Sepsis is a life-threatening response to infection that damages multiple organs, including the lungs. Now, a study in mice shows that a high-fat, very low-carb diet—known as ketogenic diet—protects against sepsis-induced lung injury by increasing the levels of specific gut bacteria that turn dietary fat into azelaic acid, which reaches the lungs, activates immune cells, and reduces inflammation.

The findings, published in Cell Metabolism, suggest a gut microbiota-mediated mechanism by which a ketogenic diet can protect the lungs during sepsis.

Gut damage during sepsis allows bacteria and their by-products to reach the lungs, creating a “gut-lung connection” that may worsen injury. A ketogenic diet may help in sepsis by altering energy metabolism and gut bacteria, but it remains unclear which effects are most important for protecting the lungs.

Researchers led by Mingyuan Wei at South China Normal University in Guangzhou, China, tested the effects of a ketogenic diet on sepsis-related lung injury in mice by feeding the animals either a very high fat, no carbs diet or a standard high-carb diet for two weeks, then inducing sepsis.

Protecting the lungs

Mice on a ketogenic diet had lower death rates and less lung damage compared with mice on a standard diet. However, the benefits disappeared in mice without gut bacteria or after antibiotics. Transferring gut bacteria from mice on a ketogenic diet to other mice reduced lung injury and mortality.

The ketogenic diet changed the gut microbiota of mice by increasing the levels of specific gut bacteria, Limosilactobacillus reuteri and Lactiplantibacillus plantarum, while decreasing others such as Lactobacillus johnsonii and Lactobacillus murinus. Similar shifts were observed in people after two weeks on a ketogenic diet.

The ketogenic diet also increased the levels of a specific metabolite in the gut, blood, and lungs of mice. This metabolite, called azelaic acid, reduced death and lung injury, the researchers found.

Dietary interventions 

The production of azelaic acid depended on gut bacteria, in particular Limosilactobacillus reuteri and Lactiplantibacillus plantarum, which use an enzyme called FMO to convert dietary fat into azelaic acid. 

Further experiments indicated that azelaic acid travels from the gut to the lungs, where it activates immune cells to reduce inflammation and protect the lungs. The researchers also found that higher levels of azelaic acid in the lungs of people with sepsis were linked to better recovery.

“These findings highlight the therapeutic potential of a combined dietary-probiotic strategy for sepsis,” the authors say, “and they suggest that dissecting the mechanisms underlying [ketogenic diet] may pave the way for targeted dietary interventions that optimize both efficacy and safety in the emerging era of personalized nutrition.”