Oral administration of docosahexaenoic acid attenuates colitis induced by dextran sulfate sodium in mice

Cho, Jae-Young; Gil, Sung; Chun, Hyang Sook

doi:10.1002/mnfr.201000070

Cited by 51 publications

(46 citation statements)

References 48 publications

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“…But these are not well tolerated and result in immunocompromised states with systemic side effects, which is particularly problematic because UC patients require persistent life-long biologic therapy. Some naturally occurring long-chain fatty acids have been reported to reduce inflammation in murine colitis models (27,28). For example, chronic feeding with an oleic acid-rich diet (C18 LC-PUFA) in mice treated with DSS delayed diarrhea and rectal bleeding but did not improve colonic histopathology compared with control mice (29).…”

Section: Discussionmentioning

confidence: 99%

Branched Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) Protect against Colitis by Regulating Gut Innate and Adaptive Immune Responses

Lee

Moraes‐Vieira

Castoldi

et al. 2016

Journal of Biological Chemistry

126

124

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We recently discovered a structurally novel class of endogenous lipids, branched palmitic acid esters of hydroxy stearic acids (PAHSAs), with beneficial metabolic and anti-inflammatory effects. We tested whether PAHSAs protect against colitis, which is a chronic inflammatory disease driven predominantly by defects in the innate mucosal barrier and adaptive immune system. There is an unmet clinical need for safe and well tolerated oral therapeutics with direct anti-inflammatory effects. Wild-type mice were pretreated orally with vehicle or 5-PAHSA (10 mg/kg) and 9-PAHSA (5 mg/kg) once daily for 3 days, followed by 10 days of either 0% or 2% dextran sulfate sodium water with continued vehicle or PAHSA treatment. The colon was collected for histopathology, gene expression, and flow cytometry. Intestinal crypt fractions were prepared for ex vivo bactericidal assays. Bone marrow-derived dendritic cells pretreated with vehicle or PAHSA and splenic CD4 ؉ T cells from syngeneic mice were co-cultured to assess antigen presentation and T cell activation in response to LPS. PAHSA treatment prevented weight loss, improved colitis scores (stool consistency, hematochezia, and mouse appearance), and augmented intestinal crypt Paneth cell bactericidal potency via a mechanism that may involve GPR120. In vitro, PAHSAs attenuated dendritic cell activation and subsequent T cell proliferation and Th1 polarization. The anti-inflammatory effects of PAHSAs in vivo resulted in reduced colonic T cell activation and pro-inflammatory cytokine and chemokine expression. These anti-inflammatory effects appear to be partially GPR120-dependent. We conclude that PAHSA treatment regulates innate and adaptive immune responses to prevent mucosal damage and protect against colitis. Thus, PAHSAs may be a novel treatment for colitis and related inflammation-driven diseases.Lipids have been a rich source of chemical matter for the development of new medicines (1). Endogenous small-molecule metabolites are another class of natural products made within the human body that have important biological activities (2). For example, the discovery and synthesis of prostaglandins revealed their diverse biological roles as autocrine and paracrine mediators in many tissues. This led to their development as therapeutic agents for a variety of indications ranging from vasodilatation to glaucoma treatment (3-6). More recently, compounds that target the sphingosine 1 receptors are emerging as novel therapeutics for autoimmune diseases (7). Thus, the discovery and characterization of bioactive lipids is of fundamental interest with broad impact. We recently discovered a structurally novel class of lipids, branched fatty acid esters of hydroxy fatty acids (FAHFAs), 6 with anti-diabetic and anti-inflammatory properties (8). These lipids are products of endogenous synthesis in mammalian tissues and are also present in food. There are more than 16 FAHFA families, and each family is distinguished by having a different fatty acid and hydroxy fatty acid composition. Furthermor...

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Section: Discussionmentioning

confidence: 99%

Branched Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) Protect against Colitis by Regulating Gut Innate and Adaptive Immune Responses

Lee

Moraes‐Vieira

Castoldi

et al. 2016

Journal of Biological Chemistry

126

124

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“…Although a recent systematic review does not allow firm recommendations about the usefulness of n-3 PUFA dietary supplements in IBD (52), other works, especially at the preclinical stage, suggest that n-3 PUFAs or their lipid-derived mediators might have a therapeutic effect (19)(20)(21)53). Indeed, the n-3 PUFAs DHA and EPA, found in fish oils, are extensively used currently as dietary supplements and are thought to exert beneficial effects in a number of inflammationrelated diseases (54,55) and in different experimental models (53,56,57). More recently, EPA and DHA lipid-derived mediators known as resolvins and protectins have been described as key mediators in the resolution of inflammation and regulators of normal homeostasis (5,9).…”

Section: Discussionmentioning

confidence: 99%

Maresin 1, a Proresolving Lipid Mediator Derived from Omega-3 Polyunsaturated Fatty Acids, Exerts Protective Actions in Murine Models of Colitis

