The Imbalance between n-6/n-3 Polyunsaturated Fatty Acids and Inflammatory Bowel Disease: A Comprehensive Review and Future Therapeutic Perspectives
<p>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.</p> "> Figure 2
<p>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.</p> "> Figure 3
<p>The immuno-suppressive and immuno-resolving approaches of inflammatory bowel disease treatment. AZA, azathioprine; PUFA, polyunsaturated fatty acid; TNF, tumour necrosis factor.</p> ">
Abstract
:1. Introduction
1.1. IBD Epidemiology and Dietary Intake of n-6/n-3 PUFAs
1.2. n-6/n-3 PUFAs and Inflammatory Processes in IBD
1.2.1. Eicosanoid Pathways and Inflammation
1.2.2. n-3 PUFAs and the Endocannabinoid Epoxides Pathway
1.2.3. n-3 PUFAs and Inflammatory Gene Expression
1.2.4. n-3 PUFAs and Adaptive Immunity
1.2.5. n-3 PUFAs, Innate Immunity, the Inflammasome, and Microbiome
1.2.6. n-3 PUFAs and Nitric Oxide
1.3. n-6 and n-3 PUFAs in IBD Clinical Trials
Cochrane Reviews of n-3 PUFAs Treatment in IBD
1.4. New Formulations and Bioavailability of n-3 PUFAs
2. Conclusions and Future Perspectives
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
5-ASA | 5-aminosalicylic acid |
AA | Arachidonic acid |
AE | Adverse event |
ALA | α-linolenic acid |
CD | Crohn’s disease |
CI | Confidence interval |
COX | Cyclooxygenase |
CDAI | Crohn’s Disease Activity Index |
CRP | C reactive protein |
DHA | Docosahexaenoic acid |
DPA | Docosapentaenoic acid |
EET | Epoxyeicosatrienoic acid |
ELOVL | Elongase of very long chain fatty acids |
EPA | Eicosapentaenoic acid |
EPIC | European Prospective Investigation into Cancer and Nutrition |
FADS | Fatty acid desaturase |
FC | Faecal calprotectin |
FFA | Free fatty acid |
GLA | n-6 gamma linolenic acid |
HETEs | Hydroxyeicosatetraenoic acid |
HR | Hazard ratio |
IBD | Inflammatory bowel disease |
IL | Interleukin |
LA | Linoleic acid |
LOX | Lipoxygenase |
LT | Leukotriene |
LX | Lipoxin |
MAPK | Mitogen-activated protein kinase |
NFkβ | Nuclear factor kB |
NLRs | NOD-like receptors |
NLRP3 | NOD-like receptor protein 3 |
NO | Nitric oxide |
NOD2 | Nucleotide-binding oligomerisation domain 2 |
NOS | Nitric oxide synthase |
OA | Oleic acid |
OR | Odds ratio |
PG | Prostaglandin |
PPAR-γ | Peroxisome proliferator-activated receptor γ |
PUFAs | Polyunsaturated fatty acids |
RBC | Red blood cell |
SNPs | Single nucleotide polymorphisms |
SPM | Specialised pro-resolving mediator |
TLRs | Toll-like receptors |
TNFα | Tumor necrosis factor α |
TX | Thromboxane |
UC | Ulcerative colitis |
VCAM-1 | Vascular cell adhesion molecule 1 |
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Study | Study Type—Duration | Number of Subjects-Inclusion Criteria | Age (years) | Supplementation | Placebo | Concurrent Medications | Outcomes | Results * |
---|---|---|---|---|---|---|---|---|
Hawthorne, 1992 | Double-blind, placebo-controlled, multicentre 1 year | 34 adults: 19 (n-3 PUFAs arm) 15 (placebo arm) In remission or while recovering from relapse No diet restrictions | 17–77 | n-3 PUFAs as 10 mL liquid form twice daily of HiEPA (5 g/day EPA + 1.2 g/day DHA, as triglyceride concentrate) | Olive oil, 10 mL twice daily | 5-ASA, steroids (≤20 mg/day) | Relapse rates (active symptoms and/or inflamed rectal mucosa) | 42% vs. 48%; (p = 0.54) |
