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Supplements for Vitiligo

Vitiligo is an autoimmune condition and as such certain dietary protocols as well as supplements can be used to support the immune system for those that experience the characteristic skin depigmentation. The scope of this article however is to discuss the supplements that have been shown in clinical trials to help the repigmentation of the skin.

In most cases supplementation was accompanied by the use of light therapy.

Khellin.

For thousand of years the treatment of “leukoderma” (vitiligo) involved the topical application or ingestion of seeds or plant extracts and the subsequent exposure to sunlight. Khellin is an extract from the seeds of the plant khella found in the eastern Meditteranean area. Supplementation of Khellin has been repeatedly shown (Abdel-Fattah, A. et al., 1982, Orecchia, G. et al., 1998, de LEEUW, J. et al., 2003) to improve the repigmentation of the skin.

 

There have been cases though (Ortel, B. et al., 1988) that after 4-6 weeks of khellin supplementation the elevation of transaminases was observed and for these individuals had to discontinue the treatment.

 

L-phenylalanine.

In search for re-pigmentation solutions for vitiligo, a group of scientists in Amsterdam – NL (Cormane R et al., 1985), noted that patients with phenylketonuria (who among other symptoms have lighter than normal skin) when administrated tyrosine and were incubated with UV-light had normal melanin production. Cormane’s team initially tried the tyrosine & UV-A protocol in a pilot study of 5 without any success. Sequentially they tried phenylalanine (a precursor of tyrosine) seeing improvement in 95% of the subjects after 6 to 8 months. The theory put forward on why phenylalanine benefits vitiligo patches was that it stops antibodies and allows sun radiation to stimulate melanocytes from other areas to migrate to the damaged ones (Camacho, F. and Mazuecos, J., 1999).

 

50 mg/kg of body weight per day of phenylalanine was administered 1 hour prior to UV A irradiation (twice per week). Of the 19 participants:

i. 5 noted dense re-pigmentation in 6 to 8 months

ii. 13 saw sparse re-pigmentation in the same period

iii. and 1 had no re-pigmentation even after 8 months.

Since the 1980’s there has been no more research examining the benefits of phenylalanine for vitiligo. All 3 studies combining the administration of the amino acid & UVA exposure as well as the 1 that used just the amino acid reported positive outcomes (Szczurko, O. and Boon, H.S., 2008).

 

Additional supplements.

PABA is an ingredient often used in sunscreen lotions. One study showed PABA to support repigmentation (Sieve B F, 1942) but currently there is limited research to confirm these findings. An 8 years old girl developed hemolytic anemia and hepatotoxicity after administration of PABA for 4 months. Symptoms were reversed 2 months after discontinuing the supplement (Tootoonchi, P., 2018). PABA has also been reported to cause depigmentation (Hughes, C. G., 1983)

 

Vitamin E (Szczurko, O. and Boon, H.S., 2008) and vitamin C have also been shown to support re-pigmentation potentially due to their antioxidant properties.

 

Conclusion.

The results in the above studies are very promising. However, as I mentioned already, in certain cases there have been adverse effects such as the development of cirrhosis which highlights the importance of complimentary testing and supervision.

 

 

References.

Abdel-Fattah, A., Aboul-Enein, M. N., Wasset, G. M., & El-Menshawi, B. S. (1982). An approach to the treatment of vitiligo by khellin. Dermatology165(2), 136-140.

 

Camacho, F. and Mazuecos, J., 1999. Treatment of vitiligo with oral and topical phenylalanine: 6 years of experience. Archives of dermatology, 135(2), pp.216-217.

 

Cormane, R.H., Siddiqui, A.H., Westerhof, W. and Schutgens, R.B.H., 1985. Phenylalanine and UVA light for the treatment of vitiligo. Archives of Dermatological Research, 277(2), pp.126-130.

 

de LEEUW, J., MAIERHOFER, G., & NEUGEBAUER, W. D. (2003). A case study to evaluate the treatment of vitiligo with khellin encapsulated in L‐phenylalanin stabilized phosphatidylcholine liposomes in combination with ultraviolet light therapy. European Journal of Dermatology13(5), 474-477.

 

Hughes, C. G. (1983). Oral PABA and vitiligo. Journal of the American Academy of Dermatology9(5), 770.

 

Szczurko, O. and Boon, H.S., 2008. A systematic review of natural health product treatment for vitiligo. BMC dermatology, 8(1), p.2.

 

Sieve, B. F. (1942). The clinical effects of a new B-complex factor, para-aminobenzoic acid, on pigmentation and fertility. South Med Surg104(135), 9.

 

Orecchia, G., Sangalli, M. E., Gazzaniga, A., & Giordano, F. (1998). Topical photochemotherapy of vitiligo with a new khellin formulation: preliminary clinical results. Journal of dermatological treatment9(2), 65-69.

 

Ortel, B., Tanew, A., & Hönigsmann, H. (1988). Treatment of vitiligo with khellin and ultraviolet A. Journal of the American Academy of Dermatology18(4), 693-701.

 

Tootoonchi, P. (2018). Hemolytic Anemia and Other Side Effects of Para-amino Benzoic Acid in an 8-Year-Old Girl. Iranian Journal of Pediatric Hematology & Oncology8(3).

How to test for Celiac Disease?

The only way you can get a definite YES or a NO for Celiac Disease (CD) is by doing intestinal biopsy. As this is an invasive and expensive procedure, many prefer measuring serum antibodies as an initial screening process. When someone decides to test for antibodies against gluten it is necessary to keep in mind:

a) that the gluten protein is fairly complex and thus all antibodies need to be tested

b) that the blood test is not a substitute for the biopsy.

Whichever assessment method one decides to use it is important to know that:

For CD, early diagnosis means early intervention with treatment and prevention of long-term complications, including the development of severe and irreversible phenotypes and of other autoimmune disorders.” (Ventura A et al., 2010)

 

Intestinal biopsy is the golden standard for diagnosing Celiac Disease.

 

An individual is classified as celiac when a biopsy of the duodenal mucosa is taken which detects:

a) a reduction or disappearance of intestinal villi &

b) intraepithelial lymphocytes (IELs) higher than 25/100 enterocytes (Sapone A. et al., 2012).

