The gut microbiome can shape health and the risk of disease, though the molecular mechanisms of these interactions are still unclear. Although host genetics is one of the factors that can shape gut microbiome variation, looking at it from the opposite perspective, it is less clear to what extent the microbiome may affect gene expression.
In a new cell culture study, researchers from Wayne State University, University of Minnesota and Loyola University Chicago (USA) have found that gut microbiota composition can induce changes in gene regulation in colonic epithelial cells.
First, Richards and colleagues quantified changes in transcriptome and chromatin accessibility in an in vitro model of human epithelial cells under hypoxic conditions after being exposed to live gut microbiotas derived from five healthy, unrelated individuals.
Exposure to human fecal samples led to consistent changes in the expression of 5,413 host genes involved in protein translation and associated with the cell surface.
In contrast, the expression of 409 genes changed in a different way across treatments. This allowed scientists to explore whether specific gut microbiota features might be involved in the differences in gene expression.
The researchers observed 588 different associations between specific taxa and host genes, which comprised changes in the expression of 121 host genes related to the abundance of 46 taxa.
Specifically, microbial genera associated with the largest number of host genes included Odoribacter, Streptococcus, Blautia, Thiovirga, Thiothrix, and Collinsella. Genes modulated by bacterial taxa were associated with complex traits that have previously been shown to involve the gut microbiome, including colorectal cancer, obesity and inflammatory bowel diseases. For instance, the abundance of Collinsella was positively associated with the gene GLTP, which takes part in glycolipid transfer, and that, in turn, has been involved in metabolic syndrome.
Changes in host chromatin accessibility by modulating transcription factor binding was found to be a regulatory mechanism by which the gut microbiota induces changes in host gene expression.
These results show that host cells and the gut microbiota are constantly interacting and interindividual variations in gut microbiota composition affect gene expression in host cells. It also seems that host genes and gut microbiota composition could act in a similar way in shaping host disease risk (e.g. correlation between the GLTP gene and Collinsella).
In a second step, the authors created a manipulated microbiota consisting of gradient doses of Collinsella and showed that gene expression in colonocytes can be modulated in a predictive way by changing the abundance of a single bacterial species.
To sum up, despite the limitations of the in vitro system, these preliminary findings show that the gut microbiota in both natural and controlled conditions can lead to changes in host gene regulation that are involved in complex functions. New studies that better mimic the in vivo conditions of the gastrointestinal tract will help provide a more complete picture of the dynamic nature of the interactions between host and microbiota.
As the authors highlight in their conclusion, “The ability to fine-tune the expression of host genes by manipulating the microbiome suggests future therapeutic routes.”
Richards AL, Muehlbauer AL, Alazizi A, et al. Gut microbiota has a widespread and modifiable effect on host gene regulation. mSystems. 2019; 4(5). doi: 10.1128/mSystems.00323-18.