Selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed medications worldwide. They are primarily used to enhance the serotonergic signaling pathway in the brain. SSRIs also show various effects beyond the central nervous system (CNS), including metabolic and immune functions. Recent evidence suggests that SSRIs may offer protective benefits against infections such as coronavirus disease 2019 (COVID-19) and sepsis in both human and animal models. However, the mechanisms responsible for this protective action remain largely unclear. This mechanism is thoroughly explored in the current paper published in the Science Advances Journal.
The objective of the study was to investigate the effect of SSRI fluoxetine on the survival and progression of diseases in an animal model (mouse) of sepsis. Specifically, it examined the protective effects of fluoxetine on immune and metabolic response through the peripheral serotonin-independent mechanism. The study assessed the fluoxetine-induced changes in levels of interleukin-10 (IL-10) and their role in preventing sepsis-related cardiac and metabolic dysfunction. Finally, researchers elucidated the relation between fluoxetine anti-inflammatory and metabolic mechanisms.
C57BL/6 mice, Tph1−/− mice, and B6.129P2-Il10tm1Cgn/J mice were included in this study. Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) were used for mouse infection. Various analysis techniques were involved in this study, like ex-vivo lipolysis assay, histology, measurement of serum triglycerides and serotonin, U-13C glucose tracing analysis, lipid-tolerance test (LTT), and pluronic test. All statistical testing was performed using Prism version 8.4.3.
Results demonstrated that pretreatment with fluoxetine showed a protective action in infection-induced mortality depending on the dose of the drug from 10mg/kg to 40mg/kg as the dose increased, higher protection was observed in mice. Drug-pretreated infected mice also exhibited similar levels of troponin 1 (cardiac muscle damage) and reduced levels of creatine kinase as well as brain natriuretic peptide (BNP) compared to vehicle-pretreated infected mice. All these levels are markers for cardiac and skeletal muscle damage. Fluoxetine mice showed minimum necrosis in addition to hemorrhage and congestion compared to vehicle mice.
A reduction in pathogen burden was observed in the fluoxetine mice by exhibiting antimicrobial activity against the growth of E. coli and S. aureus compared to vehicle mice. Drug-pretreated mice facilitated host adaptation to the infection more than non-drug-pretreated mice.
Decreased serotonin levels were reported in the lung, spleen, heart, and liver of fluoxetine pretreated mice (wild) compared to Tph1−/− mice. Additionally, Tph1−/− mice treated with the drug were 100% protected against sepsis-induced mortality compared to vehicle-treated Tph1−/− mice (50% protection)
Fluoxetine-pretreated mice showed enhanced levels of IL-10, Ly6C+ macrophages, natural killer cells, Ly6C+ monocytes, neutrophils, and Ly6C− macrophages compared to vehicle-pretreated mice at 2 hours post-infection. Also, drug pretreatment did not protect the Il10−/− mice from sepsis-induced morbidity and mortality, with a decrease of>70%.
In the ex-vivo lipolysis assay, comparable lipolysis levels were noted during infection in both the fluoxetine and vehicle-pretreated mice. At 4-hour post-pluronic F-127 injection, drug-pretreated mice had a non-significant reduction in triglyceride levels compared to vehicle mice. From LTT, it was found that peripheral uptake of triglycerides was increased in drug-pretreated mice compared to vehicle-pretreated mice. Furthermore, fluoxetine-pretreated infected Il10−/− mice showed less lipid tolerance compared to fluoxetine-pretreated wild-type mice.
Fluoxetine/pluronic pretreated mice exhibited a higher mortality rate and more signs of diseases compared to fluoxetine-pretreated mice. An increase in levels of E. coli in the kidney, liver, and spleen was observed in Fluoxetine-/pluronic mice compared to fluoxetine mice.
Fluoxetine pretreatment did not change the cardiac fatty acid oxidation (FAO) during the sepsis. This FAO was not impaired in vehicle-pretreated mice that died due to sepsis.
From U-13C glucose labeling analysis, it was demonstrated that levels of tricarboxylic acid (TCA) were significantly less in vehicle-infected mice compared to uninfected mice (control). At the same time, fluoxetine-infected mice showed comparable levels of TCA with control mice. During sepsis, fluoxetine-pretreated mice showed protection against glycolysis impairment and pyruvate dehydrogenase (PDH) inhibition in the heart compared to other mice.
“Our research work identifies the beneficial “off-target” effect of fluoxetine and demonstrates the protective mechanisms of immune and metabolic functions with significant therapeutic applications,” said Janelle S. Ayres, NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Reference: Gallant RM, Sanchez KK, Joulia E, et al. Fluoxetine promotes IL-10–dependent metabolic defenses to protect from sepsis-induced lethality. Sci Adv. 2025;11(7):eadu4034. doi:10.1126/sciadv.adu4034
