Methylation metabolism in sepsis and systemic inflammatory response syndrome

Abstract

We have recently shown that sepsis leads to alterations of methylation metabolism in a rodent model. In this study we analyzed methylation metabolism and DNA methylation in human sepsis. Patients treated in one of the Intensive Care Units (ICU) at the University Hospital Bonn diagnosed with sepsis or systemic inflammatory response syndrome (n = 12) and patients who were treated due to traumatic brain injury, or stroke without clinical or laboratory signs of sepsis or major inflammation (n = 22) were included. Blood samples were taken two times a week, until ICU treatment was discontinued. Deproteinized plasma was used for simultaneous determination of the ubiquitous methyl-group donor S-adenosylmethionine (SAM) and its demethylated residue, S-adenosylhomocysteine (SAH), by using stable isotope dilution tandem mass spectrometry. Homocysteine (Hcys), hydrolyzation product of SAH, was determined by fully automated particle-enhanced immunonephelometry, and global DNA-methylation was measured by liquid chromatography tandem mass spectrometry. SAM (p < 0.001) and SAH (p < 0.001) plasma levels were higher in septic patients suggesting an increased cellular release of SAM and SAH in septic patients. The SAM/SAH ratio was decreased in septic patients (p = 0.002). There were no differences in homocysteine plasma levels (p = 0.32) or global leukocyte DNA methylation between septic and non-septic patients (p = 0.21) suggesting that sepsis-induced changes in methylation metabolism do not affect homocysteine plasma levels or the availability of SAM-derived methyl groups for DNA methylation. Sepsis and systemic inflammatory response syndrome induce considerable changes of methylation metabolism without apparent functional consequences on homocysteine plasma levels or DNA methylation. Further studies may explore the clinical relevance of the observed changes.

Immune Cell Phenotype and Function in Sepsis

“…Furthermore, new diagnostic strategies have been currently under evaluation for potential clinical application including measurement of mitochondrial or cell free DNA by qRT-PCR or by direct fluorescence assays (90,91). Recent studies highlighted the key role of epigenetics in sepsis-associated immune dysfunction, in particular DNA methylation and histone acetylation of inflammatory genes (92,93). Among epigenetic mechanisms, microRNAs, small non-coding RNAs able to modulate gene expression in target cells, are known to be modulated in plasma during sepsis.…”

Defective Homocysteine Metabolism: Potential Implications for Skeletal Muscle Malfunction

“…Interestingly, HHcy was reported to raise inflammatory mediators in both blood and in the tissues studied [50,51]. However, systemic inflammatory conditions such as sepsis are not associated with the Hcy elevations, implying that HHcy could be a causative factor for inflammation but may not be the consequence of inflammation [52]. Based on these studies, it is important to ask whether Hcy could similarly activate NLRP-3 based inflammasomes and cause IL-1β secretion in other tissues and cells as well.…”

Methionine Metabolites in Patients With Sepsis

“…Dysregulated methionine metabolism has been implicated in cardiovascular disease 3,4 and sepsis. [5][6][7][8] Methionine is enzymatically converted to S-adenosylmethionine (SAM), the major substrate for transmethylation reactions 9 and initial precursor for homocysteine and glutathione production (Figure 1). S-adenosylhomocysteine (SAH) is the by-product of SAM transmethylation reactions, is in equilibrium with homocysteine, and provides negative feedback regulation on methyltransferase activity.…”

“…There have been reports of high, normal, and low tHcy levels in patients with infection. 6,7,18 Endotoxemia in mice is associated with higher levels of SAM, lower levels of SAH, and low glutathione production. 19 Elevated plasma SAM and SAH levels have been reported in patients with sepsis, 20 but relationships between these elevated levels and clinical outcomes are unknown.…”

“…6,7,18 Endotoxemia in mice is associated with higher levels of SAM, lower levels of SAH, and low glutathione production. 19 Elevated plasma SAM and SAH levels have been reported in patients with sepsis, 20 but relationships between these elevated levels and clinical outcomes are unknown. It is also unknown whether these associations between sepsis and elevated SAM or SAH concentrations are independent of other clinical covariables, such as age and renal function.…”