Observational studies suggest links between inflammatory factors, metabolites, and sepsis, yet their causality is uncertain. This study employs Mendelian Randomization (MR) to investigate the causality between these factors and sepsis, aiming to uncover the precise relationship and identify novel treatment approaches.
Methods
We used summary data from genome-wide association studies (GWAS) involving 91 inflammatory factors, 1400 metabolites as exposure, and STREPTO SEPSIS as outcome. Inverse variance weighting (IVW) and MR-Egger were used to evaluate the causal effect between exposure and outcome. Sensitivity analyses were performed using Cochrane's Q test, MR-Egger intercept method, MR-PRESSO method and leave-one-out method.
Results
Thymic stromal lymphopoietin levels (TSLP) (OR = 1.269; 95%CI = 1.016-1.585; P = .036) and Interleukin 15 receptor subunit alpha levels (IL-15Rα) (OR = 0.894; 95%CI = 0.801-0.998; P = .046) had a significant causal relationship with sepsis. Forty-four metabolites were associated with sepsis, including Spermidine to choline ratio (OR = 1.447; 95%CI = 1.104-1.977; P = .009), 4-hydroxyhippurate levels (OR = 1.448; 95%CI = 1.117-1.877; P = .005), and Sphingomyelin (d18:1/20:1, d18:2/20:0) levels (OR = 1.371; 95%CI = 1.139-1.651; P < .001). TSLP was associated with 19 metabolites, and IL-15Rα was associated with 30 metabolites.
Conclusions
This study uncovers the causal link between sepsis and two inflammatory factors, TSLP and IL-15Rα, and suggests metabolites’ potential in intervention. It also identifies 44 metabolites associated with sepsis, indicating possible biomarkers or therapeutic targets. The findings offer new perspectives on sepsis pathogenesis and could inform future treatment strategies.
GuarinoMPernaB CesaroAE, et al.2023 Update on sepsis and septic shock in adult patients: Management in the emergency department. J Clin Med.2023;12(9):3188.
2.
FleischmannCScheragAAdhikariNK, et al.Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med.2016;193(3):259-272.
3.
ReinhartKDanielsR KissoonNMachadoFRSchachterRDFinferS.Recognizing sepsis as a global health priority—a WHO resolution. N Engl J Med.2017;377(5):414-417.
4.
LuijksECvan der SlikkeECvan ZantenAR, et al.Societal costs of sepsis in The Netherlands. Crit Care.2024;28(1):29.
5.
JarczakDKlugeSNierhausA. Sepsis—pathophysiology and therapeutic concepts. Front Med (Lausanne).2021;8:628302.
6.
SalomãoRFerreiraBLSalomãoMCSantosSSAzevedoLBrunialtiM.Sepsis: Evolving concepts and challenges. Braz J Med Biol Res.2019;52:e8595.
7.
De BackerDDeutschmanCSHellmanJ, et al.Surviving sepsis campaign research priorities 2023. Crit Care Med.2024;52(2):268-296.
8.
GottsJEMatthayMA. Sepsis: pathophysiology and clinical management. Br Med J.2016;353:i1585.
9.
SciclunaBPVan VughtLAZwindermanAH, et al.Classification of patients with sepsis according to blood genomic endotype: A prospective cohort study. Lancet Respir Med.2017;5(10):816-826.
10.
AntcliffeDBBurnhamKL Al-BeidhF, et al.Transcriptomic signatures in sepsis and a differential response to steroids. From the VANISH randomized trial. Am J Respir Crit Care Med.2019;199(8):980-986.
11.
PuskarichMAJennaroTSGilliesCE, et al.Pharmacometabolomics identifies candidate predictor metabolites of an L-carnitine treatment mortality benefit in septic shock. Clin Transl Sci.2021;14(6):2288-2299.
12.
HarklessRSinghKChristmanJ, et al.Microvesicle-mediated transfer of DNA methyltransferase proteins results in recipient cell immunosuppression. J Surg Res.2023;283:368-376.
13.
Falcão-HolandaRBLeiteGGFBrunialtiMKCJasiulionisMGSalomãoR.Altered levels of H3K9AC, H3K4ME3, and H3K27ME3 in promoters of differentially expressed genes related to innate immune response in septic patients with different clinical outcomes. Shock. 2023;59(6):882-891.
14.
WuDShiYZhangHMiaoC.Epigenetic mechanisms of immune remodeling in sepsis: Targeting histone modification. Cell Death Dis.2023;14(2):112.
15.
SandersonEGlymourMMHolmesMV, et al.Mendelian randomization. Nat Rev Methods Prim. 2022;2(1):6.
16.
SmithGDEbrahimS. Mendelian randomization: Prospects, potentials, and limitations. Int J Epidemiol.2004;33(1):30-42.
