Start time: 12.30pm

Finish Time: 3.30pm

In addition there are case histories, practitioner to presenter interaction and a chance to exchange your experiences and information in a supportive environment.

A small booking fee of £20 secures your place, and subject to your attendance will be transferred back to you as a credit balance to your Nutri-Link account.

Held at a private, relaxed venue, these workshops  are fantastically popular and of immense value for practitioners both new and experienced. If you would like to attend or host one of these workshops please contact Claire Bain (Seminar Coordinator) on 08450 760 402 or email claireb@nutri-linkltd.co.uk.

Attendees will receive a unique discount of 10% off all Nutri-Link supplements for the 5 working days following the workshop.

Leading experts will discuss, investigations, interventions, lipid chemistry and its role as direct therapy. This 2 day conference will bring a new perspective to your clinical practice and is suited for all practitioners involved in the management of their patients using fatty acids.

Fee

BSEM Members £280, Non-members £330 ($430 BSEM Members, $500 Non-members)

Friday, November 12th

9.00 – 10.00 Life on the Membrane – Edward Kane

An Introduction to lipid biochemistry of

cell membranes and their function

10.00 – 11.00 Phospholipid Abnormalities – Patricia Kane

in Health and Disease

11.00 – 11.30 Nutrition Break

11.30 – 12.30 Lipid Signalling in Disease – Narasimham Parinandi

12.30 – 13.00 Panel Discussion

13.00 – 14.00 Lunch

14.00 – 14.45 Phospholipids and Inflammatory Bowel Disease – Wolfgang Stremmel

14.45 – 15.30 Lipids and Endothelial Plaques – Uve Ravnskov

15.30 – 15.45 Nutrition Break

15.45 – 16.45 A Testing Portal Into The Cell – John McLaren-Howard

16.45 – 17.15 Panel Discussion

17.15  - Feedback Forms and Close

Saturday, November 13th

9.00 – 10.15 Brain Regeneration with Lipid Therapy – Patricia Kane

10.15 – 11.15 Cancer Therapy From A Cell Membrane Perspective – Meinrad Milz

11.15 -11.30 Nutrition Break

11.30 -12.30 Phospholipids and Vascular Disease – Neal Speight

12.30 -13.00 Panel Discussion

13.00 -14.00 Lunch

14.00 -14.45 Analysis of Cellular Function – John McLaren-Howard

14.45 -15.30 Clinical Case Studies – Katrin Bieber, Shideh Pouria, Patricia Kane

15.30 -15.45 Nutrition Break

15.45 -16.30 Clinical Case Studies II – Damien Downing, Neal Speight, Patricia Kane

16.30 -17.00 Panel Discussion

17.00 -17.15 Closing Remarks

For further details download the British Phospholipid Medical Conference Nov2010 brochure

The debate over XMRV began back in 2009 when researchers led by Judy Mikovits of the Whittemore Peterson Institute (WPI) for Neuro-Immune Disease in Reno, Nevada, reported in Science: traces of the virus in peripheral blood mononuclear cells, a type of white blood cell, of 67% of CFS patients. By contrast, only 3.4% of healthy controls were found to harbour the virus. The team also showed that XMRV could infect human cells and concluded that the virus—which had previously been linked to prostate cancer—might play a role in causing CFS.

See previous post here

This was then challenged and I reported on this in a subsequent posting here.

The Proceeding of the National Academy of Science (PNAS) has now published the latest paper exploring this link after holding it for review for 2 months.[1] Headed up by well known viral seeker – Harvey Alter working at the National Institute of health and the US FDA they reviewed 37 CFS patients.

The samples had been collected back in the 1990’s by a Harvard specialist and 32 (87%) of these samples showed evidence of the virus, whilst a comparable healthy group showed just 3 out of 44 (6.8%).

Most scientists remain cautious despite the obvious excellent experience of the lead scientist, in part this is because retroviruses (Retroviruses are an important group of pathogens that cause a variety of diseases in humans and animals) have previously been linked to conditions that do not after time prove to be correct.[2]

The slight fly in the ointment in this paper is that the scientists did not exactly replicate the original study design. XMRV is a so-called xenotropic murine virus, which means it can no longer enter mouse cells but can infect cells of other species. (Murine means “from mice.”) The researchers in the PNAS paper say the viral sequences they find are more diverse than that and resemble more closely the so-called polytropic viruses, which is why they adopted the term MLV-related virus, for murine leukemia virus.

This means the study found another virus albeit that the genetic material closely resembles XMRV and likely reflects the same pattern of viral infection as described by Mikovits.

The authors state:

Even if subsequent studies confirm an association between MLV-like viruses and CFS, that will not establish a causal role for these viruses in the pathogenesis of this illness. For example, such a high frequency of infections with MLV related viruses in patients with CFS could reflect an increased susceptibility to viral infections due to an underlying CFS-related immune dysfunction, rather than a primary role for these viruses in the pathogenesis of CFS.

Comment

One of the questions on everyone’s mind is why do some labs seem to find it and others do not – maybe this is down to handling techniques rather than geography as was first postulated – hopefully the relevant teams will get this aspect cleared up in the coming months. The next issue of course is what does one do about it if your patient is at some time in the future tested as positive – Indications are that maintaining a competent immune capacity is a key element of prevention – but as for resolution, more work will need to be done.

References

[2] Voisset C, Weiss RA, Griffiths DJ. Human RNA “rumor” viruses: the search for novel human retroviruses in chronic disease. Microbiol Mol Biol Rev. 2008 Mar;72(1):157-96, table of contents. View Full Paper

This study, published in PLOS One this year (2010), suggests that besides these clinical indications another slightly less obvious change to body mass affects insulin resistance and increases risk of diabetes.[1]

A cross-sectional analysis of National Health and Nutrition Examination Survey III data was undertaken, utilising subjects of 20 years or older, non-pregnant (N = 14,528). Sarcopenia was identified from bioelectrical impedance measurement of muscle mass and obesity was identified from body mass index.