Time to relapse (days), median (IQR) | 365 (265–365) vs. 349 (240–365) (p = NS) | |||||||
Loeschke, 1996 | Double-blind, placebo-controlled, multicenter2 years | 64 adults: 33 (n-3 PUFAs arm) 31 (placebo arm) In remission or low disease activity (Gomez score <8) | n-3 arm: 39 ± 11 # Placebo arm: 40 ± 13 # | Fish oil capsules, as long-chain ethyl esters n-3 PUFAs (5.1 g/day of total n-3 PUFAs; dose of EPA and DHA not reported) | Maize oil | 5-ASA (discontinued 3 months after randomisation) | Relapse rate (≥4-point increase in Gomez score) | 58% vs. 55%; (p = 0.81) |
Mean clinical disease activity score at the third month of treatment | 2.2 vs. 4.4 (p < 0.05) | |||||||
Mantzaris, 1996 | Double-blind, placebo-controlled,single-centre 1 year | 50 adults: 27 (n-3 PUFAs arm)23 (placebo arm) Clinical, endoscopic remissionNo diet restrictions | 17–65 | n-3 PUFAs as 10 mL liquid form twice daily of MaxEPA (3.2 g/day EPA + 2.1 g/day DHA, as triacylglycerol) | Olive oil, 10 mL twice daily5-ASA | 5-ASA (3.6 g/day) | Relapse rate (active symptoms or endoscopic signs of relapse) | 27% vs. 28% (p = 1.0) |
Time to relapse (days), median (IQR) | 235 (100–365) vs. 218 (79–365) (p > 0.1) | |||||||
Aslan, 1992 | Double-blind, placebo-controlled;crossover design 8 months (3 intervention period + 2 washout period) | 17 adultsMild to moderate disease activity | 31–74 | MaxEPA capsules (2.7 g/day EPA + 1.8 g/day DHA) | Corn oil (10.3 g OA + 2.1 g PA + 1.8 g LA) | Oral steroids (<20 mg/day) or SASP | Clinical response (decrease in DAI score after MaxEPA) | 56% vs. 4% p < 0.05 |
Steroid-sparing effects during MaxEPA therapy | 72% reduced anti-inflammatory dosage and/or eliminated steroids (p value not reported) | |||||||
Stenson, 1992 | Double-blind, placebo-controlled, randomised, multicentre; crossover design 5 months (4 intervention period + 1 washout period) | 24 adults Active disease | 25–62 | MaxEPA capsules (3.24 g/day EPA + 2.16 g/day DHA, as triacylglycerol) | Vegetable oil (12.36 g OA + 2.52 g PA + 2.16 g LA) | Prednisone, SASP | Endoscopic score improvement | n-3 PUFAs group: mean decrease of −2.09 (95% CI: −4.63 to 0.45; p = 0.06) Placebo group: mean decrease of −0.17 (95% CI: −1.75 to 1.41; p = 0.10) |
Steroid-sparing effect | NS in both groups | |||||||
Stack, 1997 | Double-blind, controlled, randomised; parallel design 4 months | 66 adults: 14 (n-3 PUFAs group) 13 (n-6 PUFAs group) 13 (n-3 and n-6 PUFAs group) 13 (placebo group) | n-3 PUFAs group: 1.5 g EPA | n-6 PUFAs group: 2.1 g GLA Placebo group: sunflower oil | Steroids | Steroid-sparing effect | No evidence with n-3 or n-6 PUFAs compared to placebo either alone or in combination (p value not reported) | |
Almallah, 1998 | Double-blind, placebo-controlled, randomised, single-centre; parallel design 6 months | 18 adults: 9 (n-3 PUFAs arm) 9 (placebo arm) Low disease activity (Gomez score < 8) On Western diet | n-3 PUFAs arm: 29–64Placebo arm: 32–72 | n-3 PUFAs as 15 mL fish-oil extract (3.2 g/day EPA + 2.4 g/day DHA) | Sunflower oil, 15 ml (2.6 g/day oleic acid + 7.9 g/day linoleic acid) | SASP or 5-ASA | Clinical response | p < 0.05 |
