Nutrición e Inmunomodulación II

Essential Fatty Acids
Essential fatty acids (EFA) refer to dietary constituentsthat cannot be synthesized endogenouslyand must be obtained via the diet for optimal health.By definition, these EFA can be subdivided into -3and -6 polyunsaturated fatty acids according to theposition of the initial double bond from the methylend of the fatty acid. -6 EFA are markedly morecommon in the current Western diet and may have aproinflammatory effect.  Although -3 EFA are foundin a wide variety of foods, including wild plants,eggs, nuts, and berries, they are particularly abundantin fish, and, not surprisingly, -3 EFA supplementationhas become synonymous with fishoil.110,111  Typical fish oil is extracted from fish bodiesand is composed of a variety of long-chain -3 EFA. The 2 most common EFA are eicosapentaenoic acid(EPA) and docosahexaenoic acid (DHA), which comprise18% and 12% of fish oil, respectively, in typicalmarine fish.112,113 Fish oil can also be obtained fromcod liver; however, cod liver oil has slightly less EPA(10%) and DHA (10%) than other marine oils andcan be associated with vitamin A toxicity at highdoses.  Administration of fish oil has not been associatedwith any serious acute treatment-related syndromes;however, long-term use raises theoreticalconcerns for possible increased bleeding, lipid peroxidation,and toxicity of mercury and halogenatedbiphenyls.112,114  Fish oil can be administered aseither raw fish oil or as an enteric-coated capsule. Adose of up to 3 g per day of EPA plus DHA has beendetermined to be safe for general consumption.112 The health benefits of fish oil in a broad array ofdisease processes are widely heralded.  Hu and colleagueshave reported that in a cohort of 84,688women enrolled in the Nurses’ Health Study andfollowed for a period of 16 years, deaths related tocardiovascular disease were 50% lower in womenwho consumed fish 5 times per week, and a significantreduction in cardiovascular disease was notedeven with fish consumption as infrequently as 1-3times per month.115  In fact, a PubMed search of «fishoil» and «cardiovascular disease» results in morethan 2000 entries. Other disease processes in whichfish oil has been postulated to be of benefit includehyperlipidemia,116,117 asthma,118,119 cystic fibrosis,120,121 rheumatoid arthritis,113 depression,122,123and dementia.124,125 This is by no means an exhaustivelist, as more than 11,000 papers have beenpublished to date on the benefits of fish oil.-3  EFA seem to work through a plethora ofmechanisms. To begin with, eicosanoids seem toaffect both the COX pathway (primarily COX-2) andthe 5-lipoxygenase pathway (Figure 3). ProstaglandinE2 is a proinflammatory, nociceptive factor thatis produced through the COX-2 pathway. Arachidonicacid (AA) is the usual substrate for this pathway. EPA is a chemical homolog that differs fromAA by only the presence of the -3 double bond.Therefore, EPA represents both an inhibitor of AAand an alternate substrate for COX. In addition, through similar means, EPA also results in inhibitionof the 5-lipoxygenase pathway and decreasedproduction of leukotriene B4.112,125 In addition todecreasing production of proinflammatory mediators,it has been recently shown that EPA and DHAcan act themselves as substrates for the formation ofnovel protective mediators, termed E- and D-seriesresolvins, that may have direct anti-inflammatoryeffects.127-129 -3 EFA are also thought to play a rolein the control of transcription factors such as peroxisomeproliferator-activated receptors (PPARs), withresultant down-regulation of inflammatory processes. Through these, and possibly other mechanisms,-3 EFA inhibit NFB and decrease therelease of the proinflammatory cytokines IL-1 and TNF.113,130  Fish oil and inflammation are closely intertwined. A PubMed search for the 2 terms results in morethan 600 publications and, given the mechanismsdetailed above, this is hardly surprising. Althoughthere are abundant data evaluating multiple diseasemodels of inflammation, including rheumatoidarthritis, asthma, and multiple sclerosis, the discussionin this paper will be restricted to IBD. Interestingly,the rate of IBD has traditionally been very lowin the Japanese population; however, this appears tobe changing, and one theory as to why this change isoccurring is the dietary shift from an -3 EFA-based diet to an -6 EFA-based diet.131 Numerous studies have evaluated the effects offish oil on ulcerative colitis. Several early studiessupported the notion that enteral fish oil supplementsled to improvement in IBD in animal models,132,133 and these findings were corroborated insmall clinical trials.134-136 Although a variety ofstudies have been performed exploring the roles of-3 EFA in the treatment of ulcerative colitis, themethodology and endpoints have been varied, and itis difficult to directly compare the results obtained.When clinical scores were used as an outcome (DiseaseActivity Index, Ulcerative Colitis ActivityIndex, or undefined «clinical score»),137 3 of 5 studiesshowed significant clinical improvement in the fishoil arm of the study at some point during the courseof therapy138-140 (although only 2138,140 of these 3studies showed significant benefit at the predeterminedendpoint of the study). Two studies showedno significant change between the 2 groups.134,141When endoscopic endpoints were used to evaluatethe role of fish oil in the treatment of ulcerativecolitis, 3 of 3 studies showed statistically significantimprovement in the study group that received fishoil supplementation134,140,141 (although it should benoted that one of the studies134 included patientswith both ulcerative colitis and Crohn’s disease andstatistical significance was not met when the 2subgroups were analyzed individually). When examiningthe endpoint of histologic improvement, only1141 of 3138,141,142 studies reported significantimprovement in the fish oil-treated arm of thestudy.137  However, the data that pertain to theeffects of -3 fatty acids on steroid requirementssuggest that -3 fatty acids may reduce the need ordose for corticosteroids among patients with IBD. Future studies should assess the effects of pharmaceuticalgrade enteric-coated -3 fatty acids on clinicaloutcomes in IBD, including requirements forcorticosteroids.142  Recently, a randomized, controlled trial evaluateda «nutritionally balanced oral supplementenriched with fish oil, fructooligosaccharides, gumarabic, vitamin E, vitamin C, and selenium» ondisease activity and medication use in patients withmild to moderate ulcerative colitis. A total of 121patients were randomized to this dietary supplementor placebo. The subjects were instructed toconsume 18 oz of the oral supplement daily for a6-month period, with a resultant planned fish oilintake of 3.27 g of EPA and 1.38 g of DHA daily.Clinical and histologic parameters, as well as medicationusage, were assessed at 3 and 6 months.Eighty-six patients completed the study. Both treatmentgroups (oral supplement and placebo) showedsimilar improvement in clinical and histologic indices.However, the group treated with the supplementcontaining fish oil showed a significantlygreater rate of decrease in the dose of prednisonerequired to control clinical symptoms when comparedwith the group that received placebo.144 Thistype of integrated approach with synergistic nutraceuticalsmay achieve superior outcomes in futureIBD studies. The relationship of fish oil and Crohn’s diseasehas also been extensively evaluated. The CochraneCollaboration recently published a systematicreview evaluating this topic.145 A total of 214 publicationswere evaluated and 15 randomized, controlledtrials were identified. After exclusionary criteria(including the use of non-enteric-coated fishoil supplementation), the researchers felt that 4studies were of sufficient quality to be included inthe analysis.146-149 When all 4 studies werereviewed, the Cochrane Collaboration found thatenteric-coated -3 EFA supplementation reducedthe 1-year relapse rate by half with an absolute riskreduction of 31% and a number needed to treat(NNT) of only 3.  The conclusion of the review wasthat the limited available data suggests that dailyoral therapy with enteric-coated -3 EFA supplementationis safe and may be effective for maintenanceof remission in Crohn’s disease. However,emphasis was made that the data are limited and alarger multicenter, randomized, controlled trial isneeded to definitively evaluate the issue.145


