Propionic acid use in agriculture and food production is driving evolution of novel Escherichia coli pathotypes

丙酸在农业和食品生产中的使用正在推动新型大肠杆菌致病型的进化

• 批准号: BB/P003281/1
• 负责人: Daniel Wall
• 金额: $ 48.57万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP003281%2F1
• 关键词: Propionic; acid; use; agriculture; food

Emerging multidrug resistant strains of bacteria have forced both the agricultural and food production industries to rethink the use of antibiotics as a means of preventing both food spoilage and transmission of pathogens into the food chain. Alternative anti-microbial compounds are increasingly used such as short chain fatty acids (SCFA), commonly found in the colon but with anti-microbial properties. SCFA production and use has increased greatly in the past 40 years, particularly in the Western world, with the production of one such SCFA, propionic acid (PA), now worth approximately £1.2 billion per year and rising. PA efficacy and low cost allows farmers to treat grain and animal feed while reducing antibiotic use, resulting in PA being proposed as a solution in developing countries to antibiotic overuse. PA has proven highly successful in poultry production where through feed and water addition it has reduced carriage of Salmonella and Campylobacter, common causes of food borne sickness in the UK. PA has also proved highly popular as it is non-toxic to humans with few, if any, side effects. PA therefore can be added to foodstuffs including cakes, bread and preserves at up to 1% total weight of the food. The Western diet now contains increasing levels of food additives whose addition while prolonging the shelf life of food and reducing food borne disease, has also coincided with worrying increases in the prevalence of debilitating gut diseases. Inflammatory bowel diseases such as Crohn's Disease (CD) and ulcerative colitis (UC) while linked to underlying genetic conditions are exacerbated by dietary and other factors, such as bacteria in the intestine. A definitive explanation to link these genetic, dietary and microbial factors together has to date proved elusive. In this proposal we will show that PA is facilitating the transfer of pathogenic E. coli that are exposed to PA in poultry, to the PA rich environment of the human intestine. Adherent and invasive E. coli (AIEC) are consistently isolated from the intestine of CD sufferers. These bacteria are unusual in that they lack toxins or other factors that would set them apart as pathogens. However unlike most other bacteria AIEC can grow and survive on the preservative PA which in time induces significant changes in the behaviour of AIEC. These PA induced changes include increased invasion of cells of the intestine, persistence within these cells and an ability to form structures called biofilms that enable the bacteria to resist antibiotics at higher concentrations and for longer. When this adaptation to PA in the lab is looked at from an agricultural perspective it can be seen that if AIEC were to encounter PA in the environment it would prepare or adapt them to the human intestine where levels of PA are high and restrictive for most pathogens, particular in the lower intestine or colon. However, AIEC establish infection throughout the human intestine, even in places where Salmonella and Campylobacter cannot. AIEC therefore appear well adapted to PA begging the question of how and where this adaptation occurred. Significantly AIEC are thought to be related to pathogens called avian pathogenic E. coli (APEC) that are found in birds such as chickens. These APECs are increasingly being recognized as causative agents of human disease with E. coli isolated from infections throughout the body, including the urinary tract and meningitis, bearing striking similarities to APECs. This proposal will seek to establish if high levels of PA use in the poultry industry and elsewhere is contributing to the evolution of pathogens that are now capable of causing disease in the human intestine. This proposal will for the first time show a definitive link between Crohn's Disease, the Western diet and AIEC, and identify propionic acid as being a facilitator in driving this relationship.

