Could a ‘Bacterial Thali’ Resolve Inflammation? – A Novel Strategy

Michael Ash BSc(Hons) DO, ND, DipION reviews the possibility that strategically selected foods and food concentrates represent a valid therapy for inflammatory illnesses.

There is substantive interest in the potential translation from bench to bedside of simple safe strategies to modify the adverse effects of inflammation. Approaching from a preventative and restorative angle the numbers of papers being published on the role of orally ingested bacteria (probiotics) and in this article – the herb Tumeric (active ingredient of which is curcumin) is presenting increasingly supportive evidence for their reasonable and safe clinical use.

Modern analytical techniques are helping to reveal novel opportunities for inflammation control in the gut and the systemic tissues in new ways that even a few years ago would have been thought of as very alternative!

Human’s intestinal microbiota consists of a complex and dynamic community of microbes. The tiny cohabitants are a vital part of the human ecosystem, profoundly influencing health through their local effects on nutrition, immunity, intestinal epithelial homeostasis and intestinal development.[1]

What is also clear is scientists are yet to discover and clearly define the composition of the ‘normal healthy intestinal microbiota’ and understand all of the complex mechanisms involved. Using sophisticated analytical metagenomic analysis of bacterial compositions two early papers have associated a ‘mix’ of bacteria with health.[2]^,[3] Another has looked at the types of proteins they secrete and noted that certain strains of lactic acid bacteria had regulatory effects on the cells of the gut.[4]

This raises the question: is it the microbe derived proteins or the specific microbial composition that directs immune mediated effects? LGG L. Rhamnosus has had its proteins cloned, and these in vitro demonstrated the ability to control inflammation and apoptosis.[5]

NF-kB Management

One of the key gene controlling mechanisms in the gastric tissue is that organised by Nuclear Factor Kappa B (NF-kB) signalling. This key transcriptional factor has a powerful effect on the management of inflammation and apoptosis. When functioning in a balanced state it has a significant role in the maintenance of normal intestinal homeostasis. If it loses its normal control then significant inflammatory disruption can occur with local and systemic risks.[6] The changes in innate immune responses that initiate and drive NF-kB signalling are essential for normal immune defence, and collateral damage is to be expected but once out of control it becomes autoimmunity – a pathological process. Environmental triggers constantly bombard humans and there is still considerable debate about whether it could be a trigger or amplifier of both. What is evolving, and very rapidly is recognition that the bacterial mix in the gut is a likely player both in terms of initiation and promotion.[7] The role of food in the management of NF-kB and apoptosis is also gathering interest, and whilst it seems obvious that dietary selection will impact on bacterial communities and inflammation there are few studies yet to explore this in detail.

Dietary Impact

In 2009 a group from Portugal exploring colorectal cancer and diet noted that patients consuming higher intakes of animal protein, refined carbohydrates, saturated fat, omega 6 fats and alchohol had higher levels of NF-kB activation (p>0.01). Attractively, in terms of options of therapy, the opposite was noted in groupd who consumed a higher intake of omega 3, fibre, vitamin E, flavanoids, β-carotenes and selenium (p<0.002).[8]

Additionally, higher n-6:n-3 fatty acids ratio (median 26:1) was associated with higher NF-κB (p < 0.006) and apoptosis (p < 0.01), and more aggressive histology (p < 0.01). Conversely, lower n-6:n-3 fatty acids ratio (median 6:1) was associated with lower NF-κB (p < 0.002) and apoptosis (p < 0.002), and less aggressive histology (p < 0.002).

Following up on the fatty acid as therapy idea, a group from St James’s Hospital in Leeds have explored the therapeutic value of using the omega 3 polyunsaturated fatty acid eicosapentaenoic acid (EPA 2000mg) as an effective chemopreventative agent in patients with familial adenomatous polyposis (FAP), in a 6 month long randomised, double-blind, placebo-controlled trial. FAP is gene related risk factor for predisposition to colorectal cancer.

