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，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增长，而对低铁需求的有益细菌不利。这可能会在发育的关键阶段扭曲肠道微生物定植的模式。由于肠道微生物是免疫发展的主要驱动力，这些群体在生命早期的变化可能会改变免疫系统发展和抗击传染病的方式。我们还不清楚铁的供应如何影响微生物区系的发育或随后的免疫。在低收入国家，为了减少病原体引起的婴儿腹泻，饮食中经常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的定植。然而，由于编码抗生素抗性的基因和编码锌抗性的基因往往出现在同一质粒上，因此，氧化锌可以通过选择这些质粒来积极地促进抗生素耐药微生物的产生。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对铁的摄取，减少肠道内的病原扩张和毒力，从而减少婴儿时期的肠道感染。低铁饮食可以减少肠道病原体的生长，从而消除了对氧化锌的需求。仔猪与人类有许多共同的肠道生理、免疫、微生物区系和饮食特征，是营养研究的有价值的模型。具体到这项研究，小猪出生时铁储备非常低，很快就会患上缺铁性贫血。这意味着铁水平可以得到严格控制，使仔猪成为研究口服铁补充剂负面影响的宝贵模型。这项研究的目的是确定在婴儿时期限制鲁米铁是否会减少肠道致病生长，从而提供一种简单但有效的氧化锌替代品，从而减少肠道中耐抗生素微生物的水平。它还将使用人类婴儿的仔猪模型，探索在缺乏铁和锌的情况下，微生物区系和免疫发育模式是否恢复正常。然后，它探索了补充铁的替代方法，这种方法不会在肠道微生物区系和免疫系统的关键发育阶段充斥肠道中的铁。

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.