An excellently developed study published in the March 2010 Journal of Clinical Endocrinology and Metabolism found a depressingly high  59% of study subjects had too little Vitamin D in their blood (</=29 ng/ml).[1] Nearly a quarter of the group had serious deficiencies (less than 20 ng/ml) of this important vitamin. Even the sufficient (>/=30 ng/ml) was only 41% and if we were to apply the generally regarded 50ng/ml as the base line for sufficiency, the numbers would decline even further. Since Vitamin D insufficiency is linked to increased body fat, decreased muscle strength and a range of disorders, this is a serious health issue.

The 90 young women in this group aged between 16-22yrs of age had an increased level of fatty tissue when their Vit D levels were low. Abnormal levels of Vitamin D are associated with a whole spectrum of diseases, including cancer, osteoporosis and diabetes, as well as cardiovascular and autoimmune disorders.

This innovative study is the first to show a clear link between Vitamin D levels and the accumulation of fat in muscle tissue – a factor in muscle strength and overall health. Scientists have known for years that Vitamin D is essential for muscle strength. Studies in the elderly have showed bedridden patients quickly gain strength when given Vitamin D.

Vitamin  D deficiency is a condition that may  cause muscle weakness in elderly persons. Although only a few intervention studies with vitamin D have been conducted in elderly people, the available evidence indicates that vitamin D supplementation  preserves muscle strength and functional ability in high-risk groups, eg, frail, mostly homebound elderly people.[2]

Of particular note is that these young women lived in California – you would expect them to have adequate sunshine, outdoor activities and a diet rich in nutrients, a combination we have been encouraged to believe ensures we meet our Vit D manufacturing needs.

Comment

This study found an inverse relationship between Vitamin D and muscle fat. The lower the levels of Vitamin D the more fat in subjects’ muscles. Does this mean taking Vit D supplements will decrease fat – probably too early to state this unequivocally, but taking a supplement of Bio D Mulsion Forte every day makes good clinical sense for people living in the northern hemisphere, especially in the winter months. Having a periodic Vit D blood test may prove to be one of the least expensive ways of avoiding an unnecessary risk for a multitude of related diseases.

References

[2] Janssen HC, Samson MM, Verhaar HJ. Vitamin D deficiency, muscle function, and falls in elderly people. Am J Clin Nutr. 2002 Apr;75(4):611-5. Review. View Abstract

The university of Illinois team of researcher have written a paper due to be published in the prestigious Journal Brain Behaviour and Immunity later in the year around May.[1]

Looking at a mouse model – and we are aware of how diet affect mouse studies from a post written a few days ago- Food Choice Affects Lab Outcomes this group have extended the concept further, and presented the mice with a specially enriched diet. This study fed a low fat diet to both groups for six weeks differentiated by one having soluble fibre and the other non soluble fibre.

When challenged using a microbial wall particle called lipopolysaccharide (LPS) the group on the soluble fibre had a 50% reduction in symptoms compared to the insoluble group. They also recovered 50% faster. It seems that just 6 weeks of an increased soluble fibre intake change their immune responses in a very positive manner.

Obesity and metabolic syndrome for example are inflammation illness with the fat cells – adipocytes producing their own cytokines called adipokines. This fat derived pervasive inflammatory output is linked to risks for diabetes, cardiovascular illness, cancer, and depression.  Much of medicine is aimed at suppressing or reducing this adverse inflammation and food choice represents a safe and according to the authors, in mice at least, an effective one.

The idea that adding a positive anti inflammatory food group, say a daily intake of 2-3 apples (3-5gms ea) mimicking the citrus pectin used in the study and other good food derived sources of soluble fibre to achieve the recommended daily intake of 28-35 grams per day to generate an effect on immunity and inflammation control is an exciting discovery. This may well represent one of the viable components of why certain types of diet – the Mediterranean – for example includes a relatively high intake of fat, much of which is of the beneficial kind, as well as soluble fibre rich foods and is causally linked with a reduction in mortality and morbidity.

The Mediterranean diet, in addition to “regular physical activity,” emphasises “abundant plant foods, fresh fruit as the typical daily dessert, olive oil as the principal source of fat, dairy products (principally cheese and yogurt), and fish and poultry consumed in low to moderate amounts, zero to four eggs consumed weekly, red meat consumed in low amounts, and wine consumed in low to moderate amounts.[2]

Other good sources of soluble fibre are oat bran, barley, nuts, seeds, lentils, citrus fruits, strawberries, and carrots.

The insoluble fibres such as those in wheat, wholegrains, wheat bran, green and leafy vegetables may offer other advantages including aiding transit time but according to this study, they do not add immune support.

Comment

Food selection by many is very poor and the 5 a day campaign has often failed those most in need. The idea that a normal physiological ingestion of a daily group of foods can have an identifiable immune impact in just 6 weeks is an appealing strategic use of motivation for the right person. Communicating food benefits to a willing patient is much easier that via the public health method, this paper may add a little emphasis to your food choices when faced with a two legged inflammation riddled individual.

References

[2] Willett WC (June 1, 1995). “Mediterranean diet pyramid: a cultural model for healthy eating”. American Journal of Clinical Nutrition 61 (6): 1402S–6S View Abstract

Most clinicians understand that overt gluten reactivity is classified under coeliac disease and the the classic constellation of symptoms and signs characterising  malabsorptive syndrome is a readily recognised manifestation  of  coeliac  disease. Frank malabsorptive symptoms include steatorrhea, weight loss or failure to thrive, bloating, and flatulence, with multiple deficiency states. More common but more difficult to recognise, however, are the other diverse ways in which coeliac disease presents.