Individuals presenting with significant villous atrophy are classified as CD March stage III, whereas normal villi but increased number of intraepithelial lymphocytes are classified as Marsh I or II (Hill ID et al., 2005). Marsh type II may also suffer from CD but positive serological tests is needed to strengthen the diagnosis (Hill ID et al., 2005). When only elevated IELs are observed but no damage of the intestinal lining, it is difficult to diagnose CD (Kakar eta l., 200). In literature this state is usually referred to as latent CD (Dewar et al., 2005) and further testing is required.

 

Can elevated IELs be due to a different cause other than Celiac Disease?

The presence of IELs can be due to gastrointestinal inflammation caused by H. pylori (Memeo et al., 2005) or tropical sprue (Ross et al., 1981). Unexplained neurological or psychiatric disorders such as autism, schizophrenia, and cerebellar ataxia (Cascella N et al., 2009, Burk K et al., 2009, Genuis S and Bouchard T, 2010) are also linked with elevated IELs and no mucosal damage.

 

Can a blood test confirm Celiac Disease?

No. However, a lot of the time serum antibody testing is used in the screening process. The ones necessary are: anti-DGP IgG & anti-tTG IgA

 

Antibodies for the diagnosis of Celiac Disease

Antibodies

Accurate

Not affected by IgA deficiency

Not prone to interpretation

Cheap

Appropriate for children <2 years old

AGA IgA

AGA IgG

EMA IgA

tTG IgA

DGP IgG

Anti-Actin IgA

 

 

classic Anti-gliadin (AGA) antibody IgA

Pros:

1. relatively cheap

Cons:

1. found in healthy individuals (Bizzaro N et al., 2012)

2. May fluctuate within the first 2 years of age (Simell et al., 2007)

3. relatively insensitive (Fasano A, 2013)

 

AGA-IgG

Pros:

1. useful for pediatric patients with CD who test negative for anti-tTG (Carlsson A et al. 2001, Lagerqvist C et al., 2008).

2. useful in patients with IgA deficiency (Villalta D et al., 2007).

3. reasonably cheap

3. Same results where obtained with the DGP IgG test (Liu E et al., 2007, Agardh D 2007, Basso D et al., 2009, Naiyer A et al., 2009).

4. Remains constant the first 2 years of age (Simell et al., 2007)

Cons:

1. relatively insensitive (Fasano A, 2013)

 

EmA (Endomysial Antibodies – antigliadin) IgA (unless IgG requested)

Pros:

1. It is equally specific with the anti-tTG antibodies, meaning it recognizes the same antigens (Hill 2005)

Cons:

1. It is prone to subjective interpretation

2. It is less sensitive than the anti-tTG (Biagi F et al., 2001, Baudon J et al., 2004, Lock et al., 2004, Kaukinen K et al., 2007).

3. Not accurate in patients with selective IgA deficiency.

4. May fluctuate within the first 2 years of age (Simell et al., 2007)

5 *The IgG version has inferior sensitivity (Fasano A, 2013)

 

anti-tTG (antihuman tissue transglutaminase) IgA (unless IgG requested)

Pros:

1. As it is quantitative, automated and not prone to subjective interpretation

2. high diagnostic sensitivity (95%) specificity (97%) (Tozzoli et al., 2010)

Cons:

1. Anti-tTG IgA is not sensitive enough to be used alone and the addition of the anti-DGP IgG test would increase the accuracy for CD especially in children (Niveloni S et al., 2007, Villalta D et al., 2007, Volta U et al., 2010, Tonutti E et al., 2009, Villalta et al., 2010, Maglio M et al., 2010)

2. May fluctuate within the first 2 years of age (Simell et al., 2007)

3 *The IgG version has inferior sensitivity (Fasano A, 2013)

 

DGP antibodies IgG (deamidated gliadin peptide)

Pros:

1. antibodies comparable sensitivity and specificity to anti-tTG and EMA (Sugai E et al., 2006)

2. Remains constant the first 2 years of age (Simell et al., 2007)

3. DGP IgG test positive in 80% of cases of CD patients with IgA deficiency as compared to 40% for AGA IgG ( Villalta et al., 2010)

 

ANTI-ACTIN IgA

Pros: can evaluate the severity as it is related to the severity of intestinal damage (Granito A et al., 2004, Carroccio A et al., 2005)

Cons: limited usefulness for diagnosis

 

In monitoring of patients on a gluten-free diet, positivity with a low titer of anti-DGP antibodies suggests that the diet should be reassessed, even if the anti-tTG test is negative” (Tursi et al., 2006)

 

Interpretation of serological and biopsy test results

Biopsy

+

Serology

+

CD

Absence of CD and possible false-positive blood test. A negative genetic test can strengthen the negative diagnosis.

This result is treated as CD. However, inflammation in the lining can be due to other causes, including intolerances to other foods.

No CD. However, in the presence of other autoimmune conditions or genetic predisposition, future monitoring may be appropriate.

 

Which other blood biomarkers are available?

While the tests above are the ones most commonly done there is evidence that more thorough testing may be needed for those with negative results and positive symptoms. A complete antibody screening should include: Alpha gliadin, Omega gliadin, Gamma gliadin, Deamidated gliadin, TG2, TG3, TG6.

 

Deamidation is an acid or enzymatic treatment used by the food processing industry to make wheat, water-soluble so it mixes with other foods. It has been shown to cause severe immune responses to people (Leduc V et al., 2003).

Gliadin is broken down to alpha, omega and gamma fractions. If a lab tests only for alpha gliadin antibodies the results may be misleading (Quartesn H et al. 2001).

Elevated antibodies of TG2 indicated a reaction against the intestinal track (Thomas H et al., 2011). Transglutaminase 3 (TG3) is found in the skin. An autoimmune reaction to skin may lead to skin disorder known as dermatitis herpetidormis, which presents as itchy red blisters found usually in the knees, elbows, buttocks but can appear anywhere on the body (Stamnaes I et al., 2010). Elevated antibodies to transglutaminase 6 indicate an immune response against the nervous system (Alessio et al., 2012).

Yogis and Cold exposure

The popularity of cold exposure has increased over the last few years. Whether it is through cryotherapy or cold water immersion more and more people practice and/or hashtag #coldexposure. What are the benefits of cold exposure for the modern yoga practitioner (yogi or yogini)?

