An exclusive metabolic niche enables strain engraftment in the gut microbiota

The dense microbial ecosystem in the gut is intimately connected to numerous facets of human biology, and manipulation of the gut microbiota has broad implications for human health. In the absence of profound perturbation, the bacterial strains that reside within an individual are largely stable over time. In contrast, the fate of exogenous commensal and probiotic strains applied to an established microbiota is variable, largely unpredictable, and greatly influenced by the background microbiota. Therefore, investigation into factors governing strain engraftment and abundance is of critical importance to the emerging field of microbiome reprogramming. Here, we generate an exclusive metabolic niche via administration of a marine polysaccharide, porphyran, and an exogenous Bacteroides strain harboring a rare gene cluster for porphyran utilization. Privileged nutrient access enables reliable engraftment of an exogenous strain at predictable abundances in mice harboring diverse communities of gut microbes. This targeted dietary support is sufficient to overcome priority exclusion by an isogenic strain, and enables strain replacement. We demonstrate transfer of the 60kb porphyran utilization locus into a naïve strain of Bacteroides, and show finely tuned control of strain abundance in the gut across multiple orders of magnitude by varying porphyran dosage. Finally, we show that this system enables introduction of a new strain into the colonic crypt ecosystem. These data highlight the influence of nutrient availability in shaping microbiota membership, expand the ability to perform a broad spectrum of investigations in the context of a complex microbiota, and have implications for cell-based therapeutic strategies in the gut.肠道内致密的微生物生态系统与人类生物学的诸多方面紧密相关，肠道菌群的调控对人类健康具有广泛意义。在无显著扰动的情况下，个体定植的细菌菌株在较长时间内基本保持稳定。与之相反，施加于已成型菌群环境中的外源性共生菌与益生菌菌株的定植结局各不相同，且大多难以预测，同时极大程度受背景菌群的影响。因此，探究调控菌株定植（engraftment）与丰度的关键因素，对于新兴的微生物组重编程（microbiome reprogramming）领域至关重要。 本研究通过施用一种海洋多糖——紫菜多糖（porphyran），以及携带稀有紫菜多糖利用基因簇的外源性拟杆菌（Bacteroides）菌株，构建了专属代谢生态位。这种专属营养供给可使外源性菌株在拥有多样化肠道菌群的小鼠体内，以可预测的丰度实现稳定定植。这种靶向膳食支持足以克服同基因菌株的定植优先权排斥，实现菌株替换。 我们将60kb的紫菜多糖利用基因座转移至一株未携带该功能基因簇的拟杆菌菌株（naïve strain），并通过调整紫菜多糖的给药剂量，实现肠道内菌株丰度跨多个数量级的精细调控。最后，我们证实该系统可将新菌株引入结肠隐窝（colonic crypt）生态系统。 上述数据凸显了营养可用性在塑造菌群组成中的关键作用，拓展了在复杂菌群背景下开展广谱研究的能力，同时为肠道内基于细胞的治疗策略提供了参考依据。