Coeliac disease may also mimic many common clinical entities. These atypical modes of presentation include deficiencies of single micronutrients; nonspecific gastrointestinal complaints such as bloating, abdominal pain, diarrhoea, constipation, flatulence, secondary lactose intolerance, and dyspepsia; and non-gastrointestinal complaints such as fatigue, depression, arthralgia, milk intolerance, osteomalacia or osteoporosis, and iron deficiency anaemia.

One symptom not routinely screened for is neurological problems, although depression as an element of coeliac disease is well recognised.[2] Further elucidation of this issue has been provided through the extensive work of Fukudome and Yoshikawa, who have identified and characterised five distinct exorphins in the pepsin digests of gluten.[3],[4]

These morphine-like substances derived from the incomplete digests of dairy and cereal grain proteins are other dietary factors which may alter mood by depressing CNS serotonin, dopamine and norepinephrine levels.^[5]

The authors of this paper state:

Gluten sensitivity typically presents as coeliac disease, a chronic, autoimmune-mediated, small-intestinal disorder. Neurological disorders occur with a frequency of up to 10% in these patients. However, neurological dysfunction can also be the sole presenting feature of gluten sensitivity.

The enzyme transglutamase in celiac disease will develop antibodies, and these are a cardinal indicator for diagnosing coeliac. This paper explains the role of an additional transglutamse isozyme in relation to brain health and function.

…a novel neuronal transglutaminase isozyme and investigated whether this enzyme is the target of the immune response in patients with neurological dysfunction.

They found that:

Whereas the development of anti-transglutaminase 2 IgA is linked with gastrointestinal disease, an anti-transglutaminase 6 IgG and IgA response is prevalent in gluten ataxia, independent of intestinal involvement.

‘Ataxia’ means ‘absence of order’. People with ataxia have problems of co-ordination. This is because parts of the nervous system that normally control co-ordination and balance are affected. So when discussing problems with gluten and other protein containing grains, the only symptom presenting may be one of mood disorders and a progressive loss of balance and co-ordination

Comment

The role of gluten and the mucosal immune system are slowly being picked apart, a recent post looked at the relationship between coeliac disease and local and systemic consequences.

Of course one of the questions we should be asking is the fact that it is relatively recently introduced grains that are causing the problem simply our bodies exerting a reasonable and normal response to antigens, or is it just that many people have become capable of eating these grains and can manage the immune challenges better than others?

References

[2] Ludvigsson JF, Reutfors J, Osby U, et al. Coeliac disease and risk of mood disorders–a general population-based cohort study. J Affect Disord. 2007 Apr;99(1-3):117-26. View Abstract

[3] Fukudome S, Shimatsu A, Suganuma H, Yoshikawa M Effect of gluten exorphins A5 and B5 on the postprandial plasma insulin level in conscious rats. Life Sci. 1995;57(7):729-34. View  Abstract

[4] Fukudome S, Yoshikawa M Opioid peptides derived from wheat gluten: their isolation and characterization. FEBS Lett. 1992 Jan 13;296(1):107-11. View Abstract

[5] Hallert C et al. Psychic disturbances in adult coeliac disease III. Reduced central monoamine metabolism and signs of depression. Scand J Gastroenterol, 1982; volume 17: pages 25-28. View Abstract

In the March edition of GUT a systematic review on the randomised control trials (RCT) undertaken so far suggests that many are of good quality.[1], they determine that meta-analysis is impossible due to the various strains, phenotypes and genome vary greatly.[2] As a consequence and as stressed by the FAO/WHO joint report the benefits of one probiotic ‘cannot be extrapolated to other probiotic strains without experimentation.[3] However there tend to be properties consistent with different groups, from which strain specific organisms may be extracted.

A probiotic contains thousands of genes which may potentially influence the clinical effects. Furthermore, interaction with the host, food components or endogenous substrates or the endogenous microbiota inside the gastrointestinal lumen may generate by-products or end-products with functional properties.

The intestine has between 1012 and 1014 organisms per millilitre, which is ~100-fold greater than the number of eukaryotic cells in the human body.[4] Numerous mechanisms are involved in the action of probiotics. New discoveries which may have an impact on the understanding of the clinical effects in IBS include the demonstration of the presence of anti-inflammatory microorganisms in the endogenous microbiota (especially the phylum Firmicutes),[5] and that of the action of probiotics on intestinal motility and visceral sensivity.[6]

Summary

The use of probiotics in patients with IBS showed improvements in the following areas:

• Abdominal Pain (good improvement),
• Bloating (modest gains),
• Flatulence (good improvement),
• Urgency (modest)

They conclude:

Probiotics appear to be efficacious in IBS but the magnitude of benefit and the most effective species and strain are uncertain.

Comment

One of the issues with single therapy interventions, i.e the use of probiotics is that it may be inadequate to meet the individual needs of the patient. A clinical work up may allow for a greater degree of personalisation and in turn provide a degree of personalisation that would most like increase their benefits. In particular bloating as discussed by Michael Ash has a number of potential triggers and each of these would need to be addressed to ensure best outcome.

