Ulcerative colitis (UC) and Crohn's disease (CD) are chronic idiopathic inflammatory disorders of the gastrointestinal tract, collectively termed as Inflammatory Bowel Diseases (IBD). They are relatively common in developed countries, with reported prevalences and incidences in the USA of 200–250, and 7–9 per 100 000 people for UC, and 130–200 and 6–8 per 100 000 people for CD, respectively(Reference Kappelman, Rifas-Shiman and Kleinman1, Reference Loftus, Loftus and Harmsen2). In Europe, a North-South gradient has been described, but the incidence appears to have increased in Southern and developing countries in recent years(Reference Shivananda, Lennard-Jones and Logan3, Reference Lakatos4). While UC involves exclusively the mucosa of the colon in a variable continuous extent, CD may occur in any part of the digestive tract in a segmental transmural fashion, with the ileum and colon being the most often involved segments. Although IBD is thought to occur as a result of an inadequate and sustained immune response against luminal (most probably bacterial) antigens, its precise aetiology remains elusive(Reference Baumgart and Carding5). Therefore, there is no curative therapy (except for total proctocolectomy in UC) for these diseases, and patients should receive medical treatment for both controlling the inflammatory flares and preventing further bouts of the disease, since they typically have a relapsing and remitting course. Surgery is reserved for life-threatening acute severe refractory colitis, chronic disease unresponsive to any medical therapy, or for the treatment of local complications such as strictures, fistulas or intraabdominal abscesses. Drugs effective for inducing and/or maintaining remission in IBD include aminosalicylates, corticosteroids, immunesuppressants (such as thiopurines, cyclosporin, or methotrexate), and biologic agents (mainly anti-TNF monoclonal antibodies)(Reference Travis, Stange and Lémann6, Reference Dignass, van Assche and Lindsay7). However, the use of many of these drugs encompasses an increased risk for infections (mainly opportunistic)(Reference Toruner, Loftus and Harmsen8), and concerns about the possibility of developing malignancies have also been raised(Reference Biancone, Calabrese and Petruzziello9, Reference Bewtra and Lewis10). Therefore, alternative approaches to IBD therapy, including nutritional ones, should be looked for.
Fish oil-derived omega-3 polyunsaturated fatty acids (PUFA) – namely, EPA and DHA – are good candidates for this purpose as they may exert several anti-inflammatory biological actions(Reference Calder11, Reference Calder12). Fish oil intake results in EPA incorporation, and arachidonic acid decrease in membrane phospholipids, thereby leading to a decreased synthesis of proinflammatory eicosanoids and enhanced production of they less proinflammatory or even anti-inflammatory counterparts(Reference Calder11, Reference Calder12). Also, increased generation of EPA- and DHA-derived resolvins, with anti-inflammatory or inflammation resolving actions has been described(Reference Weylandt, Kang and Wiedenmann13). Other anti-inflammatory actions of omega 3 PUFA include a) down regulation of proinflammatory cytokine synthesis (such as TNF-α, IL-1β, IL-6 and IL-8) through either a decreased activation of some nuclear transcription factors (e.g. NF-κB) or enhanced PPAR-γ activation, b) decreased leukocyte chemotaxis, and c) decreased T-cell reactivity(Reference Calder11, Reference Calder12). In the last two decades, several trials assessing the effect of omega-3 PUFA on IBD have been reported with variable results. The purpose of the present study was to systematically review the available data on the performance of fish-oil derived omega-3 PUFA as therapeutic agents for UC and CD.
Materials and methods
Search strategy
A literature search for published full articles was performed, without language restrictions, using the following databases (from inception to April 2011): Medlars Online International Literature (MEDLINE) via PubMed©, EMBASE©, and Latin American and Caribbean Heath Sciences Literature (LILACS). The following sets of keywords – including both text words and Medical Subject Heading (MeSH) terms, and adapted for each database as appropriate – combined with the boolean operator ‘OR’, were used:
Set #1: Fish oils [MeSH] OR Fatty acids, omega-3 [MeSH] OR Eicosapentaenoic acid [MeSH] OR Docosahexaenoic acid [MeSH] OR Fatty acids, essential [MeSH] OR EPA OR DHA OR n-3 fatty acids OR n-3 PUFA.
