![]() There is only limited information about PUFA oxygenation by microorganisms in gastrointestinal tracts, amidst the generally low occurrence of oxygen-consuming enzymes therein. 5-LOX is found in myeloid cells, 12-LOX in the skin and epithelial cells, 15-LOX in dendritic and enteric glial cells, and COX-2 and CYP450 isoforms in epithelial cells. Pro-resolving M2-like macrophages can express all enzymes that are required for SPM biosynthesis other cell types expressing only selected enzymes can do so together with complementing cells via transcellular metabolism. Biosynthesis of SPM involves LOX, COX-2, and cytochrome P450 monooxygenases (CYP450), and has been described in detail for eukaryotic cells, in particular for granulocytes, monocytes, and macrophages. SPM act as potent agonists of active inflammation resolution, signaling via e.g., G-protein coupled receptors at nano- to picomolar concentrations. These products include maresins (MaR), E- and D-series resolvins (RvE and RvD), protectins (PD), lipoxins (LX), and precursors thereof such as 18-hydroxy-eicosapentaenoic acid (18-HEPE), 17-hydroxy-docosahexaenoic acid (17-HDHA), and 17,18-epoxyeicosatetraenoic acid (17,18-EEQ), collectively referred to as specialized pro-resolving mediators (SPM). More recently, several oxygenation products of n-3 PUFA and n-6 PUFA (e.g., arachidonic acid, AA) have been identified and functionally characterized as crucial mediators of their beneficial health effects, in particular with respect to the amelioration of chronic inflammatory conditions. ![]() Their modes of action involve e.g., direct scavenging of reactive oxygen species, alteration of cell membrane fluidity, which subsequently affects cellular signaling events, modulation of the activity of transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and nuclear factor κB (NFκB) that orchestrate the biosynthesis of pro- and anti-inflammatory cytokines, and competitive exclusion of substrates that are converted to pro-inflammatory lipid mediators by cyclooxygenases (COX) and lipoxygenases (LOX). n-3 PUFA, in general, have anti-inflammatory, cardio- and neuroprotective effects. n-3 PUFA can exert a range of health benefits and are ingested with the regular diet or through fortified foods, dietary supplements, or pharmaceutical products. While dietary ALA primarily derives from some plants (flaxseed, soybean, canola), dietary EPA and DHA are mainly of seafood origin (fatty fish, krill, algae). N-3 Polyunsaturated fatty acids ( n-3 PUFA) mainly comprise the long-chain fatty acids alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Further investigations are warranted to confirm and expand these findings, which may create a new class of n-3 PUFA interventions targeting inflammation resolution. To the best of our knowledge, we report here for the first time the development and in vivo application of a self-sufficient SPM-producing formulation. Supplementation with a synbiotic capsule product led to significantly increased plasma levels of hydroxy-eicosapentaenoic acids (5-HEPE, 15-HEPE, 18-HEPE) and hydroxy-docosahexaenoic acids (4-HDHA, 7-HDHA) as well as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in healthy humans. A pilot study was performed to test if a synbiotic Bacillus megaterium/ n-3 PUFA formulation increases SPM levels in vivo. All 48 tested Bacillus megaterium strains fed with the n-3 PUFA formulation produced a broad range of SPM and precursors thereof in a strain-specific manner, which may be explained by the CYP102A1 gene polymorphisms that we detected. Bacillus megaterium strains were fed highly bioavailable n-3 PUFA, followed by metabololipidomics analysis and bioinformatic assessment of the microbial genomes. To overcome the limitations of conventional n-3 PUFA supplementation strategies, we devised a composition enabling the self-sufficient production of SPM in vivo. Importantly, SPM biosynthesis is dysfunctional in various conditions, which may explain the inconclusive efficacy data from n-3 PUFA interventions. Specialized pro-resolving mediators (SPM) have emerged as crucial lipid mediators that confer the inflammation-resolving effects of omega-3 polyunsaturated fatty acids ( n-3 PUFA).
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