Vitamin D
Vitamin D is recognized as essential for optimalbone mineralization and the maintenance of ahealthy skeleton. Normal acquisition is via directexposure to sunlight, which induces the productionof cholecalciferol (vitamin D3). Vitamin D can also be ingested orally as either ergocalciferol (vitamin D2)or cholecalciferol (vitamin D3). Recently, there hasbeen recognition that vitamin D receptors arepresent in tissues not believed to be involved withcalcium and phosphate metabolism. This has led torenewed investigation into the role of vitamin D,and there is now increasing evidence that vitamin Dis involved in regulation of the immune system andcancer prevention.150The mechanisms by which vitamin D modulatesthe immune system are being studied extensively.Vitamin D receptors have been identifiedon almost all cell types involved in immunemodulation. Currently, it is believed that themain mechanism by which vitamin D affectsinflammation is through T-cell regulation, specificallythrough modulation of the Th1 and Th2pathways (Figure 4). Vitamin D deficiency favorsa Th1, or proinflammatory, response, whereassupplementation of vitamin D (at least in vitro)appears to shift T-cell activity toward a Th2response.  Numerous studies have been done toelucidate these mechanisms, and these studieshave recently been reviewed by one of theauthors, along with the role of Th1/Th2 responsesin IBD (G.E.M.).150,151  In addition, like most ofthe substances reviewed in this paper, vitamin Dhas also recently been shown to be an inhibitor ofthe NFB pathway (with resultant decrease inproinflammatory cytokines).152One interesting observation that may suggest arole for vitamin D in the pathogenesis of IBD is thefact that the prevalence of IBD appears to be highestin North America and Northern Europe, where direct sunlight exposure is lower.153 Further, vitaminD deficiency is common in patients with IBD,even when their disease is well controlled.154,155 Todate, there have been at least 3 animal experimentsthat have evaluated the role of either vitamin D elimination (via knockout of vitamin D receptors) orvitamin D supplementation on the development andseverity of IBD. All 3 studies have shown a consistentlink between the presence of vitamin D andeither improved parameters or delayed developmentof colitis.156-158