新兴的多药细菌抗菌菌株迫使农业和食品生产行业重新考虑使用抗生素，以防止食物变质和病原体传播到食物链中。越来越多地使用了替代性抗微生物化合物，例如在结肠中通常发现但具有抗微生物特性的短链脂肪酸（SCFA）。在过去的40年中，SCFA的生产和使用量大大增加，尤其是在西方世界，其中一种这样的SCFA，丙酸（PA）的生产，现在每年价值约12亿英镑，增长约12亿英镑。 PA效率和低成本使农民可以在减少抗生素使用的同时治疗谷物和动物饲料，从而在发展中国家抗生素过度使用中提出PA作为解决方案。 PA已被证明在家禽生产中取得了很大的成功，通过饲料和供水，它减少了沙门氏菌和弯曲杆菌的携带者，这是英国食品出生疾病的常见原因。事实证明，PA也非常受欢迎，因为它对副作用很少（如果有的话）无毒。因此，可以将PA添加到食品，包括蛋糕，面包和蜜饯，最多可容纳1％的食物。现在，西方饮食含有越来越多的食物添加剂，在延长食物的保质期和减少食物传播疾病的同时，还引起了人们担心的衰弱肠道疾病的兴趣的担忧。饮食和其他因素（例如肠中的细菌）加剧了炎症性肠病，例如克罗恩病（CD）（CD）和溃疡性结肠炎（UC）。将这些遗传，饮食和微生物因素联系在一起的明确解释已证明是难以捉摸的。在此提案中，我们将表明PA正在促进在家禽中暴露于PA，人类肠道中富含PA的环境的病原大肠杆菌的转移。粘附和侵入性的大肠杆菌（AIEC）始终与CD患者的肠道肠道隔离。这些细菌是不寻常的，因为它们缺乏毒素或其他将它们作为病原体脱颖而出的因素。但是，与大多数其他细菌不同，AIEC可以在防腐剂PA上生长和生存，而PA会及时引起AIC行为的显着变化。这些PA诱导的变化包括增加肠道细胞的侵袭，这些细胞内的持久性以及形成称为生物膜的结构的能力，使细菌能够在较高浓度和更长的时间内抵抗抗生素。当从农业的角度看待对实验室中PA的适应性，可以看出，如果AIEC在环境中遇到PA，它将准备或使其适应人类肠道，在大多数病原体中，PA的水平很高，尤其是在较低的肠或结肠中。但是，即使在沙门氏菌和弯曲杆菌不能的地方，AIEC在整个人类肠道中的建立感染也是如此。因此，AIEC似乎很好地适应了PA，开始了这种适应的方法和地点的问题。明显地，人们认为AIEC与在鸡（例如鸡）中发现的称为禽致病大肠杆菌（APEC）的病原体有关。这些APEC越来越被认为是人类疾病的严重药物，大肠杆菌从整个体内的感染中分离出来，包括尿路和脑膜炎，与APEC具有惊人的相似性。该提案将寻求确定在家禽行业和其他地方的大量PA使用是否有助于病原体的进化，这些病原体现在能够在人类肠道中引起疾病​​。该提议将首次显示克罗恩病，西方饮食和AIEC之间的明确联系，并确定丙酸是推动这种关系的促进者。

项目成果

Mapping the influence of the gut microbiota on small molecules in the brain through mass spectrometry imaging

• DOI: 10.1101/2020.03.13.987164
• 发表时间: 2020-03
• 期刊: bioRxiv
• 作者: Heather Hulme;Lynsey M. Meikle;Nicole Strittmatter;J. Swales;G. Hamm;S. Brown;S. Milling;A. MacDonald;R. Goodwin;R. Burchmore;D. Wall

Mapping the Influence of the Gut Microbiota on Small Molecules across the Microbiome Gut Brain Axis.

• DOI: 10.1021/jasms.1c00298
• 发表时间: 2022-04-06
• 期刊: JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
• 影响因子: 3.2
• 作者: Hulme, Heather;Meikle, Lynsey M.;Strittmatter, Nicole;Swales, John;Hamm, Gregory;Brown, Sheila L.;Milling, Simon;MacDonald, Andrew S.;Goodwin, Richard J. A.;Burchmore, Richard;Wall, Daniel M.
• 通讯作者: Wall, Daniel M.

SipA Activation of Caspase-3 Is a Decisive Mediator of Host Cell Survival at Early Stages of Salmonella enterica Serovar Typhimurium Infection.

SipA 激活 Caspase-3 是肠沙门氏菌鼠伤寒血清型感染早期宿主细胞存活的决定性介质。

• DOI: 10.1128/iai.00393-17
• 发表时间: 2017-09
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: McIntosh A;Meikle LM;Ormsby MJ;McCormick BA;Christie JM;Brewer JM;Roberts M;Wall DM
• 通讯作者: Wall DM

Monocytes mediate Salmonella Typhimurium-induced tumor growth inhibition in a mouse melanoma model.

• DOI: 10.1002/eji.202048913
• 发表时间: 2021-12
• 期刊: European journal of immunology
• 影响因子: 5.4

Draft Genome Sequence of the Tumor-Targeting Salmonella enterica Serovar Typhimurium Strain SL7207.

• DOI: 10.1128/genomea.01591-16
• 发表时间: 2017-02-02
• 期刊: Genome announcements
• 作者: Johnson SA;Ormsby MJ;Wall DM
• 通讯作者: Wall DM