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）是一种高效的治疗干预手段，但其临床作用模式与潜在的微生物组动态变化机制仍未得到充分阐明。本研究针对5种疾病适应证开展了基于时间序列的荟萃研究，共分析了142例FMT相关的宏基因组数据。研究基于1089种微生物的泛基因组，对其菌株水平的动态变化进行了定量分析，并补充了47548条新构建的宏基因组组装基因组（metagenome-assembled genomes）。本研究利用操作相关、宿主相关及微生物组相关变量的子集，构建LASSO正则化回归模型，可精准预测供体与受体微生物的定植能力、恢复力，以及单个物种的种群更替情况。将上述结果与推定的生态机制相结合后，我们发现这些变量集可有效反映塑造FMT术后肠道微生物组的核心过程。受体因素以及供体与受体微生物组的互补性（涵盖从整体群落到单个菌株的所有层级）是影响单个菌株种群动态的主要决定因素，且该相关性大多不受临床结局的影响。受体微生物群落状态以及残留菌株的耗竭程度，为供体菌株的成功定植提供了中性基准；除此之外，物种与同种菌株间的抑制性优先效应，以及推定的适应性过程也参与其中。本研究结果揭示了若干具有应用前景的可调节参数，可用于在临床实践中增强供体菌群的定植能力或促进受体菌群的置换，从而助力开发更具针对性的个性化治疗方案。