Se anexa una excelente revisión de aproximaciones nutricionales complementarias en inmunomodulación.
A Review of Complementary and Alternative Approaches to Immunomodulation
Nutrition in Clinical Practice, Vol. 23, No. 1, 49-62 (2008)
John O. Clarke, MD; and Gerard E. Mullin, MDDivision of Gastroenterology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
ABSTRACT: Current Western therapies for inflammatorydiseases are suboptimal; increasingly, patients are turning to complementary and alternative medicine forsymptom relief and improved quality of life. There isemerging evidence that many of these therapies have theability to modulate the immune system and disrupt theproinflammatory cascade through a variety of mechanisms,including antioxidant effects, alterations in cellsignaling (in particular the nuclear factor (NF)-B pathway),cytokines, proinflammatory mediators, and disruptionof bacterial flora. Using inflammatory bowel disease(IBD) as a model of inflammation, we explore the principalcomplementary and alternative medicine treatments thatshow promise in this regard, namely, resveratrol, greentea, curcumin, boswellia, fish oil, vitamin D, and probiotics.With each agent, we detail the mechanisms that havebeen described with regard to immune modulation, discussthe medical conditions for which it has been evaluated,and explore the data to date for the prevention or treatment of IBD.
The majority of reimbursed care in the UnitedStates today is via Western medicine, a traditionthat harkens back, in a primitive form, only to theRenaissance. Complementary and alternative medicine(CAM) refers to medical practices that are notcurrently considered to be part of conventional medicine.However, these “alternative” and “natural”approaches have significant time-proven history,just not in Western literature. Traditional Chinesemedicine stretches back 5000 years, and traditionalIndian (Ayurvedic) medicine can trace its history forover 2000 years. At the start of the 20th century, infact, there were already 30,000-40,000 booksregarding these practices already in existence.With all the focus on drug development andmarketing, it is easy to forget that nutrition representsthe world’s earliest medicinal therapy. In thewords of Hippocrates (obviously translated) “He whodoes not know food-how can he cure the disease ofman?” Many of the medicinal agents used for therapytoday are directly derived from food sources. Therole of functional foods in health and disease preventionis a rapidly growing field.1 Who knows howmany other agents are present in everyday foodsthat have not yet been tapped?This article will aim to clarify what is knownabout alternative and nutrition therapies for immunomodulation.Obviously, this is a broad therapy,and so discussion will be restricted to a few keycategories: polyphenols (including resveratrol, epigallocatechin,curcumin, and boswellia), -3 essentialfatty acids (EFA; fish oil), vitamin D, and probiotics.Although many diseases can be examined as amodel for inflammation (including inflammatorybowel disease [IBD], rheumatoid arthritis, and multiplesclerosis, to name a few), we have elected tofocus on IBD exclusively because: (a) we are gastroenterologistsand this is our bias, and (b) to dwell onevery inflammatory condition would make thispaper too unwieldy to be readable without coercion.In the words of Hippocrates: “Let food be thymedicine.”
Polyphenols are phytochemicals that are found infood substances produced from plants. Polyphenols are separated from essential micronutrients in that a deficiency state has not been identified; nevertheless, these chemicals are believed to play a biologically active role and have been shown to be potentially immunomodulating.2 Although numerouspolyphenols have been identified, 4 in particular have a preponderance of evidence in the role of immune modulation and will be addressed in this review: resveratrol, epigallocatechin, curcumin, andboswellia. The findings of polyphenols to preventand treat animal models of IBD are summarized inTable 1.(3-22)
Resveratrol, trans-3,5,4-trihydroxy-trans-stilbene,is a phytochemical produced by plants. It hasbeen identified in 70 plant species, includinggrapes, peanuts, berries, and pines; however, it isbelieved to be most abundant in the skin of redgrapes, contributing to a high concentration in redwine and grape juice.23 Since the initial reportlinking resveratrol to the possible cardioprotectivebenefits seen with red wine, hundreds of papershave been published showing purported health benefits.24 These have encompassed a wide array ofillnesses, including cardiovascular disease,25-29 cancer,23,30-33 immunomodulation,34-38 and longevity.39,40Numerous mechanisms for resveratrol have beenproposed, including inhibition of cyclooxygenase(COX), hydroperoxidase, protein kinase C, Bcl-2phosphorylation, Akt (an anti-apoptic kinase), focaladhesion kinase, nuclear factor (NF)-B, matrixmetalloprotease-9, and cell cycle regulators.23 Withregard to anti-inflammatory