A metabonomic approach to identify biomarkers for bovine mycotoxicosis

真菌毒素是真菌代谢产物，可存在于谷物、谷类、草和保存的饲料中。几个风险因素增加了霉菌毒素和霉菌中毒（因摄入霉菌毒素而引起的动物疾病）的可能性，包括作物开花和收获前的高降雨量，因此2012年等潮湿的夏季导致谷物中的霉菌毒素水平较高。尽管对供人类食用的谷物中霉菌毒素的浓度有强制性的测试和立法限制，但对牲畜饲料没有法律的要求。欧盟指南建议谷物和全价饲料中镰刀菌毒素-脱氧雪腐镰刀菌烯醇和玉米赤霉烯酮的最大限量。这些指南是由于真菌毒素的主要研究领域集中在使用单胃动物模型（如猪和家禽）的谷物真菌毒素（主要是镰刀菌属）。然而，这并不包括广谱真菌毒素，也不适用于反刍动物。最近的研究报告说，稻草中的霉菌毒素浓度可能高于相关的谷物样本。青贮饲料（整株作物（谷物和秸秆）、玉米和草）是奶牛和肉牛的主要饲料来源，是真菌毒素的重要来源，对此研究相对较少。该项目将通过反刍动物模型系统研究来自主要真菌属的更广泛的真菌毒素来填补这一科学知识的空白。由于瘤胃内微生物的多样性，反刍动物可以比单胃动物更好地抵抗真菌毒素的影响，但这种能力可能会在应激时期（例如饮食变化或疾病）受到影响。特别地，向高产奶牛提供饮食（富含淀粉的谷类和谷物），这导致由纤维分解（纤维降解）细菌占据的标准瘤胃微生物区系发生变化，有利于更多的淀粉降解生物体，这最终降低瘤胃的pH。在这一点上，瘤胃解毒真菌毒素的能力大大降低。已经提出了不同物种的指导耐受水平，但这些指导的可靠性尚不清楚。最近在英国进行的一项兽医调查显示，奶牛和肉牛群中真菌中毒的发病率很高（10 - 80%），这与用谷物为基础的口粮喂养时不符合标准的好氧腐败玉米和牧草青贮饲料有关。霉菌中毒的严重程度取决于霉菌毒素的类型、动物健康状况、生产阶段和食用剂量。有些类型直接损害器官（如肝脏，肾脏和瘤胃），而其他类型则损害生殖或导致癌症。身体影响范围从性能损失到死亡。不同的霉菌毒素可以在瘤胃中相互作用，加剧这种影响，有些已知会抑制免疫功能。反刍动物真菌中毒的症状包括食欲不振、产奶量减少或体重增加不佳。由于缺乏特异性症状和其他代谢性疾病（如牛酸中毒）的重叠症状，真菌中毒的早期兽医诊断很困难。这个问题并没有最终导致动物疾病或产量损失，因为产奶动物饲料中的真菌毒素会导致其代谢产物出现在乳制品中，这对人类健康构成风险，特别是对婴儿。因此，需要一种快速早期检测反刍动物真菌中毒的方法。本项目将从患有真菌中毒的动物的尿液、唾液和血浆中产生代谢物谱，用作疾病的生物标志物。这些信息在未来更多的应用项目中可以发展成为兽医的快速诊断工具。作为一个工业合作伙伴奖项目，与动物饲料，生物化学和制药产品相关的主要行业成员已经签约，将该项目的基础科学发展为工业发展，以最大限度地发挥研究的影响。

Mycotoxins are fungal metabolites that can be present on grain, cereals, grass and conserved forage. Several risk factors increase the likelihood of mycotoxins and mycotoxicosis (disease in animals caused by mycotoxin ingestion), including high rainfall at crop flowering and during pre-harvest, hence wet summers such as 2012 result in high mycotoxin levels in grain. Although there is compulsory testing and legislative limits to concentrations of mycotoxins in grain destined for human consumption, there are no legal requirements for livestock feeds. The EU guidelines suggest maximum limits for Fusarium mycotoxins - Deoxynivalenol, and Zearalenone - for grains and complete feeds. These guidelines have been produced as a result of the major research area in mycotoxins concentrating on grain based mycotoxins (mainly Fusarium) using monogastric animal models e.g. pigs and poultry. However, this does not cover the broad spectrum of mycotoxins nor is it applicable to ruminants. Recent research has reported higher concentrations of mycotoxins can occur in straw than the associated grain samples. Silage (whole crop (grain and straw), maize and grass) the main forage source for dairy and beef cattle represents a significant source of mycotoxins, for which there is comparatively little research. This project will address this gap in scientific knowledge by investigating a broader spectrum of mycotoxins from the main fungal genera with a ruminant model system.Due to the resilient microorganism diversity in the rumen, ruminants can withstand the effects of mycotoxins better than monogastrics, but this capacity may be compromised during times of stress (e.g. diet change or disease). In particular high production dairy cows are offered diets (cereals and grains rich in starch) which result in a change in the standard rumen microflora populated by fibrolytic (fibre degrading) bacteria in favour of more starch degrading organism which ultimately reduces the pH of the rumen. At this point the ability of the rumen to detoxify mycotoxins is substantially reduced. Guideline tolerance levels for different species have been proposed, but it is unknown how reliable these guidelines are. A recent veterinary survey in the UK showed a high incidence (10 - 80%) of mycotoxicosis in dairy and beef herds associated with sub-standard aerobically spoiled maize and grass silage when fed with cereal based rations. The severity of mycotoxicosis depends on the mycotoxin type, animal health, stage of production and dose eaten. Some types damage organs directly (e.g. liver, kidney and rumen), whilst others impair reproduction or cause cancer. Physical effects range from performance loss to mortality. Different mycotoxins can interact in the rumen to exacerbate the effect and some are known to suppress immune function. Signs of mycotoxicosis in ruminant animals include loss of appetite, reduced milk yield or poor weight gain. Early veterinary diagnosis of mycotoxicosis is difficult due to a lack of specific symptoms and overlapping symptoms of other metabolic diseases such as acidosis in cattle. The problem does not end in animal disease or production losses as mycotoxins in the feed of dairy animals can lead to their metabolites appearing in dairy products, which pose a risk in human health, particularly for infants. A rapid early detection method of mycotoxicosis for ruminants is therefore required.This project will produce a metabolite profile from urine, saliva and plasma of animals suffering mycotoxicosis to be used as biomarkers of the disease. This information in future more applied projects could be developed into a rapid diagnosis tool for veterinarians. As an industrial partner award project key industry members associated with animal feed, biochemistry and pharmaceutical products have already signed up to develop the basic science from this project into industrial development for maximum impact of the research.