基于宏基因组学研究艾滋病患者肠道菌群动态变化对疾病进程的影响

HIV-1 infection causes microbial translocation through damaging the gastrointestinal mucosal surface of the host,which affects HIV progression.Intestinal flora plays an important role in maintaining normal intestinal function.Currently,research in the field has been focused on microbial translocation following HIV infection and its effect, however,little attention has been paid on microbial community during disease progression.Our previous study identified significant changes in intestinal microbial community in AIDS patients.Additionally,using metagenomics-based methods,we detected intestinal microbial community changes in Chinese rhesus monkeys infected by SIVmac239. As of today,it is unclear whether or not the structural and functional changes in intestinal microbial community are associated with HIV disease progression.Facing the crisis of high AIDS occurrence rate in Yunnan province, in this proposed work,we will study the association between intestinal metagenomic structure and the disease process among AIDS patients by using the next-generation sequencing technology and metagenomic analysis methods,search for the core microbiome that affect AIDS disease progression,compare the difference of structure and function of microbial community between AIDS patients and healthy individuals in different stages of disease progression,construct microbial-occurrence network, analyze the effect of intestinal microflora on the disease progression and reveal interaction patterns of core microbiome.This study will provide theoretical and practical basis for developing interventional measures that slow HIV disease progression and designing novel biological therapeutic methods based on microbial community.

HIV-1感染可破坏宿主肠粘膜屏障，引发肠道菌群移位，从而影响艾滋病疾病进程。肠道菌群对肠道正常功能具有重要作用，目前研究关注于菌群移位对疾病进程的影响，忽略对肠道菌群本身的研究。课题组前期研究发现艾滋病患者肠道微生态结构显著改变，并应用宏基因组学方法发现感染SIVmac239的中国猕猴肠道移位菌群的变化。肠道菌群结构和功能变化是否与细菌移位及疾病进程有关目前尚不明确。本项目针对云南AIDS患者众多的现状，采用第二代测序方法和宏基因组学理论，研究艾滋病患者肠道菌群结构与疾病进程的相关性；鉴定影响疾病进程的核心菌属；比较不同疾病期艾滋病患者与正常人群肠道菌群结构和功能的异同；构建肠道菌群共变异网络；分析肠道菌群变异对疾病进程的影响。揭示核心菌属间的相互作用模式。为延缓艾滋病患者疾病进程并研发基于肠道菌群为主要干预手段的新型生物治疗方法提供理论依据和实践基础。

HIV-1感染可破坏宿主肠粘膜屏障，引发肠道菌群移位，从而影响艾滋病疾病进程。肠道菌群对肠道正常功能具有重要作用，而肠道菌群结构和功能变化是否与细菌移位及疾病进程有关目前尚不明确。本项目对20例健康自愿者、27例HIV-1感染者和29例AIDS患者及其跟踪者的肠道微生物进行16S rDNA测序，研究艾滋病患者肠道菌群动态变化对疾病进程的影响。主要包括（1）门水平上，随着艾滋病疾病的发生发展，Bacteroidetes的丰度逐渐减少、Firmicutes和变形菌门Proteobacteria的丰度逐渐增加；（2）属水平核心菌群分析显示，HIV感染组核心菌59个属、AIDS组115个属、AIDS跟踪组109个属、健康对照组47个属；所有组共有肠道核心菌16个属；（3）差异显著性分析显示种水平上，G. formicilis、R. inulinivorans、F. prausnitzii和D. succinatiphilus菌可能是影响艾滋病发生发展的driver bacteria；（4）基因功能预测，Global and overview maps、Membrane transport、Cell motility和 Substance dependence代谢途径在艾滋病组中的丰度显著高于HIV感染组，而Membrane transport、Infectious diseases:Viral和Cardiovascular diseases在艾滋病组的丰度显著高于健康组；（5）种水平菌与移位marker的相关性分析显示，E. fergusonii、A. putredinis、M. micronuciformis、P.copri、和D. succinatiphilus的增加可能推动了疾病的发展，而提高A. sp.FB24、B. stercoris和F. prausnitzi的相对丰度可能有利于延缓疾病进展。.本项目通过对艾滋病疾病进程中肠道微生物群落结构的研究，比较不同疾病期艾滋病患者与正常人群肠道菌群结构和功能的异同，发现艾滋病患者肠道菌群结构严重失调同时也造成肠道微生物基因功能的紊乱；项目构建了肠道菌群共变异网络，分析不同疾病期肠道菌群变异对疾病进程的影响，鉴定了影响疾病进程的核心菌属，这些菌可作为潜在的靶向干预艾滋病患肠道菌。