Richards Allison L, Muehlbauer Amanda L, Alazizi Adnan, Burns Michael B, Findley Anthony, Messina Francesco, Gould Trevor J, Cascardo Camilla, Pique-Regi Roger, Blekhman Ran, Luca Francesca
Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, USA.
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA.
mSystems. 2019 Sep 3;4(5):e00323-18. doi: 10.1128/mSystems.00323-18.
Variation in gut microbiome is associated with wellness and disease in humans, and yet the molecular mechanisms by which this variation affects the host are not well understood. A likely mechanism is that of changing gene regulation in interfacing host epithelial cells. Here, we treated colonic epithelial cells with live microbiota from five healthy individuals and quantified induced changes in transcriptional regulation and chromatin accessibility in host cells. We identified over 5,000 host genes that change expression, including 588 distinct associations between specific taxa and host genes. The taxa with the strongest influence on gene expression alter the response of genes associated with complex traits. Using ATAC-seq, we showed that a subset of these changes in gene expression are associated with changes in host chromatin accessibility and transcription factor binding induced by exposure to gut microbiota. We then created a manipulated microbial community with titrated doses of , demonstrating that manipulation of the composition of the microbiome under both natural and controlled conditions leads to distinct and predictable gene expression profiles in host cells. Taken together, our results suggest that specific microbes play an important role in regulating expression of individual host genes involved in human complex traits. The ability to fine-tune the expression of host genes by manipulating the microbiome suggests future therapeutic routes. The composition of the gut microbiome has been associated with various aspects of human health, but the mechanism of this interaction is still unclear. We utilized a cellular system to characterize the effect of the microbiome on human gene expression. We showed that some of these changes in expression may be mediated by changes in chromatin accessibility. Furthermore, we validate the role of a specific microbe and show that changes in its abundance can modify the host gene expression response. These results show an important role of gut microbiota in regulating host gene expression and suggest that manipulation of microbiome composition could be useful in future therapies.
肠道微生物群的变化与人类的健康和疾病相关，但这种变化影响宿主的分子机制尚不清楚。一种可能的机制是改变宿主上皮细胞的基因调控。在这里，我们用来自五个健康个体的活微生物群处理结肠上皮细胞，并量化宿主细胞中转录调控和染色质可及性的诱导变化。我们鉴定出超过5000个表达发生变化的宿主基因，包括特定分类群与宿主基因之间588种不同的关联。对基因表达影响最强的分类群改变了与复杂性状相关基因的反应。使用ATAC-seq，我们表明这些基因表达变化的一个子集与暴露于肠道微生物群诱导的宿主染色质可及性和转录因子结合的变化有关。然后，我们用滴定剂量的[具体物质未给出]创建了一个经过操纵的微生物群落，表明在自然和受控条件下对微生物群组成的操纵会导致宿主细胞中不同且可预测的基因表达谱。综上所述，我们的结果表明特定微生物在调节参与人类复杂性状的单个宿主基因的表达中起重要作用。通过操纵微生物群来微调宿主基因表达的能力为未来的治疗途径提供了思路。肠道微生物群的组成与人类健康的各个方面相关，但这种相互作用的机制仍不清楚。我们利用细胞系统来表征微生物群对人类基因表达的影响。我们表明，这些表达变化中的一些可能由染色质可及性的变化介导。此外，我们验证了一种特定微生物的作用，并表明其丰度的变化可以改变宿主基因表达反应。这些结果表明肠道微生物群在调节宿主基因表达中起重要作用，并表明操纵微生物群组成在未来治疗中可能有用。
