The impact of gut microbiome on the innate immune response against enteric coronaviruses

冠状病毒在猪中出现的频率相对较高，最常见的是会导致仔猪出现严重的肠道疾病。导致仔猪腹泻的肠道疾病影响其福利，是农民损失的主要来源，因为死亡率很高，而那些幸存下来的猪在疾病和康复期间的生长往往会减慢。农民经常给小猪服用抗生素，以保护它们免受可能导致腹泻的细菌的伤害，但这并不能保护它们免受肠道疾病的非细菌来源的影响，如病毒，或由抗生素耐药性细菌引起的疾病。有证据表明，生活在动物肠道中的共生微生物--肠道微生物群--在启动免疫系统以更快、更有效地应对病原体方面发挥了作用。幼猪缺乏成熟的肠道微生物群，用抗生素治疗会进一步耗尽它们的微生物群。鉴于微生物群在启动免疫系统对病原体做出反应方面的作用，在接触病原体之前引入能够启动免疫系统的微生物可能会导致对这些病原体的更强大的免疫反应，并导致较轻微的疾病，或者没有疾病，就像成年猪所看到的那样。在挑战传染性胃肠炎病毒(TGEV)之前，我将操纵猪的微生物群来改变肠道中存在的物种的多样性。在整个试验过程中，将对猪进行插管，以便能够接触到它们的回肠微生物群。我将使用尖端技术来了解引入的微生物如何改变肠道微生物群和猪的免疫反应，并确定微生物群中可能有助于免疫反应变化的功能潜力。我将测试细胞和猪器官中的候选细菌，以确定触发体内平衡免疫信号变化并影响对TGEV感染反应的细菌。确定对TGEV有保护作用的候选者也可能对其他肠道冠状病毒具有更广泛的保护作用，并可用作益生菌来保护猪免受疾病的侵袭。总之，这一建议将对肠道微生物群对猪病毒性疾病的影响以及微生物群与免疫系统的相互作用提供重要的见解。这不仅将为理解微生物组在猪对疾病的反应中所起的作用提供关键信息，而且还将使人们能够制定新的策略来抗击病毒、细菌和复杂疾病，特别是在减少抗菌剂使用的同时。

Coronaviruses emerge relatively often in pigs, and most commonly cause severe enteric disease in young pigs. Enteric diseases that cause diarrhea in young pigs impact their welfare and are a major source of loss to farmers as there is a high rate of mortality, and those that survive often have reduced growth for the duration of disease and recovery. Often farmers treat young pigs with antibiotics to protect them from bacteria that can cause diarrhea, however this does not protect them from non-bacterial sources of enteric disease, such as viruses, or from disease caused by antibiotic resistant bacteria. There is evidence that commensal microbes that inhabit the guts of animals, the gut microbiome, play a role in priming the immune system to more quickly and efficiently respond to pathogens. Young pigs lack a mature gut microbiome, and treating them with antibiotics further depletes their microbiomes. Given the microbiome's role in priming the immune system to respond to pathogens, introducing microbes that are capable of priming the immune system prior to exposure to pathogens could lead to a more robust immune response to these pathogens and lead to a milder disease, or no disease, as is seen in adult pigs.I will manipulate the microbiomes of pigs to change the diversity of species present in the gut prior to challenging with Transmissible Gastroenteritis Virus (TGEV). The pigs will be cannulated to allow for access to their ileum microbiome throughout the trial. I will use cutting edge technology to understand how the introduced microbes change the gut microbiome and the pigs' immune responses, and I will identify functional potential in the microbiome that may contribute to changes in the immune response. I will test candidate bacteria in cells and pig organoids to identify bacteria that trigger changes in homeostatic immune signalling and that impact the response to TGEV infection. Identifying candidates that protect against TGEV may also be protective more broadly against other enteric coronaviruses and could be used as probiotics to protect pigs from disease.Overall, this proposal will give important insights into the impact of the gut microbiome on viral diseases of pigs and into microbiome-immune system interactions. This will not only give crucial information on understanding the microbiome's role in pigs' responses to disease but also allow to devise new strategies in combating viral, bacterial, and complex disease, particularly whilst reducing antimicrobial use.