Outcomes were homeostasis model assessment of insulin resistance (HOMA IR), glycosylated haemoglobin level (HbA1C), and prevalence of pre-diabetes (6.0≤ HbA1C<6.5 and not on medication) and type 2 diabetes. Covariates in multiple regression were age, educational level, ethnicity and sex.

Sarcopenia (from the Greek meaning “poverty of flesh” is the degenerative loss of skeletal muscle mass and strength associated with aging) crosses the population whether the patient is overweight or of normal body mass. As we age muscle mass declines, in part due to the reduced ability to reproduce muscle cells and in the main because people do less resistance exercise.

Sarcopenic obesity, the mutual existence of sarcopenia and obesity, appears in approx 10% of western adults aged in their 60’s.[2] This rises to a staggering 50% in those over 80,[3] with most people demonstrating a 50% muscle mass reduction if they reach the age of 90.[4]

Since muscle is the primary tissue contributing to whole-body insulin-mediated glucose disposal, sarcopenia is an important causal factor in age-induced insulin resistance and type 2 diabetes susceptibility.

The primary causes of sarcopenia include a sedentary lifestyle and malnutrition

The researchers concluded:

Sarcopenia, independent of obesity, is associated with adverse glucose metabolism, and the association is strongest in individuals under 60 years of age, which suggests that low muscle mass may be an early predictor of diabetes susceptibility

Comment

You can maintain muscle mass at any age, via resistance training

Low grade inflammation is also a common finding with sarcopenia and suggests that apart from gross nutritional strategies, that there may well be a role for targeted use of antioxidants and insulin sensitizers along with a graded exercise program.

25OHD may also be important for the maintenance of muscle function, and higher skeletal muscle mass and function, so checking Vit D and supplementing adults with at least 2000iu daily or in combination with the other key fat soluble nutrients makes a sensible intervention strategy

Exercise (both resistance and aerobic) in combination with adequate protein and energy intake is the key component of the prevention and management of sarcopenia. Adequate protein supplementation alone only slows loss of muscle mass. Adequate protein intake (leucine-enriched balanced amino acids and possibly creatine) may enhance muscle strength. Low 25(OH) vitamin D levels require vitamin D replacement.[5]

In view of these findings, dieting to be thin is by itself not enough to reduce the risk of diabetes. It is also important to be fit and, in particular, to have good muscle mass and strength.

References

[2] Davison KK, Ford ES, Cogswell ME, Dietz WH (2002) Percentage of body fat and body mass index are associated with mobility limitations in people aged 70 and older from NHANES III. J Am Geriatr Soc 50: 1802–1809 View Abstract

[3] Baumgartner RN, Stauber PM, Koehler KM, Romero L, Garry PJ (1996) Associations of fat and muscle masses with bone mineral in elderly men and women. Am J Clin Nutr 63: 365–372. View Abstract

[4] Roubenoff R (2001) Origins and clinical relevance of sarcopenia. Can J Appl Physiol 26: 78–89.  View Abstract

[5] Morley JE, Argiles JM, Evans WJ, Bhasin S, Cella D, Deutz NE, Doehner W, Fearon KC, Ferrucci L, Hellerstein MK, Kalantar-Zadeh K, Lochs H, MacDonald N, Mulligan K, Muscaritoli M, Ponikowski P, Posthauer ME, Rossi Fanelli F, Schambelan M, Schols AM, Schuster MW, Anker SD; Society for Sarcopenia, Cachexia, and Wasting Disease. Nutritional recommendations for the management of sarcopenia. J Am Med Dir Assoc. 2010 Jul;11(6):391-6. View Abstract

The paper goes on to say that over the past decade there has been a  dramatic increase in the understanding of the many biological actions that result from vitamin D acting through its daughter steroid  hormone, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] in collaboration with its cognate vitamin D receptor (VDR). In other words Vitamin D does more than support bone health.

Evidence has accumulated that beside intestine and bone, there are five additional physiological systems where the Vitamin D Receptor with 1α,25(OH)2D generates biological responses.
These include the

1. Immune system (both the innate and adaptive),
2. Pancreas and metabolic homeostasis,
3. Heart-cardiovascular,
4. Muscle and brain systems
5. as well as the control of the cell cycle, and thus of the disease process of  cancer

It does this by acting through the Vitamin D Receptor, 1α,25(OH)2D3  to produce a  wide array of favourable biological effects that collectively are projected to contribute to the improvement of human health. Responsible medicine and Nutritional Therapy demands that worldwide vitamin D nutritional guidelines should reflect current scientific knowledge about vitamin D’s spectrum of activities. Thus, worldwide vitamin D nutritional policy is now at a crossroads. This paper presents several proposed policy changes with regard to the amount of vitamin D daily intake that if implemented will maximise vitamin D’s contribution to reducing the frequency of many diseases, which would then increase the quality and longevity of life and significantly reduce the cost of medical care worldwide.

Contribution of Vitamin D to good health. The three columns on the right side, respectively, indicate the following: Physiological systems (the six physiological systems that the essential nutrient vitamin D3 supports by its metabolism to 25(OH)D3 and 1α,25(OH)2D3; biological responses (examples of biological responses generated by 1α,25(OH)2D3 in the six physiological systems); and vitamin D-deficient related diseases (identifies for each system some of the disease states that are associated with an inadequate vitamin D nutritional status)

Comment

The paper reinforces an up to date acceptance of the very issue I have been describing for a number of years; Vit D can really only be maintained at an optimal level in humans by increased exposure to sunlight or UVB – yet this is contraindicated because of increased UVB related risks, lack of sunshine, social restraints etc.

