Omega‐3 fatty acids protect from colitis via an Alox15‐derived eicosanoid

Rohwer, Nadine; Chiu, Cheng-Ying; Huang, Dan; Smyl, Christopher; Rothe, Michael; Rund, Katharina M.; Schebb, Nils Helge; Kühn, Hartmut; Weylandt, Karsten H.

doi:10.1096/fj.202002340rr

Cited by 18 publications

(21 citation statements)

References 48 publications

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“…An impaired SPM biosynthesis has been reported for IBD [ 11 , 55 ], which may explain the overall lack of benefit from n -3 PUFA supplementation for IBD patients [ 46 , 47 ]. On the other hand, 15-HEPE [ 56 ], RvE1 [ 24 ], 17-HDHA, RvD 1 , RvD 2 [ 57 ], MaR 1 [ 58 ], and LXA 4 [ 59 ] are protective in murine models of IBD, whereas 15-HETE and 18-HEPE have proposed roles in supporting intestinal barrier resistance and epithelial healing in patients with Crohn’s disease [ 36 ]. As we observed significant production of several of these LM by our synbiotic combination both in vitro and in humans, it is meaningful to test its therapeutic potential in IBD.…”

Section: Discussionmentioning

confidence: 99%

Synbiotic Compositions of Bacillus megaterium and Polyunsaturated Fatty Acid Salt Enable Self-Sufficient Production of Specialized Pro-Resolving Mediators

Speckmann

Kleinbölting²,

Börner³

et al. 2022

Nutrients

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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). Importantly, SPM biosynthesis is dysfunctional in various conditions, which may explain the inconclusive efficacy data from n-3 PUFA interventions. To overcome the limitations of conventional n-3 PUFA supplementation strategies, we devised a composition enabling the self-sufficient production of SPM in vivo. Bacillus megaterium strains were fed highly bioavailable n-3 PUFA, followed by metabololipidomics analysis and bioinformatic assessment of the microbial genomes. 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. A pilot study was performed to test if a synbiotic Bacillus megaterium/n-3 PUFA formulation increases SPM levels in vivo. 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. 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. Further investigations are warranted to confirm and expand these findings, which may create a new class of n-3 PUFA interventions targeting inflammation resolution.

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Section: Discussionmentioning

confidence: 99%

Synbiotic Compositions of Bacillus megaterium and Polyunsaturated Fatty Acid Salt Enable Self-Sufficient Production of Specialized Pro-Resolving Mediators

Speckmann

Kleinbölting²,

Börner³

et al. 2022

Nutrients

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“…A protective role for 12/15-LO has also been described in arthritis ( Kronke et al, 2009 ) and in IL-33-induced eosinophilic airway inflammation which seems to be at least partially due to the 12/15-LO product 14-HDHA ( Miyata et al, 2021 ). In a context of high EPA and DHA tissue levels, 12/15-LO led to protection from DSS-induced colitis, which was abolished by functional inactivation of the enzyme ( Rohwer et al, 2021 ), further underlining a context-specific pro- or anti-inflammatory role of the enzyme. When human 15-LO1 is overexpressed in transgenic rabbits and in mice, an anti-atherogenic effect was observed ( Serhan et al, 2003 ; Merched et al, 2008 ).…”

Section: Spms and Lipoxygenase Knockout Datamentioning

confidence: 99%

Formation, Signaling and Occurrence of Specialized Pro-Resolving Lipid Mediators—What is the Evidence so far?

et al. 2022

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Formation of specialized pro-resolving lipid mediators (SPMs) such as lipoxins or resolvins usually involves arachidonic acid 5-lipoxygenase (5-LO, ALOX5) and different types of arachidonic acid 12- and 15-lipoxygenating paralogues (15-LO1, ALOX15; 15-LO2, ALOX15B; 12-LO, ALOX12). Typically, SPMs are thought to be formed via consecutive steps of oxidation of polyenoic fatty acids such as arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid. One hallmark of SPM formation is that reported levels of these lipid mediators are much lower than typical pro-inflammatory mediators including the monohydroxylated fatty acid derivatives (e.g., 5-HETE), leukotrienes or certain cyclooxygenase-derived prostaglandins. Thus, reliable detection and quantification of these metabolites is challenging. This paper is aimed at critically evaluating i) the proposed biosynthetic pathways of SPM formation, ii) the current knowledge on SPM receptors and their signaling cascades and iii) the analytical methods used to quantify these pro-resolving mediators in the context of their instability and their low concentrations. Based on current literature it can be concluded that i) there is at most, a low biosynthetic capacity for SPMs in human leukocytes. ii) The identity and the signaling of the proposed G-protein-coupled SPM receptors have not been supported by studies in knock-out mice and remain to be validated. iii) In humans, SPM levels were neither related to dietary supplementation with their ω-3 polyunsaturated fatty acid precursors nor were they formed during the resolution phase of an evoked inflammatory response. iv) The reported low SPM levels cannot be reliably quantified by means of the most commonly reported methodology. Overall, these questions regarding formation, signaling and occurrence of SPMs challenge their role as endogenous mediators of the resolution of inflammation.

