Bacteria, viruses, and fungi in the mammalian gut microbiome vastly outnumber the cells in the human body; however, the detailed mechanisms these gut-dwelling commensal partners use to communicate with their generous hosts and induce responses represent somewhat of a “missing link” in this research. Now, a new epigenetics-based study shows that we should have been searching for a missing lncRNA!
Strong-stomached researchers headed by Yuhao Wang and Lora V. Hooper (University of Texas Southwestern Medical Center) understood that alterations to the gut microbiota promote the development of metabolic disorders. Given the rapidly increasing worldwide prevalence of metabolic disease, the team sought to dive into the mechanisms by which the intestinal microbiota communicate with their hosts and potentially affect metabolism. Their gut-wrenching new study focused on the differential transcription of lncRNAs (long non-coding RNAs) in the small intestinal epithelial cells that play a central role in the microbial modulation of lipid absorption and metabolism.
Let’s hear more from Wang and Colleagues on the missing lncRNA that lets the microbiota communicate with their hosts:
- RNA-sequencing in small intestinal epithelial cells from conventionally raised and germ-free mice identifies sixty differentially expressed non-protein-coding genes, including forty-two lncRNA genes
- Snhg9 expression reduces in the presence of the microbiota, which associates with body fat accumulation
- Forced expression of Snhg9 in the intestinal epithelium of conventional mice impairs lipid absorption, reduces body fat, and protects against diet-induced obesity
- RNA-protein pull-down assays in epithelial cell lysates coupled with mass spectrometry identify CCAR2 as the most abundant directly interacting protein with Snhg9
- The microbial repression of intestinal Snhg9 expression requires the function of myeloid cells (e.g., dendritic cells and macrophages) and group 3 innate lymphoid cells (ILC3s)
- In this model, bacteria activate myeloid cells, which use interleukin-23 to activate ILC3s, which themselves signal to intestinal epithelial cells through interleukin-22
Overall, this gutsy study provides evidence that the denizens of the human intestines promote lipid absorption and metabolism by repressing the expression of Snhg9 – a potential “missing lncRNA.” Subsequent research hopes to identify specific components of the gut microbiota that promote lipid absorption through Snhg9 repression, discover the evolutionary rationale for microbial regulation of lipid absorption, and explore any insight into the regulation of human lipid metabolism.
For more on how this missing lncRNA supports communication between the microbiota and their hosts to regulate metabolism, see Science, August 2023.