News and analysis on the global poultry
and animal feed industries.
Chemical structure of the new molecule, OHHL
on June 30, 2009

The end of the AGP paradigm?

Cutting-edge technology offers the opportunity to control the micro-organisms in the gastrointestinal tract of poultry. Could quorum sensing' succeed the industry's use of antibiotic growth promoters within the next decade?

Today, there is an industry-wide understanding that the interplay between animals and the bacteria that live within their gastrointestinal (GI) tract is highly complex. The GI tracts of both monogastric and ruminant animals contain beneficial bacteria that contribute to the health and nutrition of the animal as well as deleterious species that deprive the animal of its nutrients or, worse still, cause disease. The GI tract contains a diverse ecology of micro-organisms, all competing for reproductive advantage. Control of this gut flora has been a most useful tool in modern agriculture both in terms of performance and animal health.

Historically, antibiotic growth promoters (AGPs) have targeted those types of bacteria that share a common characteristic. Most in-feed AGPs select against gram-positive bacteria although some of this group contribute to the overall health of the animal. For example, both lactobacilli and bifidobacilli are gram-positive and, indeed, are frequently found in probiotic additives. Equally, formulations designed to promote and nourish beneficial bacteria very often support pathogenic bacteria just as well as the intended recipient. These are in-built limitations on the effectiveness of our current strategies: the use of antimicrobial agents natural or otherwise is a hit-and-miss approach.

New technology cracks the communication code

Recent advances in microbiology suggest that an entirely new group of molecules may offer a way of precisely targeting individual species of bacteria and allow the promotion of beneficial micro-organisms while at the same time diminishing the threat from pathogens. Bacteria have been found to possess a communication system, called quorum sensing', that gives them the benefits of co-operation using small molecules to talk' to each other. These molecules, called auto-inducers, are signal molecules that activate or de-activate different behaviours of bacteria. For example, a particular auto-inducer may cause one species to express surfactants, toxins or to attack another species using defence chemicals. Another auto-inducer may switch off' those same behaviours. Bacteria have evolved these sophisticated trigger mechanisms so that recognition of, and reaction to, their own cell densities and the population of competing types of bacteria is possible. A good example is the light-emitting bacteria that live symbiotically on certain deep sea jellyfish. Here, the bacteria are able to flash on and off en masse providing a defence for the host. This would be impossible without a communication circuit between the millions of bacteria required to produce a visible light. In just the same way for individual bacteria in the gut, switching on or off virulence factors in isolation will have a negligible overall effect but a co-ordinated attack of many millions of cells can profoundly alter the balance of power in the gut.

So far, a couple of dozen signals have been identified although the interaction of these compounds in mixed bacteria populations is less well understood. One problem in the elucidation of these interactions is that any particular auto-inducer may act as both an antagonist and an agonist depending upon conditions and isomeric structure. Most of the research carried out on these chemicals has been focused on ways to use them in medical science. There is hope that this work will reveal new ways of dealing with intractable infections such as methicillin-resistant Staphylococcus aureus (MRSA), which causes a significant number of deaths each year in hospitals as the result of poor hygiene following surgical procedures.

Using the technology in poultry feed

Once auto-inducers had been discovered functioning in the gut of animals, it was only a matter of time before scientists attempted to control gut bacteria artificially by adding additional signal molecules to the feed. It has now been shown that one such signal oxo-hexanoyl homoserine lactone (OHHL) can increase dry matter digestion in ruminants. It was also shown to have lowered mortality and increased daily growth in poultry, as shown in the accompanying table and graph. Interestingly, auto-inducers work at very low concentrations they can trigger a response at levels of just a few nanomoles in practice, less than one gramme of the active compound per tonne of feed.

Use of these molecules gives nutritionists access to the control systems that govern bacteria. At present, we can only imagine what could be accomplished when more signals have been tested on a range of species in different environments. It is possible to envisage a time when the nutritionist is able to pick and choose which of the bacteria colonising his livestock need to be promoted and which need to be stopped in their tracks. Unlike antibiotics, resistance to the influence of auto-inducer signals cannot build up over time. With antibiotics, the target micro-organism is not completely eradicated and so the survivors live on and multiply. With this new technology, bacteria are not killed: they are merely manipulated into behaving as the nutritionist requires. For example, lactobacilli could be encouraged to multiply while clostridial species are directed to stop producing the toxin that causes disease.

The distinction between a synthetic AGP and a naturally sourced antimicrobial is a subtle one. Both kill bacteria in a fairly indiscriminate manner and both can result in resistance. The range of natural antimicrobial agents currently available to feed formulators has never been larger due to the regulatory issues surrounding AGPs but they are widely regarded as a less effective substitute.

Quorum sensing technology has far reaching implications for both medical science and agriculture. Once the research has been completed and the individual functionalities of the various auto-inducers have been characterised, the use of these agents to improve animal health and performance could be a revolution a welcome break-through as AGPs fall by the wayside.

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