There is NO sufficient naturally vitamin D-rich food available to correct the world wide insufficiency either, therefore the only options are direct supplementation with vitamin D3 or indirect via food fortification. This also needs to be undertaken on an ongoing basis, so compliance and ease of delivery inevitably become important factors. I have found that a liquid form of Vitamin D is best tolerated and adhered to, as well as a winter holiday in the sun!

Current RDA levels are inadequate and in many cases even these are not being reached. In the absence of blood tests – and it is recommended that prior to significant supplementation >2000iu per day of VitD3 per day for months, that a blood test is arranged the doses below are recommended as meeting current scientific opinion.

Doses in the region of 5000iu per day for an adult during the winter months is regarded as safe, but for clinical purposes we suggest a periodic 25(OH)D test.

Nutritional status levels for Vitamin D as determined by circulating levels of 25(OH)D

References

[1] Norman AW, & Bouillon R (2010). Vitamin D nutritional policy needs a vision for the future. Experimental biology and medicine (Maywood, N.J.) PMID: 20667908

[2] Food and Nutrition Board. Dietary Reference Intakes for Calcium, Magnesium, Phosphorus, Vitamin D and Fluoride. Washington DC: National Academy Press, Institute of Medicine, 1997:250-87

[3] Need AG. Bone resorption markers in vitamin D insufficiency. Clin Chim Acta. 2006 Jun;368(1-2):48-52. Epub 2006 Feb 9. Review. View Abstract

[4] Vieth R, Bischoff-Ferrari H, Boucher BJ, Dawson-Hughes B, Garland CF, Heaney RP, Holick MF, Hollis BW, Lamberg-Allardt C, McGrath JJ, Norman AW, Scragg R, Whiting SJ, Willett WC, Zittermann A. The urgent need to recommend an intake of vitamin D that is effective. Am J Clin Nutr 2007;85:649–50  View Full Paper

[5] Heaney RP. The case for improving vitamin D status. J Steroid Biochem Mol Biol 2007;103:635–41 View Abstract

[6] Barger-Lux MJ, Heaney RP. Effects of above average summer sun exposure on serum 25-hydroxyvitamin D and calcium absorption. J Clin Endocrinol Metab 2002;87:4952–6 View Abstract

[7] Better OS, Shabtai M, Kedar S, Melamud A, Berenheim J, Chaimovitz C. Increased incidence of nephrolithiasis in lifeguards in Israel. In: Massry SG, Ritz E, Jaihresi G, eds. Phosphate and Minerals in Health and Disease.New York: Plenum Publishers, 1980:467–72

[8] Haddad JG, Chyu KJ. Competitive protein-binding radioassay for 25-hydroxycholecalciferol. J Clin Endocrinol Metab 1971;33:992–5  View Abstract

[9] Jacobus CH, Holick MF, Shao Q, Chen TC, Holm IA, Kolodny JM, Fuleihan GE, Seely EW. Hypervitaminosis D associated with drinking milk. N Engl J Med 1992;326:1173–7 View Abstract

Vitamin D and Vitamin A are essential co-partners in immunological and bone health.[1],[2] I’m particularly excited about vitamin A because of its profound effects on the gut mucosal immune system—a specialty of mine. Just as vitamin D has attracted attention for its ability to increase antimicrobial peptides and help us defeat pathogens, it’s fascinating to me that vitamin A is also essential for the very tissues that protect us from the same pathogens.

The availability of vitamin A in our food is a key factor in a tolerant, highly functional immune system. To quote from the title of a brilliant commentary in the March 2008 issue of Nature’s Mucosal Immunology, “Vitamin A rewrites the ABCs of oral tolerance.”[3]

Vitamin A is crucial to a very sophisticated bi-directional mechanism that takes place in the digestive system and leads to immune tolerance across the entire gut lining. Immune tolerance is the essence of good health. An intolerant immune system will lead to a wide range of illnesses, and the gut is where many people first lose immune tolerance. Vitamin A (retinoic acid) is key to our ability to consume a wide range of antigens (food) and yet not react adversely, and it’s quite fascinating.

When we speak of vitamin A, we are usually speaking of three essential fat-soluble molecules, retinol, retinal and retinoic acid. Retinol is the form in which vitamin A is stored. Retinal is crucial for vision. And retinoic acid actually functions like a hormone, binding to two receptors (RAR and RXR) and impacting over 500 different genes. Vitamin A is required for innate and adaptive immunity and is an immune enhancer that potentiates the antibody response, maintains and restores the integrity and function of all mucosal surfaces.[4]

Vitamin A is also of fundamental importance for energy homeostasis. New research finds that retinol is essential for the metabolic fitness of mitochondria. When cells are deprived of retinol, respiration and ATP synthesis fall. They recover energy output as soon as retinol is restored to physiological concentration. This may answer the nearly 100-yr-old question of why vitamin A deficiency causes so many pathologies that are independent of retinoic acid action.[5] Most important of all, the forgotten genius of vitamin A is its amazing ability to direct immune tolerance in the body through the cooperative interactions of gut-associated lymphoid tissues, Secretory IgA, bacterial communities and dendritic cells.

Immunity Starts in the Mucosa—with Vitamin A

Vitamin A cannot be synthesised by the human body; it must be absorbed by the intestine from the diet. In the presence of innate danger signals Vitamin A effects can diminish or synergise with innate responses to promote or enhance protective immunity, ensuring suitable plasticity.[6]

The cells along the vast mucosal surfaces of your body are constantly in contact with foods, microbes and toxins. They make innumerable immunological decisions every day—so many that a single day’s encounters exceed that of the rest of your immune system over a lifetime. As the gut makes its decisions, it then relays information from the innate to the adaptive, systemic immune system. Mucosal tolerance is a necessity for us to survive; without it we would not survive a single day.

