How gut microbes manipulate the immune system to trigger fat absorption

2023-10-25   |  

Microorganisms are often in battle with the immune system. But research in mice has shown that gut microbes work in tandem with it to determine how much fat the gut absorbs.

Microbes have been found to harness the immune system to suppress the production in the gut of genetic material — called long non-coding RNA (lncRNA) — which increases fat absorption from food. The finding may hint at new ways to treat obesity and type 2 diabetes.

Gut microbes are known to influence metabolism, but the details have been unclear until now, says WANG Yuhao, a biochemist at Zhejiang University, who led the study. “The relationships between gut microbiota and host metabolism are intricate and complex,” he says.

The experiments were performed on mice, but humans carry the same lncRNA, says Wang. “Our findings reveal intriguing therapeutic targets and raise the prospect of novel therapies for metabolic diseases, such as obesity and type 2 diabetes.”

Fat control

Wang’s team had already identified the mouse circadian clock as one factor in the relationship between gut microbiota and mice metabolism. lncRNAs were another factor shown to influence metabolism, but whether the microbes could direct lncRNA production remained unclear1.

For their study, published in Science, the team first analysed all the lncRNAs produced by cells lining the intestines from mice that were devoid of gut microbes, and compared them to  those of normal mice. The gut microbe-free mice contained many more copies of one lncRNA called Snhg9, suggesting that microbes may suppress levels of it.

The researchers found that Snhg9 bound tightly to CCAR2 in the intestinal cells, a protein called which inhibits an enzyme that decreases fat absorption from food. They hypothesized that when Snhg9 blocked the action of CCAR2 in this way, it unleashes the fat-regulating enzyme, resulting in less fat being absorbed by the intestine. 

To test their idea, the researchers edited mice the genes of mice so that they produced more Snhg9 and then fed them a high-fat diet. Compared to the unaltered mice, also on a high-fat diet, the edited mice had less fat in their intestines and excreted more fat.

Once they reached 10 weeks of age, the gene-edited mice had less body fat and less liver fat compared to the unaltered mice. Unaltered mice that had their gut microbiota eradicated with antibiotics, also had less body and liver fat, suggesting that without the gut microbes they were less efficient at absorbing fat.

Immune mechanisms

Further testing by the Zhejiang team revealed that the gut microbiota achieves control of the production of Snhg9 via the mouse immune system.

Microbial signals are first recognised by immune cells called myeloid cells which secrete an immune signaling protein called interleukin-23. This triggers a cascade of different immune proteins, until one, called interleukin-22, is secreted. This triggers cells lining the intestine to stop producing Snhg9.

The researchers are now confirming the type of gut microbe that induces this immune cascade, and working on ways to control the production of Snhg9 by adjusting microbial communities in mouse intestines.

“ControllingSnhg9 with targeted compounds, or developing other therapies through microbiome alterations with probiotics or prebiotics, could be novel avenues for treating metabolic disorders,” Wang says.


Wang, Y., et al. Science 357, 912-916 (2017). DOI: 10.1126/science.aan0677

Wang, Y., et al. Science 381, 851-857 (2023). DOI: 10.1126/science.ade0522