Health Benefits of Apples: Phenolic Compounds and Inflammation Control, Notas de aula de Bioquímica Médica

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April 2011 | Stewed Healing Apples and Immune Cofactors 2

A proposal by Michael Ash BSc(Hons) DO, ND, F.DipION

Functional and pathological digestive tract conditions reflect a change in the relationship between the host microbiota and the mucosal immune and nervous system. These result in a wide range of distressing symptoms for which there are a variety of strategies, but no single intervention of consistent benefit. A component of patient care we sometimes overlook is that of the application of therapeutically relevant foods. For over 20 years I have been using a tried and tested formula that contemporary scientific research is now explaining why it has proven so effective for many patients.

What do I mean by effective? – Changes in inflammatory markers, reduced need for anti- inflammatory medication, better gastrointestinal function, weight loss, mood uplift and change in colonic and small intestinal flora ratios with improved digestive and eliminative function fit the bill for me.

In part these changes in symptoms are due to changes in dendritic cell (DC) regulatory function and increased oral tolerance which I hypothesise is due to increased regulatory T cell (Treg) promotion in the periphery especially in the GI Tract. This immune modulating food combination may be eaten for breakfast and dinner or as a meal substitute (no more than 1 substitution per day for many days) and as a quick and soothing snack.

Reactivity to Apples

I accept that there are patients that display reactivity to apples – the principle ingredient of this meal- and in part this is due to cross reactivity with birch pollen or latex allergy, and for others it relates to lipid transfer protein reactivity. For them, exchanging the apples for pears with all the other ingredients may offer a satisfactory alternative but as always must be judged on outcome or relevant investigations which may include changes of apple selection.^1

Stewed Healing Apples and Immune Cofactors

Recipe:

Ingredients for primary stage

6 Bramley cooking apples (or apples of choice preferably grown organically) 1/2 cup water 1/2 cup raisins/sultanas 2 tsp. cinnamon

you ate of these foods the better equipped your immune system is to handle antigen exposure. 2

Antibiotic Impact

The However, the positive health effects of apple-derived polyphenols which from in vivo studies have been identified as some of the key immune modulating elements that give apples their therapeutic value still depend on their absorption, metabolism, distribution, and elimination from the body after consumption. This process requires the availability of relevant commensal organisms and the absence of antibiotics. Antibiotics produce adverse alterations of polyphenolic breakdown. 3

Phenolic Compounds

Apples vary in their phenolic content, Honeycrisp and Red Delicious (USA) varieties had the highest total phenolic contents in one study and a there was significant correlation with antioxidant capacity (r = 0.91). 4

At individual compound level, epicatechin and procyanidin B2 were the major contributors to the antioxidant activity of apple. 5

The phenolic compounds in apples are also indicated for use in common chronic conditions; the consumption of apples could provide health benefits by reducing the risk for chronic diseases such as metabolic syndrome disease, including type 2 diabetes. 6

Apple Skins

Whilst this recipe suggests peeling the apples to obtain a satisfactory stewed consistency, the content of phenolic compounds, dietary fibre, and minerals are higher in apple peel, compared to other edible parts of this fruit. Hence apple peel may be left on some of the slices to add additional benefits.^7

Organic or Not?

Common questions arise relating to the growing methods employed and whether there is any benefit in choosing, where possible, to eat organically grown apples. Organic apples appear to have higher total phenolic content than integrated grown ones. Apples from organic production have also shown a higher content of hydroxycinnamic acids, flavanols, dihydrochalcones, quercetins and total phenolics than apples from integrated cultivation. 8

The very high levels of phenolic compound in organically grown cultivars, and with it, its importance for human health leads to my recommendation to eat regional fruits from organic fruit growing instead of those grown under integrated cultivation. Sugar levels are also higher in non-organically grown cultivars making it a valid consideration for diabetics and the additional recommendation to include the herb cinnamon for its blood sugar managing benefits.^9

However, both organic and non-organic apples display antigenotoxic potential by decreasing DNA damage after ingestion (Golden Delicious) and will still provide adequate phenols to aid immune maturation.^10

Inflammation Control

Apples through their polyphenolic compounds protect the intestinal tissues from inflammatory damage and cytokine activity via the management of a primary gene related amplifying component of immune defence called Nuclear Factor Kappa B (NFk-β) inhibition.^11

Serum C-Reactive Protein (CRP), a marker of acute inflammation levels have also been shown to have an inverse relationship with an intake of apples via flavonoid inhibition.^12

Apples also aid immune regulation and diminish mucosal sensitivity via histamine suppression through reduction of mast cell degranulation. In addition they may be able to induce oral tolerance via inhibition of specialised tolerance inducing T cells (γδ T cell) degradation under allergen exposure in the gut.^13

Brain Benefits

Apples also confer a benefit away from the GI Tract improving beta-adrenergic receptor physiology in the brain via down regulation of inflammatory cytokines.^14

Sickness behaviour (an immune driven response characterised by malaise, fatigue, anhedonia, anxiety and depression) has also been beneficially mediated via mucosal tissue activation of T helper cell phenotype Treg and cytokine management, at a human dose equivalent of 3 apples per day.

