The developing gut microbiota and immune system: Iron and zinc - friend or foe?

发育中的肠道微生物群和免疫系统：铁和锌——朋友还是敌人？

• 批准号: 2604618
• 金额: --
• 依托单位: University of Reading
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2604618
• 关键词: developing; gut; microbiota; immune; system

Under normal conditions, the pre-weaned gut is largely iron-free since breastmilk contains only limited iron. However, the sudden introduction of oral iron at weaning generates an iron-rich gut environment. This promotes the growth of pathogenic microbial populations in the gut with high-iron requirements whilst disadvantaging beneficial bacteria that have low-iron requirements. This is likely to skew the pattern of microbial colonisation of the gut during a critical phase of development. Since gut microbes are the primary drivers of immune development, changes to these populations during early life is likely to change how the immune system develops and combats infectious disease. We do not have clear understanding of how luminal iron availability affects microbiota development, or subsequent immunity.To reduce pathogen-induced infant diarrhoea in low-income countries, diets are often supplemented with high levels of zinc oxide (ZnO). This is because it has antimicrobial properties leading to reductions in pathogen growth and colonisation of the gut. However, since genes encoding antibiotic resistance and genes encoding zinc resistance often occur on the same plasmids, ZnO could actively promote the generation of antibiotic resistant microbes by selecting for these plasmids. The mechanisms of ZnO actions are unknown making it difficult to develop alternatives which do not promote antibiotic resistance.We hypothesis that ZnO reduces enteric infection during infancy by inhibiting microbial iron uptake and reducing pathogenic expansion and virulence in the gut. Low-iron diets could reduce enteropathogen growth and thus negate the need for ZnO. Piglets are valuable models for nutrition studies since they share many characteristics of gut physiology, immunity, microbiota and diet with humans. Specific to this study, piglets are born with very low iron reserves and quickly develop iron deficiency anaemia. This means iron levels can be tightly controlled making piglets valuable models to study the negative effects of oral iron supplementation.The aim of this study is to determine whether limiting luminal iron during infancy reduces enteropathogenic growth and therefore provides a simple, yet effective, alternative to ZnO, thus reducing levels of antibiotic resistant microbes in the gut. It will also explore whether patterns of both microbiota and immune development return to normal in the absence of iron and zinc using a piglet model for human infants. It then explores alternative methods of iron supplementation which do not flood the gut with iron during a critical phase of development for both the gut microbiota and immune system.

在正常情况下，断奶前的肠道基本上不含铁，因为母乳中只含有有限的铁。然而，在断奶时突然引入口服铁会产生一个富含铁的肠道环境。这促进了肠道中高铁需求的致病微生物种群的生长，同时不利于低铁需求的有益细菌。在发育的关键阶段，这可能会扭曲肠道微生物定植的模式。由于肠道微生物是免疫系统发育的主要驱动因素，生命早期这些群体的变化可能会改变免疫系统的发育和对抗传染病的方式。我们对肠道铁的可用性如何影响微生物群的发育或随后的免疫尚不清楚。在低收入国家，为了减少由病原体引起的婴儿腹泻，通常在饮食中补充高水平的氧化锌（ZnO）。这是因为它具有抗菌特性，可以减少病原体的生长和肠道定植。然而，由于编码耐药基因和编码耐锌基因经常出现在同一质粒上，ZnO可以通过选择这些质粒积极促进耐药微生物的产生。氧化锌的作用机制尚不清楚，因此很难开发出不促进抗生素耐药性的替代品。我们假设氧化锌通过抑制微生物铁摄取和降低肠道致病性扩张和毒力来减少婴儿期肠道感染。低铁饲粮可以减少肠道病原菌的生长，从而减少对氧化锌的需求。仔猪是有价值的营养研究模型，因为它们在肠道生理、免疫、微生物群和饮食方面与人类有许多共同的特点。具体到本研究，仔猪出生时铁储量非常低，并迅速发展为缺铁性贫血。这意味着可以严格控制铁水平，使仔猪成为研究口服补铁负面影响的有价值的模型。本研究的目的是确定婴儿期限制肠道铁是否会减少肠道致病性生长，从而提供一种简单而有效的氧化锌替代品，从而降低肠道中抗生素耐药微生物的水平。它还将探索在缺乏铁和锌的情况下，使用人类婴儿的仔猪模型，微生物群和免疫发育模式是否会恢复正常。然后，它探索了在肠道微生物群和免疫系统发育的关键阶段不会使肠道充斥铁的补充铁的替代方法。