The gut is where health begins, and is also home to a huge microbiome made of innumerable species of bacteria. Vitamin A is the key to the gut making the right decisions. When you are deficient in vitamin A, you veer towards a type of effector T cell called TH17 and its production of IL-17—inflammation pro-inflammatory cytokine, with propensity to causing autoimmune disease. In contrast, when your stores of vitamin A are sufficient, you’ll have enough peripheral naïve T cells converted to T regulatory cells (Tregs) to help maintain tolerance across the immune system, and quench ‘inappropriate inflammation’ derived from the effector T Cells: TH17, TH1 and TH2. [7]

The discovery of T cells that secrete IL-17 and other inflammatory cytokines-is profoundly important. The TH17 subset is centrally involved in autoimmune disease and is important in host defense at mucosal surfaces. [8]

Tregs can help control excess IL-17, and retinoic acid is essential to promote Tregs. New research also implicates IL-17 in rheumatoid arthritis; IL-17 may drive the production of harmful auto-antibodies (antibodies to our own tissue) and may trigger and support an inflammatory cascade. We now have a fascinating and emerging area of clinical investigation: finding out if is possible to use vitamin A to actually convert T cells already polarised to an inflammatory subset, back to tolerance. This would allow a restorative use of this nutrient as opposed to preventative only.

In addition to self-tolerance, a functional immune system also needs to be able to tolerate non-self-antigens that do not pose a threat. Such harmless non-self-antigens are abundant in the intestine where trillions of commensal bacteria colonise the colon and where digested food is continuously absorbed via the small intestine epithelium.

Effective immune-regulation is a condition sine qua non for the healthy gut physiology. [12] The importance of Treg cells to control and prevent aberrant immune responses directed towards self- or non-self-antigens and to establish tolerance has already been demonstrated at length.[9]

An important molecule in this context is TGF-β, abundantly produced in the gut through the gut microbes. TGF-β is a multifunctional peptide that controls proliferation, differentiation, and other functions in many cell types, promoted by commensal organisms in the gut. This is one of the roles where suitable probiotics can really add health benefits, as certain strains are known to increase human originating TGF-β.[10]

Given that effector T cells responsible for the adaptive immune responses can have a long life – sometimes years, and that inappropriate development could produce inadequate immune defenses or autoimmunity, regulatory cell formation is a powerful element of human health. And, since TH17 cells reside mainly in the mucosa of the gut, it is an elegant serendipity that our food (nutrient) choice should have such a potentially powerful effect on our local and systemic immune plasticity.

In brief, then: the achievement of oral tolerance requires the availability of vitamin A (retinoic acid) by enhancing a gut-specific mechanism of retinoic acid-enhanced, TGF-ß–dependent conversion of T cells into Treg cells.

In addition to their crucial roles in development, TGF-β and retinoic acid are involved at almost every level of immune differentiation and function, affecting passive immunity as well as innate and adaptive immunity. Both TGF-β and retinoic acid are actively produced by the intestinal epithelium and play important roles in maintaining the integrity of its barrier function, vital for systemic health.[11] The use of probiotics and suitable Vitamin A supplementation provides a combination of TGF-β and retinoic acid that will support immune tolerance in the immune compromised patient.

Vitamin A and Secretory IgA

Vitamin A has been well known for its protective roles against infections. An important part of the protective roles might be through its ability to enhance antibody responses, especially IgA antibody responses in mucosal tissues.[12]

IgA is secreted into the gut lining and provides protection against harmful pathogens. It thus helps maintain a healthy flora. Retinoic acid, derived from vitamin A in the diet, exerts a positive impact on the precursors for IgA-producing plasma cells.

In the intestine, induction and regulation of mucosal immunity takes place primarily in Peyer’s patches, together with other parts of gut-associated lymphoid tissue (GALT) and the gut-draining mesenteric lymph nodes. Every hour of every day your Peyer’s patches, clusters of cells in the lining of the small intestine, are a hotbed of signaling and conversation about the food you’re eating. Their job is to help us share our gut with trillions of bacteria in a reasonably diplomatic manner, so we have friendly handshakes at the dinner table, not food fights and drunken brawls. With adequate vitamin A our gut won’t be chronically inflamed by inappropriate T-cell conversion leading to a myriad of inflammatory diseases.[13]

Our diets have changed dramatically over time, and to try to compensate for what we’ve lost in fresh, farm grown produce and pastured dairy and meat, we’ve fortified our foods. But if people don’t tolerate fortified milk, wheat and cereals—which are common allergens—and if they don’t eat organ meats and are poor converters of carotene, they may well be deficient in vitamin A.[14] The more deficient in retinoic acid they are, the greater their risk of loss of immunological tolerance.

I give these patients a preformed vitamin A supplement of 12,500 units a day. I often find that will calm a patient’s mucosal immune system down so the foods they’re ingesting don’t act as provocateurs. Adequate vitamin A with suitable probiotics and SIgA promotion with Sacharomyces boulardii is the first step in restoring immunological health.

Carotenoids: Beautiful But Not Sufficient, and Possibly Harmful in Excess

Carotenoids have been called the colors of nature. Over 600 have been identified, and they give vegetables their gorgeous rainbow of hues, from green to orange to red to purple. About fifty can be converted into vitamin A. The major carotenoids in humans are beta-carotene, alpha-carotene, lycopene, lutein, and beta-cryptoxanthin.

However, the conversion of carotenoids to vitamin A is not as efficient or perfect as we’ve been led to believe. They can be difficult to convert, and a recent study from Newcastle University in England found that as many as 50% of women studied were unable to efficiently convert carotenoids into vitamin A—and thus may be retinoic acid deficient.