References

[1] Moayyedi P, Ford AC, Talley NJ, Cremonini F, Foxx-Orenstein A, Brandt L, Quigley The efficacy of probiotics in the therapy of irritable bowel syndrome: a systematic review. E.Gut. 2008 Dec 17. View Abstract

[2] Klaenhammer TR, Altermann E, Pfeiler E, et al. Functional genomics of probiotic Lactobacilli. J Clin Gastroenterol 2008;42(Suppl. 3 Pt 2):S160–2. View Abstract

[3] Pineiro M, Stanton C. Probiotic bacteria: legislative framework—requirements to evidence basis. J Nutr 2007;137(3 Suppl 2):850S–3S. View Abstract

[4] Macpherson AJ, Geuking MB, McCoy KD. Immune responses that adapt the intestinal mucosa to commensal intestinal bacteria. Immunology 2005;115:153–62. View Abstract

[5] Sokol H,Pigneur B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A 2008;105:16731–6. View Abstract

[6] Bär F, Von Koschitzky H, Roblick U, et al. Cell-free supernatants of Escherichia coli Nissle 1917 modulate human colonic motility: evidence from an in vitro organ bath study. Neurogastroenterol Motil 2009;21:559–66. View Abstract

Mice with altered immune systems developed metabolic disorders and were prone to overeating. When microbes from their stomachs were transplanted into other mice, they also become obese. These latest findings add weight to the growing appreciation about the role of the bacteria in and on our bodies.  We are all outnumbered in terms of human versus bacterial cells and the concept of human and bacteria symbiosis as a super-organism is gaining traction.

Already there have been strong associations between asthma, some cancers, autoimmune conditions and unwanted weight gain.

Gut flora have also been linked to obesity. In 2006, researchers led by Washington University microbiologist Jeffrey Gordon documented bacterial changes in the stomachs of mice who became obese on high-fat diets. Michael Ash wrote a review article in CAM magazine on this subject back in 2005 and it can be read in our review section.

This paper discusses a serendipitous discovery concerning metabolic syndrome, a western world problem leading to hyperglycaemia, hyperlidemia, insulin resistance, obesity and liver steatosis.[2]

This is thought mainly due to dietary changes and reduction in exercise that in turn contributes to inflammation and loss of insulin sensitivity. This paper explores the role that gut bacteria may have in contributing to this, in particular the firmicutes and bacteroidites.[3][4]

Our results suggest that the specific composition of microbiota to which individuals are first exposed may be an important means by which early environment exerts a lasting influence on metabolic phenotype. They also suggest that the excess caloric consumption driving the current epidemic of metabolic syndrome may be caused, at least in part, by alterations in host-microbiota interactions.

The gut microbiota is shaped by both environment and host genetics with the innate immune system in particular, long-appreciated for its role in defending against infection by pathogenic microbes, now suggested to play a key role in regulating the gut microbiota.[5] Thus, in addition to its role in infection/inflammation, innate immunity may play a key role in promoting metabolic health. One of the mucosal immune proteins that seems to be developing an important role in this balance is SIgA.

Comment

An explanation for some of the changes in gut microbiota is founded in the hygiene theory, and the almost ubiquitous presence of antibiotics both as prescribed medication and present in the environment may be partly to blame. We know that a single course is able to disrupt bacterial colonies for up to 6 months. It may be a secondary effect of antibiotic use, that metabolic syndrome and obesity are developing in medicalised countries.

There may also be relevance in terms of the introductory bacteria that each human is exposed to from in utero[6]^,[7] and ex utero experiences. If the mothers bacteria are supporting her obesity, then the transfer of this microbial species may also contribute to difficulty in managing weight in the child through to adult hood.

References

[2] Wang Y, Beydoun MA, Liang L, Caballero B, Kumanyika SK. Will all Americans become overweight or obese? estimating the progression and cost of the US obesity epidemic. Obesity (Silver Spring). 2008 Oct;16(10):2323-30. Epub 2008 Jul 24. View Abstract

[3] Wexler HM. Bacteroides: the good, the bad, and the nitty-gritty. Clin Microbiol Rev. 2007 Oct;20(4):593-621. View Abstract

[4] Mahowald MA, Rey FE, Seedorf H, Turnbaugh PJ, Fulton RS, Wollam A, Shah N, Wang

C, Magrini V, Wilson RK, Cantarel BL, Coutinho PM, Henrissat B, Crock LW, Russell

A, Verberkmoes NC, Hettich RL, Gordon JI. Characterizing a model human gut microbiota composed of members of its two dominant bacterial phyla. Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5859-64. Epub 2009 Mar 24. View Abstract

[5] Slack E, Hapfelmeier S, Stecher B, Velykoredko Y, Stoel M, Lawson MA, Geuking MB, Beutler B, Tedder TF, Hardt WD, Bercik P, Verdu EF, McCoy KD, Macpherson AJ. Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism. Science. 2009 Jul 31;325(5940):617-20. View Abstract

[6] Jiménez E, Fernández L, Marín ML, Martín R, Odriozola JM, Nueno-Palop C, Narbad A, Olivares M, Xaus J, Rodríguez JM. Isolation of commensal bacteria from umbilical cord blood of healthy neonates born by cesarean section. Curr Microbiol. 2005 Oct;51(4):270-4. Epub 2005 Sep 20. View Abstract

[7] Jiménez E, Marín ML, Martín R, Odriozola JM, Olivares M, Xaus J, Fernández L, Rodríguez JM. Is meconium from healthy newborns actually sterile? Res Microbiol. 2008 Apr;159(3):187-93. Epub 2008 Jan 11. View Abstract

By Michael Ash BSc(Hons) DO, ND, FDipION

Published in CAM 2005

Overweight and obesity are serious, chronic medical condition associated with a wide range of debilitating and life threatening and economically burdensome conditions. The recent and extensive increases in obesity among Europeans are eroding many recent health gains.

Paradoxically the economically wealthier communities of the world continue to over consume food and food products, whilst other nation communities still suffer from food deprivation and starvation, due in the main to drought, floods, ‘acts of God’, corruption and conflict. Approximately 9.5% of the global burden of disease is currently attributable to being underweight,[1] whilst there are now hundreds of millions of people (>500) in developed and developing countries that are overweight or obese. This condition of excessive weight is now so common that it is rapidly replacing malnutrition and infectious diseases as the most significant cause of ill health[2]. An escalating global epidemic of overweight and obesity – “globesity” – is taking over many parts of the world.