Set #2: Crohn disease [MeSH] OR Colitis, ulcerative [MeSH] OR Inflammatory Bowel Diseases [MeSH] OR Ileitis [MeSH] OR Pouchitis [MeSH] OR Crohn's OR ileocolitis OR enteritis, regional OR ileitis, regional OR rectocolitis.
Both sets of keywords were the combined with the boolean operator ‘AND’. The search was not restricted to study design, since the overall literature concerning IBD and omega-3 PUFA is not very extensive. No specific search for studies published only as abstract was performed; however, abstract studies reported in the most recent systematic reviews(Reference De Ley, De Vos and Hommes14–Reference Turner, Zlotkin and Shah16) on the field were also included in the present one. No search for ongoing studies was performed.
Eligibility
Every randomised controlled trial (RCT) of fish oil or omega-3 PUFA therapy in both active and inactive UC or CD, reporting at least one of the primary or secondary outcomes (see below), was considered potentially eligible for this systematic review. Since the broadest qualitative review (without meta-analysis) was intended, there was no limitation on either the length of therapy or the form it was given (capsules, liquid, enteric coated preparation), including nutritional supplements and enteral formula diets. Concomitant IBD therapies were allowed if they were balanced between the study groups. Studies dealing with conventional diets enriched with fish foods were not considered eligible since the dose of omega-3 PUFA is not clear in these studies. Papers reporting pooled results in UC and CD, or in active and inactive patients were also excluded.
Outcomes
Primary outcomes were remission rate (for active patients) and relapse rate (for patients in remission) during the observation period. Possible secondary outcomes included change in disease activity scores (either clinical or endoscopic), time to remission, time to first relapse, adverse events, hospitalisation rate, steroid sparing effect, disease activity at the end of follow-up period, and quality of life. Studies reporting only surrogate outcomes, such as serum/tissue levels of cytokines, eicosanoids or other inflammatory markers, were excluded.
Methods of review and data extractions
All abstracts identified by the search strategy were assessed for eligibility by one author (E. C.). Full-text studies were retrieved if they were potentially eligible or if they were relevant systematic review articles. The full-text articles were independently reviewed by two authors (E. C. and M. M.) for eligibility. Disagreements were resolved by consensus.
E. C. and M. M. also assessed eligible articles for methodological quality on the basis of the adequacy of the randomisation process, concealment of allocation, blinding of intervention and outcome, possible biases, and completeness of follow-up. The five-point Oxford quality score(Reference Jadad, Moore and Carroll17) was calculated. Final decisions for eligibility were done by mutual agreement.
For every eligible article the following data were extracted: (a) Design of the study (i.e. parallel groups, cross-over), (b) Number and characteristics of participant subjects with particular reference to activity, and extension/location and of the disease according to the Montreal classification of IBD(Reference Silverberg, Satsangi and Ahmad18), time in remission (for patients with inactive IBD), (c) details on both the therapeutic intervention and that used for comparison (i.e. placebo or other widely accepted therapy for IBD), and (d) the reported outcomes.
Results
The initial search yielded a total of 284 articles, 28 of which being considered potentially eligible as they reported results of clinical trials. Of these, one was an open trial(Reference Salomon, Kornbluth and Janowitz19), six reported pooled results of UC and CD and/or active and inactive patients(Reference Lorenz, Weber and Szimnau20–Reference Brunborg, Madland and Lind25), three investigated only surrogate endpoints(Reference Geerling, Badart-Smook and van Deursen26–Reference Nielsen, Nielsen and Gronbaek28), one dealt with omega-3 FA rich conventional foods(Reference Uchiyama, Nakamura and Odahara29), and two compared enteral formulas not enriched with omega-3 PUFA(Reference Sakurai, Matsui and Yao30, Reference Bamba, Shimoyama and Sasaki31). The remaining 15 articles, as well as three studies published only as abstract and reported in the most recent systematic reviews on the field(Reference De Ley, De Vos and Hommes14–Reference Turner, Zlotkin and Shah16), were finally included in the present review for a total of 19 RCT(Reference Aslan and Triadafilopoulos32–Reference Grogan, Casson and Terry49), since two independent trials were reported in a single paper(Reference Feagan, Sandborn and Mittmann48) (Fig. 1). None of the eligible articles was excluded because of poor quality. Details of quality assessment of the included studies are presented in Table 1.