Soluble fibre, as derived from apples is resistant to digestion but fermentable. Fermentation of soluble fibre by GI bacteria (primarily in the ileum/colon) generates short-chain fatty acids (SCFAs). These SCFAs are described as two- to five-carbon weak acids, with butyrate appearing to have the greatest potential role in immunity due to its recently described palliative effect in inflammatory bowel diseases. 15 In part this appears due the improved quality of the epithelial barrier and diminished bacterial translocation and immune activation.

Butyrate is a well recognised histone deacetylase inhibitor and transcription of certain cytokines appears reliant on acetylation of histones associated with their promoters. One way that diet could regulate the innate immune system is by changing T-helper (Th) cell polarisation and impacting T helper cell cytokine signalling ratios: Th 1/2 & Th17. These effector cell determining cytokines especially the anti-inflammatory IL-4 via suppression of IFN-γ then confer a greater state of immunological tolerance. The results in this trial showed

agent by targeting the generation of regulatory APCs and IL-10(+) regulatory T cells all of which contribute to the management of aberrant inflammation.^23

Cinnamon also offers an insulin modifying role that helps to counteract the impact of consuming cooked apples (which increases the release of fruit sugars) providing access to this recipe by patients with metabolic syndrome and diabetes. The available in vitro and animal in vivo evidence suggests that cinnamon has anti-inflammatory, antimicrobial, antioxidant, antitumour, cardiovascular, cholesterol-lowering, and immunomodulatory effects. The use of cinnamon as an adjunct to the treatment of type 2 diabetes mellitus is the most promising area of research so far.^24

Yoghurt

Yoghurt derived from cow’s milk confers a number of potentially relevant immunomodulating effects in which suppression of cyclooxygenase 2 (COX2) proteins and lower pro-inflammatory cytokines feature.^25

Yoghurt derived from soy may also offer immunomodulating properties depending on the cultures using during fermentation.^26

Berries

Blueberries have been well studied to assess their effects in vivo and in vitro. Combining them with yogurt provides a synergistic effect that contributes to the suppression of colitis after just 9-10 days of ingestion.^27

Arabinogalactans

Larch arabinogalactans are high molecular weight, highly branched, water-soluble polysaccharides, which contain units of D-galactose and L-arabinose and confer sweetness to the stewed apple whilst also providing mucosal immune activation. This includes natural killer cell (NKc) cytotoxicity and complement promotion both of which operate as part of the innate and adaptive immune systems. Other changes have been noted in anaerobe combinations – changes to the balance of bacteria in the gut - and ammonia reductions suggesting it has a role as a prebiotic as well.^28 ,^29

Honey (Manuka)

Seeking to add additional bacterial modulating food ingredients may be done with Manuka Honey derived from New Zealand. This honey has shown potential in the treatment of antibiotic resistant organisms in the gastrointestinal tract.^30

Almonds in Skins

Provide protein and immune modulating effects when consumed and their skins are intact.^31 Consumed as part of the dish they also provides a protein to carbohydrate ratio benefit