This growing epidemic has manifested as huge increases in body mass index (BMI) in most, if not all, countries, and is due to a combination of differing influences, the most commonly perceived ones being “over nourishment” and “under activity”.

Obesity is a multifactorial condition understood to be a result of the interplay between internal and external environments, psychosocial influences, dietetic choices, immune activation and genetic tendencies.  The rate of its development in the latter half of the 20^th century and its apparent ongoing speed of expansion in the 21^st century requires innovative and effective intervention.

Compelling evidence identifying the rapid rate of change in obesity prevalence comes from various countries, including North America, the United Kingdom and Australia. In the United States, the Centers for Disease Control and Prevention have reported 60% of the population have a BMI > 25 kg/m², and 27% are obese.[3] This reflects a substantive 61% increase in obesity since 1991, a period covering only 8 years in this study.[4]

Similar trends have been observed in Canada, where the prevalence of obesity increased from 10% in 1970–72 to 15% in 1998.[5] The UK has not escaped the expansion of adiposity with the prevalence of obesity rising among men from 13% in 1993 to 21% in 2000, and among women from 16% to 21%.[6]

Innovative interventions, manageable and sustainable ongoing strategies including selective macro nutrient intake and increased physical activity are required to halt and reverse this condition.  The individual with a normal BMI is now in the minority and is likely to become a rarity in the future without substantive nationwide change.

In the search for resolution of obesity there have been extensive proposals to explain the apparent insatiable demand for the growth our bodies’ adipocytes have achieved.  There are many sound and tested concepts and beliefs, but the fact remains we are losing the battle.

Our genome it seems is hard wired for storage; the era of food abundance in evolutionary terms has covered only a short time span in comparison to the extended period of inadequate food availability our species has endured. We have yet to persuade our genetic code to fail to prepare our adipocytes for a prolonged period of food deprivation.  Consequently the central DNA make up involved in energy storage appears to have been pushed into a state of over expression through it’s constant exposure to gene modifying factors, including food choice, rate and type of consumption, persistent inflammation,  aberrant immune activity and intestinal microbial change[7].

The research exploring the evolutionary theories has focused on the potential survival advantages of “thrifty” genes and has concluded they are now maladaptive or over expressed.  Other important and modifiable factors have been exposed through many mechanistic studies which have revealed numerous fat-derived molecules and a link to chemicals associated with inflammation that, together, underlie the obesity-diabetes connection and represent for clinicians, prospective targets for therapeutic intervention.

So next time you are considering how to manage the weight loss resistant patient or even your own difficulties with weight, it may be clinically advantageous to think outside the traditional models.

One component of our being covers the combination of the above; the cross talk between our genetic make up and our co evolutionary partners, our microbiota, appears to be an area of profound opportunity for genetic nutritioneering[8].  A second and associated component, the immune regulatory disturbances so noted at the mucosal tissues, when innate immunity loses its ability to manage adaptive immune responses in a reasonable manner is also a key factor. The common site for these mixed impacts is found in the Common Mucosal Immune System (CMIS) and most specifically in the gastro intestinal tract (GIT) and its composite bacterial bed fellows.

Obesity is a disease of inflammation and disturbed microbial balance

The bulk of research examining the increased burden of inflammation within the obese patient has to date considered the source of excess cytokines and adipokines as the sole responsibility of the adipocytes.  Current opinion is now evolving from single source production to a multi-factorial origination with the adaptive and innate immune systems as significant contributors[9].  This evolving comprehension is now expanding the role of mucosal immunity as an important component in systemic pathologies including insulin resistance, syndrome X and obesity. Disruption of the mucosal anti inflammatory function through down regulation of secretory immunoglobulin A (SIgA) will lead to increased production of inflammatory cytokines[10].

Although once considered a metabolically inactive fuel depot, adipose tissue is now recognised to be an endocrine organ communicating with the brain and peripheral tissues through the secretion of various hormones regulating appetite and metabolism. By virtue of its mass it is the largest endocrine organ in the body^[11]. These functions are modulated and determined by the location of the adipose tissue (visceral versus subcutaneous)^[12] by the mass of the average adipocyte present in the tissue^[13]and by the adipocytes metabolism of glucose^[14] and corticosteroids^[15].

One such adipokine (fat derived cytokine) is adiponectin a hormone with antidiabetic properties. The ability of adiponectin to increase insulin sensitivity in conjunction with its anti-inflammatory and anti-atherogenic properties has made this novel adipocytokine a promising therapeutic tool[16]. Adiponectin one of the beneficial adipokines induces increased sensitivity to insulin but is down regulated in the face of inflammation and reactive oxygen species (ROS)[17].

Modifying the production of this protein as well as minimising those less helpful agents constitutes a potential target for therapies aimed at uncoupling insulin resistance from obesity.