A success rate of 22.4% reduction in numbers of polyps and a 29.8% reduction in their size was achieved by the therapy group, matching the benefits achieved by approved Cox-2 inhibiting medication (celecoxib & rofecoxib) and the NSAID (sulindac) yet avoiding their long term health risks.[9]

Bacterial Control

Gut bacteria and their role in NF-κB control is the new strategy for inflammation management. NF-κB is a target for the effects of microbes on immune function. For example, L reuteri, LGG, B infantis and L salivarius suppress tumour necrosis factor (TNFα)- or S typhimurium-induced IL8 gene expression and secretion by intestinal epithelial cells in a NF-κB-dependent manner.[10],[11],[12]

Another mechanism of probiotic regulation of NF-κB transcriptional activity in the nucleus is through activation of peroxisome proliferators activated receptor (PPAR)γ.[13] Other inflammatory control mechanisms employed by our microbiome include control via reactive oxygen species[14] and bacterial secreted soluble factors.[15]

Commensal (at the same table) bacteria rely on fibre for the conversion to butyrate a short chain fatty acid Butyrate is an important energy source for intestinal epithelial cells and plays a role in the maintenance of colonic homeostasis

Another mechanism of significant interest in the local and systemic control of inflammation is in the production of regulatory Tcells (Treg) in the luminal tissues and their potential benefits locally and systemically via their inflammatory controlling mechanisms and reduction of barrier dysfunction.[16] Treg cells determine the threshold between non-inflammatory homeostasis and intestinal inflammation. A balance between the function of Treg cells and the CD4⁺ effector T cells in the intestinal mucosa is also crucial for homeostasis.

SIgA

Secretory IgA plays multiple roles in maintaining immune tolerance and inflammatory control in the gut, and is essential for bacterial homeostasis.[17]^,[18]It also acts as a tagging chemical through various mechanisms for excluding unwanted bacteria and preventing bacterial contact with epithelial cells.[19]

The mechanism by which bacteria pass over their regulatory messages to the B cells for SIgA induction relies on a specialist antigen presenting call called a dendritic cell.[20] These cells are powerful messengers[1] to the mucosal tissues and the sub set called regulatory DC’s have the greatest tolerogenic effects and mostly induce Tregs.

Spice Control

Curcumin, a non-steroidal yellow pigment found in rhizomes of the perennial herb Curcuma longa, has been used for centuries in Ayurvedic medicine to cure a wide range of gastrointestinal disorders, and is a component of the spice turmeric. [21]^,[22]

Curcumin has been shown to favourably induce Treg cells by inducing IL-10 and converting naive Tcells into Treg cells by the induction of DC promoted retinoic acid (Vitamin A) and the cytokines IL-10 and TGF-Beta. Whilst this study used bone derived DC’s the end product inhibited colitis in vivo.[23] Much is yet to be learnt, but Curcumin is the object of many researchers interest as it appears to offer a number of immune benefits, when consumed. Whilst it is a poor nutrient to absorb, the co-ingestion of a black pepper extract called piperine significantly enhances absorption and provides anti-inflammatory benefits of its own.[24]^,[25]

Retinol tag teams Vit D

Vitamin A& D are also very important in terms of maintaining mucosal immunity. Vitamin D mainly produced from sunlight conversion following bodily exposure is required to make sure that effector T cells are capable of reacting when provoked.[26] However, in terms of inflammation control in the gut and related barrier integrity retinoic acid is essential for Treg formation and as both vitamins use the same receptors excess intake of Vit D may lead to a functional Vit A deficiency and related TH-17 induction of the inflammatory IL-17 cytokine.[27] IL-17 has been linked with a number of inflammatory pathologies and retinoic acid apparently, is poorly converted from β-carotene, as described by a recent Newcastle University study, where they found as many as 50% of their female subjects lacked the gene for β-carotene conversion.[28]

Comment

The potential for an exotic meal containing suitable bacteria (yogurt), curcumin, essential fatty acids and soluble fibre such as apple pectin and nuts as a therapeutic strategy is appealing. Gastronomically and therapeutically food provides us with many answers and questions about the validity of its use as a therapy but Indian food may have more to offer than a weekend treat.

