Daily Sepsis Research Analysis
Three studies advance sepsis science across mechanisms, biomarkers, and causal epidemiology. New work identifies IDO1/Kyn/AhR-driven ferroptosis causing acute thymic involution with survival rescue by IDO1 inhibition in mice, reveals a lipid-metabolic brake on macrophage IL-1β via ACOT11 and IFNGR2 palmitoylation (with protective fatty acids in vivo), and provides Mendelian randomization evidence linking specific bile acids to sepsis risk and 28-day mortality.
Summary
Three studies advance sepsis science across mechanisms, biomarkers, and causal epidemiology. New work identifies IDO1/Kyn/AhR-driven ferroptosis causing acute thymic involution with survival rescue by IDO1 inhibition in mice, reveals a lipid-metabolic brake on macrophage IL-1β via ACOT11 and IFNGR2 palmitoylation (with protective fatty acids in vivo), and provides Mendelian randomization evidence linking specific bile acids to sepsis risk and 28-day mortality.
Research Themes
- Immunometabolism and ferroptosis in sepsis-induced immune dysfunction
- Lipid signaling and post-translational modifications regulating innate immunity
- Gut–liver axis metabolites (bile acids) causally linked to sepsis risk and outcomes
Selected Articles
1. Ferroptosis mediated by the IDO1/Kyn/AhR pathway triggers acute thymic involution in sepsis.
In pediatric sepsis, elevated Kyn/Trp ratios indicate IDO1 activation, which drives AhR signaling and thymocyte ferroptosis, resulting in acute thymic involution. Pharmacologic IDO1 inhibition restored thymic function and improved survival in septic mice, identifying a targetable immunometabolic pathway.
Impact: This study uncovers a mechanistic link between tryptophan catabolism, ferroptosis, and immunosuppression in sepsis, with interventional evidence in vivo. It suggests a plausible therapeutic strategy (IDO1/AhR/ferroptosis axis) to reverse immune dysfunction.
Clinical Implications: Measuring Kyn/Trp or downstream signatures could stratify immune dysfunction in sepsis. IDO1 inhibitors or ferroptosis modulators merit translational evaluation to prevent thymic involution and improve host defense in selected patients.
Key Findings
- Pediatric sepsis patients exhibited elevated Kyn/Trp ratios and higher Kyn levels; Kyn inversely correlated with thymus-to-thorax ratio.
- Inflammation-induced IDO1 increased Kyn, activated AhR, and triggered ferroptosis-related transcription in thymocytes during sepsis.
- IDO1 inhibition with 1-methyltryptophan restored thymic function and improved survival in septic mice.
Methodological Strengths
- Integration of human pediatric data with mechanistic mouse experiments and pathway interrogation.
- Pharmacologic intervention demonstrating reversibility and survival benefit, supporting causality.
Limitations
- Human sample size and detailed cohort characteristics are not specified; human data are correlative.
- Preclinical mouse findings may not fully generalize to heterogeneous clinical sepsis.
Future Directions: Validate Kyn/AhR/ferroptosis signatures in larger human cohorts; assess safety and efficacy of IDO1 inhibitors or ferroptosis modulators in early-phase sepsis trials; explore combinatorial immunometabolic therapies.
Acute thymic involution (ATI) is frequently observed during sepsis, however the underlying mechanisms remain poorly understood. This study demonstrates that ferroptosis plays a crucial role in sepsis-associated ATI. We found that pediatric sepsis patients showed significantly elevated kynurenine (Kyn)/tryptophan (Trp) ratios, indicating increased indoleamine 2,3-dioxygenase 1 (IDO1) activity, along with higher Kyn levels compared to controls. Moreover, Kyn levels were negatively correlated with thymus-to-thorax ratio. Further mechanistic analysis revealed that the enhanced expression of IDO1, induced by inflammatory signals, drives the accumulation of Kyn and subsequent activation of the aryl hydrocarbon receptor (AhR), triggering lipid oxidation-related gene transcription and ferroptosis in thymocytes during sepsis. Treatment with 1-methyltryptophan (IDO1 inhibitor) effectively restore thymic function and improve survival in septic mice. Our findings reveal a novel role for the IDO1/Kyn/AhR pathway in ferroptosis, suggesting that targeting this pathway may offer a promising therapeutic strategy for sepsis. Created with BioRender ( https://app.biorender.com/ ).
