Sepsis is characterized by dysregulated immunity and coagulopathy. The authors investigated whether ursodeoxycholic acid (UDCA) influences platelet function in sepsis through the immunoreceptor TREM2, which has an emerging role in platelet biology. The study aimed to integrate population-level associations, mechanistic animal data, computational docking, and preliminary clinical observations to test a TREM2-associated mechanism for UDCA’s effects on platelets and outcomes in sepsis.
The investigators analyzed a retrospective cohort of 6,476 sepsis patients from the MIMIC‑IV database to evaluate the association between UDCA exposure and hospital mortality. UDCA use was associated with reduced hospital mortality (reported total effect -0.2287, P < 0.001). A causal mediation analysis examined whether changes in platelet counts mediated the observed association. The analysis indicated that 69.8% of the UDCA–mortality association was mediated by increased platelet counts (natural indirect effect -0.1597, P < 0.001), supporting the hypothesis that modulation of platelet homeostasis contributes substantially to the observed outcome association.
Mechanistic studies employed lipopolysaccharide (LPS)-induced septic mice and TREM2-knockout animals. In LPS-treated mice, platelet TREM2 expression was downregulated while phosphorylation of downstream signaling components Syk, PI3K, and Akt was increased; these signaling changes were accompanied by platelet hyperactivation. Administration of UDCA was associated with increased platelet TREM2 expression and attenuation of the Syk–PI3K–Akt phosphorylation cascade, alongside reduced platelet activation. In TREM2-knockout mice, the UDCA-associated increases in TREM2 expression and the attenuation of downstream signaling and platelet activation were weakened or absent, indicating that the effects observed depend in large part on TREM2.
The authors performed computational docking to explore a possible direct interaction between UDCA and TREM2. The abstract reports that the docking suggested a potential interaction, which supported further mechanistic testing. Specific docking parameters, binding affinities, or structural details were not provided in the abstract and would require consulting the full text for exact results.
A small prospective pilot study enrolled eight septic patients who received UDCA. In this cohort UDCA was associated with an increase in platelet counts from 161.6 ± 106.2 to 211.4 ± 100.1 × 10^9/L (P = 0.001). UDCA also selectively inhibited ADP-induced platelet aggregation, which decreased from 49.23 ± 20.45% to 31.63 ± 26.28% (P = 0.001). Global coagulation parameters were not significantly altered in this small pilot group. These preliminary clinical observations align with the retrospective and preclinical data that UDCA can raise platelet counts and reduce platelet reactivity without major changes in standard coagulation tests.
Across complementary data sources, the study links UDCA exposure with improved sepsis outcomes through effects on platelet homeostasis that appear to be mediated largely via TREM2. The retrospective cohort analysis showed a mortality association with a substantive mediation contribution from platelet counts. Mechanistic mouse experiments demonstrated that LPS suppresses platelet TREM2 and activates Syk–PI3K–Akt signaling and that UDCA reverses these changes in a TREM2-dependent manner. The pilot clinical data in eight patients provide preliminary translational support: UDCA increased platelet counts and reduced ADP-induced aggregation without significant global coagulation changes.
Together, these findings suggest that modulation of platelet TREM2 and its downstream signaling may be a mechanistic pathway by which UDCA affects sepsis-associated coagulopathy and outcomes. The authors propose TREM2 as a potential therapeutic target in sepsis-associated platelet dysfunction.
The abstract presents multiple lines of evidence but leaves several details to the full text. The retrospective analysis establishes association but cannot prove causation beyond mediation modeling. The computational docking is reported as suggestive; specific binding metrics are not provided in the abstract. The prospective human pilot enrolled only eight patients, limiting generalizability and statistical power for safety and efficacy endpoints. Dose, timing, and duration of UDCA treatment, as well as longer-term clinical outcomes, are not detailed in the abstract and would require review of the full manuscript. Finally, while mouse genetic data implicate TREM2, translation of this mechanism to broader, heterogenous clinical populations requires further randomized clinical study.
The integrated analysis reported in this paper supports a model in which UDCA modulates platelet homeostasis and reduces platelet hyperactivation in sepsis via a TREM2-linked signaling pathway. Retrospective cohort data, preclinical mechanistic experiments, computational docking, and a small human pilot collectively suggest UDCA may improve sepsis outcomes through effects on platelets, and identify TREM2 as a candidate target for interventions addressing sepsis-associated coagulopathy. Further controlled clinical trials and full-methods review are needed to establish causality, optimal use, and safety in larger patient populations.