Ketogenic diet alleviates septic lung injury via microbial gut-lung axis.

Ketogenic diet alters gut microbiota in both mice and humans, specifically enriching Limosilactobacillus reuteri and Lactiplantibacillus plantarum.

• KD-induced microbiota changes were observed in both murine models and human subjects.
• The enrichment of these two bacterial species was a consistent finding across species.
• These bacterial changes were upstream of the identified gut-lung signaling axis.

Specific strains of L. reuteri and L. plantarum produce a flavin-dependent monooxygenase (FMO) that converts oleic acid present in KD into azelaic acid (AZA).

• The enzymatic conversion is catalyzed by a flavin-dependent monooxygenase (FMO).
• Oleic acid, a fatty acid abundant in ketogenic diet, serves as the substrate for this bacterial enzymatic reaction.
• Azelaic acid (AZA) is the downstream metabolite produced through this diet-microbiome interaction.
• Only specific strains within these species carried the FMO capable of this conversion.

During sepsis, azelaic acid translocates from the gut to the lung where it exerts protective effects.

• AZA produced in the gut was detected in the lung during sepsis, indicating translocation across the gut-lung axis.
• The translocation of AZA represents a mechanistic link between dietary intervention, gut microbiota activity, and pulmonary outcomes.
• This gut-to-lung translocation was identified as a key step in the protective pathway.

AZA promotes neutrophil apoptosis and expands MerTK+ alveolar macrophages via PPAR-γ activation in the lung during sepsis.

• AZA promoted apoptosis of neutrophils in the lung during sepsis.
• AZA expanded the MerTK+ alveolar macrophage (AM) population.
• The mechanism involved activation of PPAR-γ signaling.
• Expansion of MerTK+ AMs enhanced efferocytosis, the process of clearing apoptotic cells.
• These combined effects contributed to resolution of lung injury.

In sepsis patients, elevated azelaic acid levels correlate with improved clinical outcomes including survival rates, ventilation-free days, and pulmonary function.

• Higher AZA levels were associated with improved survival rates in patients with sepsis.
• Elevated AZA correlated with increased ventilation-free days (VFDs).
• Higher AZA levels were also associated with better pulmonary function.
• Patient lung specimens showed increased MerTK+ alveolar macrophages and apoptotic neutrophils consistent with the mechanistic findings in mice.

The lung is identified as the most vulnerable organ in sepsis, which is characterized by impaired immunity leading to multi-organ dysfunction.

• Sepsis is characterized by impaired immunity to infection.
• Multi-organ dysfunction is a hallmark of sepsis.
• The lung is described as the most vulnerable organ in the context of sepsis-induced organ damage.

The ketogenic diet alleviates sepsis-induced lung injury through a microbial-gut-lung axis.

• KD intervention was protective against sepsis-induced lung injury in mouse models.
• The protective effect was dependent on gut microbiota, establishing a microbial-gut-lung axis.
• The findings highlight the therapeutic potential of KD and microbiome modulation in sepsis.
• The pathway represents a diet-microbiome interaction mechanism governing gut-lung crosstalk.