Fig. 1 Disposition of trials in the present systematic review. *De Ley et al. (Reference De Ley, De Vos and Hommes14), Turner et al. (Reference Turner, Steinhart and Griffiths15), and Turner et al. (Reference Turner, Zlotkin and Shah16). **Two independent trials published in the same article(Reference Feagan, Sandborn and Mittmann48).
Table 1 Methodological quality of included studies
* Gamma-linolenic acid.
Clinical effectiveness of omega-3 PUFA in IBD
Active ulcerative colitis
Seven out the 19 selected RCT, investigated the effect of omega-3 PUFA in patients with active UC(Reference Aslan and Triadafilopoulos32, Reference Stenson, Cort and Rodgers34, Reference Stack, Cole and Makhdoom40–Reference Varghese, Coomansingh and Richardson43, Reference Seidner, Lashner and Brzezinski47) (Fig. 1, Table 2). Three trials used a cross-over(Reference Aslan and Triadafilopoulos32, Reference Stenson, Cort and Rodgers34, Reference Dichi, Frenhane and Dichi42) and four a parallel-groups design(Reference Stack, Cole and Makhdoom40, Reference Almallah, Richardson and O'Hanrahan41, Reference Varghese, Coomansingh and Richardson43, Reference Seidner, Lashner and Brzezinski47). Liquid fish oil as active treatment, with sunflower oil as placebo, were used in three trials(Reference Stack, Cole and Makhdoom40, Reference Almallah, Richardson and O'Hanrahan41, Reference Varghese, Coomansingh and Richardson43), while fish oil capsules were compared with capsules with a mixture of fatty acids (mostly oleic acid) in two(Reference Aslan and Triadafilopoulos32, Reference Stenson, Cort and Rodgers34). One cross-over trial used sulfasalazine capsules as comparator instead of placebo(Reference Dichi, Frenhane and Dichi42). Finally, one trial compared a nutritional supplement enriched with omega-3 PUFA, prebiotics (fructooligosaccharides, Arabic gum), and antioxidant micronutrients, with a sucrose-based placebo supplement(Reference Seidner, Lashner and Brzezinski47). Details on the sample size, as well as severity and extension of UC are summarised in Table 2.
Table 2 Characteristics and outcomes of studies in active ulcerative colitis
* Composite clinical and endoscopic Disease Activity Index.
Only one small trial in patients with active proctitis or distal UC reported on the primary end-point (i.e. remission rate during the observation period)(Reference Almallah, Richardson and O'Hanrahan41). After 3 months of treatment, this occurred in 9/9 patients on omega-3 PUFA v. 0/9 treated with placebo(Reference Almallah, Richardson and O'Hanrahan41). Three studies reported a significantly greater improvement in the clinical score with omega-3 PUFA as compared with placebo(Reference Aslan and Triadafilopoulos32, Reference Almallah, Richardson and O'Hanrahan41, Reference Varghese, Coomansingh and Richardson43). In two of them, this was accompanied with a significant improvement in the endoscopic(Reference Almallah, Richardson and O'Hanrahan41, Reference Varghese, Coomansingh and Richardson43) and histological score(Reference Almallah, Richardson and O'Hanrahan41). A cross-over study did not disclose differences in the clinical and endoscopic scores between fish oil or placebo therapy, but the histological index significantly improved during the fish oil period(Reference Stenson, Cort and Rodgers34). Steroid-sparing effect could not be demonstrated in two trials(Reference Stenson, Cort and Rodgers34, Reference Stack, Cole and Makhdoom40) while, in the trial where omega-3 PUFA were administered along with probiotics and antioxidants, this was the only benefit of active treatment since similar improvements in clinical, endoscopic and histological indices in both therapeutic arms were found(Reference Seidner, Lashner and Brzezinski47). Finally, in the cross-over study comparing fish oil capsules with sulfasalazine, the former resulted in a significant endoscopic improvement which was paradoxically associated to clinical worsening (as assessed by serum C-reactive protein, ESR and platelet count)(Reference Dichi, Frenhane and Dichi42).