and immunomodulatoryeffects, the exact mechanism by which resveratrolworks has not been clearly established; nevertheless,significant interest has been paid to thispotential role, given that COX inhibitors are commonlyused as anti-inflammatory drugs and resveratrolis a potent inhibitor of COX activity in vivo.41,42However, the effect of resveratrol on the immunesystem does not seem to be mechanistically as simpleas nonspecific inhibition of inflammation; resveratrolseems to enhance the immune response ofmice treated with the arylating substance dinitrofluorobenzeneand prevents immunosuppression byethanol.36 Resveratrol also appears to protect micefrom infection with herpes simplex viruses.43,44 Theexact mechanisms by which resveratrol differentiallyinhibits and enhances the immune systemhave not been clearly elucidated.In rodent models of inflammatory colitis, intragastricresveratrol given acutely before and aftercolonic injury has been shown to reverse weight loss,increase stool consistency, improve mucosal appearance,improve histopathology, decrease inflammatoryinfiltrate, and decrease mucosal levels of interleukin(IL)-1, COX-2, and prostaglandin (PG) D2.45 In another study by the same group, intragastricresveratrol was given for a 14-day period aftercolonic injury and was shown to increase stool consistency;improve colonic appearance and histopathology;decrease tumor necrosis factor- (TNF),NFB, and colonic myeloperoxidase (MPO) activity;and normalize prostaglandin E2 (PGE2) levels.4 Todate, resveratrol has not yet been studied in humansubjects with IBD; however, given its impressiveresults in the rodent model, it seems like a reasonablenext step, if issues of cost, bioavailability, andtoxicity can be ironed out.24,46
Catechins refer to monomers of flavonols withsimilar composition such as catechin, epicatechin,epigallocatechin, epicatechin gallate (EGC) and epigallocatechingallate (EGCG). These compounds areparticularly abundant in green (nonfermented) tea,whereas black tea contains theaflavins and thearubigins.47,48 Given that tea is the most consumedbeverage in the world other than water,49,50 thehealth benefits present in these chemicals maytranslate to significant public health benefits on aglobal scale. Reports have linked green tea to beneficialeffects in the prevention or treatment of cancer(breast,51,52 ovarian,53 prostate,54 stomach,55-57 andlung58), hypertension,59-61 cardiovascular disease,56,62-66 oral health (dental caries, periodontaldisease, and tooth loss),67 skin disease,68,69 weightmanagement,70,71 osteoporosis,48 and glucose tolerance.72,73 There is also significant data evaluatingthe role of catechins in immune modulation, whichwill be detailed below.The mechanisms by which catechins achieve theirbeneficial effects is still not entirely clear; however,there is mounting evidence that they likely workthrough a combination of both antioxidant effect andalteration of intracellular signaling (primarilythrough inhibition of the NFB pathway). Catechins,particularly EGCG, are effective free radicalscavengers in vitro74; however, it has been suggestedby some researchers that these compoundsmay play a relatively minor role as antioxidants in vivo due to low circulating levels and rapid metabolism.75 This has led to investigation into the role ofcatechins in cell signaling, and it has now beendemonstrated that EGCG can modulate and inhibitNFB activity.76 Given that expression of IL-8, amajor human inflammatory mediator, is dependenton IL-1 activation of NFB, it stands to reason thatinhibition of the NFB cascade may result in aprofound effect on inflammation. To support this,studies have shown that administration of EGCGcan affect and inhibit the infiltration of CD8 T cellsinto sites of inflammation.77Using IBD as a marker of a chronic inflammatorydisease, the current data on catechin administrationare promising. Using a murine colitis model withIL-2 deficiency, investigators were able to show thatoral administration of green tea extract for 6 weeksafter disease presentation resulted in weight gain,improved colonic histopathology, decreased colonicweight, and increased hematocrit (Table 1).6 Inanother study involving a murine IBD model, it wasshown that green tea polyphenol extract given for 3days before and 7 days after a caustic triggerresulted in decreased weight loss, improved diarrhea,improved histopathology, decreased seruminflammatory cytokines, and improved hematocrit.5 Similar findings were reported in a rat model ofcolitis given green tea polyphenols extract for aperiod of 5 days.3 An in vitro study involving humancolonic tissue showed that administration of EGCGresulted in decreased proinflammatory cytokine productionand down-regulation of genes involved ininflammation.78 To date, there are no in vivo humanstudies evaluating the role of green tea extract inIBD; however, given the encouraging results aboveand the excellent safety profile of these agents, it ishard to imagine that these studies are far away.
