November 30, 2016

Understanding mycotoxins: Complicated biochemistry, a diversity of causation mechanisms, and a roadmap for improving animal health

An eFeedLink Hot Topic
  • Many mycotoxins work by wrecking the cellular structures where protein synthesis occurs
  • Another causation mechanism is the inflammation (immune response) they create, which can reduce growth by up to 30%
  • As we remove antibiotics from livestock diets, mycotoxin levels need to be reduced or new, anti-inflammatory natural supplements must be discovered
  • We are learning to harness nature, which has a billion-year head start on us in neutralizing mycotoxins
  • This will take decades of large investments in R&D, genetic engineering and enzyme making capacity

Mycotoxins could be called the 'sleepers' or dark horse of livestock biochemistry. Though we have been aware of their existence for over fifty years, we are still in the early stages of understanding how they undermine livestock performance and human health.

Moreover, toxin binders are very primitive solutions relative to the sophisticated biochemistry of mycotoxins. They only remove a portion of the total mycotoxin load in the gut, and are not effective against all fungal toxins. Binders themselves in no way stop or mitigate fungal toxins from causing damage.

By comparison, through their impacting everything from fertility to the mRNA-to-protein transcription process to intestinal inflammation levels, mycotoxins challenge us with a myriad diversity of causation mechanisms –and more are being discovered all the time.
Wulf-Dieter Moll, Research Team Leader Molecular Biology at the BIOMIN Research Center, Moll provides a fascinating insight into the relationship between perverse fungal toxin biochemistry and the protein economy. According to Moll, "When I asked myself 'what do mycotoxins have to do with the protein economy?' I realized that some mycotoxins are right at its heart. Deoxynivalenol inhibits transcription within the eukaryotic ribosome responsible for producing proteins."

–Like a large object stuck in a drain pipe, a DON molecule blocks the ribosome pathway that assembles organic molecules into protein –and literally jams nature's protein synthesis assembly line. Moll adds that, "Aflatoxin has a similar blocking effect on mRNA's template, interfering with [protein] transcription."
Through such perverse biochemistry, mycotoxins create microcosmic links between the microscopic worlds of nanometer level biochemistry and vital macroeconomic details like carcass weight. Moll concludes that, "Mycotoxins are literally putting a spanner in the middle of the protein economy and even protein synthesis itself."
But this is hardly the only molecular causation route or the worse damage mycotoxins do. The harm they do is mostly invisible and in many cases, makes us mistake by-product livestock health diseases as actual problems, rather than underlying symptoms.
Such a causation route is outlined by Todd Applegate, University of Georgia's poultry science department head. He states that FUM increases the incidence of diseases like necrotic enteritis by damaging the integrity of the gastrointestinal tract's cellular barrier –but in doing so, it also boosts immune system response, which in turn leads to inflammation. The latter of course, is implicated in a wide variety of other livestock diseases and even human health conditions.