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“…Additionally, 14‐HDHA, 17‐HDHA, 15‐HEPE, and 18‐HEPE, which could be the precursors and/or pathway indicators 10 of the resolvin and protectin families of SPMs, were also significantly increased after the introduction of fish oil in PN, raising the possibility that the enhanced formation of 17‐HDHA and 18‐HEPE may improve liver function and dampen inflammation in our patients receiving PN, similar to their protective role in animal studies 40,41 . 18‐HEPE was recently shown to be metabolized by different human LOX isoforms to different resolving products 42 .…”

Section: Discussionmentioning

confidence: 75%

“…20 Additionally, 14-HDHA, 17-HDHA, 15-HEPE, and 18-HEPE, which could be the precursors and/or pathway indicators 10 of the resolvin and protectin families of SPMs, were also significantly increased after the introduction of fish oil in PN, raising the possibility that the enhanced formation of 17-HDHA and 18-HEPE may improve liver function and dampen inflammation in our patients receiving PN, similar to their protective role in animal studies. 40,41 18-HEPE was recently shown to be metabolized by different human LOX isoforms to different resolving products. 42 However, within the limitations of our analysis, we were not able to detect dihydroxy and trihydroxy SPMs such as maresin-1, resolvin D1 (RvD1), RvD3, RvD5, and RvE1, which might reflect differences in methodology, as discussed in a recent review in this field.…”

Section: Discussionmentioning

confidence: 99%

Impact of intravenous fish oil on omega‐3 fatty acids and their derived lipid metabolites in patients with parenteral nutrition

Weylandt

Karber

Xiao

et al. 2022

J Parenter Enteral Nutr

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Background Long‐term parenteral nutrition (PN) can lead to intestinal failure–associated liver disease (IFALD). Omega‐3 (n‐3) polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were shown to prevent IFALD. EPA‐derived and DHA‐derived oxylipins could contribute to this protective effect. Methods We analyzed the effect of parenteral fish oil on oxylipins in patients with chronic intestinal failure receiving PN (n = 8). Patients first received no fish oil for 8 weeks and then switched to PN with 25% of fat as fish oil for another 8 weeks. Fatty acid profiles of red blood cells, PUFA‐derived oxylipins generated by cyclooxygenase, lipoxygenase (LOX), and cytochrome P450 (CYP) pathways, inflammatory markers, and liver function were assessed before and during fish‐oil PN. Results EPA plus DHA in erythrocytes (the Omega‐3 Index) was high with a median of 11.96% at baseline and decreased to 9.57% without fish oil in PN. Addition of fish oil in PN increased the median Omega‐3‐Index to 12.75%. EPA‐derived and DHA‐derived CYP‐dependent and LOX‐dependent metabolites increased significantly with fish oil in PN, with less pronounced changes in arachidonic acid and its oxylipins. There were no significant changes of inflammation and liver function parameters. Conclusions This study shows that fish oil–containing PN leads to primarily CYP‐ and LOX‐dependent n‐3 PUFA–derived inflammation‐dampening oxylipins arising from EPA and DHA. Within this short (16‐week) study, there were no significant changes in inflammation and clinical readout parameters.

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Omega‐3 fatty acids protect from colitis via an Alox15‐derived eicosanoid

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 18 publications

References 48 publications

Synbiotic Compositions of Bacillus megaterium and Polyunsaturated Fatty Acid Salt Enable Self-Sufficient Production of Specialized Pro-Resolving Mediators

Synbiotic Compositions of Bacillus megaterium and Polyunsaturated Fatty Acid Salt Enable Self-Sufficient Production of Specialized Pro-Resolving Mediators

Formation, Signaling and Occurrence of Specialized Pro-Resolving Lipid Mediators—What is the Evidence so far?

Impact of intravenous fish oil on omega‐3 fatty acids and their derived lipid metabolites in patients with parenteral nutrition

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