Endoscopic score improvement (RSS) | p = 0.013 (n-3 PUFAs arm) p = NS (placebo arm) | |||||||
Histological score improvement | p = 0.016 | |||||||
Dichi, 2000 | Randomised, single-centre; crossover design 6 months (2 intervention period + 2 washout period + 2 crossover intervention period) | 10 adults Mild to moderate disease activity | 33–65 | 5.4 g/day n-3 PUFAs fish-oil capsule, as fatty acids (180 mg EPA + 120 mg DHA in each capsule) | 2.2 g/day SASP | Laboratory blood parameters | ↑ of CRP, ERS, PLT during n-3 PUFAs treatment (p < 0.01) Changes during SASP therapy: p = NS | |
Improvement in sigmoidoscopy score | At entry, mean 9.6 (SD ± 2.8) After n-3 PUFAs treatment, mean 5.0 (SD ± 5.7) p < 0.01 | |||||||
Varghese, 2000 | Double-blind, randomised; parallel design 6 months | 51 adults: 21 (n-3 PUFAs arm) 30 (placebo arm) Active and extensive disease | Fish oil 5.6 mg/day | Sunflower oil | Clinical scores improvement | n-3 PUFAs arm: p = 0.001 (no quantitative data presented) | ||
Endoscopic score improvement | n-3 PUFAs arm: p = 0.054 (no quantitative data presented) |
Author | Study Type-Duration | Number of Subjects-Inclusion Criteria | Age (years) | Supplementation | Placebo | Concurrent Medications | Outcomes | Results (n-3 PUFAs Arm vs. Placebo arm) |
---|---|---|---|---|---|---|---|---|
Belluzzi, 1996 | Double-blind, placebo-controlled, single-centre 1 year | 78 adults: 39 (n-3 PUFAs arm) 39 (placebo arm) CDAI < 150 at baseline, but at high risk of relapse No diet restrictions | 18–67 | Enteric-coated, time-released, fish-oil capsule (1.8 g/day EPA + 0.9 g/day DHA, as FFAs) | Capsules 500 mg Miglyol 182 (caprylic acid + capric acid) | None | Relapse rate (CDAI >150 or ≥100 points increase in CDAI from baseline) | 11.28% vs. 27.69% (p < 0.001) |
Time to first relapse | >1 year vs. 4 months (log rank test 0.006) | |||||||
Adverse events | 10.3% vs. 2.6% (diarrhoea) | |||||||
Lorenz-Meyer, 1996 | Double-blind, placebo-controlled, multicenter 1 year | 135 adults: 70 (n-3 PUFAs arm) 65 (placebo arm) CDAI < 150 at baseline (steroid-induced remission after an acute relapse) Diet low in AA and rich in fibre | 17–65 | Non-enteric-coated n-3 PUFAs capsules (3.3 g/day EPA + 1.8 g/day DHA, as ethyl ester) | Corn oil | Low-dose prednisolone in the first 8 weeks | Relapse rate (CDAI >200 or ≥60 points increase in CDAI from baseline, plus ≥2 SD above normal mean CRP increase | 57.00% vs. 36.55% (p = 0.84) |
Time to first relapse | 159 days vs. 133 days (NS) | |||||||
Adverse events | 1.4% vs. 1.5% (diarrhoea) 14.3% vs. 3.1% (halitosis) 14.3% vs. 3.1% (upper GI symptoms) | |||||||
Belluzzi, 1997 | Double-blind, placebo-controlled, single-centre 1 year | 50 adults; 26 (n-3 PUFAs arm) 24 (placebo arm) CDAI <150 one month after ileal resection | Enteric-coated, time-released, fish-oil capsule (1.8 g/day EPA + 0.9 g/day DHA, as FFAs) | Capsules 500 mg Miglyol 182 (caprylic acid + capric acid) | None | Clinical relapse rate (CDAI >150 with an increase of >50 points from baseline) Histological relapse | 2.8% vs. 5.21% (p = 0.24) 9.34% vs. 15.62% (p = 0.09) | |