Mycotoxin-induced gastrointestinal inflammation also points to a challenge for the emerging nature-based, antibiotic-free means of raising farm animals: According to Theo A. Niewold, professor of Bioscience Engineering at Belgium's Katholieke Universiteit Leuven, antibiotic growth promoters (AGPs) boost livestock growth not through their antimicrobial properties but because they reduce gastrointestinal inflammation.
Noting that, "there is a tradeoff between immune system activity and growth", Niewold notes that inflammation is merely a symptom of the former, and can lead to a 30% reduction in animal protein mass. Niewold states by keeping both inflammation and mycotoxin-induced pathogens in check, AGPs kept mycotoxins from reducing livestock growth as much as they otherwise would have. It also explains why in countries like China (which have high corn mycotoxin levels) find it more difficult to maintain animal performance when antibiotics are removed from feed.
Niewold's conclusions are supported by those of Jae Cheol Kim, professor at Murdoch University's School of Veterinary and Life Sciences. In his studies, which compared stressed and unstressed pigs, swine undergoing continual immune system challenges, "Showed reduced body protein deposition by 26% to 28%".  By reducing immune system induced inflammation, AGPs essentially 'hid' the damage and symptoms that would otherwise be caused by the presence of mycotoxins.
Consequently, with AGP use being reduced, either natural substances with similar anti-inflammatory properties must be found or the background mycotoxin levels must be reduced. Needless to say, not every AGP has a natural equivalent with similar anti-inflammatory effects. This implies that to maintain high animal performance levels without recourse to AGPs or equivalent natural supplements, new means of reducing background mycotoxin levels must be developed.
Whether it is by blocking ribosome protein, damaging intestinal cell wall integrity or switching DNA gene sequences 'on' or 'off', mycotoxins use numerous, subtle biochemical causation routes to create an entire array of symptoms, ranging from poor livestock growth to compromised animal immunity, infertility to cancer. Indeed, before mycotoxin biochemistry was understood, problems such as outbreaks of various diseases or miscarriages were treated as problems to be overcome, when they were merely symptoms of mycotoxin animal poisoning.
But there is nothing to be gained in treating diseases and conditions which, while severe in themselves, are merely indicators of fungal toxin-induced damage, as each mycotoxin class impacts livestock performance in fundamentally different ways than the others. At this time, the only commonality may be the genetic and biomolecular engineering that will be required to create antidotes.
In some cases, rather than merely poisoning the cell environment or its biochemistry, mycotoxins degrade animal performance by disrupting the cellular machinery responsible for protein synthesis. Depending on the cellular organ, RNA or DNA sequence being disrupted, this manifests itself in an almost countless variety of ways.
But having said that, considerable progress is being made. While the fruits of today's research are still years away, the past two decades have seen great strides being made in not only understanding how mycotoxins work, but also towards engineering longrun solutions to them.
Speaking at BIOMIN's 2016 World Nutrition Forum at Vancouver, Canada, Christopher Elliot, chair of food safety and microbiology at Queens University in Belfast, Ireland, opined that the most brilliant methods of controlling mycotoxins lie literally below our feet. While he notes that, "there is a great shortage of information that describes how mycotoxins work", bacteria have lived with mycotoxins for billions of years –and cracked their biochemical weaknesses long before humans ever existed.
According to Elliot, "In a gram of soil you will find 107 different bacterial genomes. Each bacterial species contains genetic sequences dedicated to neutralizing the mycotoxins found in their host environments." This implies that innovative enzymatic mycotoxin degradation methods are literally beneath our feet, manufacturing enzymes that literally rip apart key molecular structures and rendering them harmless. He concluded that, "One of the great innovations in mycotoxin control is not to bind them but find ways to degrade them."
But while research is continually uncovering new mycotoxin disarming enzymes used by microbes, industrial scale mass production is required before we leverage use this knowledge to improve livestock performance –and that is still quite some time away.
Having provided mechanisms by which they compromise animal performance, Moll outlined a road map for producing enzymatic mycotoxin solutions. According to Moll, it entails, "Cloning the [bacterial] gene for a newly discovered enzyme that can catabolize a particular fungi's mycotoxin." This step will entail inserting the genetic sequence in question into yeast or similarly suited microbial species.
Thereafter, we must, "Develop a fermentation process, then build it out to a large scale for mass production. Then repeating the entire process for all the other known mycotoxins." –These two simple sounding steps will require investments in R&D, genetic engineering and enzyme manufacturing capacity for every known mycotoxin known amounting to billions of dollars. 
Although BIOMIN has the distinction of creating the first enzyme-based mycotoxin solution, Moll notes that, "We have a long way to go before we can make enzymatic solutions for [all] mycotoxins".
In conclusion, our ever-growing mountain of insights into mycotoxin biochemistry is changing the way we approach livestock health issues. We now know that many regional outbreaks of livestock diseases, infertility, etc. are symptomatic of the fungal species common to the geographic area, especially if the region's feed crops recently had a wet growing season or early frost. On a more hopeful note, we now understand that the some of the productivity losses arising from banning AGPs can be regained by reducing livestock exposure to mycotoxins.
While it will take decades to map existing bacterial genetic solutions to mycotoxins and subsequently build mass enzyme manufacturing capacity, we at least now have a road map for profoundly improving animal performance in the first half of the 21st century.

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