The gastrointestinal tract is a sterile environmentat the time of birth; thereafter, the situationrapidly changes and the human gastrointestinalsystem is colonized by at least 300-500 differentbacterial species, with concentrations of bacteria inthe large intestine that can reach 1012 cells/g ofluminal contents.159 This dynamic system of intestinalmicroflora plays a vital role in the maintenanceof intestinal health, and, increasingly, data areemerging to show that this community plays animportant role in the regulation of the mucosalinflammatory cascade.Probiotics are defined as «living microorganismsthat, upon ingestion in certain numbers, exerthealth benefits beyond those of basic nutrition.»160Although the concept of oral consumption of bacteriawas initially described over a century ago by theRussian Nobel Prize winner Metchnikoff (whoespoused the benefits of yogurt consumption onlongevity), it is only in recent years that this theoryhas gained credence and received serious scientificattention.161 In the past 5 years, over 2000 papershave been published on probiotics and a wide varietyof medical conditions, including, but not limited to,IBD, pouchitis, traveler’s diarrhea, hepatic encephalopathy,nosocomial infections, prevention of infectionafter pancreatitis, allergic diseases, irritablebowel syndrome, prevention of preterm labor,asthma, and other etiologies.The mechanisms by which probiotics exert theireffect are not entirely clear and several theoriesabound. In patients with IBD, the bacterial microflorabecome aberrant, and this may contribute tosome extent to the underlying pathogenesis of thedisease.162 One route by which probiotics may exertbenefit is through competition with the nativemicrobial pathogens for limited epithelial receptors,resulting in inhibited epithelial attachment and,thus, decreased intracellular invasion by a largevariety of toxic bacteria.163 Probiotics can also stabilizethe intestinal barrier and epithelial tightjunctions.164 However, it seems that probiotics act ina systemic manner and do not simply perform abarrier function. There is now evidence to suggestthat probiotics modulate the mucosal immuneresponse to IBD through a number of differentpathways, including inhibition of NFB, modulationof PepT1 activity, reduction of the number of CD4intraepithelial lymphocytes, regulation of the antiinflammatoryeffect via the Toll-like receptor-9(TLR9) signaling pathway, modulation of immunecell apoptosis and proliferation via TLR2 signaling,and modulation of the PPAR- pathway (Table 2). Inaddition, certain probiotics may be active secretorsof antimicrobial agents and may serve a role indecomposition of luminal pathogenic antigens.162Over 20 trials have been published in the lastfew years evaluating the role of probiotics in theprevention, treatment, and maintenance of IBD,and several excellent reviews have been recentlypublished on the matter.161,165-167 The results todate have been mixed, with probiotics thus farbenefiting ulcerative colitis more so than Crohn’sdisease.168-176 The reader is referred to these excellentreviews for a full analysis of this topic.


Over 30% of the Western population are nowusing some form of CAM.177  In the field of IBD, these numbers are estimated to be even higher (50%) given the data present in this discipline and thequestionable efficacy of existing medical therapies.178  Although many of the treatments in thispaper are not included in the texts of most medical training institutions, it is important to recognize that there is a mountain of scientific data behindthese supplements. A PubMed search for resveratrol, green tea, curcumin, boswellia, fish oil, vitaminD, or probiotics results in over 50,000 publications,and the quality of the data, in many cases, isexcellent.The immune system is a complicated process, andthere are many ways to disrupt and gently modulate this equilibrium. Polyphenols, fish oil, probiotics ,and vitamin D all promise a novel approach toattenuation and possible reversal of the inflammation cascade and do so from the safety of (in somecases) centuries of usage. Rigorous randomized, controlled,multicenter studies are needed to clarify the role of these agents in the armamentarium of Westerntherapy; however, the data are promising, and these therapies should be considered as adjuncttherapies for select patients with IBD and other inflammatory conditions.With increasing data regarding these agents, it istempting to speculate on a world in which patients would supplement their diet with natural agentsdesigned to treat their individual ailments and modify their diets early in life according to familial andenvironmental risk factors. Inflammation would bea carefully regulated phenomenon acting at thediscretion of the patient, rather than being anunwieldy albatross. A new term would have to bedevised for CAM as it would be neither complementarynor alternative any longer. The term «integrative medicine,» devised by Dr Andrew Weil for incorporatingaspects of sound diet, lifestyle factors, and nutraceuticals, together with conventional care forsuperior outcomes, may be the future direction for clinical trials and patient care. Given the exciting research detailed above, perhaps this day is coming sooner than we think.

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