Gut Microbiota Has a Widespread and Modifiable Effect on Host Gene Regulation

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.

Tracing the Anti‐Inflammatory Mechanism/Triggers of d‐Allulose: A Profile Study of Microbiome Composition and mRNA Expression in Diet‐Induced Obese Mice

“…Several studies have reported a correlation between the gene expression profile and microbiome abundance, suggesting the co-expression of genes with differential microbiome composition has a significant effect on trait differences. [34][35][36] Gm12250 has the highest average correlation value, in the four correlation tests we took. Therefore, it is the most probable candidate for interaction between the two genera.…”

Interspecies variation in hominid gut microbiota controls host gene regulation

“…To assess how host genes respond to variation in the microbiome, we extracted live microbiota from 19 fecal samples from four hominid species (4 humans, 3 chimpanzees, 6 gorillas, and 3 orangutans), and treated human colonic epithelial cells (colonocytes) with the extracted microbiota using an experimental technique from a previously published method (see SI Table 1) (Richards et al, 2016(Richards et al, , 2019 . We quantified changes in gene expression in the colonocytes as a response to the primate microbiota using RNA-seq (Fig.…”

“…A likely mechanism by which the microbiome can affect host physiology is through regulating the expression of host genes in interacting intestinal epithelial cells (Luca et al, 2018;Richards et al, 2016Richards et al, , 2019 . Studies in animal models have demonstrated that gut microbiota can drive changes in host gene expression by altering epigenetic programming, such as histone modification, transcription factor binding, and methylation (Camp et al, 2014;Krautkramer et al, 2016;Pan et al, 2018;Qin et al, 2018) .…”

“…In addition, Pan et al found that the microbiome can alter DNA methylation in the gut epithelial cells of mice (Pan et al, 2018) . Moreover, in cell culture, inter-individual variation in microbiome composition can drive differential responses in host gene expression at the intestinal level (Richards et al, 2019) . However, we do not know how interspecies variation in the microbiome affects gene regulation in host cells.…”

“…Here, we use an in vitro experimental system (Richards et al, 2016(Richards et al, , 2019 to assess host gene expression changes in response to diverse gut microbiota from four great ape species: humans ( Homo sapiens ), and captive chimpanzees ( Pan troglodytes ), gorillas ( Gorilla gorilla gorilla ), and orangutans ( Pongo abelii ). This experimental design allows us to determine causal relationships between gut microbiome composition and gene expression changes in colonic epithelial cells that are induced by the microbiome while controlling for potentially confounding environmental and technical effects (Richards et al, 2016(Richards et al, , 2019 . We have leveraged this design to ascertain how host genes respond to between-species variation in microbiome composition across hominids, characterize the function of host genes that respond to microbiota from each great ape species, and identify microbial taxa and pathways that likely drive expression of specific host genes.…”