Inactive ulcerative colitis
Four placebo-controlled RCT of parallel groups investigated the effect of omega-3 PUFA therapy for one(Reference Hawthorne, Daneshmend and Hawkey33, Reference Mantzaris, Archavlis and Zografos38, Reference Middleton, Naylor and Woolner44) or two years(Reference Loeschke, Ueberschaer and Pietsch36) in patients with UC in remission (Fig. 1, Table 3). Fish oil – either liquid(Reference Hawthorne, Daneshmend and Hawkey33, Reference Mantzaris, Archavlis and Zografos38) or encapsulated(Reference Loeschke, Ueberschaer and Pietsch36) – was used in three trials, whereas in the fourth study the active treatment was a mixture of omega-3 PUFA and the omega-6 gamma-linolenic acid(Reference Middleton, Naylor and Woolner44). Olive oil(Reference Hawthorne, Daneshmend and Hawkey33, Reference Mantzaris, Archavlis and Zografos38), corn oil(Reference Loeschke, Ueberschaer and Pietsch36), and sunflower oil(Reference Middleton, Naylor and Woolner44) were used as placebos in these trials. Details on the sample size, time in remission before entry, and extension of UC are summarised in Table 3.
Table 3 Characteristics and outcomes of studies in inactive ulcerative colitis
* Gamma-linolenic acid.
The four trials reported on the primary end-point (i.e. relapse rate during the observation period). This ranged from 27 % to 58 % in the omega-3 PUFA groups, and from 28 % to 55 % with placebo (P = non significant in all studies)(Reference Hawthorne, Daneshmend and Hawkey33, Reference Loeschke, Ueberschaer and Pietsch36, Reference Mantzaris, Archavlis and Zografos38, Reference Middleton, Naylor and Woolner44) (Table 3). Of note, in the study by Mantzaris et al., a significant benefit with fish oil was found in the subgroup of patients at high risk of relapse (those with a history of more than two relapses per year) where 3/9 on fish oil relapsed, as compared to 5/7 on placebo (P < 0·04)(Reference Mantzaris, Archavlis and Zografos38).
Active Crohn's disease
Only two RCT were identified on the effect of omega-3 FA in active CD(Reference Nielsen, Jorgensen and Nielsen45, Reference Grogan, Casson and Terry49) (Fig. 1, Table 4). In both studies, omega-3 FA were included in complete enteral formulas to be used as supplements or total enteral nutrition.
Table 4 Characteristics and outcomes of studies in active Crohn's disease
* Crohn's Disease Activity Index.
$ Alpha-linolenic acid.
‡ Paediatric Crohn's Disease Activity Index.
The first trial, conducted in adult patients, assessed the effect of an enteral supplement enriched with omega-3 FA (not only EPA and DHA, but also alpha-linolenic acid), as well as l-arginine, and RNA, as adjuvant therapy of steroid treatment in active CD(Reference Nielsen, Jorgensen and Nielsen45). Control supplement was an isocaloric standard enteral formula without any of those components, and both formulas were administered for nine weeks(Reference Nielsen, Jorgensen and Nielsen45).
The second trial was conducted in paediatric patients as a trial comparing two enteral formulas as primary treatment for active CD, with no other active therapy allowed, for six weeks(Reference Grogan, Casson and Terry49). The active formula was a polymeric diet with 1·5 % of energy as omega-3 alpha-linolenic acid (with increased amounts of antioxidant vitamins C and E), whereas the control one was an isocaloric, quasi-isonitrogenous elemental diet with only 0·4 % of energy as alpha linolenic acid(Reference Grogan, Casson and Terry49). Details on the sample size, severity, and extension of CD in these trials are shown in Table 4.
The primary end-point (i.e. remission rate during the observation period) was reported only in the paediatric trial. There were no differences in the remission rate between the alpha-linolenic enriched enteral feeding and control groups both on an intention-to-treat (70 v. 93 %) and as per protocol analysis (71 v. 70 %)(Reference Grogan, Casson and Terry49). In the adult trial, there were significant reductions in the disease activity index and serum C-reactive protein in both therapeutic groups, but again without significant between-group differences(Reference Nielsen, Jorgensen and Nielsen45). No endoscopic assessment of the effect of therapy was performed in either trial.