Adverse events | None (personal communication) | |||||||
Romano, 2005 | Double-blind, placebo-controlled, multicenter 1 year | 38 children: 18 (n-3 PUFAs arm) 20 (placebo arm) PCDAI <20 for at least 2 months at baseline | 5–16 | Enteric-coated n-3 PUFAs capsules (1.2 g/day EPA + 0.6 g/day DHA, as triglycerides) | Olive oil | Time-dependent 5-ASA (50 mg/kg/day) | Relapse rate (PCDAI > 20) | 61% vs. 95% (p < 0.001) |
Time to first relapse | 8 months vs. 1 month | |||||||
Adverse events | None | |||||||
Feagan, 2008 (EPIC-1) | Double-blind, placebo-controlled, multicenter 52 weeks | 363 adults: 183 (n-3 PUFAs arm) 180 (placebo arm) CDAI <150 for at least 3 months but <12 months at baseline | n-3 PUFAs arm: 40.5 ±15.2 # Placebo arm: 38.2 ± 13.1 # | Enteric-coated, time-released n-3 PUFAs capsules (2.2 g/day EPA + 0.8 g/day DHA, as FFAs) * | 4 g/day medium-chain triglyceride oil | None | Relapse rate (CDAI >150 or >70 points increase from baseline) | 31.6% vs. 35.7% HR 0.82, 95% CI: 0.51–1.19 (p = 0.30) |
Adverse events | 18.7% vs. 11.4% (diarrhoea)1% vs. 0.5% (dysgeusia) 9.1% vs. 2.2% (nausea) 14.4% vs. 6.5% (all upper GI symptoms) | |||||||
Change in mean CDAI | NS | |||||||
Change in SF-36 scores | NS | |||||||
Feagan, 2008 (EPIC-2) | Double-blind, placebo-controlled, Multicenter 58 weeks | 375 adults: 187 (n-3 PUFAs arm) 188 (placebo arm) CDAI < 150 after 8 weeks of steroid-induced remission | n-3 PUFAs arm: 38.5 ±13.8 # Placebo arm: 40 ± 13.6 # | Enteric-coated, time-released n-3 PUFAs capsules (2.2 g/day EPA + 0.8 g/day DHA as FFAs) * | Four 1 g of medium-chain triglyceride oil | Prednisone 20 mg/day or budesonide 6 mg/day tapered off over 8 weeks from randomisation | Relapse rate (CDAI >150 or >70 points increase from baseline) | 47.8% vs. 48.8% HR 0.90, 95% CI: 0.67–1.21 (p = 0.48) |
Adverse events | 23.2% vs. 19.7% (diarrhoea) 5.3% vs. 1.1% (dysgeusia) 15.9% vs. 10.1% (nausea) 35.4% vs. 23.9% (all upper GI symptoms) | |||||||
Change in mean CDAI | NS | |||||||
Change in SF-36 scores | NS |
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Scaioli, E.; Liverani, E.; Belluzzi, A. The Imbalance between n-6/n-3 Polyunsaturated Fatty Acids and Inflammatory Bowel Disease: A Comprehensive Review and Future Therapeutic Perspectives. Int. J. Mol. Sci. 2017, 18, 2619. https://doi.org/10.3390/ijms18122619
Scaioli E, Liverani E, Belluzzi A. The Imbalance between n-6/n-3 Polyunsaturated Fatty Acids and Inflammatory Bowel Disease: A Comprehensive Review and Future Therapeutic Perspectives. International Journal of Molecular Sciences. 2017; 18(12):2619. https://doi.org/10.3390/ijms18122619
Chicago/Turabian StyleScaioli, Eleonora, Elisa Liverani, and Andrea Belluzzi. 2017. "The Imbalance between n-6/n-3 Polyunsaturated Fatty Acids and Inflammatory Bowel Disease: A Comprehensive Review and Future Therapeutic Perspectives" International Journal of Molecular Sciences 18, no. 12: 2619. https://doi.org/10.3390/ijms18122619