The lead researcher, Dr. George Lietz, told Science News, “What our research shows is that many women are simply not getting enough of this vital nutrient because their bodies are not able to convert the beta-carotene.”¹⁴

Other studies echo Lietz’s. Research reported in the American Journal of Clinical Nutrition in 2000 found no evidence of benefit on vitamin A status from the increased consumption of dark-green or yellow vegetables. Beta-carotene from vegetables provided an estimated vitamin A equivalence of 25 to 1—not the reported 6 to 1 for beta carotene and 12 to 1 for other carotenes. In addition, up to 50% of beta-carotene is highly dependent on fat consumption at the same time, and cooked carotenoids are better absorbed than raw. Poor protein status or zinc deficiency also affects beta-carotene uptake, and its conversion to retinol (vitamin A).[15]

In addition, carotenoids may not always be beneficial. It appears that high doses of beta-carotene under highly oxidative conditions lead to breakdown products that have toxic biological activity. Beta-carotene molecules in vitro can split into carotenoic acids that can lead to toxic cleavage products.

“What happens when these eccentric cleavage products accumulate in large amounts?” asks Robert Russell in an article in the American Journal of Clinical Nutrition, adapted from an award-winning lecture. “Do they have biological activity of their own? Could [they] interfere with the action of retinoic acid?

This may, in fact, partially explain the results from 2 carotene intervention trials…These studies showed a higher incidence of lung cancer in smokers who consumed high doses of beta-carotene.” Animal studies exposing ferrets to smoke and beta-carotene supplements showed “severe proliferation of alveolar cells and squamous metaplasia…in the beta-carotene-supplemented, smoke-exposed ferrets.”

In sum, although carotenoids offer a rainbow of important nutrition, they are not necessarily a reliable source of vitamin A.

What About Toxicity?

I believe vitamin A may, in some cases, decrease bone mineral density and increase the risk of fracture—when vitamin D stores are not adequate.[16] The Council for Responsible Nutrition reviewed all the evidence on vitamin A and fracture risk in a 2004 report, and concluded that:

“the overall database remains…conflicted and unresolved…if anything, the preponderance of evidence may have moved away from the suggestion that vitamin A might increase the risk of hip fracture.”

The council considers supplements of 10,000 IU daily of preformed vitamin A (retinol) to be generally safe. They note a long history of safe use of supplements containing up to 10,000 IU daily. Those who regularly consume liver or organ meats may be getting enough from their diet and may exercise more caution about vitamin A supplements.

Our friend, our helper, is vitamin A, a beautiful nutrient, like vitamin D. Both are sophisticated and capable of wonderful things, but having too much or too little of either one interferes with the other’s capacity to be lovely.

Read Other articles in Focus by downloading the journal here

References

[1] Maruotti N, Cantatore FP. Vitamin D and the immune system. J Rheumatol. 2010 Mar;37(3):491-5. Epub 2010 Jan 15. View Abstract

[2] Dong P, Tao Y, Yang Y, & Wang W (2010). Expression of retinoic acid receptors in intestinal mucosa and the effect of vitamin A on mucosal immunity. Nutrition (Burbank, Los Angeles County, Calif.), 26 (7-8), 740-5 PMID: 19932006

[3] Strober, W. (2008). Vitamin A rewrites the ABCs of oral tolerance Mucosal Immunology, 1 (2), 92-95 DOI: 10.1038/mi.2007.22

[4] Iwata, M., Hirakiyama, A., Eshima, Y., Kagechika, H., Kato, C., & Song, S. (2004). Retinoic Acid Imprints Gut-Homing Specificity on T Cells Immunity, 21 (4), 527-538 DOI: 10.1016/j.immuni.2004.08.011

[5] Acin-Perez R, Hoyos B, Zhao F, Vinogradov V, Fischman DA, Harris RA, Leitges M, Wongsiriroj N, Blaner WS, Manfredi G, Hammerling U. Control of oxidative phosphorylation by vitamin A illuminates a fundamental role in mitochondrial energy homoeostasis. FASEB J. 2010 Feb;24 (2):627-36. Epub 2009 Oct 7. View Abstract

[6] Brandtzaeg P. ‘ABC’ of mucosal immunology. Nestle Nutr Workshop Ser Pediatr Program. 2009;64:23-38; discussion 38-43, 251-7. Epub 2009 Aug 19 View Abstract

[7] Nolting J, Daniel C, Reuter S, Stuelten C, Li P, Sucov H, Kim BG, Letterio JJ, Kretschmer K, Kim HJ, von Boehmer H. Retinoic acid can enhance conversion of naive into regulatory T cells independently of secreted cytokines. J Exp Med. 2009 Sep 28;206(10):2131-9. Epub 2009 Sep 8. View Abstract

[8] Peck A, Mellins ED. Precarious balance: Th17 cells in host defense. Infect Immun. 2010 Jan;78(1):32-8. Epub 2009 Nov 9. Review. View Abstract

[9] A. Izcue, J.L. Coombes and F. Powrie, Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation, Immunol Rev 212 (2006), pp. 256–271 View Abstract

[10] Amit-Romach E, Uni Z, Reifen R. Multistep mechanism of probiotic bacterium, the effect on innate immune system. Mol Nutr Food Res. 2010 Feb;54(2):277-84. View Abstract

[11] Mucida D, Park Y, Cheroutre H. From the diet to the nucleus: vitamin A and TGF-beta join efforts at the mucosal interface of the intestine. Semin Immunol. 2009 Feb;21(1):14-21. Epub 2008 Sep 21. Review. View Abstract