 

Cold exposure as a meditation TECHNIQUE

Those that practice cold water immersions for some time report a sensation of stillness in mind (usually 30 seconds to a minute after the initial exposure). A friend of mine Luke Wills (founder of the Optimal Health Method) said he reached the same state of mind in his 2nd ice bath, with that on the 7th day in a vipassana meditation retreat. Anecdotal evidence like this were confirmed to be valid in a study published in May 2018 titled “Brain over Body” [1].  In this study participants with no previous experience in cold exposure and Wim Hof (a Dutch man with chronic practice in cold environments) were interchangeably exposed to cold and neutral temperatures. One of the most striking differences between the inexperienced subjects and Wim was the Dutchman’s ability to reduce activity in the insular cortex part of the brain during cold exposure. Insular cortex is an area involved in emotional attachment to external stimuli and self-reflection. Activity in this part of the brain has been shown to be linked with meditation and control in emotional eating.

 

Meditation is the 5th of the 8 limbs of yoga.

 

Cold exposure To overcome fears

Iyengar’s book “Light on Yoga” has the subtitle: “the yoga journey to wholeness, inner peace and ultimate freedom.” In our yogic journey (our journey to wholeness) we will have to ultimately face our fears. I believe that cold exposure offers a unique opportunity to learn how to do that.

Cold exposure is demanding on many levels; the adrenals, musculoskeletal system, circulation and the brown fat tissue (if existent) are activated at low temperatures. Aside though the multiple biochemical adaptations in the rest of the body, our brain also changes when we are exposed to cold. The initial response is that of: “fight or flight” [2]. A small area of the brain called amygdala (Greek word for almond) – by activating the HPA (Hypothalamic Pituitary Adrenal) axis – signals a Stress response to the rest of the body. While this initial stage is universal the way one deals with cold thereafter depends on her experience and ability to use her breath.

By training the body to deal with a stressful situation (ie. a cold immersion) in a controlled environment (such as a shower or a bath) we can reprogram our mind to deal with stressful situations which are out of our control. Our main tool in this process is our breath. Dealing with fear was the focus of a workshop I gave in 2017 to a group of actors. You can see footage from it in the video.

 

Cold exposure to improve Circulation / Cardiovascular Function

The benefits of an asana practice to physical health are far reaching. The improvement of respiratory function, the increase of muscle flexibility and joint mobility are just a few.  Depending though on the style of yoga one practices she may be getting more or less of a cardiovascular workout. Cold exposure is a unique way to strengthen one’s cardiovascular system.

Our cardiovascular system is surrounded by epithelial muscles which facilitate the circulation of the blood. At low temperatures the epithelial muscles surrounding the veins and arteries of our extremities constrict – preserving the blood and the nutrients carried in it for the more vital organs in the trunk and the head. When the body returns to higher temperatures the epithelial muscles in our extremities dilate again allowing for the blood to flow freely there. In a similar way that our biceps get stronger as they contract during chaturangas our cardiovascular system can get stronger through cold exposure.

 

 

Good circulation means no athletes foot, no cold extremities, better cognitive function, ability to heal/recover faster and perform better in sports.

 

Conclusion

The list above is not exhaustive of the benefits one can get from cold exposure; controlling pain perception [2], generation of Brown Far [3], strengthening of the immune system [4], improved tolerance to cold [5] are also good reasons for modern yogis and yoginis to practice cold exposure.

 

Future workshops are listed here.

 

References:

  1. Muzik, O., Reilly, K. T., & Diwadkar, V. A. (2018). “Brain over body”–A study on the willful regulation of autonomic function during cold exposure. NeuroImage172, 632-641.
  2. Kanosue, K., Sadato, N., Okada, T., Yoda, T., Nakai, S., Yoshida, K., … & Kobayashi, K. (2002). Brain activation during whole body cooling in humans studied with functional magnetic resonance imaging. Neuroscience letters329(2), 157-160.
  3. van der Lans, A. A., Hoeks, J., Brans, B., Vijgen, G. H., Visser, M. G., Vosselman, M. J., … & Schrauwen, P. (2013). Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. The Journal of clinical investigation123(8), 3395-3403.
  4. Buijze, G. A., Sierevelt, I. N., van der Heijden, B. C., Dijkgraaf, M. G., & Frings-Dresen, M. H. (2016). The Effect of Cold Showering on Health and Work: A Randomized Controlled Trial. PloS one11(9), e0161749.
  5. Vosselman, M. J., Vijgen, G. H., Kingma, B. R., Brans, B., & van Marken Lichtenbelt, W. D. (2014). Frequent extreme cold exposure and brown fat and cold-induced thermogenesis: a study in a monozygotic twin. PloS one9(7), e101653.

Carbon Dioxide: The missing piece in a metabolic jigsaw puzzle

Our body’s capacity to produce energy is dependent on oxygen. Our cells  are capable of producing much more energy in the presence of oxygen compared to a non-aerobic state *. Approximately 90% of the oxygen in our cells is used for energy production (1). So how can we ensure the delivery of adequate oxygen to our cells?

When most people are out of breath, they tend to breathe faster and take bigger breaths. Both of these actions will offer a temporary release for the air-hunger sensation but will not improve cell oxygenation – at least not in the long run.

 

In order to grasp how erroneous the idea of air hunger equating lack of oxygen is, think of the following: During an asthma attack patients are advised to breathe through a brown bag. If they need more oxygen, why should they restrict their oxygen intake?

 

 

The two breath parameters: Frequency & volume

Most people take between 10 and 16 breaths per minute. The volume of air that we inhale is approximately 500 millilitres per breath . This translates to approximately 6 litres per minute. When increasing the frequency of breaths, the volume of air per breath is reduced and vice versa, keeping the total volume of air inhaled the same.

 

Strange as it may sound, the increase of air in the lungs is not what is required for better oxygenation of our cells. Inhalations allow the body to take oxygen in. Most of the time though, the body retains high oxygen saturation levels. By using an oxygen meter we can prove that our blood contains 95-99% of its total oxygen capacity most of the time. If our blood constantly contains good levels of oxygen, why do we “run out of breath” at the end of a strenuous workout or when walking quickly up stairs?

 

 

The role of carbon dioxide in oxygen transport

Carbon Dioxide** is a by-product of fat and carbohydrate metabolism (aerobic and anaerobic). It exists in the fresh air at concentrations of 0.036-0.041% (36-41ppm). At 1% (10,000 ppm) concentration it can cause sleepiness and between 7 – 10%*** suffocation.