Turmeric, the major spice in curry, is a naturalspice made from the herb Curcuma longa, a memberof the ginger family. Besides being a culinary staple,it has been used in Ayurvedic medicine since ancienttimes. The major chemical constituents of turmericare curcuminoids, the most prominent of which iscurcumin. In traditional medicine, it has been usedas an oral and topical agent to treat a wide variety ofailments, including-but not limited to-pain, rheumatism,amenorrhea, liver disease, common colds,and pulmonary diseases.79-81 Given the longstandinghistory of this medication, patient preference fora “natural” remedy and the excellent safety profilein studies to date,82,83 research has exploded in theuse of curcumin for medicinal treatment, and thereis emerging literature for gastrointestinal disease.To date, over 1900 papers have been published oncurcumin (and most of these have been published inthe last 4 years). Studies to date have suggestedpossible benefits in the prevention or treatment ofnumerous diseases, including atherosclerosis,84,85cancer,86,87 neurodegenerative diseases includingAlzheimer’s dementia,88,89 pancreatitis,90,91 andrheumatoid arthritis.92,93 The number of mechanisms by which curcuminacts seems to be rivaled only by the number ofdisease processes in which it has been shown to be ofbenefit. Its antioxidant activity was initially demonstratedin 1976,94 and it has been shown to be apotent free radical scavenger both in vitro and invivo.95 Recently, investigational focus has shiftedtoward the role of curcumin as an intracellularsignaling agent, and studies have demonstratedthat curcumin, much like green tea polyphenols, isan inhibitor of NFB96,97 and leads to downstreamregulation and inhibition of proinflammatory genesand cytokines (Figure 1).47 Interestingly, the cellsignaling effects of curcumin seem to be pleiotropicas administration of curcumin has also beenreported to modulate a host of other cytokines andsignaling pathways, including inducible nitric oxidesynthase (iNOS), matrix metalloproteinase-9(MMP-9), TNF, c-Jun N-terminal kinase (JNK),p38, Akt, Janus kinase (JAK), extracellular signalregulatedprotein kinase (ERK), and protein kinaseC (PKC).47,98,99 Given the wide array of pathwaysaffected by curcumin, it is difficult to distinguishwhether the anti-inflammatory effects of this agentare due primarily to inhibition of one specific pathwayor due to the combination of multiple interlockedsystems. Hopefully, this will be clarified withongoing and future research.Given that curcumin may act through NFBinhibition and would be expected to down-regulateproinflammatory genes and decrease cytokinesinvolved in inflammation, it would stand to reasonthat IBD would be a natural avenue to explore forpossible therapeutic efficacy. Not surprisingly, thestudies to date examining this have been encouraging.Studies involving curcumin to date in the fieldof IBD have been consistently positive. Four studiesinvolving curcumin administration to murine colitismodels showed clinical and histopathologicalimprovement and, where measured, decreasedinflammatory cytokine production.8,9,12,100 Thesefindings were echoed in 3 studies involving rodentmodels of colitis.7,10,11 The natural next step wouldbe a pilot study in human subjects with IBD. Holtand colleagues101 reported in 2005 the preliminaryresults of a pilot study involving open-label administrationof curcumin preparation to 5 patients withulcerative colitis and 5 patients with Crohn’s disease.Of the 10 patients, 9 reported improvement atthe conclusion of the 1-month study. Four of the 5patients with ulcerative colitis were able to decreaseor eliminate their medications. In a larger, randomized,double-blind, multicenter trial involving 89 patients with quiescent ulcerative colitis, administrationof 1 g of curcumin twice daily resulted inboth clinical improvement and a statistically significantdecrease in the rate of relapse.102 Given its 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 andTNF.113,130Fish 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.131Numerous 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.142Recently, 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 excellent safety profile, plausible mechanism for affecting inflammation, and the results above, curcuminis poised to have a prominent role in thefuture management of IBD.