17.
LinJZhouJXuY. Potential drug targets for multiple sclerosis identified through Mendelian randomization analysis. Brain. 2023;146(8):3364-3372.
18.
LinZXueHPanW. Combining Mendelian randomization and network deconvolution for inference of causal networks with GWAS summary data. PLoS Genet.2023;19(5):e1010762.
19.
LouckLECaraKCKlattKWallaceTCChungM.The relationship of circulating choline and choline-related metabolite levels with health outcomes: A scoping review of genome-wide association studies and Mendelian randomization studies. Adv Nutr. 2023;15(2):100164.
20.
ChenJZengLZhaoY, et al.Causal effects of gut microbiota on sepsis: A two-sample Mendelian randomization study. Front Microbiol.2023;14:1167416.
21.
XiangMWangYGaoZ, et al.Exploring causal correlations between inflammatory cytokines and systemic lupus erythematosus: A Mendelian randomization. Front Immunol.2023;13:985729.
22.
ChenYLuTPettersson-KymmerU, et al.Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases. Nat Genet.2023;55(1):44-53.
23.
BurgessSCronjéHT. Incorporating biological and clinical insights into variant choice for Mendelian randomisation: examples and principles. Egastroenterology. 2024;2(1):e100042.
24.
KimMSSongMShinJIWonH.How to interpret studies using Mendelian randomisation. BMJ Evidence-Based Med. 2023;28(4):251-254.
25.
BowdenJDavey SmithGHaycockPCBurgessS.Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol.2016;40(4):304-314.
26.
GrecoMFDMinelliCSheehanNAThompsonJR.Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome. Stat Med.2015;34(21):2926-2940.
27.
BurgessSButterworthAThompsonSG.Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol.2013;37(7):658-665.
28.
ProttiMPDe MonteL. Thymic stromal lymphopoietin and cancer: Th2-dependent and-independent mechanisms. Front Immunol.2020;11:2088.
29.
ZhangYZhouB. Functions of thymic stromal lymphopoietin in immunity and disease. Immunol Res.2012;52:211-223.
30.
García-ReyesMMZumaya-PérezLCPastelin-PalaciosRMoreno-EutimioMA.Serum thymic stromal lymphopoietin (TSLP) levels in atopic dermatitis patients: A systematic review and meta-analysis. Clin Exp Med.2023;23(8):4129-4139.
31.
DuttaAPaulSKatzJPSenguptaDBhargavaD.Neutrophils in cancer and potential therapeutic strategies using neutrophil-derived exosomes. Vaccines (Basel).2023;11(6):1028.
32.
KuetheJWPrakashPSMiduraEFJohnson RdBLKastenKRCaldwellCC.Thymic stromal lymphopoietin mediates the host response and increases mortality during sepsis. J Surg Res.2014;191(1):19-24.
33.
JessupHKBrewerAWOmoriM, et al.Intradermal administration of thymic stromal lymphopoietin induces a T cell-and eosinophil-dependent systemic Th2 inflammatory response. J Immunol. 2008;181(6):4311-4319.
34.
KitajimaMLeeHCNakayamaTZieglerSF.TSLP Enhances the function of helper type 2 cells. Eur J Immunol.2011;41(7):1862-1871.
35.
SoumelisVRechePAKanzlerH, et al.Human epithelial cells trigger dendritic cell–mediated allergic inflammation by producing TSLP. Nat Immunol.2002;3(7):673-680.
36.
ZhangYLiuJLuanL, et al.The tim-3-galectin-9 axis interferes with Th1/Th2 cell balance and induces lymphocyte apoptosis in patients with sepsis. Int J Clin Exp Med.2021;14:2291-2300.
37.
VallespiMGColasMGarayHReyesOAranaMJ.Differential regulation of Th1/Th2 in relevant tissues for sepsis pathogenesis with a limulus anti-LPS factor-derived peptide increases survival in gram-positive sepsis. Int Immunopharmacol.2004;4(10–11):1343-1351.
38.
LiuDHuangSSunJ, et al.Sepsis-induced immunosuppression: Mechanisms, diagnosis and current treatment options. Mil Med Res.2022;9(1):56.
39.
AliAKNandagopalNLeeS. IL-15-PI3K-AKT-mTOR: A critical pathway in the life journey of natural killer cells. Front Immunol.2015;6:141825.
40.
WangXZhaoX. Transcription factors associated with IL-15 cytokine signaling during NK cell development. Front Immunol.2021;12:610789.
41.
NandiMMoyoMMOrkhisS, et al.IL-15Rα-Independent IL-15 signaling in non-NK cell-derived IFNγ driven control of Listeria monocytogenes. Front Immunol.2021;12:793918.
42.