[12] Macpherson AJ, Slack E. The functional interactions of commensal bacteria with intestinal secretory IgA. Curr Opin Gastroenterol. 2007 Nov;23(6):673-8. Review. View Abstract

[13] Kim CH. Roles of retinoic acid in induction of immunity and immune tolerance. Endocr Metab Immune Disord Drug Targets. 2008 Dec;8(4):289-94. Review. View Abstract

[14] 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

[15] Roodenburg AJ, Leenen R, van het Hof KH, Weststrate JA, Tijburg LB. Amount of fat in the diet affects bioavailability of lutein esters but not of alpha-carotene, beta-carotene, and vitamin E in humans. Am J Clin Nutr. 2000 May;71(5):1187-93. View Abstract

[16] Caire-Juvera G, Ritenbaugh C, Wactawski-Wende J, Snetselaar LG, Chen Z. Vitamin A and retinol intakes and the risk of fractures among participants of the Women’s Health Initiative Observational Study. Am J Clin Nutr. 2009 Jan;89(1):323-30. Epub 2008 Dec 3. View Abstract

In Nutritional Therapy practice when we are faced with patients who seem to be struggling with depression and are finding recovery hard as well as trying to prevent recurrence after resolving their current symptoms we often think – B Vitamins

But what is the evidence for this apparently normal recommendation – is there anything of substance that supports the therapeutic use of these water soluble vitamins.

To date most studies have been conducted using a cross sectional approach[1],[2] (a class of research methods that involve observation of some subset of a population of items all at the same time, in which, groups can be compared at different ages with respect of independent variables) rather than the preferred prospective style investigations (an analytic study designed to determine the relationship between a condition and a characteristic shared by some members of a group). A prospective study may involve many variables or only two; it may seek to demonstrate a relationship that is an association or one that is causal. Prospective studies produce a direct measure of risk called the relative risk.

Biochemically, vitamin B-6, folate, and vitamin B-12 are involved in the metabolism of homocysteine, S-adenosyl methionine, and methionine, an essential amino acid. The latter 2 compounds are critical to the production of neurotransmitters and methylation in the brain. Although the exact mechanism is unknown, the prevailing homocysteine hypothesis of depression suggests that deficiencies in vitamin B-6, folate, and vitamin B-12 can lead to elevated homocysteine concentrations, which have been associated with depression.[3]

Key points:

Objective:

We examined whether dietary intakes of vitamins B-6, folate, or vitamin B-12 were predictive of depressive symptoms over an average of 7.2 y in a community-based population of older adults.

Design:

The study sample consisted of 3503 adults from the Chicago Health and Aging project, an ongoing, population-based, biracial (59% African American) study in adults aged 65 y. Dietary assessment was made by food-frequency questionnaire. Incident depression was measured by the presence of 4 depressive symptoms from the 10-item version of the Center for Epidemiologic Studies Depression scale.

Results:

The logistic regression models, which used generalized estimating equations, showed that higher total intakes, which included supplementation, of vitamins B-6 and B-12 were associated with a decreased likelihood of incident depression for up to 12 y of follow-up, after adjustment for age, sex, race, education, income, and antidepressant medication use. For example, each 10 additional milligrams of vitamin B-6 and 10 additional micrograms of vitamin B-12 were associated with 2% lower odds of depressive symptoms per year. There was no association between depressive symptoms and food intakes of these vitamins or folate. These associations remained after adjustment for smoking, alcohol use, widowhood, caregiving status, cognitive function, physical disability, and medical conditions.

Conclusion:

Our results support the hypotheses that high total intakes of vitamins B-6 and B-12 are protective of depressive symptoms over time in community-residing older adults.

Comment

In this large, US population–based study of older adults, higher total intakes of both vitamin B-6 and vitamin B-12 were associated with a decreased likelihood of the development of depressive symptoms over an average of 7.2 y. For example, each additional 10 mg of vitamin B-6 and 10 µg of vitamin B-12 via total intake from food and supplements were associated with 2% lower odds of development of depressive symptoms per year.

Williams et al[4] found consistent evidence to support the value of vitamin B-6 supplementation for depression among premenopausal women. In the assessment and treatment of depressive symptoms in older adults, clinicians and other health care professionals should be mindful of the patient’s nutritional status in general, and whether there are vitamin insufficiencies in these nutrients before treatment

References

[2] Kamphuis, MH, Geerlings, MI, Grobbee, DE & Kromhout, D. Dietary intake of B_6-9-12 vitamins, serum homocysteine levels and their association with depressive symptoms: the Zutphen Elderly Study. Eur J Clin Nutr 2008;62:939–45 View Abstract

[3] Bottiglieri, T. Homocysteine and folate metabolism in depression. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:1103–12 View Abstract

[4] Williams, A, Cotter, A, Sabina, A, Girard, C, Goodman, J & Katz, DL. The role for vitamin B-6 as treatment for depression: a systematic review. Fam Pract 2005;22:532–7  View Full Text

Examples of macroscopic features of villous atrophy detected by wireless capsule endoscopy in coeliac disease: A) Normal villi, B) scalloping of the mucosa on circular folds, C) fissuring of the mucosa, D) mosaic pattern. © Mayo Clinic

Researchers from the USA, Europe and other research centres are suggesting that Coeliac Disease has increased up to 4 x in the last 30 years.

They suggest that as much as 1% of the adult and child populations may have CD, and as we know there are many others that have yet to have the disease diagnosed, but experience problems with gluten and are diagnosed as being intolerant or sensitive.

Let’s be clear about what gluten intolerance is. ‘It isn’t a food allergy’. It’s a physical condition in your gut. Basically, undigested gluten proteins (prevalent in wheat and other grains) lurk around your intestines and are regarded by your body as a foreign invader, irritating your gut and flattening the essential microvilli along the small intestine wall. This reduces the surface area available to absorb the nutrients from your food. This can result in symptoms of malabsorption, including chronic fatigue, neurological disorders, nutrient deficiencies, anaemia, nausea, skin rashes, depression, and more.