Inactive Crohn's disease
Six out the 19 selected RCT, investigated the effect of omega-3 PUFA in patients with CD in remission(Reference Belluzzi, Brignola and Campieri35, Reference Lorenz-Meyer, Bauer and Nicolay37, Reference Belluzzi, Campieri and Belloli39, Reference Romano, Cucchiara and Barabino46, Reference Feagan, Sandborn and Mittmann48), two of them (EPIC-1 and EPIC-2 trials) being reported in the same article(Reference Feagan, Sandborn and Mittmann48) (Fig. 1, Table 5). One trial was conducted in paediatric patients(Reference Romano, Cucchiara and Barabino46). In five studies, omega-3 PUFA were administered to maintain medically-induced CD remission(Reference Belluzzi, Brignola and Campieri35, Reference Lorenz-Meyer, Bauer and Nicolay37, Reference Romano, Cucchiara and Barabino46, Reference Feagan, Sandborn and Mittmann48), while in the remaining one they were used to prevent postoperative recurrence of the disease(Reference Belluzzi, Campieri and Belloli39) All studies were double-blind, placebo-controlled RCT of parallel groups with 12 months of therapy. Omega-3 PUFA were supplied as free fatty acids in enteric-coated capsules in five trials(Reference Belluzzi, Brignola and Campieri35, Reference Belluzzi, Campieri and Belloli39, Reference Romano, Cucchiara and Barabino46, Reference Feagan, Sandborn and Mittmann48), while non-enteric coated capsules of ethyl esters were used in the remaining one(Reference Lorenz-Meyer, Bauer and Nicolay37). Capsules of corn oil(Reference Lorenz-Meyer, Bauer and Nicolay37), olive oil(Reference Romano, Cucchiara and Barabino46), and medium-chain triglycerides (MCT)(Reference Belluzzi, Brignola and Campieri35, Reference Feagan, Sandborn and Mittmann48) were used as placebo in those studies reporting on its composition. One study (published as abstract)(Reference Belluzzi, Campieri and Belloli39) did not report on the nature of placebo but it might conceivably be MCT as in the other trial by the same authors(Reference Belluzzi, Brignola and Campieri35). Details on the sample size, time in remission before entry, and location of the disease are summarised in Table 5.
Table 5 Characteristics and outcomes of studies in inactive Crohn's disease
$Paediatric Crohn's Disease Activity Index.
* Crohn's Disease Activity Index.
All included trials reported on the primary end-point (i.e. relapse rate during the observation period). Both the study by Lorenz-Meyer et al. (Reference Lorenz-Meyer, Bauer and Nicolay37), and the EPIC-2 trial(Reference Feagan, Sandborn and Mittmann48) – both including their patients immediately after drug-induced remission – failed to demonstrate any significant difference in the relapse rate between omega-3 PUFA and placebo capsules. There were divergent results in those trials including adult patients with longer-lasting remission; the positive results obtained by Belluzzi et al. (Reference Belluzzi, Brignola and Campieri35), with a relapse rate of 28 % with fish oil capsules v. 69 % with placebo (P < 0·001), could not be confirmed by the much largely sized EPIC-1 trial (31·6 % relapse rate with fish oil v. 35·7 % with placebo)(Reference Feagan, Sandborn and Mittmann48). The paediatric study reported a significant benefit with fish oil, but the relapse rate with placebo was unexpectedly high (95 %)(Reference Romano, Cucchiara and Barabino46). Omega-3 PUFA were unable to significantly reduce the postoperative clinical recurrence rate (8 v. 21 % with placebo, P = 0·24) in a small trial of 50 CD patients undergoing bowel resection(Reference Belluzzi, Campieri and Belloli39).