Probiotics are being mined for their immune modulating roles and studies are identifying unique strains and combinations for future treatment of immune related inflammatory disorders.[29] These include IBD, atopic dermatitis and rheumatoid arthritis, the benefits being achieved through the induction of regulatory DC’s and Tregs.

The incidence of inflammatory diseases are increasing world-wide, the practical application of a therapeutic diet, which is popular and tasty makes for a strategic intervention that may prove more popular than Jamie Olivers recent attempt to change American School dinners.

A Thali is (an Indian meal with contents varying from one regional cuisine to another) a possible solution, where therapeutic foods are selected to meet the individuals inflammatory needs and present a daily solution rather than a daily provocation, after all the approximately 1 ton of food eaten each year by western adults is a lot of antigens to handle – why not help our microbial cousins by giving them the raw materials most favoured for a homeostatic response. Request your next meal to be bacterially optimised, but avoid the pathogens!

References

[1] Yan F, & Polk DB (2010). Disruption of NF-{kappa}B signalling by ancient microbial molecules: novel therapies of the future? Gut, 59 (4), 421-6 PMID: 20332512

[2] Backhed F, Ley RE, Sonnenburg JL, et al. Host–bacterial mutualism in the human intestine. Science 2005;307:1915–20. View Full Paper

[3] Gill SR,Pop M, Deboy RT, et al. Metagenomic analysis of the human distal gut microbiome. Science 2006;312:1355–9. View Full Paper

[4] Makarova K, Slesarev A, Wolf Y,et al. Comparative genomics of the lactic acid bacteria. Proc Natl Acad Sci U S A 2006;103:15611–16. View Full Paper

[5] Yan F,Cao H,Cover TL,et al. Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth. Gastroenterology 2007;132:562–75. View Abstract

[6] Spehlmann ME, Eckmann L. Nuclear factor-kappaB in intestinal protection and destruction. Curr Opin Gastroenterol 2009;25:92–9. View Abstract

[7] Chervonsky AV (2010). Influence of microbial environment on autoimmunity. Nature immunology, 11 (1), 28-35 PMID: 20016507

[8] Ravasco P, Aranha MM, Borralho PM, Moreira da Silva IB, Correia L, Fernandes A, Rodrigues CM, & Camilo M (2010). Colorectal cancer: can nutrients modulate NF-kappaB and apoptosis? Clinical nutrition (Edinburgh, Scotland), 29 (1), 42-6 PMID: 19573959

[9] West, N., Clark, S., Phillips, R., Hutchinson, J., Leicester, R., Belluzzi, A., & Hull, M. (2010). Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis Gut DOI: 10.1136/gut.2009.200642

[10] Ma D,Forsythe P,Bienenstock J. Live Lactobacillus reuteri is essential for the inhibitory effect on tumor necrosis factor alpha-induced interleukin-8 expression. Infect Immun 2004;72:5308–14. View Full Paper

[11] Zhang L, Li N,Caicedo R,et al. Alive and dead Lactobacillus rhamnosus GG decrease tumor necrosis factor-alpha-induced interleukin-8 production in Caco-2 cells. J Nutr 2005;135:1752–6. View Full Paper

[12] O’Hara AM, O’Regan P,Fanning A,et al. Functional modulation of human intestinal epithelial cell responses by Bifidobacterium infantis and Lactobacillus salivarius. Immunology 2006;118:202–15. View Abstract

[13] Kelly D, Campbell JI, King TP,et al. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear–cytoplasmic shuttling of PPAR-γ and RelA. Nat Immunol 2004;5:104–12. View Abstract