References

(^1) Ebo DG, Bridts CH, Verweij MM, De Knop KJ, Hagendorens MM, De Clerck LS, Stevens WJ. Sensitization profiles in birch pollen-allergic patients with and without oral allergy syndrome to apple: lessons from multiplexed component-resolved allergy diagnosis. Clin Exp Allergy. 2010 Feb;40(2):339-47. Epub 2009 Aug 26. View Abstract 2 Rosenlund H, Kull I, Pershagen G, Wolk A, Wickman M, Bergström A. Fruit and vegetable consumption in relation to allergy: Disease-related modification of consumption? J Allergy Clin Immunol. 2011 Jan 6. View Abstract 3 Kahle K, Kempf M, Schreier P, Scheppach W, Schrenk D, Kautenburger T, Hecker D, Huemmer W, Ackermann M, Richling E. Intestinal transit and systemic metabolism of apple polyphenols. Eur J Nutr. 2010 Dec 24. View Abstract (^4) Titgemeyer EC, Bourquin LD, Fahey GC Jr, Garleb KA. Fermentability of various fiber sources by human fecal bacteria in vitro. Am J Clin Nutr. 1991 Jun;53(6):1418-24. View Abstract 5 Tsao R, Yang R, Xie S, Sockovie E, Khanizadeh S. Which polyphenolic compounds contribute to the total antioxidant activities of apple? J Agric Food Chem. 2005 Jun 15;53(12):4989-95. View Abstract 6 Barbosa AC, Pinto Mda S, Sarkar D, Ankolekar C, Greene D, Shetty K. Varietal influences on antihyperglycemia properties of freshly harvested apples using in vitro assay models. J Med Food. 2010 Dec;13(6):1313-23. Epub 2010 Sep 27. 7 View Abstract Henríquez C, Speisky H, Chiffelle I, Valenzuela T, Araya M, Simpson R, Almonacid S. Development of an ingredient containing apple peel, as a source of polyphenols and dietary fiber. J Food Sci. 2010 Aug 1;75(6):H172-81. View Abstract 8 Mikulic Petkovsek M, Slatnar A, Stampar F, Veberic R. The influence of organic/integrated production on the content of phenolic compounds in apple leaves and fruits in four different varieties over a 2-year period. J Sci Food Agric. 2010 Nov;90(14):2366-78. View Abstract 9 Hecke K, Herbinger K, Veberic R, Trobec M, Toplak H, Stampar F, Keppel H, Grill D. Sugar-, acid- and phenol contents in apple cultivars from organic and integrated fruit cultivation. Eur J Clin Nutr. 2006 Sep;60(9):1136-

40. Epub 2006 May 3. View Abstract 10 Briviba K, Stracke BA, Rüfer CE, Watzl B, Weibel FP, Bub A. Effect of consumption of organically and conventionally produced apples on antioxidant activity and DNA damage in humans. J Agric Food Chem. 2007 Sep 19;55(19):7716-21. Epub 2007 Aug 16. View Abstract 11 Jung M, Triebel S, Anke T, Richling E, Erkel G. Influence of apple polyphenols on inflammatory gene expression. Mol Nutr Food Res. 2009 Oct;53(10):1263-80. View Abstract 12 Chun OK, Chung SJ, Claycombe KJ, Song WO. Serum C-reactive protein concentrations are inversely associated with dietary flavonoid intake in U.S. adults. J Nutr. 2008 Apr;138(4):753-60. View Abstract 13 Enomoto T, Nagasako-Akazome Y, Kanda T, Ikeda M, Dake Y. Clinical effects of apple polyphenols on persistent allergic rhinitis: A randomized double-blind placebo-controlled parallel arm study. J Investig Allergol Clin Immunol. 2006;16(5):283-9. View Abstract 14 Gemma C, Mesches MH, Sepesi B, Choo K, Holmes DB, Bickford PC. Diets enriched in foods with high antioxidant activity reverse age-induced decreases in cerebellar beta-adrenergic function and increases in proinflammatory cytokines. J Neurosci. 2002 Jul 15;22(14):6114-20. View Abstract 15 Lewis K, Lutgendorff F, Phan V, Söderholm JD, Sherman PM, McKay DM. Enhanced translocation of bacteria across metabolically stressed epithelia is reduced by butyrate. Inflamm Bowel Dis. 2010 Jul;16(7):1138-48. View Abstract 16 Christina L. Sherry, Stephanie S. Kim, Ryan N. Dilger, Laura L. Bauer, Morgan L. Moon, Richard I. Tapping, George C. Fahey Jr., Kelly A. Tappenden, Gregory G. Freund. Sickness behavior induced by endotoxin can be mitigated by the dietary soluble fiber, pectin, through up-regulation of IL-4 and Th2 polarization. Original Research Article. Brain, Behavior, and Immunity, Volume 24, Issue 4, May 2010, Pages 631-640. View Abstract 17 Rastmanesh R. High polyphenol, low probiotic diet for weight loss because of intestinal microbiota interaction. Chem Biol Interact. 2011 Jan 15;189(1-2):1-8. Epub 2010 Oct 15. Review. View Abstract 18 Selma MV, Espín JC, Tomás-Barberán FA. Interaction between phenolics and gut microbiota: role in human health. J Agric Food Chem. 2009 Aug 12;57(15):6485-501. Review. View Abstract 19 Monagas M, Khan N, Andrés-Lacueva C, Urpí-Sardá M, Vázquez-Agell M, Lamuela-Raventós RM, Estruch R. Dihydroxylated phenolic acids derived from microbial metabolism reduce lipopolysaccharide-stimulated cytokine secretion by human peripheral blood mononuclear cells. Br J Nutr. 2009 Jul;102(2):201-6. View Abstract