Drivers and Determinants of Strain Dynamics Following Faecal Microbiota Transplantation

Faecal microbiota transplantation (FMT) is an efficacious therapeutic intervention, but its clinical mode of action and underlying microbiome dynamics remain poorly understood. Here, we analysed the metagenomes associated with 142 FMTs, in a time series-based meta-study across five disease indications. We quantified strain-level dynamics of 1,089 microbial species based on their pangenome, complemented with 47,548 newly constructed metagenome-assembled genomes. Using subsets of procedural-, host- and microbiome-based variables, LASSO-regularised regression models accurately predicted the colonisation and resilience of donor and recipient microbes, as well as turnover of individual species. Linking this to putative ecological mechanisms, we found these sets of variables to be informative of the underlying processes that shape the post-FMT gut microbiome. Recipient factors and complementarity of donor and recipient microbiomes, encompassing entire communities to individual strains, were the main determinants of individual strain population dynamics, and mostly independent of clinical outcomes. Recipient community state and the degree of residual strain depletion provided a neutral baseline for donor strain colonisation success, in addition to inhibitive priority effects between species and conspecific strains, as well as putatively adaptive processes. Our results suggest promising tunable parameters to enhance donor flora colonisation or recipient flora displacement in clinical practice, towards the development of more targeted and personalised therapies.粪便微生物群移植（Faecal microbiota transplantation, FMT）是一种有效的治疗干预手段，但其临床作用模式与潜在的微生物组动态机制仍未得到充分阐明。本研究在一项覆盖5种疾病适应症的基于时间序列的荟萃分析中，分析了142例粪便微生物群移植相关的宏基因组。研究基于1089种微生物的泛基因组，量化了它们的菌株水平动态变化，并补充了47548个新构建的宏基因组组装基因组（metagenome-assembled genomes, MAGs）。研究人员利用基于操作流程、宿主及微生物组的变量子集，通过套索正则化回归模型（LASSO-regularised regression models）准确预测了供体与受体微生物的定植能力与存留能力，以及单个物种的群落更替情况。将该模型结果与推定的生态机制相结合后发现，上述变量集可为阐明粪便微生物群移植后肠道微生物组的塑造过程提供有效依据。受体自身因素以及供体与受体微生物组的互补性（覆盖从整个群落到单个菌株的所有层面）是决定单个菌株种群动态的主要因素，且其影响大多独立于临床结局。除物种间与同种菌株间的抑制性优先效应以及推定的适应性过程外，受体群落状态与残余菌株的耗竭程度为供体菌株的成功定植提供了中性基准。本研究结果揭示了若干具有应用前景的可调控参数，有望在临床实践中用于增强供体菌群的定植或受体菌群的置换，从而助力开发更具靶向性与个性化的治疗方案。