Whilst there are better screening techniques today than there were in the 1980’s, we must also recognise that there are many other factors at work here, one of which is the changing levels of gluten in grains from hybridisation techniques.

Mayo Clinic Research Confirms Rise in CD

Researchers at the Mayo Clinic also report an increase in CD, according to an article in the summer issue of the Mayo Clinic’s research magazine.[1]

Researchers analysed stored blood samples, taken from Air Force recruits in the early 1950s, for gluten antibodies. They assumed that 1% would be positive, mirroring today’s rate. That assumption was wrong — the number of positive results was far smaller, indicating that CD was “rare”.

What’s more, Mayo has found a fourfold higher death risk for people with undiagnosed gluten intolerance.

A further 2 more recently collected sets from Olmsted County, Minnesota confirmed this finding suggesting CD is roughly 4 times more common now than in the 1950s.

“This tells us that whatever has happened with CD has happened since 1950,” Dr. Murray said. “This increase has affected young and old people. It suggests something has happened in a pervasive fashion from the environmental perspective,” he added.

Excess Mortality Seen With CD and Latent CD

The condition of latent CD or “gluten sensitivity” was described in the  Journal of the American Medical Association as having normal small intestinal mucosa but positive CD serology and is something that is estimated to occur in at least 1 in 1000 individuals.[2]

Dr. Ludvigsson’s team has also reported evidence that in 1 year, 10 of 1000 individuals with CD will die compared with an expected 7 in 1000 without the disease. He said:

Not only is the mortality raised in patients with CD but also in those individuals with latent CD, he emphasised that “although patients with CD are at increased risk of a number of disorders, and at increased risk of death, the absolute risk increase is very small.”

A Tricky Disease

CD It can be asymptomatic; have so-called traditional symptoms such as diarrhoea, weight loss, failure to grow (in children), fatigue, and malnutrition; and have non-traditional symptoms such as osteoporosis, depression, adverse pregnancy outcome; and increased risks of both malignancy and death.

The onset of certain autoimmune disorders including autoimmune liver disease, thyroid disease, type 1 diabetes, and Addison’s disease can actually be attributed to CD and means these patients should be assessed.

Detection Methods Are Improving

I wrote a post on this called what is the Best Test for Coeliac Disease in May 2010.

Alternatives to the Gluten-Free Diet?

The gluten-free diet remains the cornerstone of treatment for CD. However, another potential treatment strategy is to ingest enzymes that digest gluten, thereby increasing the safe threshold for gluten intake. Enzymes such as those found in the supplement ‘Glutengest’.

Comment

As some ‘gluten free’ foods seem to be carriers of gluten; grains like rice, oats and millet do not normally contain gluten, but the authors learned that some of those products did have trace amounts of the protein, most likely from being grown or processed near grains like wheat that do have it.[3]

A careful assessment of a person’s diet – for life, means that careful assessments need to take place regularly to ensure the best possible clinical management. It is not good enough to simply say – right avoid gluten from here on – goodbye!

References

[1] Discovery’s Edge Newsletter – Coeliac On The Rise

[2] Ludvigsson JF, Montgomery SM, Ekbom A, Brandt L, Granath F.Small-intestinal histopathology and mortality risk in celiac disease.  JAMA. 2009 Sep 16;302(11):1171-8. View Full Paper

[3] Thompson T, Lee AR, Grace T. Gluten contamination of grains, seeds, and flours in the United States: a pilot study. J Am Diet Assoc. 2010 Jun;110(6):937-40. View Abstract

To be clear, Cadwell and co-workers are not arguing that Crohn’s disease is caused by infection with norovirus (as used in this study) or by any other single microbe. The environmental factors that predispose to and protect from Crohn’s disease remain uncertain, but the balance among commensal and pathogenic gut bacteria and viral infections is likely to be part of the story. These studies make an urgent and compelling case for characterising the human virome as well as the microbiome and defining its effects on physiology and gene expression. In addition, further explanations to help us to understand how the virome interacts with polymorphisms in the host genome and how numerous toxins in the environment alter this complex interplay will need to be unravelled.

The host’s genetic make-up can account for around 50% of the risk of Crohn’s disease.[2] Genome-wide association studies (GWAS) have pinpointed more than 30 genomic regions (loci) variations in which are associated with an increased risk of developing the disease. So what contributes to the remaining 50% of risk? Certainly environmental factors, and in particular the resident microorganisms (the microbiome), are strong contenders, although direct evidence for an environmental contribution in humans with Crohn’s disease has yet to be published.

Immune responses to viruses rely on sensors of infection in the shape of ‘pattern-recognition receptors’, which recognize evolutionarily conserved motifs present in microorganisms; in the case of viruses, these are often viral nucleic acids and the number one receptor that seems to be involved in crohn’s initiation is the NOD2 a possible intracellular sensor of nucleic acid.[3]

Comment

So what does this mean to Nutritional Therapy, is understanding that a small viral particulate can knock a normal healthy gut into a chronic inflammatory state of interest – well yes! When discussing with a patient about the initiation or onset, careful history needs to look at the likelihood of viral infection and then viral prolongation – is the mucosal immune system unable to stimulate appropriate removal, or is it just ‘knocked’ forward into a persistent state of inflammation that in turn limits the commensals ability to reduce inflammation. Should a natural antiviral agent such as olive leaf extract be used.[4] Or should it be considered as a specific antimicrobial for H. pylori, C. jejuni, S. aureus and MRSA.[5]

Clinically all three organisms plus non specific viruses may be involved in patients with Crohn’s and suitable assays of the stool will help to identify the bacterial elements but not the viral ones. Olive leaf extract may also be able to confer anti-inflammatory benefits[6] and so represents a potential strategy for suspected bacterial or viral induced IBD.

