Abstract
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 Collinsella, 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.IMPORTANCE 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.
Highlights
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
To determine the impact of variation in the gut microbiota on host cells, we treated human colonic epithelial cells (HCoEpiC) with live gut microbiota extracted from 5 healthy, unrelated human individuals (Fig. 1A; see Fig. S1A to D in the supplemental material)
We identified 669 transcripts (188 genes) that were differentially expressed in all five treatments following 2 h of treatment (Fig. 1C; see 1-h and 4-h comparisons in Fig. S1F and G)
Summary
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. 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. We exposed the colonocytes to live gut microbiotas derived from human fecal samples under hypoxic conditions and measured the levels of response of host cells via transcriptome sequencing (RNA-seq) Using this technique, we identified differentially expressed (DE) genes that were enriched among genes associated with microbiomerelated diseases, such as obesity [27, 39], and among genes that were differentially expressed in germ-free mice exposed to gut microbiota [28]. These open issues are crucial for understanding the causal role of the microbiome in host physiology and for designing targeted therapies revolving around interventions in the gut microbiome
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