The plant protein osmotin found in fruits, nuts and vegetables and used by them as part of their innate defence has the effect of mimicking adiponectin in humans by binding to its receptor sites.[18] Osmotin is a stable protein resistant to heat, acidity and enzymes, meaning it could circulate through the body without being broken down by digestion. Whether osmotin plays any role in the health benefits attributed to diets high in fruits and vegetables is a tantalising possibility, certainly the maxim of eating more fruits and vegetables has many effector events within the human
Adiponectin and osmotin jump-start a process called AMP kinase phosphorylation, which increases sugar and fat use by muscle cells. By binding to the adiponectin receptor, osmotin, like adiponectin, can control the energy status of muscle cells.[19]

TNFa and IL6 Cytokines of immunity and obesity

Cytokines are intercellular signalling polypeptides produced by activated cells. Most cytokines have multiple sources, multiple targets, and multiple functions. Typical properties of cytokines in these networks are pleiotropy, redundancy, synergistic activity and antagonistic effects upon each other[20]. Inflammation-associated cytokines include interleukin-6, interleukin-1ß, tumor necrosis factor, interferon-, transforming growth factor ß,^[21] and possibly interleukin-8.^[22]

They are produced by a variety of cell types, but the most important sources are macrophages and monocytes at inflammatory sites.^[23].The cytokines TNFa and IL₆ are extensively produced by macrophages as well as by adipocytes; they act directly on inflammatory cells and also contribute indirectly to inflammation by acting on the liver to produce acute phase proteins. These cytokines also induce a suppressor of cytokine signaling-3 (SOCS-3), an intracellular signalling molecule that impairs the signalling of both leptin (a cytokine that acts as a moderator of food intake, and acts as a neuro endocrine hormone, blunted in the face of up regulated inflammation) and insulin. SOCS-3 levels are elevated in obesity and thus may represent a final common pathway of obesity-associated resistance to the actions of both leptin and insulin^[24].

TNFa has been strongly implicated as a developmental molecule in insulin resistance and obesity[25].  It appears to be ‘over expressed’ in adipocytes of obese individuals and reduces cell receptor sensitivity to insulin as well as influencing transcription of specific adipocyte genes.  This cytokine may be induced locally within the adipocyte for a variety of hormone regulatory actions and triglyceride induction, but the single largest producer of TNFa is the adaptive aspect of the cellular immune system, the largest mass of immune tissues present within the mucosal barriers of the gastrointestinal tract.

TNFa is an essential component of mucosal immunity where it has a dual role defending us and yet if allowed to be produced unchecked it has the ability to create intense health problems in the host if left unchecked, including at the worst outcome a loss of life through sepsis[26].

TNFa, it seems is more than an immune defence cytokine. Its impact is felt across many tissues and in particular it has powerful effects on insulin resistance in obesity through its effects on several important sites of insulin action[27].

Increased production of these cytokines is found in the presence of disrupted mucosal immunity and exposure to microbial or antigenic provocateurs that interfere with the normal state of immune tolerance[28]. A failure to maintain correct mucosal tolerance through the loss of innate immune system cross talk will always result in the increased production of inflammatory cytokines.  Maintaining a healthy and functional micro ecology and adequate production of the immunoglobulin Secretory IgA is essential to achieve this state.

NFkB The inflammation amplifier

The gene transcription factors IKKb and NFkB are molecular mediators of insulin resistance and also represent a target for therapeutic intervention[29].  The NFkB cascade is a major pathway for the amplification of inflammatory processes.[30] NFkB is a ubiquitous nuclear transcription factor that promotes the activation of genes that encode for inflammatory mediators and enzymes, NFkB can be thought of as the major intracellular “amplifier” which ultimately increases the production of the direct mediators of inflammation such as cytokines, prostaglandins, leukotrienes, nitric oxide and other reactive oxygen species (ROS).

Understanding this concept provides clinicians with a unique approach to their adipose abundant patients, for whilst inflammation is well understood to be a predictive risk indicator for declining insulin receptor sensitivity, it must also be considered as a therapeutic ‘foot in the door’ as modifying production of inflammatory cytokines appears to improve the ability to switch genetic expression off or at least down regulate its willingness to store fat.

Intestinal macrophages normally eat without getting upset

Our intestinal macrophages, derived from blood monocytes, are thought to conduct control over mucosal inflammatory responses. However, Lesley Smythies and colleagues have now demonstrated that resident intestinal macrophages lack many innate response receptors and do not actually produce the proinflammatory cytokines such as IL₁, IL₆, IL₈, and TNF during normal states of tolerance, although the cells retain certain immune capacity through phagocytic and bacteriocidal activity ²¹.

The inflammatory ‘anergy’ of intestinal macrophages, reflected in the cells’ reduced expression of innate response receptors and their down regulated production of cytokines, indicates a potential mechanism for the absence of inflammation in normal intestinal mucosa despite the close proximity of immunostimulatory bacteria and LPS. In effect, they are able to contribute to the mediation of ‘mucosal tolerance’ through appropriate anergic response activity.

The resultant inflammatory anergy serves to limit mucosal inflammation in normal intestinal mucosa, whereas the loss or dysregulation of macrophage inflammatory anergy may promote the inflammation associated with inflammatory bowel disease^[31]. Maintaining mucosal tolerance is one of the key roles of SIgA and bacterial commensals and is also dependant on food choice, volume of antigen and microbial exposure.

Oxidative Stress

Oxidative stress may be also be induced by obesity and increased oxidative stress in accumulated fat is at least in part responsible for the dysregulation of adipocytokines and the eventual development of metabolic syndrome with its associated hyperglycaemia, dyslipidaemia, hypertension and atherosclerosis. Obesity is, of course closely associated with metabolic syndrome[32].

Fat accumulation is closely correlated with markers of systemic oxidative stress, which in turn correlates with body mass index (BMI)[33] The insulin sensitising adipocytokines in plasma have an inverse correlation with systemic oxidative stress.

The close relationship between inflammation and diabetes is supported by the observation that stimulation of the innate immune response (by bacterial endotoxin during sepsis, for example)^[34] results in insulin resistance that contributes to the high mortality of critical illness^[35] . The interaction between inflammation and insulin signalling is also suggested by the ability of aspirin to improve insulin resistance, in part by preventing the antagonistic effects of fatty acids and cytokines^[36].