References

[2] Van Limbergen, J., Russell, R. K., Nimmo, E. R. & Satsangi, J. Am. J. Gastroenterol. 102, 2820–2831 (2007). View Abstract

[3] Sabbah A, Chang TH, Harnack R, Frohlich V, Tominaga K, Dube PH, Xiang Y, Bose S. Activation of innate immune antiviral responses by Nod2. Nat Immunol. 2009 Oct;10(10):1073-80. Epub 2009 Aug 23 View Full Paper

[4] Heinze JE, Hale AH, Carl PL.  Specificity of the antiviral agent calcium elenolate.  Antimicrob Agents Chemother. 1975 Oct;8(4):421-5.  View Full Paper

[5] Sudjana AN, D’Orazio C, Ryan V, Rasool N, Ng J, Islam N, Riley TV, Hammer KA. Antimicrobial activity of commercial Olea europaea (olive) leaf extract. Int J Antimicrob Agents. 2009 May;33(5):461-3. Epub 2009 Jan 9. View Abstract

[6] Süntar IP, Akkol EK, Baykal T. Assessment of anti-inflammatory and antinociceptive activities of Olea europaea L. J Med Food. 2010 Apr;13(2):352-6. View Abstract

The Proceedings of The National Academy of Science Journal published a paper this June 2010 exploring the differences in the microbial communities between those children on a western style diet and those from a rural African community whose diet reflected that of a the early humans – high in fibre.[1]

Key Findings:

• African children had increased levels of Bacteroides, and depletion in Firmicutes Bacteria, and a unique range of bacteria for fibre degradation absent in the EU children. They also had higher levels of short chain fatty acids. In particular, propionic and butyric acids are nearly four times more abundant in BF than in EU faecal samples
• EU children had higher levels of shigella and Escherichia and fewer of the immune modulating and fibre degrading bacteria

Microbiologists and immunologists see the changing of the supply of our food from the Neolithic Revolution forward (approx 10,000 years ago) as a significant event in terms of bacterial transformation in our guts.[2] More recently, based on the germ theory and an almost zealous use of antibiotics and vaccines has produced a conflicting outcome. Infectious diseases have declined dramatically and acute emergency orientated infections have largely been controlled, but the emergence of allergy, autoimmune diseases and inflammatory bowel diseases have increased in the developed worlds.[3]

This study took 15 children aged between 1-6 living in Burkina Faso – where their diet is low in fat and animal protein and rich in starch, fibre, and plant polysaccharides, and is predominantly vegetarian. Children are breast-fed up to the age of 2 y as a complement to a mixed diet. Then ran a comparrison investigation against 14 EU children who were breast-fed for up to 1 y of age. They were eating a typical western diet high in animal protein, sugar, starch, and fat and low in fibre and this included ‘Junk Food’.

The diet of the African children consisted mainly of cereals, black-eyed peas and vegetables. The Italians, by contrast, ate higher quantities of meat, fat and sugar.

The authors suggest that the difference in fibre intake of around 8.4 g/d (EU -2-6yrs) vs 14.2 g/d (African 2-6 yrs) provides the explanation for the bacterial diversity, and that this combined with higher caloric intake from the EU diet leads to higher levels of obesity due to the changes in Firmicutes to Bacteroides ratio.[4]

So was Burkitt right?[5] This paper indicates that exposure to the large variety of environmental microbes associated with a high-fibre diet could increase the potentially beneficial bacterial genomes, enriching the microbiome. Reduction in microbial richness is possibly one of the undesirable effects of globalisation and of eating generic, nutrient-rich, uncontaminated foods. Both in the Western world and in developing countries diets rich in fat, protein, and sugar, together with reduced intake of unabsorbable fibres, are associated with a rapid increase in the incidence of non-infectious intestinal diseases.

The results suggest that diet has a dominant role over other possible variables such as ethnicity, sanitation, hygiene, geography, and climate, in shaping the gut microbiota.

The African experience of increased gut microbial diversity and reduced quantities of potentially pathogenic strains supports the “old friend” hypothesis, indicating a role of microbiota in protecting children from pathogens as well as from gastrointestinal diseases.[6]

Comments

We have much to learn yet about the mechanisms employed by our commensal bacterial species, but what we do know is that they are capable of significant effects both good and bad on human health. If we look at recent experimentation using bacterial translocation to treat IBD, the potential for extracting bacterial species from the commensals of the traditional fibre rich diets for probiotic therapy is very appealing.

In the meantime we know that fibre has a direct impact on inflammation as well as providing raw materials for bacterial growth, but we may yet have to work hard on providing adequate quantities of live bacteria to support a substantive bacterial relationship change in the damaged or healthy gut.

In terms of assisting the reduction in allergies, the bacterial inhabitants and their role was explored in a recent post.

References

[2] Mira A, Pushker R, Rodríguez-Valera F (2006) The Neolithic revolution of bacterial genomes. Trends Microbiol 14:200–206. View Abstract

[3] Strachan DP (1989) Hay fever, hygiene, and household size. BMJ 299:1259–1260. View Full Paper

[4] Ley RE, Turnbaugh PJ, Klein S, Gordon JI (2006) Microbial ecology: Human gut microbes associated with obesity. Nature 444:1022–1023. View Abstract

[5] Burkitt DP (1973) Epidemiology of large bowel disease: The role of fibre. Proc Nutr Soc 32:145–149. View Ref

[6] Rook GAW, Brunet LR (2005) Microbes, immunoregulation, and the gut. Gut 54: 317–320. View Abstract