Biological effects (UC and CD studies combined)
Some of the included trials also evaluated some biological effects of fish oil supplementation as compared to placebo in these patients. These included: (a) decreased serum concentrations of triglycerides(Reference Mantzaris, Archavlis and Zografos38, Reference Feagan, Sandborn and Mittmann48) and total cholesterol(Reference Mantzaris, Archavlis and Zografos38); (b) increased omega-3 PUFA and decreased arachidonic acid content in plasma lipids(Reference Loeschke, Ueberschaer and Pietsch36, Reference Seidner, Lashner and Brzezinski47, Reference Grogan, Casson and Terry49) and red blood cells(Reference Belluzzi, Brignola and Campieri35, Reference Romano, Cucchiara and Barabino46); (c) increased incorporation of EPA into the rectal mucosa(Reference Hawthorne, Daneshmend and Hawkey33); (d) attenuated proinflammatory eicosanoid profile in stimulated blood neutrophils(Reference Hawthorne, Daneshmend and Hawkey33), rectal dialysate(Reference Stenson, Cort and Rodgers34), and urine(Reference Loeschke, Ueberschaer and Pietsch36); and (e) reductions of circulating CD16+ and CD56+ cells, and the cytotoxic activity of NK cells(Reference Almallah, Richardson and O'Hanrahan41). One study could not demonstrate a greater reduction of LTB4 in colonic tissue with fish oil as compared to placebo, in spite of a better clinical performance with the former(Reference Aslan and Triadafilopoulos32).
Safety issues (UC and CD studies combined)
Safety issues are addressed in some(Reference Aslan and Triadafilopoulos32, Reference Belluzzi, Brignola and Campieri35–Reference Mantzaris, Archavlis and Zografos38, Reference Stack, Cole and Makhdoom40, Reference Middleton, Naylor and Woolner44, Reference Romano, Cucchiara and Barabino46–Reference Feagan, Sandborn and Mittmann48) but not all papers included in the review. In general, adverse events related to treatment are scarce and mild – mostly consisting of fishy taste, dyspepsia or diarrhoea – and do not usually lead to treatment discontinuation. In the largest EPIC trials, including 370 patients in the fish oil groups, and 368 in the placebo groups, the rates of discontinuation due to adverse events were 4·86 and 3·26 %, respectively(Reference Feagan, Sandborn and Mittmann48).
Discussion
The rationale for using omega-3 PUFA supplementation in the treatment of patients with UC or CD lies in the anti-inflammatory effects of these lipid compounds. The first evidence of the importance of dietary intake of omega-3 PUFA to attenuate intestinal inflammation was drawn from the epidemiological observation of low incidence of IBD in Eskimos(Reference Kromann and Green50). Furthermore, there is strong indirect evidence supporting the potential of fish oil derived fatty acids in modulating intestinal inflammation. Omega-3 PUFA are readily incorporated to inflamed bowel mucosa(Reference Hillier, Jewell and Dorrell51, Reference McCall, O'Leary and Bloomfield52) thus decreasing its content of arachidonic acid and increasing the levels of weaker proinflammatory eicosanoids(Reference Hillier, Jewell and Dorrell51). On the other hand, fish oil have proven to be protective in animal models of bowel inflammation(Reference Vilaseca, Salas and Guarner53–Reference Kono, Fujii and Ogiku56). Finally, omega-3 PUFA depletion in IBD patients has been reported by some authors(Reference Siguel and Lerman57, Reference Kuroki, Iida and Matsumoto58), but not confirmed in other studies(Reference Esteve, Ramírez and Fernández-Bañares59–Reference Figler, Gasztonyi and Cseh63).