In 1904 **** physiologist Christian Bohr discovered the Bohr effect. Based on the Bohr effect, haemoglobin in the blood requires Carbon Dioxide (CO2) in order to release Oxygen (2). Low levels of CO2 in the blood, increase the affinity of oxygen to haemoglobin, preventing it from moving to the cells.

 

So, while at high levels CO2 can be toxic (3), at low levels it can deprive our cells of oxygen (based of the Bohr effect). Which raises the question, “what is the optimal level of CO2”? Before answering this question we need to review one more function of CO2: its role to signal our need to inhale!

Our brain is responsible for the control of our breathing cycle. Receptors in the brain continuously monitor a number of blood markers to signal the need for the next inhalation (4). Among these, the most critical, marker, is the levels of CO2 in the blood (5). When the levels of CO2 reach our tolerance point we get the urge for the next inhalation. Those familiar with the sport of underwater diving are aware of this concept.

 

 

So in order to deliver oxygen to our cells efficiently we need to prolong our urge for the next inhalation (i.e. increase our tolerance to CO2) and not increase our body’s levels of CO2. The beneficial metabolic effects of temporary exposure to an elevated CO2 state has been demonstrated in scientific studies. In one study the application of CO2 to transcutaneous tissue led to the proliferation of  mitochondria, similar to the one observed during aerobic exercise (6).

 

 

It is worth pointing out that in most medical centres the saturation of oxygen (SpO2) in the blood is monitored regularly. Nonetheless, good levels of SpO2 in the blood do not equate good levels of SpO2 in the organs. Our ability to deliver oxygen to our cells is dependent on our tolerance to CO2.

A good reference book on this topic is: “Oxygen Advantage” by Patrick Mckeown. On the Youtube Oxygen Advantage channel you can find several exercises to improve your tolerance to CO2.

 

 

Fun fact

The concept of better delivery of oxygen to cells is also the reason for which some athletes train at high altitude. High-altitude training became popular after the 1968 Mexico Olympics. Mexico is located at 2,300 metres above sea level. During this Olympiad, many athletes surpassed their previous performances, which prompted coaches to question if the location, was conducive to athletic performance. At high altitude the oxygen is reduced. At a hypoxic (low in oxygen) environment, the body is forced to produce more red blood cells. More blood cells means more available vehicles to carry oxygen to the cells. However, soon after an athlete, returns to sea level, the number of red blood cells returns to normal levels.

 

 

Footnotes

* One molecule of glucose will produce two molecules of Adenosine Triphosphate (ATP – our body’s energy currency) in an anaerobic state, as opposed to thirty six molecules of ATP in an aerobic state.

** Carbon Dioxide, a natural-occurring product of metabolism, that should not to be confused with Carbon Monoxide, a flammable gas that does not occur naturally in the atmosphere.

*** In one study subjects were exposed to air containing 7-14% of CO2 for 10-20 mins. All subjects had a complete recovery of their physiology 10 mins after the end of the experiment (7).

**** That was 33 years before Han’s Krebs’ discovered the eponymous Krebs cycle.

 

References

  1. Bland, J., Costarella, L., Levin, B., Liska, D., Lukaczer, D., Schiltz, B. and Schmidt, M.A., 1999. Clinical nutrition: A functional approach. The Institute for Functional Medicine, Gig Harbor, Wash, USA.
  2. Bohr, C., Hasselbalch, K. and Krogh, A., 1904. Über einen in biologischer Beziehung wichtigen Einfluss, den die Kohlensäurespannung des Blutes auf dessen Sauerstoffbindung übt. Acta Physiologica16(2), pp.402-412.
  3. Satish, U., Mendell, M.J., Shekhar, K., Hotchi, T., Sullivan, D., Streufert, S. and Fisk, W.J., 2012. Is CO2 an indoor pollutant? Direct effects of low-to-moderate CO2 concentrations on human decision-making performance. Environmental health perspectives120(12), p.1671.
  4. Huckstepp, R.T. and Dale, N., 2011. Redefining the components of central CO2 chemosensitivity–towards a better understanding of mechanism. The Journal of physiology589(23), pp.5561-5579.
  5. Cheung, S., 2010. Advanced environmental exercise physiology. Human Kinetics.
  6. Oe, K., Ueha, T., Sakai, Y., Niikura, T., Lee, S.Y., Koh, A., Hasegawa, T., Tanaka, M., Miwa, M. and Kurosaka, M., 2011. The effect of transcutaneous application of carbon dioxide (CO 2) on skeletal muscle. Biochemical and biophysical research communications407(1), pp.148-152.
  7. Sechzer, P.H., Egbert, L.D., Linde, H.W., Cooper, D.Y., Dripps, R.D. and Price, H.L., 1960. Effect of CO 2 inhalation on arterial pressure, ECG and plasma catecholamines and 17-OH corticosteroids in normal man. Journal of Applied Physiology15(3), pp.454-458.

 

Reversing Vitiligo

(Updated: 17th Oct 2018)

Vitiligo (also called “leukoma”) is an autoimmune condition where loss of pigment from areas of the skin result in irregular white patches, the texture of which remain normal. Similar with all autoimmune disorders:

i. the body is attacking its own tissue. In the case of vitiligo the body is attacking the melanocytes (the cells responsible for skin colouring).

ii. the triggering cause may vary. I have seen 1 case where it started after a car accident at an early stage of life & another where it developed after a stressful period at late 40s.

iii. the development of the disease is the result of genetic predisposition as well as environmental factors.

iv. there is a higher than normal risk for the simultaneous presence of other autoimmune conditions.

 

Cease the Fire.

As an autoimmune condition vitiligo has to be treated as an immunological problem and not solely as a skin one. While the symptoms manifest in the skin it is the immune system that is over-reacting. This is the reason why in many cases immunosuppressive drugs are prescribed (Boone B., et al., 2007). Stopping the over-activity of the immune system may not be as straight forward as we wish. Foods, heavy metals, infections have been shown or speculated to be the root cause of this unfavourable behaviour of the immune system (IS).

In order to address each of the above one can:

i. follow an anti-inflammatory diet.

ii. remove any obvious toxic deposits in the body (i.e. mercury fillings, tattoos)

iii. get tested for carrying any of the common viruses associated with autoimmunity (i.e. Epstein Barr virus)

 

Test for other AI conditions.