2. Porcine GWAS identifies ACOT11 as regulator for macrophage IL-1β maturation via IFNGR2 palmitoylation.
A cross-species strategy identified ACOT11 as a negative regulator of macrophage IL-1β maturation via IFNGR2 palmitoylation and JAK–STAT dampening. Supplementation with eicosatetraenoic acid protected mice from LPS-induced sepsis, highlighting a lipid-metabolic axis as a therapeutic target.
Impact: This work uncovers a previously unrecognized post-translational control of IFNγ receptor signaling that restrains inflammasome cytokine maturation and demonstrates protection in a sepsis model via defined fatty acids.
Clinical Implications: Targeting ACOT11–IFNGR2 palmitoylation or leveraging specific fatty acids (e.g., eicosatetraenoic acid) could modulate hyperinflammation in sepsis. This supports testing lipid-based adjuncts to reduce IL-1β–driven pathology.
Key Findings
- Porcine GWAS nominated ACOT11 as an IL-1β–related gene; inflammatory macrophages have low ACOT11 expression.
- ACOT11 overexpression suppresses IL-1β maturation by promoting intracellular fatty acids that induce IFNGR2 (C261) palmitoylation and dampen JAK–STAT signaling.
- Eicosatetraenoic acid attenuated LPS-induced sepsis in mice, supporting translational relevance of the pathway.
Methodological Strengths
- Cross-species approach (porcine GWAS, human-relevant macrophage biology, mouse in vivo validation).
- Mechanistic dissection including receptor palmitoylation site mapping and pathway readouts.
Limitations
- Translational gap from porcine and LPS mouse models to heterogeneous human sepsis.
- No clinical trial or patient-level intervention data; dosing/availability of fatty acids for therapy remain undefined.
Future Directions: Validate ACOT11–IFNGR2 palmitoylation in human sepsis samples; test targeted lipid formulations or ACOT11 modulators in preclinical polymicrobial sepsis; explore synergy with IL-1–targeted therapies.
Fatty acid metabolism mediates macrophage function; however, the underlying mechanism by which fatty acid metabolism regulates macrophage interleukin (IL)-1β production remains to be uncovered. Here, we used genome-wide association studies (GWAS) to identify several porcine serum IL-1β-related genes, such as the fatty acid metabolizing enzyme acyl-CoA thioesterase 11 (ACOT11). We then demonstrated that inflammatory macrophages have low expression of ACOT11, and ACOT11 overexpression inhibits IL-1β maturation from inflammatory macrophages. Mechanistically, ACOT11 promotes intracellular fatty acids accumulation, including eicosatetraenoic acid (EA) and stearic acid (SA), which inhibit activation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling through palmitoylation of interferon (IFN)-γ receptor (IFNGR) 2 at C261site. Furthermore, we also found that EA attenuates lipopolysaccharide (LPS)-induced sepsis in mice. Collectively, our findings reveal a mechanism involving ACOT11-mediated post-translational modification that regulates macrophage function and provide a promising therapeutic target for the treatment of inflammatory diseases associated with macrophages.
3. Gut-Liver Axis Metabolites and Sepsis: Insights From Mendelian Randomization.
Bidirectional and multivariable MR implicate TDCA as protective against sepsis, while GCA and TCDCA associate with higher 28-day mortality in sepsis. Mediation analyses suggest ALT partly mediates the protective association of UDCA with sepsis risk.