In spite of these arguments, data collected in the present systematic review do not allow to overtly support the use of omega-3 PUFA supplementation for the treatment of both active and inactive IBD. Negative results are quite consistent in trials assessing the use of omega-3 PUFA to maintain disease remission, particularly UC(Reference Hawthorne, Daneshmend and Hawkey33, Reference Loeschke, Ueberschaer and Pietsch36, Reference Mantzaris, Archavlis and Zografos38, Reference Middleton, Naylor and Woolner44), and to a lesser extent CD(Reference Belluzzi, Brignola and Campieri35, Reference Lorenz-Meyer, Bauer and Nicolay37, Reference Belluzzi, Campieri and Belloli39, Reference Romano, Cucchiara and Barabino46, Reference Feagan, Sandborn and Mittmann48). However, it is harder to reach any conclusion from trials evaluating the role of these lipid compounds for treating active IBD. Most trials carried-out in active UC patients included a quite small number of patients, and some of them had a cross-over design(Reference Aslan and Triadafilopoulos32, Reference Stenson, Cort and Rodgers34, Reference Dichi, Frenhane and Dichi42) which does not seem to be the better approach for a disease that exhibits a natural tendency to have a relapsing-remitting course. On the other hand, the largest sized of these trials evaluated the usefulness of omega-3 PUFA associated to prebiotics and antioxidants(Reference Seidner, Lashner and Brzezinski47), making difficult to ascertain which of these compounds accounted for the observed therapeutic effect. Finally, only two trials evaluated omega-3 fatty acids for active CD both in the setting of total enteral nutrition; in the first one, omega-3 PUFA were administered in association with other potentially immunomodulatory compounds (i.e. l-arginine, and RNA)(Reference Nielsen, Jorgensen and Nielsen45), whereas the precursor α-linolenic acid, but not their long-chain derivatives (i.e. EPA, DHA), was used in the second one(Reference Grogan, Casson and Terry49).
Other reasons may account for the observed disappointing results. First, the doses of omega-3 PUFA used might have be too low to elicit a clinical therapeutic effect. It would be difficult to ascertain which is the optimal dose of omega-3 PUFA both in active and inactive IBD patients since, as previously mentioned, there is no agreement regarding the PUFA status in these patients(Reference Siguel and Lerman57–Reference Figler, Gasztonyi and Cseh63). Anyway, many studies did not monitorise either dietary omega-6 to omega-3 ratio, or plasma, red blood cell or even mucosal fatty acid profiles. Second, the different formulations used have different pharmacokinetic behaviour. Enteric-coated capsules containing free fatty acids, with a release time of one hour, appear to have a faster blood and cell fatty acid incorporation than other timed release systems or triacylglycerols(Reference Belluzzi, Brignola and Campieri64). Other studies have shown that EPA and DHA are better absorbed when administered as free fatty acids as compared to ethyl esters or triacylglycerols(Reference El Boustani, Colette and Monnier65, Reference Lawson and Hughes66). Finally, but not less important, the choice of placebo might have been not optimal in most trials. Some of them used placebos containing significant amounts of olive oil or oleic acid(Reference Aslan and Triadafilopoulos32–Reference Stenson, Cort and Rodgers34, Reference Mantzaris, Archavlis and Zografos38, Reference Romano, Cucchiara and Barabino46). Oleic acid readily incorporates to intestinal mucosa(Reference Hillier, Jewell and Dorrell51) and exhibits immunomodulatory effects both in vitro (Reference Alzoghaibi, Walsh and Willey67) and in vivo (Reference Serizawa, Miura and Imaeda68). Furthermore, olive oil has been reported to be useful in animal models of intestinal inflammation(Reference Camuesco, Gálvez and Nieto55, Reference Sanchez-Fidalgo, Villegas and Cardeno69). Other trials, including the largest EPIC trials, have used MCT as placebo(Reference Belluzzi, Brignola and Campieri35, Reference Feagan, Sandborn and Mittmann48). Although traditionally considered as immunologically inert, MCT may have anti-inflammatory properties(Reference Wanten and Naber70). In the last years, there is growing evidence that MCT may attenuate experimental intestinal inflammation(Reference Kono, Fujii and Ogiku56, Reference Tsujikawa, Ohta and Nakamura71–Reference Mañé, Pedrosa and Lorén74). Moreover, some clinical data from patients with CD suggest that replacing part of the dietary fat with MCT may help in inducing clinical remission(Reference Sakurai, Matsui and Yao30, Reference Middleton, Rucker and Kirby75–Reference Borrelli, Cordischi and Cirulli77).
In summary, although the available data are in general discouraging, the present systematic review does not allow to make firm recommendations about the usefulness of omega-3 PUFA in IBD. Extra attention about the manufacturing of placebo (perhaps using edible mineral oil) should be paid in future large-sized, high quality trials.
Acknowledgements
The authors have no conflict of interest to declare. There was no specific funding for this work. EC designed the search strategy, reviewed the potentially eligible articles, and wrote the manuscript. MM reviewed the potentially eligible articles, and approved the manuscript. MAG designed the search strategy and reviewed the manuscript.