The lipophilic fraction of the gum from the treeBoswellia serrata, termed “frankincense,” is a traditional Ayurvedic remedy. It has been used in Asiaand Africa as a medical therapy for at least 3500 years and has been used to treat a wide variety ofailments, including respiratory problems, diarrhea,constipation, flatulence, central nervous system disorders,rheumatism, liver disease, wound healing,fat reduction, and fevers. It has also been used as amental tonic, taste enhancer, and even as an aphrodisiac.103,104 When the resin of different Boswellia species isanalyzed, over 200 different compounds can be identified.However, the main biologic effects of theBoswellia species are thought to be derived from agroup of chemicals referred to as tetracyclic triterpenesand pentacyclic triterpenes. These substancesare referred to commonly as boswellic acids (BA). How these agents work is not completelyunderstood. It has been shown that BA interferewith the 5-lipoxygenase pathway, with a resultantdecrease in leukotriene formation (Figure 2). This has been demonstrated in a number of invitro experiments103,105; however, there is considerabledebate as to whether suppression of 5-lipoxygenaseand leukotriene production is ofpharmacologic relevance in vivo.103 Other postulatedmolecular targets for BA include humanleukocyte elastase, CYP 2C8/2C9/3A4, topoisomeraseI, topoisomerase IIa, and IKK /. In addition,recent reports have also suggested that BAmay also exert some effect through calcium mobilizationand mitogen-activated protein kinasephosphorylation.103 A recent paper has alsoshown that BA, similar to the previously discussedpolyphenols, may have a role in inhibitionof NFB and down-regulation of the proinflammatorycascade.106 The relative contribution ofeach of the above mechanisms to the in vivoanti-inflammatory activity of Boswellia has notbeen clearly established at this time. There are now emerging data to suggest thatBoswellia may have a role to play in the managementof IBD. In a study involving a rat model ofcolitis, investigators showed that oral administrationof Boswellia extract or acetyl-11-keto--BA (AKBA) over a 2-day period resulted in adose-dependent decrease in rolling (up to 90%)and adherent (up to 98%) leukocytes. In addition, necropsy showed improvement of inflammatorychanges on both a macroscopic and microscopiclevel.20 In a murine model of colitis, a semisyntheticform of AKBA was shown to blunt diseaseactivity both grossly and histologically, reducerecruitment of adherent leukocytes and platelets,and prevent up-regulation of P-selectin (normallyobserved with this particular model of colitis). These anti-inflammatory effects were comparableto effects seen in the same murine model treatedwith corticosteroids.22 However, a benefit was notobserved in a study by a different investigationalgroup evaluating the effects of BA on a murinemodel of chemically-induced colitis, although theformulation by which BA was derived varied andthis may have partially explained the negativeresults of this study.21Few studies have been performed evaluating therole of Boswellia in human subjects with IBD.Researchers from India compared administration ofBoswellia (350 mg 3 times daily for 6 weeks) tosulfasalazine (1 g 3 times daily for 6 weeks) andfound similar improvement in clinical, laboratory,and histopathological parameters.107 The sameinvestigators reported a subsequent study comparing30 patients treated with Boswellia or sulfasalazine(at the same doses as above). Of the 20 patientstreated with Boswellia, 18 (90%) had improvementin at least 1 secondary endpoint, and 14 (70%) wentinto remission. In contrast, in the 10 patientstreated with sulfasalazine, only 6 (60%) hadimprovement in at least 1 secondary endpoint andonly 4 (40%) went into remission.108 Investigatorsfrom Germany compared B serrata extract H15 withmesalazine for the treatment of Crohn’s disease in arandomized, double-blind controlled trial involving102 patients. The primary outcome was the changein the Crohn’s Disease Activity Index, whichdecreased by 90 in the H15-treated group anddecreased by 53 in the mesalazine-treated group.The authors concluded that B serrata extract H15″appears to be superior over mesalazine in terms ofa benefit-risk-evaluation”109; however, as the studywas powered only to be a noninferiority study, theseconclusions must be interpreted with caution, andfurther research, hopefully in the form of a multicenter,randomized, controlled trial, is necessary todefinitively evaluate the role of Boswellia in thetherapeutic armamentarium of IBD.