official encouragement from the FDA, large-scale American integrators are still technically fine-tuning the raising of red meat livestock without antimicrobials. It will take until sometime in the 2020s before they can achieve the mass market production of AGP free hogs and cattle at competitive cost levels.
A similar multi-track AGP elimination curve exists in farmed seafood. On one hand, Norwegian salmon (and increasingly, their Chilean rivals) are raised almost completely without antibiotics. From the 1990s onwards, they leveraged salmon's unique metabolic characteristics to substitute an array of vaccines in place of antimicrobials.
This, however, is far from being achieved for most farmed aquaculture species. In the case of shrimp for example, even with help from antimicrobials, it can no longer be raised at the high stocking densities taken for granted ten years ago. Moreover, some scientific research implies that the removal of key ingredients like fishmeal from aqua feed may have made it more difficult to cultivate certain species without the aid of AGPs. Hence, while agribusiness has learned to sustainably raise poultry in a cost-effective manner without using AGPs, it will be more difficult to do so for red meat, let alone seafood.
Each animal line has unique metabolic pathways that respond to a different set of antibiotics than other species. –Researchers must first deconstruct these species-specific metabolic pathways, then determine how a given antimicrobial acts on it in a manner that raises animal productivity. Thereafter natural growth promoters (NGPs) that boost species metabolism and meat making productivity in a similar manner must then be discovered, invented, tested and patented.
This must then be repeated for each antibiotic given to an animal line and the unique, species specific metabolic pathway it influences. The same must then be done for every farmed animal or aquaculture species. –Hence the dream of achieving high animal productivity levels without using antimicrobials will be just challenging (or even more challenging) for each unique animal line as it was for poultry –but at least now we have the technology and paradigm to do so.
It was only after 2000 that researchers finally understood the mechanism by which AGPs boost productivity: According to Theodore A. Niewold, health and nutrition professor at Belgium's University of Leuven, regardless of the species or metabolic pathway in question, AGPs stimulate livestock growth by minimizing livestock immune system activity, which is a proxy for inflammation. This in itself explains why many AGPs remained effective growth promoters even after bacteria developed immunity that made them useless for treating human infections.
At BIOMIN's 2016 World Nutrition Forum, Niewold stated that immune system-induced inflammation is known to reduce appetite, trigger muscle (a.k.a. meat) wasting, generate excess abdominal fat and induce high gut pathogen populations. –And until recently, without the use of AGPs, modern high animal stocking densities would result in stressed-out animal immune systems and a state of constant metabolic inflammation.
Through such causation pathways, Niewold estimates that an episode of full-scale antibody production pinches livestock meat volume by 3%. Constant inflammation can result in a whopping 30% growth reduction. Unless alternative methods to AGP supplementation are found, modern high stocking density poultry, livestock and aquaculture environments put animal immune systems in a stressed state of perpetual inflammation.
Moreover, the hygiene problems created by high stocking densities create hygiene problems that which simultaneously boost animal stress while promoting the growth and transmission of pathogens. With inflammation itself degrading the animal's gut flora, conditions for "a perfect storm" are created.

Hence the inevitable inflammatory immune response and subsequent, above-mentioned 3% to 30% fall in animal growth productivity.
It is not a coincidence that from the 1950s to the 1990s, higher animal stocking densities and antibiotic usage rose in tandem, or that they enjoyed an inverse relationship with unit production costs, which fell over this time: Partly through their antimicrobial properties, partly due to their ability to reduce immune system inflammation, AGPs made it possible for high stocking densities to coincide with high animal productivity.
Sir Alexander Fleming, who discovered the first antibiotic, predicted that their uncontrolled use would lead to the evolution of resistant bacteria.  –But Fleming never anticipated that his predicted reservoir of antibiotic-resistant bacteria would develop on farms more than they would in hospitals.

