Intestinal cGAS signalling is activated in obesity and promotes diet-induced obesity by suppressing microbiota-derived indole-3-acetic acid (IAA), which normally drives adipose thermogenesis through a gut-to-fat signalling axis.
Key Findings
Results
cGAS-STING signalling is activated in the intestines of humans and male mice with obesity, leading to increased type I interferon production and heightened immune activity in intestinal cells.
Intestinal cGAS activation was documented in both human obese subjects and diet-induced obese male mice.
Activation of cGAS led to downstream STING pathway engagement and elevated type I interferon (IFN) production in intestinal epithelial cells.
The finding establishes obesity as a condition associated with chronic intestinal innate immune activation via the cGAS-STING axis.
Results
Intestinal epithelial cell-specific deletion of cGAS protects male mice against diet-induced obesity and improves metabolic health.
Mice with cGAS deleted specifically in intestinal epithelial cells (IEC-specific knockout) showed enhanced energy expenditure compared to controls.
The knockout mice were protected against diet-induced obesity, indicating a causal role for intestinal cGAS in promoting weight gain.
Metabolic improvements in the knockout mice included parameters consistent with improved metabolic health beyond body weight alone.
Results
The metabolic protection conferred by intestinal cGAS deletion depends on the gut microbiota, particularly Lactobacillus murinus.
The beneficial effects of intestinal cGAS deletion were dependent on an intact gut microbiota, as shown by experiments manipulating microbial composition.
Lactobacillus murinus was identified as a key microbial species mediating the metabolic effects downstream of cGAS signalling.
cGAS-STING-IFN signalling downregulated Lactobacillus murinus abundance in the gut, linking immune activation to microbiota composition changes.
Results
Lactobacillus murinus-derived indole-3-acetic acid (IAA) promotes adipose thermogenesis and is suppressed by intestinal cGAS-STING-IFN signalling.
IAA, a tryptophan-derived metabolite produced by Lactobacillus murinus, was identified as the key effector molecule mediating gut-to-fat communication.
IAA promotes thermogenesis in adipose tissue, representing a mechanism by which gut microbiota influence whole-body energy expenditure.
Intestinal cGAS activation leads to downregulation of microbiota-derived IAA, thereby suppressing adipose thermogenesis and promoting obesity.
This identifies a gut-to-fat signalling axis connecting intestinal immune sensing to peripheral metabolic tissue function.
Discussion
The intestinal cGAS-microbiota-IAA axis is proposed as a therapeutic target for obesity and related metabolic diseases.
The findings position intestinal cGAS as a key driver of obesity through gut-to-fat signalling.
Targeting the intestinal cGAS-microbiota IAA axis is suggested as a promising strategy to combat obesity and related metabolic diseases.
The study identifies multiple intervention points along the axis including cGAS itself, Lactobacillus murinus, and IAA supplementation.
Background
The gut immune-metabolic balance is regulated by intestinal cGAS acting as a regulator linking gut immunity to whole-body metabolism.
The study addresses how the gut balances responses to both pathogens and dietary signals.
cGAS is identified as a DNA sensor that serves a dual function as both an immune mediator and a metabolic regulator in the intestinal context.
This represents a previously unrecognized role for intestinal innate immune DNA sensing in systemic energy homeostasis.
What This Means
This research suggests that a protein called cGAS, which normally helps the body detect harmful DNA from pathogens, becomes overactive in the intestines of obese humans and mice. When cGAS is activated, it triggers an immune response that, as a side effect, disrupts the gut microbiome — specifically reducing levels of a beneficial bacterium called Lactobacillus murinus. This bacterium normally produces a molecule called indole-3-acetic acid (IAA), which travels from the gut to fat tissue and promotes calorie-burning (thermogenesis). By suppressing IAA production, overactive intestinal cGAS effectively reduces the body's ability to burn energy, contributing to weight gain and metabolic problems.
When researchers deleted cGAS specifically from intestinal cells in male mice, those mice were protected from diet-induced obesity, burned more energy, and had better overall metabolic health. These benefits disappeared when the gut microbiota was disrupted, confirming that the protective effect works through the microbiome and its IAA production. This establishes a previously unknown communication pathway from the gut immune system to fat tissue that regulates how much energy the body expends.
This research suggests that the intestinal cGAS immune sensing pathway is not just relevant to fighting infections but also plays an important role in obesity development. It opens potential new avenues for treating obesity by targeting the cGAS protein itself, boosting Lactobacillus murinus levels in the gut, or supplementing with IAA — though all of these approaches would require further research before any clinical applications could be considered.
Deng J, Meng W, Yang Y, Xiao T, Jin Z, Wang J, et al.. (2026). Intestinal cGAS-STING-IFN signalling promotes obesity by downregulating microbiota-derived IAA in male mice.. Nature metabolism. https://doi.org/10.1038/s42255-026-01562-4