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

随着窝产仔数的增加，窝产仔中约有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，断奶前仔猪的总体死亡率高达35%。这在道德上是不可接受的，而且效率极低。仔猪LBW和IUGR与出生后生长减慢、肠道大小和成熟度降低、肠道屏障功能和粘膜免疫功能受损有关。研究表明，肠道通透性增加与线粒体功能低下有关。初乳和乳汁的摄入和组成对哺乳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影响宿主线粒体能量代谢。与正常体重仔猪相比，低体重仔猪和/或IUGR仔猪能量储备较低，出生后立即摄入初乳的时间较晚，因此，为仔猪量身定制营养解决方案可能是优化肠道健康和发育的一种手段。谷氨酰胺（GLN）是一种肠道友好型营养物质，在仔猪断奶前或断奶后给予谷氨酰胺可促进肠道和全身生长发育，防止肠道氧化损伤和炎症。因此，在提供乳汁的基础上，额外摄入GLN可能会产生有益的影响，这在生命的这一阶段尤其对IUGR仔猪特别有用。有证据表明，饲粮中添加额外的谷氨酰胺可能有利于哺乳仔猪的肠道发育和线粒体功能。然而，添加GLN与哺乳仔猪肠道微生物群及其代谢物和宿主线粒体之间是否存在相互作用并对肠道功能起作用，目前尚不清楚。拟议合作研究的目标是调查生命早期补充GLN是否对肠道有有益的影响。此外，我们旨在了解肠道上皮及其线粒体与微生物群的急性和长期（断奶后）相互作用。因此，我们将在功能和分子水平上描述肠上皮（线粒体特征、增殖、局部防御机制、氨基酸和谷胱甘肽代谢）和微生物组组成及其代谢活性。在总体评估中，我们将确定解释变异的成分，并描述肠道线粒体转录组和微生物群、线粒体和肠道性状复合物、微生物群和肠道性状复合物以及GLN代谢之间的关系。我们希望阐明这些相互作用如何与新生仔猪的发育和健康相关。

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.