The Imbalance between n-6/n-3 Polyunsaturated Fatty Acids and Inflammatory Bowel Disease: A Comprehensive Review and Future Therapeutic Perspectives

Abstract

Eating habits have changed dramatically over the years, leading to an imbalance in the ratio of n-6/n-3 polyunsaturated fatty acids (PUFAs) in favour of n-6 PUFAs, particularly in the Western diet. Meanwhile, the incidence of inflammatory bowel disease (IBD) is increasing worldwide. Recent epidemiological data indicate the potential beneficial effect of n-3 PUFAs in ulcerative colitis (UC) prevention, whereas consumption of a higher ratio of n-6 PUFAs versus n-3 PUFAs has been associated with an increased UC incidence. The long-chain dietary n-3 PUFAs are the major components of n-3 fish oil and have been shown to have anti-inflammatory properties in several chronic inflammatory disorders, being involved in the regulation of immunological and inflammatory responses. Despite experimental evidence implying biological plausibility, clinical data are still controversial, especially in Crohn's disease. Clinical trials of fish-oil derivatives in IBD have produced mixed results, showing beneficial effects, but failing to demonstrate a clear protective effect in preventing clinical relapse. Such data are insufficient to make a recommendation for the use of n-3 PUFAs in clinical practice. Here, we present the findings of a comprehensive literature search on the role of n-3 PUFAs in IBD development and treatment, and highlight new therapeutic perspectives.

Keywords: Crohn’s disease; inflammatory bowel disease; n-3 polyunsaturated fatty acids; omega-3 fatty acids; ulcerative colitis.

Figure 1

Outline of the pathways of synthesis for the n-3 and n-6 polyunsaturated fatty acids eicosanoids and the specialised pro-resolving mediators. AA, arachidonic acid; ALA, α-linolenic acid; COX, cyclooxygenase; CYTP450, cytochrome P450 enzymes; DHA, docosahexaenoic acid; EET, epoxyeicosatrienoic acid; EPA, eicosapentaenoic acid; HDHA, dihydroxy-docosahexaenoic acid; HPETE, hydroperoxyeicosatetraenoic acid; LA, linoleic acid; LT, leukotriene; LOX, lipoxygenase; MaR, maresin; NPD1, neuroprotectin D1; PD1, protectin D1; PG, prostaglandin; PLA2, phospholipase A2; PLC, phospholipase C; PUFA, polyunsaturated fatty acid; RvD, D series resolvins; RvE, E series resolvins; TX, thromboxane.

Figure 2

The n-3 polyunsaturated fatty acid targets of intestinal innate immunity. ALA, α-linolenic acid; CARD, caspase recognition domain; COX, cyclooxygenase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; GPR, G-protein coupled receptor; ICAM, intracellular adhesion molecule; IL, interleukin; iNOS, inducible nitric oxide synthase; MAPK, mitogen-activated protein kinase; MMPs, matrix metalloproteinase; NF-κB, nuclear factor kB; NLRP3, NOD-like receptor protein 3; NOD2, nucleotide-binding oligomerisation domain 2; PGN, bacterial peptidoglycan; PPAR-γ, peroxisome proliferator-activated receptor γ; RXR, retinoid X receptor; TLR, toll-like receptor; TNFα, tumour necrosis factor α.

Figure 3

The immuno-suppressive and immuno-resolving approaches of inflammatory bowel disease treatment. AZA, azathioprine; PUFA, polyunsaturated fatty acid; TNF, tumour necrosis factor.