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Is this a Perfect Functional Meal for Mucosal Tolerance?

Stewed apples as medicine

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.

In response to numerous requests, you may down load a PDF version of this article by simply clicking: Perfect Functional Meal for Mucosal Tolerance

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 (for added sweetness and fibre)
• 2 tsp. cinnamon

Directions

Peel and core the apples and chop them into small evenly sized pieces.

Put all the ingredients in a covered, heavy-bottomed pan and cook for about 15 minutes, stirring regularly. Cook until soft with rough shapes, no longer identifiable as apple slices. The colour should be a russet brown with the cinnamon effect.

These may be eaten warm, or cold. I suggest making up as many ramekins (sized to hold 1 – 1.5 apple equivalent in each and covered and put in the fridge for easy recovery and to avoid food deviation due to lack of availability and so maintain compliance.

Ingredients for secondary stage

• 1 tsp. of larch arabinogalactans stirred into the apple to add sweetness – if required
• 1 Saccharomyces Boulardii 250mg capsule sprinkled on the top – or swallowed separately
• 1 mix of Bifidobacteria (mixed strains) (500mg) 5billion CFU sprinkled on top – or swallowed separately
• 1 x LGG sprinkled on top – or swallowed separately
• ½ container of organic natural yogurt (dairy) or soy equivalent approx. 75mg
• Add 6-8 blueberries and 4-5 almonds in their skins
• Finally, if required, a teaspoon of Manuka honey

The Scientific Rationale.

Foods confer information to humans through the direct delivery of micro and macronutrients via different signalling mechanisms. The immune system in the gastrointestinal system is a highly active component of human health and its commensal bacterial load, in conjunction with the foods selected confer a wide range of opportunities for the delivery of specialised data to alter genetic and non-genetic derived immune outcomes.

The principle food group in this dish is apple, the reason being that they are generally well tolerated, enjoyed and well-studied. They are also easy to cook and for patients with limited access to cooking facilities or a lack of interest in cooking this dish makes a simple but powerful connection between food and health.

Allergy Protection

In analyses of individual foods, intake of apples/pears and carrots (all favourites of mine) was inversely associated with rhinitis, asthma, and atopic sensitisation. Essentially the more you ate of these foods the better equipped your immune system is to handle antigen exposure.[2]

Antibiotic Impact

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 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]

cytokines promoting cellular inflammation

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 a neuroimmune benefit and faster recovery from lipopolysaccharide (LPS) induced sickness behaviour by up to 50% over the non-soluble fibre supported group in fact the non-soluble fibre had an inverse relationship with these effects.[16]

Prebiotic

A diet high in apples also has a direct impact on bacterial colonisation in the colon and may have benefits outside of immune management in the local tissues which in part is mediated by gene to gene interactions that includes altering genetic expression related to adiposity and so aids in weight management. It does this via bacterial gene expression changes associated with a favouring of Bacteroidetes growth promotion (a genus of bacteria found in abundance in normal weight humans and deficient in obese humans), and suggests a reduction in Lactobacillus species supplementation as supportive agents in this meal if weight management is a part of the desired outcome.[17]

Phenolic compounds found in apples as already described actually rely on bacterial species in the gut to modify them and so improve or otherwise their bioactive metabolites.[18]

The dihydroxylated phenolic acids derived from the microbial metabolism of apples present marked anti-inflammatory properties, providing additional information about the health benefits of dietary polyphenols and their potential value as therapeutic agents.[19]

Apples also help to alter the pathobiont (these are commensals that alter their relationship with the host depending on environmental triggers) mix of bacteria in human guts when consumed regularly; suggesting a role for their use in mild to moderate dysbiosis induced inflammation and loss of tolerance.[20] In a small but clinically interesting study, healthy adults noted an increase in Bifidobacteria species and Lactobacillus numbers also rose, but Clostridium. Perfringens, Pseudomonas and Enterobacteriaceae declined on a diet of 2 apples a day for 2 weeks.[21]

These findings indicate that apple consumption is related to an improved intestinal environment. Apple pectin is one of the effective apple components improving the faecal environment, citrus pectin produces a better total SCFA production in human gut than, soy, sugar beet, oat and pea fibre.[22]

Cinnamon

Cinnamon is added to the apples at the time of cooking as this herb has demonstrated a number of benefits to add value to the stewed apple.