Marcon

Bento

Dutra

et al. 2013

The Journal of Immunology

173

149

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It has been previously reported that dietary fish oils, which are rich in the polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid, can exert beneficial effects in inflammatory bowel disease. In this study, we investigated the effects of docosahexaenoic acid–derived lipid mediator maresin 1 (MaR1) in dextran sulfate sodium (DSS)– and 2,4,6-trinitrobenzenesulfonic acid–induced colitis in mice. Systemic treatment with MaR1 significantly attenuated both DSS- and 2,4,6-trinitrobenzene sulfonic acid–induced colonic inflammation by improving the disease activity index and reducing body weight loss and colonic tissue damage. MaR1 treatment also induced a significant decrease in levels of inflammatory mediators, such as IL-1β, TNF-α, IL-6, and IFN-γ, in the acute protocol, as well as IL-1β and IL-6, but not TNF-α and INF-γ, in the chronic DSS colitis protocol. Additionally, MaR1 decreased ICAM-1 mRNA expression in both the acute and chronic protocols of DSS-induced colitis. Furthermore, the beneficial effects of MaR1 seem to be associated with inhibition of the NF-κB pathway. Moreover, incubation of LPS-stimulated bone marrow–derived macrophage cultures with MaR1 reduced neutrophil migration and reactive oxygen species production, besides decreasing IL-1β, TNF-α, IL-6, and INF-γ production. Interestingly, macrophages incubated only with MaR1 showed a significant upregulation of mannose receptor C, type 1 mRNA expression, an M2 macrophage phenotype marker. These results indicate that MaR1 consistently protects mice against different models of experimental colitis, possibly by inhibiting the NF-κB pathway and consequently multiple inflammatory mediators, as well as by enhancing the macrophage M2 phenotype.

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“…In fact, PUFAs are potent anti-inflammatory mediators in controlling disease activity in DSS-induced colitis. For example, oral administration of DHA has been shown to result in a significant inhibition of body weight loss, colon shortening, and histological damage (20). Furthermore, systemic treatment with RvE1, derived from EPA, has shown marked reduction in inflammatory signals in DSS-and TNBS-induced colitis (25), which were associated with a decrease in PMN infiltration in mouse colon (25).…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidence has suggested a role of PUFAs on ameliorating disease activity in both human and experimental IBD (20)(21)(22)(23)(24). These beneficial effects on disease severity have been, in most cases, associated with a reduction in the production of arachidonic acid-derived eicosanoids, such as PGE 2 , and downregulation of proinflammatory mediators, such as TNF-a, IL-1b, and leukotriene B 4 (20,23,24).…”

mentioning

confidence: 99%

“…These beneficial effects on disease severity have been, in most cases, associated with a reduction in the production of arachidonic acid-derived eicosanoids, such as PGE 2 , and downregulation of proinflammatory mediators, such as TNF-a, IL-1b, and leukotriene B 4 (20,23,24). Furthermore, the v-3 fatty acid-derived mediator resolvin E1 (RvE1) has shown important positive effects on dextran sulfate sodium (DSS)-and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, reducing mortality and colon damage in addition to reducing PMN infiltration and production of TNF-a and IL-1b in colonic tissue (7,25).…”

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confidence: 99%

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Omega-3 Fatty Acid-Derived Mediators 17(R)-Hydroxy Docosahexaenoic Acid, Aspirin-Triggered Resolvin D1 and Resolvin D2 Prevent Experimental Colitis in Mice

Bento

Claudino

Dutra

et al. 2011

The Journal of Immunology

226

193

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Resolvins of the D series are generated from docosahexaenoic acid, which are enriched in fish oils and are believed to exert beneficial roles on diverse inflammatory disorders, including inflammatory bowel disease (IBD). In this study, we investigated the anti-inflammatory effects of the aspirin-triggered resolvin D1 (AT-RvD1), its precursor (17(R)-hydroxy docosahexaenoic acid [17R-HDHA]) and resolvin D2 (RvD2) in dextran sulfate sodium (DSS)- or 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Our results showed that the systemic treatment with AT-RvD1, RvD2, or 17R-HDHA in a nanogram range greatly improved disease activity index, body weight loss, colonic damage, and polymorphonuclear infiltration in both colitis experimental models. Moreover, these treatments reduced colonic cytokine levels for TNF-α, IL-1β, MIP-2, and CXCL1/KC, as well as mRNA expression of NF-κB and the adhesion molecules VCAM-1, ICAM-1, and LFA-1. Furthermore, AT-RvD1, but not RvD2 or 17R-HDHA, depended on lipoxin A4 receptor (ALX) activation to inhibit IL-6, MCP-1, IFN-γ, and TNF-α levels in bone marrow-derived macrophages stimulated with LPS. Similarly, ALX blockade reversed the beneficial effects of AT-RvD1 in DSS-induced colitis. To our knowledge, our findings showed for the first time the anti-inflammatory effects of resolvins of the D series and precursor 17R-HDHA in preventing experimental colitis. We also demonstrated the relevant role exerted by ALX activation on proresolving action of AT-RvD1. Moreover, AT-RvD1 showed a higher potency than 17R-HDHA and RvD2 in preventing DSS-induced colitis. The results suggest that these lipid mediators possess a greater efficacy when compared with other currently used IBD therapies, such as monoclonal anti-TNF, and have the potential to be used for treating IBD.

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Oral administration of docosahexaenoic acid attenuates colitis induced by dextran sulfate sodium in mice

Abstract: DHA was effective in alleviating DSS-induced colitis in mice, partly by modulating the expression levels of genes involved in colitis.

Cited by 51 publications

References 48 publications

Branched Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) Protect against Colitis by Regulating Gut Innate and Adaptive Immune Responses

Branched Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) Protect against Colitis by Regulating Gut Innate and Adaptive Immune Responses

Maresin 1, a Proresolving Lipid Mediator Derived from Omega-3 Polyunsaturated Fatty Acids, Exerts Protective Actions in Murine Models of Colitis

Omega-3 Fatty Acid-Derived Mediators 17(R)-Hydroxy Docosahexaenoic Acid, Aspirin-Triggered Resolvin D1 and Resolvin D2 Prevent Experimental Colitis in Mice

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