Impact: Provides quasi-causal human genetic evidence linking discrete bile acids to sepsis incidence and short-term mortality, generating testable therapeutic hypotheses (e.g., UDCA).
Clinical Implications: Bile acid profiling could aid risk stratification. Trials evaluating UDCA or modulating bile acid pools and liver function (e.g., ALT) may be warranted in high-risk populations.
Key Findings
- Genetically predicted higher TDCA levels were associated with lower sepsis risk (OR 0.797, p=0.012).
- Higher GCA and TCDCA were associated with increased 28-day mortality among sepsis patients.
- Two-step mediation MR indicated ALT mediates part of the association between UDCA and reduced sepsis risk (supported by Sobel and bootstrap tests).
Methodological Strengths
- Bidirectional two-sample and multivariable MR reduce confounding and reverse causation concerns.
- Mediation analysis with ALT, supported by Sobel and bootstrap, offers biological plausibility.
Limitations
- MR assumptions (instrument validity, no pleiotropy) may be violated; bile acid GWAS instruments may be limited.
- Summary-level data from UK Biobank limit phenotype granularity; no interventional or individual-level validation.
Future Directions: Validate bile acid–sepsis associations in independent cohorts; integrate metabolomics with longitudinal clinical data; test UDCA or bile acid–modulating interventions for sepsis prevention or outcome improvement.
BACKGROUND: Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection. Alterations in gut-liver axis metabolites, particularly bile acids, are commonly observed in sepsis. However, the associations between bile acids and sepsis risk or outcomes remain unclear. This study aimed to investigate the potential associations between genetically predicted levels of gut-liver axis metabolites-primarily bile acids-and sepsis risk and prognosis using bidirectional two-sample Mendelian randomization (MR), multivariable MR, and two-step mediation MR analyses. METHODS: Genetic instruments for circulating bile acids were obtained from genome-wide association studies (GWAS) curated in the OpenGWAS database. Summary-level data for sepsis and 28-day mortality were derived from the UK Biobank. We conducted bidirectional two-sample MR to assess the associations between nine bile acids and both sepsis incidence and short-term prognosis. In addition, two-step mediation MR was performed to evaluate whether the associations between specific bile acids and sepsis risk might be mediated through intermediate traits, such as liver function markers. The statistical significance of mediation effects was further tested using both the Sobel test and bootstrap resampling methods. RESULTS: Univariable MR analyses suggested that higher genetically predicted levels of taurodeoxycholate acid (TDCA) were associated with a lower risk of sepsis (OR = 0.797, 95%CI: 0.668-0.952, p = 0.012). In contrast, glycocholate acid (GCA) (OR = 1.964, 95%CI: 1.220-3.164, p = 0.005) and taurochenodeoxycholate acid (TCDCA) (OR = 1.998, 95%CI: 1.085-3.678, p = 0.026) were positively associated with an increased 28-day mortality risk among sepsis patients. Results from the two-step mediation MR analysis indicated that alanine aminotransferase (ALT) may act as a mediator in the association between ursodeoxycholate acid (UDCA) and sepsis risk. The statistical significance of this mediation effect was further supported by both the Sobel test and bootstrap resampling analysis, suggesting that UDCA may be associated with a reduced risk of sepsis, at least in part, through its influence on circulating ALT levels. CONCLUSIONS: This MR study provides genetic evidence consistent with potential relationships between specific bile acids and sepsis risk and prognosis. Taurodeoxycholate acid (TDCA) may be associated with a reduced risk of sepsis, whereas glycocholate acid (GCA) and taurochenodeoxycholate acid (TCDCA) might relate to worse outcomes. Moreover, among these liver enzymes, ALT exhibited the most significant mediation effect, suggesting that it may play a crucial role in the process by which UDCA influences the occurrence of sepsis. These findings suggest a possible role of bile acids in the pathophysiology of sepsis and may inform future mechanistic studies or therapeutic considerations.