[14] Iyer C, Kosters A, Sethi G,et al. Probiotic Lactobacillus reuteri promotes TNF-induced apoptosis in human myeloid leukemia-derived cells by modulation of NF-kappaB and MAPK signalling. Cell Microbiol 2008;10:1442–52. View Abstract

[15] Heuvelin E, Lebreton C, Grangette C, et al. Mechanisms involved in alleviation of intestinal inflammation by Bifidobacterium breve soluble factors. PLoS One 2009;4:e5184. View Abstract

[16] Cong, Y., Weaver, C. T., Lazenby, A. & Elson, C. O. Bacterial-reactive T regulatory cells inhibit pathogenic immune responses to the enteric flora. J. Immunol. 169, 6112–6119 (2002). View Abstract

[17] Macpherson, A. J. et al. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 288, 2222–2226 (2000). View Abstract

[18] Suzuki K, Ha SA, Tsuji M, Fagarasan S. Intestinal IgA synthesis: a primitive form of adaptive immunity that regulates microbial communities in the gut. Semin Immunol. 2007 Apr;19(2):127-35. Epub 2006 Dec 11. Review. View Abstract

[19] Fagarasan, S. & Honjo, T. Intestinal IgA synthesis: regulation of front-line body defences. Nature Rev. Immunol. 3, 63–72 (2003). View Abstract

[20] Macpherson, A. J. & Uhr, T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303, 1662–1665 (2004). View Abstract
This study shows that DCs harbouring live commensal bacteria are restricted to the mucosal immune compartment by mesenteric lymph nodes, which thus function as an immune firewall that limits systemic penetration of commensal bacteria.

[21] Aggarwal BB, Bhatt ID, Ichikawa H, et al . Curcumin — biological and medicinal properties. 2006:297–368 View PDF

[22] Goel A,Kunnumakkara AB,Aggarwal BB. Curcumin as “Curecumin”: from kitchen to clinic. Biochem Pharmacol 2008;75:787–809. View Abstract

[23] Cong Y, Wang L, Konrad A, Schoeb T, Elson CO.Curcumin induces the tolerogenic dendritic cell that promotes differentiation of intestine-protective regulatory T cells. Eur J Immunol. 2009 Nov;39(11):3134-46. View Abstract

[24] Khajuria A, Thusu N, Zutshi U. Piperine modulates permeability characteristics of intestine by inducing alterations in membrane dynamics: influence on brush border membrane fluidity, ultrastructure and enzyme kinetics. Phytomedicine. 2002 Apr;9(3):224-31. View Abstract

[25] Srinivasan K. Black pepper and its pungent principle-piperine: a review of diverse physiological effects.Crit Rev Food Sci Nutr. 2007;47(8):735-48. Review. View Abstract

[26] von Essen MR, Kongsbak M, Schjerling P, Olgaard K, Odum N, Geisler C.Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat Immunol. 2010 Apr;11(4):344-9. Epub 2010 Mar 7.  View Abstract

[27] Strober W.Vitamin A rewrites the ABCs of oral tolerance. Mucosal Immunol. 2008 Mar;1(2):92-5. Epub 2008 Jan 16. Review. View Abstract

[28] Leung WC, Hessel S, Méplan C, Flint J, Oberhauser V, Tourniaire F, Hesketh JE, von Lintig J, Lietz G.Two common single nucleotide polymorphisms in the gene encoding beta-carotene 15,15′-monoxygenase alter beta-carotene metabolism in female volunteers. FASEB J. 2009 Apr;23(4):1041-53. Epub 2008 Dec 22. View Abstract

[29] Kwon HK, Lee CG, So JS, Chae CS, Hwang JS, Sahoo A, Nam JH, Rhee JH, Hwang KC, Im SH. Generation of regulatory dendritic cells and CD4+Foxp3+ T cells by probiotics administration suppresses immune disorders.Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2159-64. Epub 2010 Jan 13. View Abstract