Why is Obesity is a disease of inflammation

Why is obesity an inflammatory state and why does inflammation cause diabetes? The search for answers to these questions takes us again to evolutionary considerations. Perhaps the response to infection is more effective when glucose is shunted from muscle to the inflammatory cells involved in the immune response and tissue repair.

A potentially unifying view is that the body’s ability to survive major stress, including infection and starvation, is enhanced by peripheral insulin resistance that preserves the brain’s glucose supply^[37]. This hypothesis might explain why cortisol, the major stress hormone, causes insulin resistance and stimulates the innate immune response¹² , even though chronic cortisol exposure is anti-inflammatory because of down-modulation of the acquired immune response.

The stress connection may extend to individual cells, as it has recently been shown that intracellular stress induces insulin resistance in a manner that is exacerbated by obesity, potentially through adipocyte-secreted factors^[38]. Moreover, chronic metabolic stress impairs the ability of pancreatic beta cells to secrete sufficient insulin to overcome insulin resistance, which is a hallmark of type 2 diabetes^[39].

Our body produces a wide range of cytokines, proteins and other communication molecules.  The gastro intestinal tract (GIT) is responsible for the origination of many of these. The interplay between those induced or stimulated in the GIT and elsewhere makes for clinically interesting connections and functional interaction.  Certain of these cytokines are now well known to have an impact on weight and metabolic syndrome, others are less well understood.

The interconnectiveness of the mucosal tissues through their many layered communication networks including microvasculature, enteric and central nervous system and immune cells establishes them as a prime site for investigation and development of clinical interventions for their modification.

Advanced Glycosolation End Products AGE’s

Inflammatory chemicals are also promoted by dietary glycotoxins[40].  Diet is a major source of the proinflammatory chemicals AGE’s (heat generated advanced glycation end products) These AGE’s are created in common foods during spontaneous reactions between reducing sugars and proteins or lipids[41].

The inclusion of supplemental antioxidants adds further control to the production of proinflammatory cytokines indicating that dietetic modulation and enhancement of antioxidant status at the GIT produces diminished circulating inflammatory markers^{Error! Bookmark not defined.}.  Inappropriate immune and bacterial associated immune regulation induces increased ROS[42] and contributes to amplified problems associated with diabetes and may well increase the development of obesity.

Increased oxidative stress can now be linked to food choice, volume and composition, in addition immune activation at the tissue sites these macro molecules are meeting will contribute to upregulated reactive oxidative species production and other chemicals aimed at achieving immune tolerance.⁴²

Bugs Make YOU Fat

Humans and other mammals are colonised by a vast, complex, and dynamic consortium of micro-organisms.  One of the evolutionary driving forces for maintaining this metabolically active microbial biomass is to aid in the salvage of carbohydrates that would otherwise be indigestible.

This complex dynamic collection predominately found in the GIT means we are more prokaryotic than eukaryotic as estimates define us as being 90% microbial cell and 10% human cell.[43] This collection of organisms may as a result be perceived of as being a ‘metabolically’ active organ, playing a critical role in nutrition and energy expenditure and storage.[44]

This intestinal eco system is constantly shaped by interactions between its microbes (both intra and inter species communications), epithelium, mucosal immune system, microvasculature and enteric nervous system.[45] Initially sterile the human gut goes through dramatic changes in it gut microflora until it reaches its ‘climax community’ which in turn remains highly modifiable by environmental and host gene factors.[46]

The commensal (‘at the table together’) is particularly apropos with the intestinal microflora as both depend on the dietetic intake from the host.  One might think that both host and microflora would now engage in competition for the same nutrients.  However, conventionally raised animals with an intact biomass require 30% less caloric intake to maintain their body weight than their germ free counterparts, indicating that the microbiota is involved in nutrient optimisation.[47]

This concept exposes the question ‘is the composition of microflora a risk factor for obesity?’ The implication being that the caloric value of a meal should not be seen as a fixed entity, but rather as a value influenced by the consumers’ intestinal microbiota. In order to fully define our metabolic potential we would have to include that of our microbial colleagues, as these master ‘physiologic chemists’ have over our evolutionary history developed complex chemical strategies for regulating nutrient processes to the benefit of them and the host. After all we originated from single cell evolution and the earth has been populated with bacteria for over 2.5 billion years[48].

One of these ancient host signalling pathways appears to have a potential implication for fat storage and obesity. Research conducted by Washington University Medical Dept led by Prof Gordon has demonstrated that inclusion of a dietetically similar mice chow diet to germ free mice against conventionally microbiota populated mouse revealed a huge 42% increase in total body fat in the microbially populated mice despite a 29% reduction in calorific intake.

When microbiota harvested from conventionalised mice was then added to 8-10 week old germ free mice the effect was again dramatic with a 61% increase in body fat against their GF counterparts despite 27% decreased chow consumption.  Both sexes were affected with female mice showing a higher deposition.

In addition there was increased insulin resistance and increased triglycerides, as well as clear evidence of increased monosaccharide uptake. The transport of this nutrient to the liver is assisted by the microbiota induced increase in capillary density.[49] Once there the liver can either increase inefficient metabolism or export for peripheral storage as fat. The increase in fat storage resulted in enlarged adipocytes, and circulating fatty acids which in turn diminish availability of leptin for the brain and reducing glucose uptake by cells.