While there are 100s of autoimmune conditions, Hashimoto’s & Celiac Disease have been shown to have a higher prevalence among patients of vitiligo. Hashimoto’s can be easily diagnosed through an inexpensive blood test for TPO (Thyroid peroxidase) & TgAB (Thyroglobulin) antibodies. The diagnosis of Celiac Disease requires a biopsy which is why a lot of patients with vitiligo decide to eliminate gluten from their diet without going through the hustle of testing.

 

If the body is attacking more than one of its own tissue it is best for all autoimmune cases to be supported at the same time.

 

Light Therapy.

For the depigmentation is of the “milky” patches the 2 versions of light therapy have been used successfully are: Narrowband UVB & Targeted light therapy (Grimers PE 2005).

 

Narrowband UV-B involves the use of UV lamps with a peak emission around 311 nm. It induces local immunosuppression while stimulating the production of melanocyte-stimulating hormone, and the increase of melanocyte proliferation and melanogenesis. In a study (Njoo M D et al., 2000) where 51 children with generalised vitiligo were treated with narrowband UV-B:

a) 53% achieved >75% of repigmentation

b) 29% had 26-50% of repigmentation

c) 18% had <25% of repigmentation

 

The main advantages of narrowband UV-B include:

a) safety for both adults & children

b) lack of systemic adverse effects

Source: Njoo M D et al., 1998

 

A number of supplements have been shown to help reverse vitiligo. Accompanying light therapy with supplementation is likely to amply its benefits.

 

Which Genes?

NLRP1 gene

NLRP1 is a gene involved in the production of proteins called inflammasomes. Inflammasomes participate in the regulation of the immune system & mutations in NLRP1 have been associated with the presence of autoimmune disorders. The rs6502867 variant of the NLRP1 gene (risky allele: T) was associated with vitiligo in an Indian study (Dwivedi M et al., 2013).

 

Phytonutrient (EGCG) in green tea has been shown to inhibit the action of the NLRP1 gene (Ellis L et al., 2010).

 

Methylation

Methylation is a process responsible for many functions in the body including cell replication and DNA repair. A study published among 80 individuals (40 with vitiligo & 40 controls) (Yasar, A et al., 2012) showed no correlation between mutations in MTHFR or the levels of serum folate & vitamin B12 among the patients. Had the study measured red blood cell folate and vitamin B12 their findings would have been more significant.

Both folate & vitamin B12 (which directly support the methylation pathway) have been used by vitiligo patients with positive outcomes.

 

Case Study.

The photos in the image above are from a female client in her 50’s. She was following the Wahls dietary protocol for 6 months as an anti-inflammatory / auto-immune friendly approach. The main adjustments in her diet where the increase of fats through nuts & seeds as well as progressing from 2 meals and 1 snack a day to a 16-8 hours fast and then to 1 meal a day (twice per week). Breathing exercises as well as progressive exposure to cold (through showers) were also part of her protocol.

 

References.

Boone, B., Ongenae, K., Van Geel, N., Vernijns, S., De Keyser, S. and Naeyaert, J.M., 2007. Topical pimecrolimus in the treatment of vitiligo. European Journal of Dermatology, 17(1), pp.55-61.

Dwivedi, M., Laddha, N.C., Mansuri, M.S., Marfatia, Y.S. and Begum, R., 2013. Association of NLRP1 genetic variants and mRNA overexpression with generalized vitiligo and disease activity in a Gujarat population. British Journal of Dermatology, 169(5), pp.1114-1125.

Ellis, L.Z., Liu, W., Luo, Y., Okamoto, M., Qu, D., Dunn, J.H. and Fujita, M., 2011. Green tea polyphenol epigallocatechin-3-gallate suppresses melanoma growth by inhibiting inflammasome and IL-1β secretion. Biochemical and biophysical research communications, 414(3), pp.551-556.

Grimes, P. E. (2005). New insights and new therapies in vitiligo. Jama293(6), 730-735.

Njoo, M. D., Bos, J. D., & Westerhof, W. (2000). Treatment of generalized vitiligo in children with narrow-band (TL-01) UVB radiation therapy. Journal of the American Academy of Dermatology42(2), 245-253.

Njoo, M. D., Spuls, P., Bos, J. T. A., Westerhof, W., & Bossuyt, P. M. M. (1998). Nonsurgical repigmentation therapies in vitiligo: meta-analysis of the literature. Archives of dermatology134(12), 1532-1540.

Yasar, A., Gunduz, K., Onur, E. and Calkan, M., 2012. Serum homocysteine, vitamin B12, folic acid levels and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism in vitiligo. Disease markers, 33(2), pp.85-89.

 

 

How to detect vitamin B12 deficiency

Vitamin B12 is common and unfortunately one cannot rely on serum vitamin B12 to detect a deficiency. Vitamin B12 is carried in the blood by either of 2 proteins: haptocorrin and holotranscobalamin. While the majority of vitamin B12 is carried by haptocorrin, this vitamin B12 is considered inactive* [1]. A serum vitamin B12 test cannot differentiate between the active and inactive form and as a result while the level may appear healthy, the active form of vitamin B12 may be significantly low.

 

Which test is best to identify vitamin B12 deficiency?

The most direct why to detect vitamin B12 deficiency is to measure your active form of B12: holotranscobalamin. Biolab in UK offers that test.

If that test is not available to you, your 2nd best option is to measure your homocysteine levels. Homocysteine is a protein humans synthesise in their body and it’s considered one of the most significant biomarkers of cardiovascular health. Its production relies on the availability of vitamin B12, folate & protein.

source: PMID 16702348 [4]

As multiple other factors though affect the levels of Homocysteine, one cannot drive conclusive results for her vitamin B12 just knowing her homocysteine level.

 

 

Which symptoms indicate vitamin B12 deficiency?

Vitamin B12 plays a critical role in the methylation cycle [3] (which consists of the folate & methionine cycle). As a result any problems associated with methylation may be driven due to:

  1. low vitamin B12 intake (important for vegans and vegetarians)
  2. poor absorption (relevant for those with poor gastrointestinal function) [2] or
  3. compromised metabolism (possibly due to MTR & MTRR polymorphisms)

 

 

 

* due to the fact that haptocorrin receptors are found mainly in the liver.