Cinnamon inhibits experimental colitis by maturing antigen presenting dendritic cells into a tolerogenic format, increasing IL-10 production and TGFβ production whilst reducing IL-1, IFN-γ and TNFα. This suggests the potential of cinnamon extract as an anti-inflammatory 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, anti-tumour, 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

[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. View Abstract

[7] 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

[20] Chow J, Mazmanian SK. A pathobiont of the microbiota balances host colonization and intestinal inflammation. Cell Host Microbe. 2010 Apr 22;7(4):265-76. View Abstract

[21] Shinohara K, Ohashi Y, Kawasumi K, Terada A, Fujisawa T. Effect of apple intake on fecal microbiota and metabolites in humans. Anaerobe. 2010 Oct;16(5):510-5. Epub 2010 Mar 19. View Abstract

[22] 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

[23] Kwon HK, Hwang JS, Lee CG, So JS, Sahoo A, Im CR, Jeon WK, Ko BS, Lee SH, Park ZY, Im SH. Cinnamon extract suppresses experimental colitis through modulation of antigen-presenting cells. World J Gastroenterol. 2011 Feb 28;17(8):976-86.

[24] Qin B, Panickar KS, Anderson RA. Cinnamon: potential role in the prevention of insulin resistance, metabolic syndrome, and type 2 diabetes. J Diabetes Sci Technol. 2010 May 1;4(3):685-93. View Abstract

[25] Urbanska AM, Paul A, Bhahena J, Prakash S. Suppression of tumorigenesis: modulation of inflammatory cytokines by oral administration of microencapsulated probiotic yogurt formulation. Int J Inflam. 2010 Oct 31;2010:894972. View Abstract

[26] Wagar LE, Champagne CP, Buckley ND, Raymond Y, Green-Johnson JM. Immunomodulatory properties of fermented soy and dairy milks prepared with lactic acid bacteria. J Food Sci. 2009 Oct;74(8):M423-30.

[27] Osman N, Adawi D, Ahrné S, Jeppsson B, Molin G. Probiotics and blueberry attenuate the severity of dextran sulfate sodium (DSS)-induced colitis. Dig Dis Sci. 2008 Sep;53(9):2464-73. Epub 2008 Feb 15 View Abstract

[28] Robinson RR, Feirtag J, Slavin JL. Effects of dietary arabinogalactan on gastrointestinal and blood parameters in healthy human subjects. J Am Coll Nutr. 2001 Aug;20(4):279-85. View Abstract

[29] Nantz M, Painter A, Parker E, McGill C, Percival S. Evaluation of arabinogalactan’s effect on human immunity. FASEB J. 2001;15:A633. View Abstract

[30] Lin SM, Molan PC, Cursons RT. The controlled in vitro susceptibility of gastrointestinal pathogens to the antibacterial effect of manuka honey. Eur J Clin Microbiol Infect Dis. 2011 Apr;30(4):569-74. Epub 2010 Dec 17. View Abstract

[31] Arena A, Bisignano C, Stassi G, Mandalari G, Wickham MS, Bisignano G. Immunomodulatory and antiviral activity of almond skins. Immunol Lett. 2010 Aug 16;132(1-2):18-23. Epub 2010 May 11. View Abstract

Related articles:

1. Specialised Protein Operates Independantly of Bacteria to Induce Mucosal Tolerance
2. Immune Tolerance in the GUT Relies on Dendritic Cells
3. Apples and Nuts Reduce Inflammation Via Mucosal Immune System
4. All Immunity is Mucosal – The GUT is No 1
5. Mechanisms of Immune Tolerance to Allergens

Keywords:Apples, Berries, cytokines, inflammation, Larch Arabino Galactans, mucosal, Phenols

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