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

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富含铁的肠道环境。这促进了肠道中具有高铁需求的致病微生物种群的生长，同时消除了具有低铁需求的有益细菌。这可能会在发育的关键阶段扭曲肠道微生物定殖的模式。由于肠道微生物是免疫发育的主要驱动力，因此这些群体在生命早期的变化可能会改变免疫系统发育和对抗传染病的方式。我们还没有清楚地了解管腔铁的可用性如何影响微生物群的发育，或随后的免疫力。为了减少低收入国家病原体引起的婴儿腹泻，饮食中通常补充高水平的氧化锌（ZnO）。这是因为它具有抗菌特性，导致减少病原体生长和肠道定植。然而，由于编码抗生素抗性的基因和编码锌抗性的基因通常发生在相同的质粒上，ZnO可以通过选择这些质粒来积极促进抗生素抗性微生物的产生。氧化锌的作用机制是未知的，很难开发替代品，不促进抗生素resistance.We假设，氧化锌减少肠道感染在婴儿期通过抑制微生物铁的吸收，减少肠道病原体的扩张和毒力。低铁饮食可以减少肠道病原体的生长，从而否定了对ZnO的需要。仔猪是营养学研究的重要模型，因为它们与人类在肠道生理学、免疫力、微生物群和饮食方面具有许多共同特征。具体到这项研究，仔猪出生时铁储备非常低，并迅速发展缺铁性贫血。这意味着铁水平可以严格控制，使仔猪成为研究口服铁补充剂负面影响的有价值模型。本研究的目的是确定婴儿期限制管腔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ZnO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，微生物群和免疫发育的模式是否会恢复正常，使用人类婴儿的仔猪模型。然后，它探索了补充铁的替代方法，这些方法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满铁。

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.