Understanding the impact of neonatal glutamine supplementation on the interaction between gut epithelia, its mitochondria, and microbiota, and its importance for the development in low birthweight piglets

随着饲养规模的增加，一窝中约有10%-20%的仔猪受到低出生体重(LBW)和/或宫内生长受限(IUGR)的影响，断奶前仔猪的总死亡率高达35%。这在道德上是不可接受的，而且效率极低。仔猪LBW和IUGR与出生后生长发育迟缓，肠道体积和成熟度降低，肠道屏障功能和粘膜免疫功能受损有关。已有研究表明，肠道通透性增加与线粒体功能低下有关。初乳和乳汁的摄入量和组成对仔猪早期机体和肠道的生长发育以及微生物群的功能成熟起着重要的刺激和调节作用。微生物组释放的代谢物可能会影响宿主线粒体的能量代谢。与正常体重的小猪相比，LBW和/或IUGR仔猪的能量储备较低，出生后立即获得初乳的时间也较晚，因此，为幼猪量身定做的营养解决方案可能是优化肠道健康和发育的一种手段。一种肠道友好型营养物质可能是谷氨酰胺(Gln)，它可以促进肠道和全身的生长发育，并在断奶前或断奶后不久给仔猪服用，防止肠道氧化损伤和炎症性疾病。因此，在提供乳汁的基础上增加谷氨酰胺摄入量的有益影响，这在生命的这一阶段可能特别有用，特别是在IUGR仔猪中。有提示的证据表明，提供额外的饲料谷氨酰胺可能有益于乳猪的肠道发育和线粒体功能。然而，在哺乳仔猪中，谷氨酰胺是否与肠道微生物区系、其代谢产物和宿主线粒体之间存在相互作用，从而对肠道功能起作用，目前还知之甚少。这项拟议的合作研究的目标是调查早期补充谷氨酰胺是否对肠道有好处。此外，我们的目标是了解肠道上皮及其线粒体与微生物区系的相互作用，并在较长时间内(在断奶后)。因此，我们将在功能和分子水平上描述肠道上皮(线粒体特征、增殖、局部防御机制、氨基酸和谷胱甘肽代谢)以及微生物组组成及其代谢活性。在总体评估中，我们将确定解释肠道线粒体转录组和微生物区系、线粒体和肠道特征复合体、微生物区系和肠道特征复合体以及谷氨酰胺代谢之间差异和关系的组件。我们希望阐明这些相互作用是如何与新生仔猪的发育和健康相关的。

With breeding for increasing litter size, approximately 10-20% of piglets within a litter are affected by low birthweight (LBW) and/or intrauterine growth restriction (IUGR), and the overall pre-weaning piglet mortality is up to 35%. This is ethically unacceptable, and grossly inefficient. Piglet LBW and IUGR are associated to lower postnatal growth, reduced intestinal size and maturity, impaired gut barrier function and mucosal immunity. It has been shown that increased intestinal permeability is associated with poor mitochondrial functions. Intake and composition of colostrum and milk play a major role in the stimulation and regulation of body and intestinal growth and development during early life as well as the functional maturation of the microbiome in suckling piglets. The microbiome releases metabolites that may affect host mitochondrial energy metabolism. In contrast to normal-weight litter mates, LBW and/or IUGR piglets have lower energy reserves and delayed access to colostrum intake immediately after birth, and thus, tailored nutritional solutions for young pigs might be a means to optimize gut health and development. One gut-friendly nutrient might be glutamine (GLN), which can improve intestinal and whole body growth and development, and prevent intestinal oxidative injury and inflammatory disease when given to piglets shortly before or after weaning. Thus a case was made for beneficial effects of additional GLN intake beyond its provision with milk, which might be particularly useful in this phase of life especially in IUGR piglets. There is suggestive evidence that the provision of additional dietary GLN could be beneficial to intestinal development, and mitochondrial function in suckling neonatal pigs. However, whether there is an interaction between GLN supplementation, intestinal microbiota, their metabolites and host mitochondria in suckling piglets which play a role for gut function is still poorly understood. The goal of the proposed collaborative research is to investigate whether early life GLN supplementation impacts the gut in a beneficial way. Moreover, we aim to understand the interaction of gut epithelium and its mitochondria with microbiota acutely and in the longer-term (after weaning). We will thus characterize the intestinal epithelium (mitochondria characteristics, proliferation, local defense mechanisms, amino acid and glutathione metabolism) and the microbiome composition and its metabolic activity at functional and molecular levels. In an overarching evaluation, we will determine components explaining the variation and delineate relationships between intestinal mitochondria transcriptome and microbiota, mitochondrial and intestinal trait complexes, microbiota and intestinal trait complexes, as well as GLN metabolism. We expect to elucidate how these interactions are associated with the development and health of neonatal piglets.