L. reuteri and its metabolite indole-3-carboxaldehyde (IAld) exert a protective effect against sepsis through the DUSP1/ERK/NOX2/ROS axis, enhancing macrophage bactericidal activity and alleviating sepsis-associated organ damage.
Intestinal L. reuteri abundance was significantly reduced in patients with bacterial sepsis and negatively correlated with disease severity.
Fecal microbiota transplantation (FMT) and live L. reuteri supplementation effectively attenuated sepsis progression in a cecal ligation and puncture (CLP) mouse model.
Integrated metabolomic and network pharmacological analysis identified indole-3-carboxaldehyde (IAld) as a key L. reuteri-derived metabolite that enhances macrophage bactericidal function.
IAld directly targets DUSP1 in macrophages and inhibits its phosphatase activity.
IAld promotes ERK phosphorylation, upregulates NOX2 expression, and stimulates reactive oxygen species (ROS) production to enhance bacterial clearance.
Circulating IAld levels in septic patients were significantly inversely correlated with SOFA score, APACHE II score, and arterial lactate levels.
IAld safely enhanced the bactericidal function of human macrophages in vitro.
This research suggests that a beneficial gut bacterium called Limosilactobacillus reuteri plays an important role in protecting against sepsis — a life-threatening condition caused by the body's extreme response to infection. The researchers found that patients with bacterial sepsis had significantly lower levels of this bacterium in their guts, and the more severe the sepsis, the lower the levels. Experiments in mice confirmed that supplementing with live L. reuteri helped reduce the severity of sepsis. The researchers then identified a specific chemical produced by this bacterium, called indole-3-carboxaldehyde (IAld), as the key active ingredient responsible for these protective effects. The study traced exactly how IAld works at the molecular level inside immune cells called macrophages, which are responsible for detecting and killing bacteria. IAld binds to and blocks a protein called DUSP1, which normally acts as a brake on immune activity. By blocking this brake, IAld triggers a chain reaction — activating ERK signaling, increasing a protein called NOX2, and ultimately boosting production of reactive oxygen species (ROS), which are chemical weapons that macrophages use to kill bacteria. This enhanced killing ability was observed both in mouse models and in human immune cells in the laboratory. Importantly, patients with sepsis who had higher levels of IAld in their blood had less severe disease, as measured by standard clinical scoring systems. This research suggests that both L. reuteri supplementation and IAld itself could be explored as potential new approaches to treating or preventing sepsis by helping the immune system fight infections more effectively. The findings also identify DUSP1 as a potential drug target and highlight the broader importance of gut microbiome health in influencing outcomes during serious infections.
Li Z, Li P, Peng T, Zhou X, Liu Y, Ai C, et al.. (2026). Indole-3-carboxaldehyde from Limosilactobacillus reuteri targets the DUSP1/ERK/NOX2/ROS axis to enhance the bactericidal activity of macrophages and protects against sepsis.. Gut microbes. https://doi.org/10.1080/19490976.2026.2671382