The microbiota acts through FIAF to coordinate increased hepatic lipogenesis with increased LPL activity in adipocytes, thereby promoting storage of calories harvested from the diet into fat

Lipoprotein Lipase (LPL) is a key regulator of fatty acid release from triglyceride-rich lipoproteins in muscle, heart, and fat[50] increased adipocyte LPL activity leads to increased cellular uptake of fatty acids and adipocyte triglyceride accumulation. The increase fat storage is mediated by a protein like chemical called FIAF (Fasting Induced Adipocyte Factor).  FIAF appears to have been preserved over the course of vertebrate evolution[51].  FIAF is one of many host factors influenced by gut microbes. There are 10-100 trillion microbes co-existing in the adult human gut, and this vast community of microbes has evolved ways of manipulating our biology to benefit them and us.

In fact, the gut microbiota may be considered as one of the body’s organs, one exquisitely attuned to our physiological needs.

“Over their millions of years of co-evolution with us, microbes have learned to manipulate networks of human genes,”. “By defining these networks, we can learn ‘new ways’ to promote health.”

The ability to store foods would have been advantageous to ancient humans who had variable access to food, in contemporary society, the ready access means this feature becomes a disadvantage. In the face of specific bacterial colonisation or overgrowth via provocational exposure to preferred food substrates FIAF is suppressed leading to fat storage.

Lower colonic bacteria appear to be the controlling organisms, and the rate appears dependant on population mix and exposure to polysaccharides[52]. The researchers discovered that the lean, bacteria-free rodents had more of the enzyme called fasting-induced adipocyte factor (FIAF) produced in the gut lining, liver, and fat cells. It lowers the amount of fat in these cells, but when Bacteroides is hard at work in the gut, FIAF is suppressed and absent, and fat cells load up increasing adiposity. FIAF represents a novel endocrine signal involved in the regulation of metabolism and is found in the plasma in higher levels during fasting[53].

Bacteroides thetaiotaomicron is the species currently associated with the manipulation of FIAF its genome is one of the largest examined, and it is dedicated to breaking down complex carbohydrates that enzymes in the human gut cannot otherwise process. The complex carbohydrates are polysaccharides, common to foods such as vegetables and other plant materials. Our bodies should consume 15 to 20 percent of daily caloric intake this way, but many dietary choices will adversely affect this ratio. The bacteria also exhibit an elaborate environment-sensing system to help them thrive in the highly competitive community within the human digestive system.

In order to be successful in the gut where there are literally trillions of bacteria competing for the nutrients their human host eats, the successful microbe must develop a system to determine what nutrients to go after and a strategy to capture them. B. thetaiotaomicron has evolved to do this with great facility. It has developed a unique ability to grab polysaccharides in the GIT and then release specific enzymes to harvest these nutrients as they enter its mucosal niche.  The results benefit the host and the organisms.  It is this competence at managing polysaccharides that appears to add complications when suppression of FIAF is also associated with this species.

These findings imply that microbial suppression of intestinal FIAF promotes adiposity, and suggests that increasing FIAF expression and/or activity may promote leanness. It is reasonable to speculate that changes in microbial ecology prompted by Western diets, and medication use and/or differences in microbial ecology between individuals living in these societies, may function as an “environmental” factor that affects predisposition toward energy storage and obesity.

Case History

Patient J, a 57 year old obese self employed male, with insulin resistance, hypertension, hypercholestralaemic, raised triglycerides and with mild depression.

Had followed a dietetic and lifestyle programme using macro food adjustments and exercise regimes as well as blood sugar and adrenal nutritional support.  Successfully reduced the weight from 24 stone to 21 stone but had been unsuccessful in reducing further his weight or markers of metabolic syndrome.

In an attempt to see if competitively inhibiting Thetaiotaomicron and managing the mucosal immune system would have any effect he was given a diet with slightly increased protein intake, 750mg of Saccharomyces Boulardii to raise SigA and 90 billion Lactic acid bacteria (Culturelle) and 60 billion Bacteroides without FOS (BifidoBactT) per day.

In 30 days he lost 8lb in weight, had a 25% reduction in BP, and noticed a significant change in mood and energy.  Three months on he has lost 1 stone, maintained his BP reduction and reduced medication, mood has remained buoyant and energy is high, insulin resistance has declined and triglycerides has also fallen.

This single case illustrates that there may be a route to manipulate entrenched weight and associated dysfunction via the master chemists living inside our body and assisting them in maintaining an effective level of mucosal tolerance.

References

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[9] Plevy S. The immunology of inflammatory bowel disease. Gastroenterol Clin North Am. 2002 Mar;31(1):77-92

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Overview

• There is currently no consensus about how the beneficial associations between the consumption of foods and food constituents and body health can be tested and firmly established. Conclusive proof is plainly required today as the basis for setting nutrient intake recommendations and for assessing the substantiating evidence for nutritional and physiological benefits in the form of health claims on foods and food constituents.
• The current imperative is that any opinions and recommendations should be ‘evidence based’, an objective with which it would be hard to disagree. However, the key questions relate to what constitutes the totality of the evidence and by what means it should be developed and weighed.
• The purpose of the workshop is therefore to review some of the problems associated with evidence-based nutrition, to discuss what constitutes efficacy for foods and food constituents and how the strength and consistency of the evidence can be assessed.

Specific questions will be addressed concerning how to:

• Define the ‘totality of the evidence’
• Take into account the strength and limitations of different sources of evidence
• Determine the appropriateness of the application of evidence-based medicine, which relies on randomised clinical trials (RCTs) to evaluate the efficacy and safety of drugs for individual patient care and for public health policy, to the assessment of dietary factors and health.
• Develop a scientific framework to assess the amount and quality of the evidence and the overall levels of certainty about food and health relationships.
• Utilise, develop and validate physiological risk factors (biomarkers) and behavioural risk factors (including dietary risk factors) in evidence-based nutrition.
• Apply evidence from preclinical and clinical studies and biomarkers developed for disease identification and progression to the normal healthy population.
• Identify functional biomarkers within the normal healthy homeostatic ranges.
• Provide policymakers and regulators with a practical scientific framework for making decisions and recommendations about diet and health.