 

  1. Morkbak, A.L., Poulsen, S.S. and Nexo, E., 2007. Haptocorrin in humans. Clinical Chemical Laboratory Medicine, 45(12), pp.1751-1759.
  2. Schjønsby, H., 1989. Vitamin B12 absorption and malabsorption. Gut, 30(12), p.1686.
  3. Miller, A., Korem, M., Almog, R. and Galboiz, Y., 2005. Vitamin B12, demyelination, remyelination and repair in multiple sclerosis. Journal of the neurological sciences, 233(1), pp.93-97.
  4. Refsum, H., Nurk, E., Smith, A.D., Ueland, P.M., Gjesdal, C.G., Bjelland, I., Tverdal, A., Tell, G.S., Nygård, O. and Vollset, S.E., 2006. The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. The Journal of nutrition, 136(6), pp.1731S-1740S.

Fasting Diet: progressions

 

Updated: 26 Sep 2018

 

This article is written with deep respect in the process of fasting and consciousness that its epigenetic effects are far reaching. Fasting in my opinion is something we all need to be comfortable with. There are many disputes on what the healthiest diet is, with advocates of the different diets often trying to support their view using ethnological and ancestral data. It is clear though to everyone that our ancestors had to survive periods of fasting independent of their diet (whether the famine was caused due to lack of game or a disaster in the crops).

My Journey with the Fasting Diet

I have been following a Fasting Diet on and off since September 2009. In my first attempt to fast (after reading my first book on nutrition called: Food Governs your Destiny) I set x3 2hour slots in the day during which I allowed myself to eat. Outside these windows I would consume only liquids. I stayed on the diet for 6 months, during which I:

👉🏻 reduced my waist circumference from 34 to 29 inches.

👉🏻 lost 7.5 kilos.

👉🏻 achieved mental clarity I have never experienced before.

During a big part of these 6 months I was vegetarian.

In 2016 I decided that as a way of monitoring my metabolism I would like to measure the production of ketones in my body. Between October 2016 and February 2017 I monitored my Blood Glucose (BG) and Ketone Bodies (KB) – beta-hydroxybutyric acid on a daily basis. Monitoring can be useful:

👉🏻 as feedback for one’s response to food / exercise.

👉🏻 for compliance when BG & KB targets are set.

During this period there were weeks of following a vegetarian diet but most days I consumed meat.

Fast Diet: Progressions

Bellow I share what I consider to be a natural progression of fasting. Of course everyone’s starting point is different: not everyone starts with a: 3 meals and 2 snacks diet and neither do we all have the same tolerance to the changes each step requires. I imagine you have not been eating the same way all your life, after all. If you are not sure how quickly you should progress from one stage to the next I suggest you err on the safe side. Most people will find progressions comfortable if they spend 1-2 months on each stage. Those with a healthy relationship to food will evolve our fasting practice over our lifespan.

⏱ Time Restrict your Eating

I consider the 16-8h type-diet to be an easy one for most people to adopt. During this diet you restrict your caloric intake over an 8 hour window. The remaining 16 hours one is allowed to have non-caloric drinks such as water, coffee and tea. The easiest way to get into it, is to prolong the overnight fast. Assuming one sleeps for 8 hours and stops eating 4 hours prior to going to bed, she / he can achieve the 16/8h fast by eating 4 hours after waking up. If the idea still feels daunting here are a few tips to ease your way into it:

👉🏻 Start with a 12-12h diet and gradually increase the fasting window. The danger here is not to be consistent. Decide which window schedule suits you and stick to it for at least 1 week before increasing the fasting phase.

👉🏻 Take days off if you find the idea of doing it daily suffocating. However have the days scheduled before hand and do not change them. You know you are ready to proceed when you have completed 4 consecutive weeks with 5 days per week on your “Time Restricted Eating” schedule.

🌞 Eat while the Sun is up

While I acknowledge that many people working in offices have more physically active evenings than mornings; the body’s biological clock will not flip upside down because you signed up at the 20:30 CrossFit class. Neither your sleeping time can accommodate all the digestion you wish just because your gym class finishes at 22:00. As a next step to a “Time Restricted Eating” I consider to be the swift of the eating window earlier in the day. How early is early? – you decide. My suggestion is to finish eating prior to the sunset and ideally by midday. As you can see in the infographic from a 2018 paper [1], time restricting food to the earlier part of the day causes an number of beneficial effects:

Actions that helped me with this transition:

👉🏻 Exercise earlier in the day.

👉🏻 Make sure the quality of my sleep is not compromised. Supplements as well as breathing practices can support a good night sleep. Initially prolonged fasts can lead to elevated cortisol levels which will mess up with sleep. Poor sleep leads to tiredness and erratic appetite the next day.

⏰ Set your Eating Times

That stage could also be called: Stop snaking. Most of us (living a western lifestyle) have constant access to food and numerous stressors during our day. The combination of the two in many cases lead to binging / snaking. Whether you call it comfort food or not, every extra meal (and by meal let’s call anything containing more than 20 calories) requires the activation of the pancreas and the subsequent release of insulin. Insulin is a hormone with multiple roles in our biochemistry other than food metabolism. With that in mind I don’t find strange that hormonal imbalances are common in those with erratic eating patterns.

If one attempts to “Set her Eating Times” while she is eating during daytime only, I expect this transition not to be a big challenge. On the other hand shifting from a 16-8h fast to a “Set Eating Times” schedule can be a bigger step.

Setting the times when someone eats is a personal issue and can be scheduled around her lifestyle. My suggestion is to schedule no more than 3 meals a day and if for whatever reason a meal is lost not to be replaced.

☝🏻 Eat Once a Day

If you have been following the progression described above I would be surprised if you are eating more than twice a day by now. Eating once can be something you want to try occasionally based on your energy expenditure & mood.

😶 Eat only When Hungry & As much as you Need

Even when I eat once a day I sometimes find hard not to overeat. I consider our relationship with food complex and the addictive aspect of it multidimensional. We can be addicted to:

👉🏻 certain foods.

👉🏻 the sensation of fullness.

Whatever the addiction is it will always manifest to emotions which make it hard to break loose off. To that extent I would like to clarify that:

“I consider eating one of the big joys of life & fasting can only enhance this sensation.”