DuboisSMarinerJWaldmannTATagayaY.IL-15Rα recycles and presents IL-15 in trans to neighboring cells. Immunity. 2002;17(5):537-547.
43.
ZhaoXQiHZhouJXuSGaoY.Treatment with recombinant interleukin-15 (IL-15) increases the number of T cells and natural killer (NK) cells and levels of interferon-γ (IFN-γ) in a rat model of sepsis. Med Sci Monit.2019;25:4450.
44.
InoueSUnsingerJDavisCG, et al.IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis. J Immunol. 2010;184(3):1401-1409.
MortierEQuéménerAVusioP, et al.Soluble interleukin-15 receptor α (IL-15Rα)-sushi as a selective and potent agonist of IL-15 action through IL-15Rβ/γ: Hyperagonist IL-15· IL-15Rα fusion proteins. J Biol Chem.2006;281(3):1612-1619.
47.
KarampelaIChristodoulatosGSDalamagaM. The role of adipose tissue and adipokines in sepsis: Inflammatory and metabolic considerations, and the obesity paradox. Curr Obes Rep.2019;8:434-457.
48.
ChoiEJJeonCHParkDHKwonT.Allithiamine exerts therapeutic effects on sepsis by modulating metabolic flux during dendritic cell activation. Mol Cells.2020;43(11):964-973.
49.
KoutroulisIBatabyalRMcNamaraBLeddaMHoptayCFreishtatRJ.Sepsis immunometabolism: From defining sepsis to understanding how energy production affects immune response. Crit Care Explor. 2019;1(11):e0061.
50.
SiegelJH. Relations between circulatory and metabolic changes in sepsis. Annu Rev Med.1981;32(1):175-194.
51.
AhnSLeeSHChungKS, et al.Development and validation of a novel sepsis biomarker based on amino acid profiling. Clin Nutr.2021;40(6):3668-3676.
52.
ZengZHuangQMaoL, et al.The pyruvate dehydrogenase complex in sepsis: Metabolic regulation and targeted therapy. Front Nutr.2021;8:783164.
53.
WheelerMDIkejemaKEnomotoN, et al.Glycine: A new anti-inflammatory immunonutrient. Cell Mol Life Sci.1999;56:843-856.
54.
GrotzMRWPapeHvan GriensvenM, et al.Glycine reduces the inflammatory response and organ damage in a two-hit sepsis model in rats. Shock. 2001;16(2):116-121.
55.
YangSKooDJChaudryIHWangP.Glycine attenuates hepatocellular depression during early sepsis and reduces sepsis-induced mortality. Crit Care Med.2001;29(6):1201-1206.
56.
ChenQLiangXWuT, et al.Integrative analysis of metabolomics and proteomics reveals amino acid metabolism disorder in sepsis. J Transl Med.2022;20(1):123.
57.
ClowesGHJr.HirschEGeorgeBCBigatelloLMMazuskiJEVilleeCAJr.Survival from sepsis. Ann Surg.1985;202(4):446-458.
58.
SoubaWWHerskowitzKKlimbergVS, et al.The effects of sepsis and endotoxemia on gut glutamine metabolism. Ann Surg.1990;211(5):543-551.
59.
KarinchAMPanMLinCStrangeRSoubaWW.Glutamine metabolism in sepsis and infection. J Nutr.2001;131(9):2535S-2538S.
60.
DrobnikWLiebischGAudebertF, et al.Plasma ceramide and lysophosphatidylcholine inversely correlate with mortality in sepsis patients. J Lipid Res.2003;44(4):754-761.
61.
WuX HouJLiH, et al.Inverse correlation between plasma sphingosine-1-phosphate and ceramide concentrations in septic patients and their utility in predicting mortality. Shock. 2019;51(6):718-724.
62.
ChungHHupeDCOttoGP, et al.Acid sphingomyelinase promotes endothelial stress response in systemic inflammation and sepsis. Mol Med.2016;22:412-423.
63.
ZhangWJiangHWuG, et al.The pathogenesis and potential therapeutic targets in sepsis. MedComm. 2023;4(6):e418.
64.
Joana Da CostaPSantiagoAPSAmâncioRTGalinaA OliveiraMF BozzaFA.Sepsis induces brain mitochondrial dysfunction. Crit Care Med.2008;36(6):1925-1932.
65.
LiaudetL. Poly (adenosine 5′-diphosphate) ribose polymerase activation as a cause of metabolic dysfunction in critical illness. Curr Opin Clin Nutr Metab Care. 2002;5(2):175-184.
66.
ChengSSciclunaBPArtsRJ, et al.Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat Immunol.2016;17(4):406-413.
67.
ZhuCYaoR LiL, et al.Mechanism of mitophagy and its role in sepsis induced organ dysfunction: A review. Front Cell Dev Biol.2021;9:664896.