Booking details

For further details and registration please visit the Royal Society of Medicines Web Site.

Considerable complications in the food industry are being faced as the European Food Safety Agency apply very tight filters to allow different levels of claims to be applied to products. One complaint is that the pharmaceutical approach to validation is unsuitable and therefore unworkable as foods are not the same as medicines in terms of mechanisms and actions.

Though it is of course accepted that food is vital to managing health and lmiting disease risk there is a central dogma that protecting the consumer is paramount, even if the blind conviction in this aim results in the exclusion of safe and health contributing food and supplements.

It might be considered that the pharmaceutical approach must therefore be water tight or at least a very robust approach and accordingly that advertisments for medicine would be reliable and based on high quality research relevant to the medicine being advertised. In particular they use an extensive amount of data extracted from randomised clinical trials (RCT’s) regarded by many as the only applicable standard of evidence gathering. An earlier post looked at a JAMA that through significant doubt on the validity of many medical research trials that actually make it to publication.

Now, a recent study, supporting previous investigations of a similar nature, confirms that ‘claims’ made in advertisements in high quality medical journals such as the Journal of the American Medical Association, the Lancet, the New England Journal of Medicine, etc might not always be supported by high-quality evidence, and referenced studies may have been sponsored by the pharmaceutical industry itself. [1]

By and large they found, only 17% of referenced RCTs investigated between 2003 – 2005 attached to all adverts in high quality medical journals are of good quality, supportive, and not sponsored by the company itself.

This investigation supports the Lancet study from 7 years ago in which a similar analysis found a considerable discrepancy between medical claims made and the supportive studies.

The 1993 Lancet article concluded:

Doctors should be cautious in assessment of advertisements that claim a drug has greater efficacy, safety, or convenience, even though these claims are accompanied by bibliographical references to randomised clinical trials published in reputable medical journals and seem to be evidence-based.

The free access journal PLOS in 2009 undertook a systematic review of 24 journal articles looking at the quality of medical advertising they discovered overall that only 67% of the claims in adverts were supported by a systematic review, a meta-analysis or a randomised control trial and concluded:

Evidence from this review indicates that low quality of journal advertising is a global issue. As information provided in journal advertising has the potential to change doctors’ prescribing behaviour, ongoing efforts to increase education about drug promotion are crucial. The results from our review suggest the need for a global pro-active and effective regulatory system to ensure that information provided in medical journal advertising is supporting the quality use of medicines. [2]

Comment

What does this mean to us as nutritional therapists, well medicine and nutrition are disciplines in which the purported benefits linked to supplement of medicine consumption need to be explained to the consumer as well as the practitioner both disciplines have a responsibility to be accurate and fair.

The budgets available to pharmaceutical products are vast compared to those available to bodies exploring the potential benefits for food/supplements. The very financial difference should allow the medical adverts to apply a more rigorous level of qualification, espescially as they are normally associated with a level of risk. Foods and supplements need to be carefully described and as legislation evolves this will be enforced by law as well as moral and financial decisions.

It is of use to us to remember that for all the criticism that is leveled at the alternative medicine community for lack of credible (RCT) research, it appears that the very organistaions that hve promoted the RCT strategy as qualifying research are unable to be relied upon to use them appropriately anyway.

References

[1] Heimans L, van Hylckama Vlieg A, Dekker FW.Are claims of advertisements in medical journals supported by RCTs? Neth J Med. 2010 Jan;68(1):46-9. View Abstract View Full Paper

[2] Othman N, Vitry A, Roughead EE (2009) Quality of Pharmaceutical Advertisements in Medical Journals: A Systematic Review. PLoS ONE 4(7): e6350. doi:10.1371/journal.pone.0006350 View Full Paper

[3] Villanueva P, Peiró S, Librero J, Pereiró I. Accuracy of pharmaceutical advertisements in medical journals. Lancet. 2003 Jan 4;361(9351):27-32. View Abstract

Vitamin D is unique – unlike ALL other vitamins very little comes from our food. Almost all of our Vitamin D is produced by the upper surface of our skin during direct exposure to UV radiation in strong sunlight. However in the UK and most of the USA the sun is too low in the sky from November until March to produce any Vitamin D from sunlight exposure. The fat soluble nutrient supplies are meant to rely on a summer exposure to increase our stores to supply what we need during the winter.

Papers published in the last few years confirm that many people in non-equatorial regions have very low Vitamin D levels – especially during the winter. People of African descent, now living in more northerly areas, are at highest risk as the darker the skin tone the slower the Vitamin D production. If there is little or no strong sunlight exposure Vit D deficiency will occur. This condition increases as a risk as you age, as older skin is less efficient at converting radiation into Vitamin D.

Vitamin D is well understood to contribute essential mechanisms for calcium metabolism vital for bone, muscle and nerve function – but recent research shows it is also critical to your immune response against viruses, bacteria and cancer.

Researchers have discovered that as you run low on Vitamin D your immune response weakens. Trials have proved that people taking “high dose” Vitamin D3 supplements (>2000 IU/day) are extremely resistant to colds and flu – and it now appears that resistance to some cancers is also proven.

The grassroots web site have produced a summary chart showing how risk for disease declines in the face of optimal vitamin D blood serum levels. Collated from a collection of recently published articles it easily demonstrates that establishing and maintaining optimal Vitamin D status is exceptionally beneficial for long term health and disease risk reduction.

View Disease Prevention Chart

Host: Rosie Millen
Location: London, SW6

Date: 15-04-2010
Time: 11:00 – 14:30