Fasting works as a challenge for the body. This doesn’t mean it makes it makes the body weaker. In the same way that you would not assume a runner to be doing harm to her body just because her legs are weak at the end of a training session, don’t be afraid of fasting.

Fast Diet: Considerations

Most people when they consider fasting, they are worried about their energy levels and muscle mass maintenance. The energy levels may fluctuate initially : that is due not to lack of energy but to poor hormone regulation. Even if you have 9% of body fat, there is enough energy stored in your body to keep you alive for days. Fluctuations in energy levels can be caused because your metabolism has no access to your fat. If you are concerned with maintaining muscle mass I suggest you keep your protein intake high when you eat (~x1.6 gr of protein per body weight in kg)

Those that depend on constant energy supply (ie. 3 meals a day + 2 snacks), are the ones that would benefit the most from fasting.

🔑  Things to consider

👉🏻 Always keep your (AME) Appetite, Mood and Energy levels in check. If one of them is not under control adjustments may be necessary. In most cases soon after one gets out of control the other 2 follow.

👉🏻 Our life changes constantly and so will our mood, circadian cycle, appetite, needs for nutrients etc. I hope this article works as a road map not an itinerary.

👉🏻 Food composition can affect your Blood Glucose and consequently your fasting phases. Fibre, fat, protein can slow down your meals’ metabolism which is necessary initially.

👉🏻 Metabolism is complex and its efficiency depends on many factors including: oxygen availability & insulin sensitivity. Practicing yoga, breathing exercise and cold exposure can be very useful towards improving metabolic efficiency and supporting a fasting practice.

Things to consume while fasting

In order to maintain the calories low during fasting my suggestion is to limit your liquid intake to coffee & teas. If stimulants play havoc in your metabolism & appetite you should avoid caffeinated drinks all together. I have been consuming them freely. Two things that can help a lot in extending your fasting periods are:
👉🏻 Water – in particular carbonated. I think it is easier if one takes sips during the day aiming for 1-3 litters as opposed to drinking 3 glasses when filling peckish.

👉🏻 Magnesium Citrate powder (I like the one from Designers for Health). Its sweet taste can help deal with a sweet tooth while the Magnesium supports the adrenals & promotes gut mobility.

👉🏻 Brushing teeth after eating. Making sure mouth hygiene is in check can help in 2 ways: 1. some associate a clean mouth with the end of eating 2. food leftovers will stop triggering taste buds receptors.

 

 

References:

1. Sutton, E. F., Beyl, R., Early, K. S., Cefalu, W. T., Ravussin, E., & Peterson, C. M. (2018). Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes. Cell Metabolism.

Leaky gut: the trojan horse to food allergies?

Leaky Gut is a digestive track with a compromised permeability (like a hose with holes).

 

While the SYMPTOMS OF A LEAKY GUT ARE NOT ONLY ASSOCIATED WITH DIGESTION many people suffering from it experience food sensitivities. That’s why in my opinion:

  1. Elimination diets (i.e. FODMAP, low oxalate, low histamine diets) do not work long term: foods that cause reactions are removed but the reason why the reaction was there are 1st place stays.
  2. Most chronically ill patients have restricted diets: the body is not able to renew the epithelial tissue in the gut  leading to poor gut integrity ➛ increased gut permeability  ➛ food sensitivities.
  3. Diversity in gut flora is positively associated with health: A diverse gut flora supports gut integrity.

 

The reason why the above hold true can be traced to the double role of the gut:

  1. digest and absorb nutrients
  2. host part of the immune system

The immune system in the gut has the delicate role of balancing between: Tolerating or Reacting to the foods it comes in contact with. The evolutionary benefit of this role is the following:

Foods we consume can be degraded or containing toxins and thus be poisonous to the body. In these cases the activation of the immune system can kill the pathogenic substances and protect us.  This process is mediated through a series of steps leading to the increase of intestinal permeability.

 

Unfortunately in certain people the same reaction is triggered not only by toxins but also by regular foods. In these cases after the consumption of the “trigger food” the individual experiences a reaction such as: foggy brain, bloatness, diarrhea, stomach cramps, increased heart rate, running nose, anxiety, irritability. Reducing gut permeability (i.e. healing leaky gut) can make previous “trigger foods” tolerable again.

 

Testing for leaky gut.

Our gut wall consists of just one cell thick epithelial tissue (Sturgeon, C. and Fasano, A., 2016) . The space between each epithelial cell is called tight junction.

 

Lactulose/Mannitol test

The test that has been used the longest for detecting leaky gut is the lactulose/mannitol urine test. The test is simple: after an overnight (12 hour) fast you collect the urine then have a solution of lactulose & mannitol and 6 hours later you collect the urine again.

Mannitol enters the body through the epithelial cell membrane, while lactulose goes through the tight junctions (FlemIng, S.C. et al., 1990)

The loss of absorptive areas ➛ ↓ the absorption of mannitol.

The loss of mucosal integrity ➛ ↑ lactulose absorption.

 

An elevated lactulose : mannitol ratio indicates the presence of leaky gut. The test is available from many labs including Genova Diagnostics. The results can be affected by the use of  NSAIDS, alcohol and according to Dr. Alesio Fasano the results are very sensitive to the collection process and thus may not be reliable when done outside a lab.

 

3 stool markers of leaky gut (α1-Antitrypsin – sIgA – calprotectin)

 

α1-Antitrypsin

is a protein of the liver. When detected in stool (sourced from the intestines) it indicates a severe case of intestinal permeability and thus is not a sensitive enough marker of leaky gut (Biancone, L. et al., 2003)

sIgA

is part of the immune system and functions as a tag for substances that need to be excreted.

Calprotectin

is a protein linked with intestinal inflammation. It is used to distinguish between IBD & IBS (Leblhuber, F., et al., 2015).

3 blood markers of leaky gut (Zonulin – LPS – DAO)

 

Zonulin

Zolulin is a protein responsible for the modulation of tight junctions (Sturgeon, C. and Fasano, A., 2016).

