肠道菌群与宿主基因互作影响猪瘦肉率的机制研究

People are always favorable for the lean meat because excess fat consumption will not be benefit for human health. Increasing the percentage of porcine lean meat is one of the main objectives in the pig production industry. Besides genetics, environmental factors, e.g. feeding also play important roles in porcine lean meat production. Recent years, more and more studies have illustrated that gut microbiome is significantly associated with host fat deposition. In our previous study, we also observed that gut microbiota significantly influences porcine backfat thickness and lean meat percentage in a large scale of Duroc population. Based on this knowledge, in this project, we will firstly validate the association of gut microbiota with lean meat percentage in 300 Duroc pigs with the detailed and accurate phenotype records. And then, metagenomic sequencing of gut microbiota will be performed to identify the bacterial strains, functional genes and metabolic pathways significantly associated with porcine lean meat percentage. The causality of the isolated bacterial strains with lean meat percentage will be confirmed by the specific pathogen free (SPF) pigs. We will determine porcine serum metabolites and compare the composition and abundances of serum metabolites between pigs with extremely high and low lean meat percentage. Furthermore, the correlations among gut microbiome, serum metabolites and host lean meat percentage will be constructed. We will also compare the differential gene expression levels in cecum, colon, adipose and muscle between pigs with extremely high and low lean meat percentage. Combining the data of serum metabolites and host gene expressions in multiple tissues, we will finally elucidate the mechanism of gut microbiome affecting porcine lean meat percentage through interaction with host genes.

日常生活中人们更喜欢瘦肉，因为过多的脂肪摄取对人体健康有害。改善瘦肉率是猪育种的重要目标之一。除遗传因素外，饲养等环境因素等对猪瘦肉率具有重要影响。近年来，越来越多的研究表明肠道微生物与宿主脂肪沉积相关。本研究前期在大规模杜洛克群体中已初步发现，肠道微生物影响猪背膘厚和瘦肉率。在此基础上，本项目将首先利用300头有精准表型记录的杜洛克猪群体，验证肠道菌群对猪瘦肉率的影响，然后利用宏基因组测序，鉴别与瘦肉率相关的菌株和宏基因组功能基因及代谢通路，并用特定菌群缺失猪验证菌株与瘦肉率的因果关系。测定和比较高、低瘦肉率个体间血液代谢组差异，建立肠道菌群、血液代谢组和瘦肉率间的关系。分析比较高、低瘦肉率猪盲肠、结肠、脂肪和肌肉组织基因表达差异，结合血液代谢组和宿主基因表达数据，阐明肠道菌群与宿主互作影响猪瘦肉率的分子机制，为通过调控肠道菌群提高猪瘦肉率奠定基础。

课题组首先利用16S rRNA基因V3-V4高突变区测序，在698头商业杜洛克猪中系统地研究了肠道微生物组与猪瘦肉率（LMP）的相关性，发现P. copri与猪脂肪沉积密切相关，肥猪肠道中的P. copri丰度显著较高。然后利用宏基因组测序，进一步确定P. copri是导致猪脂肪沉积、降低瘦肉率的关键菌。同时鉴别到与猪LMP相关的CAZymes和宏基因组KEGG功能通路。测定了验证群体38个血清样品的血液代谢组，并鉴别到与脂肪沉积显著相关的代谢物及其与脂肪沉积相关菌种的关联性，发现高丰度的P. copri导致与肥胖相关的血清代谢物，如脂多糖、支链氨基酸、芳香族氨基酸和花生四烯酸的代谢产物浓度显著增加，宿主肠道屏障通透性和慢性炎症反应也增加。课题组从实验猪群体中分离培养了P. copri菌株，使用无菌小鼠进行分离菌株的灌胃实验，证实分离的P. copri是一种增加宿主脂肪沉积和改变血清代谢物的因果菌株。P. copri灌胃小鼠的结肠、脂肪组织和肌肉转录组分析表明，P. copri定殖产生的代谢产物脂多糖、支链氨基酸等通过TLR4和mTOR信号通路激活宿主慢性炎症反应，显著上调与脂肪生成和脂肪沉积相关的基因表达，但降低与脂肪分解、脂质转运和肌肉生长相关的基因表达，从而显著增加宿主脂肪沉积、降低瘦肉率。研究结果为通过调节肠道微生物组成来减少猪脂肪沉积提供了重要的参考数据，具有重要的应用前景。项目执行期间在《Microbiome》、《Frontiers in Microbiology》等SCI刊物发表论文4篇，其中第一标注2篇，第二标注2篇。培养博士研究生5人，毕业2人。