But 50 years ago, all this was not known: All farmers knew is that with help from AGPs, they could have their cake and eat it too –boost stocking densities and animal productivity while minimizing costs. By the late 1960s, over 80% of the antibiotics were administered to animals instead of people.
–That meant that pathogens now many times more opportunities to accelerate the evolution of their antibiotic resistance in animals than in humans. Furthermore, farms contain uncountable tonnes of bacteria-saturated, antibiotic tainted animal intestines, manure, contaminated housings and slaughtered remains.
It was soon discovered that bacteria are capable of sharing and transmitting antibiotic resistant DNA "plasmids" (snippets) to other bacteria and even across different species. In 1976, Tufts University researcher named Stuart Levy fed chickens tetracycline. Within a week, tetracycline-resistant bacteria began to populate poultry gut flora and were detected in their feces. While he did not prove a causative link between AGPs and antibiotic-resistant human infections, Levy published the first major study warning that using AGPs could lead to untreatable human infections.
Follow up studies established that bacterial resistance to antibiotics was rising. Resistance to multiple antibiotic classes was detected in many livestock pathogen populations. These included Staphylococcus, E. Coli and salmonella. Scientists warned that we were running out of new antibiotic types and classes that could be invented
During the 1990s new, highly virulent strains of methicillin-resistant staphylococcus bacteria (MRSA) evolved. Within 20 years, it was responsible for half the 23,000 US deaths from antibiotic-resistant infections and an alarmingly high number of limb amputations. -Unlike previous antibiotic-resistant outbreaks, MRSA infected healthy people with no pre-existing medical conditions.
What was most fascinating (and frightening) about MRSA is that methicillin had never been used in livestock farms! -The DNA "plasmids" which conferred resistance to chemically related β-lactam AGPs such as penicillin and ampicillin also made ST398 bacterium resistant to methicillin: Even if a particular antibiotic is never administered to livestock, bacteria can evolve resistance to a wide array of antimicrobials belonging to the same antibiotic class.
As the disease spread, victims ranged from hospital patients to American high school athletes to a senior Canadian politician, who was forced to undergo a leg amputation. By the late 2000s, MRSA victims included several dozen professional baseball and football player, some of whom had to undergo amputations. 
Gene mapping technology soon traced human MRSA cases back to genetically identical bacteria at hog farms. A link between farm worker MRSA infections and AGP use at hog farms was soon also found.
Scientific proof that antibiotic-resistant bacteria could spread from farms to surrounding communities finally came in a 2004 USDA-funded study. Philip N. Smith a researcher at Texas Tech University discovered that "Tetracycline resistance [in bacteria] was 400,000% more prevalent downwind [from a cattle feedlot] than upwind. At some downwind locations, the tetracycline resistance was in 100% of the [bacteria] samples."

Fortunately, all this bad news was counterbalanced by new scientific findings: A wide range of natural substances including organic acids, plant extracts, essential oils, table spices and even mundane compounds found in butter mimicked the metabolic action of AGPs.
Similarly, a wide range of compounds found in mundane substances including lemongrass, butter, cinnamon and organic acids such as formic or propionic were all found to act as natural growth promoters (NGPs) -each with a similar causation mechanism as an antibiotic they could replace:

According to Niewald, non-microbial supplements like salicylic acid (a.k.a. aspirin) shares similar metabolic pathways and produces the same anti-inflammatory biomarkers as many AGPs. Thus, by testing for the presence of such anti-inflammatory biomarkers, non-antibiotic growth promoters are gradually being identified and substituted in place of existing antibiotic supplementation.
With the replacement of AGPs with NGPs comes a trade-off: While bacteria will not develop resistance to these substances, they do not permit the same high stocking densities as their AGP predecessors. But science has also found a way around that trade-off: Norwegian salmon demonstrated that by using developing pathogen-specific vaccines, AGPs could be eliminated and overall antimicrobial use reduced by 99% while boosting protein production by several hundred percent.
While vaccines will probably not control animal diseases as effectively for other species as they did salmon, they too must play a role. A species-by-species substitution of AGPs with NGPs will maintain animal productivity in an ecologically sustainable manner. Vaccines will also play a role in making high stocking densities possible without recourse to AGPs
--But what was done with salmon must be done individually, taking into account the unique metabolic characteristics and needs of every livestock and seafood species under cultivation. Like a war that conquers inch-by-inch, house by house, substituting NGPs and vaccines in place of AGPs will take decades of research. Outside of America and Europe for example, mass production of antibiotic-free poultry can be found in Thailand, South Korea and Japan but not many other nations.
It will take decades for developing nations to achieve AGP free poultry production, by which time advanced nations will have begun mass production of antibiotic-free red meat and several seafood species.
All this makes antibiotic-free meat an expensive, difficult, complicated –but highly worthwhile goal.

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