↑ levels of Zonulin ➛ Opening of tight junctions ➛ influx of dietary & microbial antigens in the blood

 

The 2 main triggers of Zonulin release have been found to be:

  1. Bacteria: including Eschericha coli, lab E. coli, virulent E. coli, and Salmonella typhi (El Asmar et al. 2002)
  2. Gliadin: a protein found in gluten (Clemente, M et al., 2003)

Elevated levels of Zonulin have been linked in literature (Sturgeon, C. and Fasano, A., 2016) to:

  1. autoimmune conditions such as: Type 1 Diabetes, Celiac Disease, Multiple Sclerosis, Intestinal Bowel Diseases
  2. metabolic disorders such as: Obesity & PCOS
  3. Asthma
  4. Coronary Heart Disease
  5. Systemic infections
  6. Gluten Sensitivity
  7. Necrotizing Enterocolitis
  8. Brain cancer (Skardelly, M et al., 2009) by altering the integrity of the Blood Brain Barrier.

 

Lipopolysaccharide Bacterial Endotoxin

Lipopolysaccharide (LPS) is a component of the wall of gram-negative bacteria (Trent, M.S et al., 2006) responsible for the activation of the innate immune system. LPS have 3 regions. Lab tests measure the lipid A region which is also known as endotoxin. Germ-negative bacteria live in the lumen of the gut but should not be found in the blood. Detection of LPS endotoxins in the blood is sign of leaky gut.

 

DAO

Dunwoody Labs measures the levels of DAO enzyme in their intestinal permeability test. DAO is responsible for the break down of histamine. Histamine while necessary for good gut health when elevated can cause problems. Low levels of DAO thus is also a sign of leaky gut. Genetic polymorphisms in the AOC1 gene (which encodes the DAO enzyme) can impair the body’s ability to produce the DAO. Those with low levels can check their genetic burden using the table bellow.

source: InstagramOpus23

 

The future of leaky gut testing

While not currently available for the general public I-FABP is a marker of gut permeability used in laboratories. Intestinal fatty acid binding protein (I-FABP), is a marker of early enterocyte cell death (Derikx, J.P. et al., 2010)

 

 

How to support leaky gut.

When it comes to supporting leaky gut I like to split the nutrients in 2 categories:

  1. the ones affecting the mechanisms that cause the problem (these are the ones that ultimately will heal the intestines)
  2. the ones that suppress the symptoms – commonly referred to as anti-inflammatory (these are the ones that should help ameliorate the symptoms)

 

Avoid trigger foods

While I consider elimination diets not a good idea long-term in the short run it is important to remove any trigger foods to control inflammation. IgG food intolerance tests can be very useful for that matter.

 

Probiotics

I consider the use of probiotics the most potent yet the most tricky in implementation among all interventions. Certain probiotic strains have been found to induce cell proliferation in gut cells:

Bifidobacterium breve R0070 & Lactococcus lactis R1058 when taken taken together seem to have synergistic effects and both can be found in the Jarrow-Dophilus EPS. (Grimoud, J. et al., 2010 *)

Some others that were shown to suppress inflammation induced by LPS levels are:

  1. Bifidobacterium longum subsp. Infantis, Bifidobacterium longum, Bifidobacterium bifidum, Lactobacillus rhamnosus – in the order mentioned (Laetitia, R. et al., 2013)
  2. Lactobacillus reuteri strain, ATCC PTA 6475 – available from Biogaia. (Thomas, C.M. and Versalovic, J., 2010)
  3. Bifidobacterium infantis 35624 (Groeger, D. et al., 2013)

 

* The French study by Julien Grimoud is a goldmine of information.

 

Mushrooms

Edible & medicinal mushrooms have been shown to activate & modulate the  immune system in the gut acting this way as anti-inflammatory in LPS toxicity.  A. bisporus, C. cibarius and L. deliciosus (Saffron Milkcap mushroom) are mushroom extracts available in supplemental form (Moro, C. et al., 2012).

Berberine

Berberine is an alkaloid found in some plants shown to inhibit the inflammatory effects of LPS (Mo, C. et al., 2014Wu, Y.H., et al., 2012). Berberine has been shown to interact with 57 genes, so cross-checking polymorphisms related to other symptoms is worth doing.

 

 

 

 

 

 

 

 

 

 

source: Opus23

 

Other agents

Quercetin & CoQ10 were also shown to have anti-inflammatory effects in  LPS toxicity (Abd el-gawad, H.M. and Khalifa, A.E., 2001). Fish Oils were shown to restore intestinal integrity by increasing DAO enzyme concentration in the gut (Liu, Y. et al., 2012).

 

L-glutamine

L-glutamine acts as fuel for intestinal cells (Larson, S.D, et al., 2007) and to that extent supplementation can benefit leaky gut. Gradually building the dosage from as little as 2.5 gr per day to 20 gr should be a safe way to avoid adverse reactions. I have not seen any studies demonstrating the benefits of L-glutamine supplementation for leaky gut however it does support overall intestinal health.

 

Larazotide acetate

Larazotide acetate is a protein shown to inhibit Zonulin production without any adverse effects (Paterson, B.M et al., 2007). Alba Therapeutics an Indian pharmaceutical company is in the process of developing a drug with this protein.

 

 

References

Abd el-gawad, H.M. and Khalifa, A.E., 2001. Quercetin, coenzyme Q 10, and l-canavanine as protective agents against lipid peroxidation and nitric oxide generation in endotoxin-induced shock in rat brain. Pharmacological research, 43(3), pp.257-263.

 

Biancone, L., Fantini, M., Tosti, C., Bozzi, R., Vavassori, P. and Pallone, F., 2003. Fecal α1-antitrypsin clearance as a marker of clinical relapse in patients with Crohn’s disease of the distal ileum. European journal of gastroenterology & hepatology, 15(3), pp.261-266.

 

Clemente, M.G., De Virgiliis, S., Kang, J.S., Macatagney, R., Musu, M.P., Di Pierro, M.R., Drago, S., Congia, M. and Fasano, A., 2003. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut, 52(2), pp.218-223.

 

Derikx, J.P., Luyer, M.D., Heineman, E. and Buurman, W.A., 2010. Non-invasive markers of gut wall integrity in health and. World J Gastroenterol, 16(42), pp.5272-5279.

 

El Asmar, R., Panigrahi, P., Bamford, P., Berti, I., Not, T., Coppa, G.V., Catassi, C. and Fasano, A., 2002. Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure. Gastroenterology, 123(5), pp.1607-1615.

 

FlemIng, S.C., Kapembwa, M.S., Laker, M.F., Levin, G.E. and Griffin, G.E., 1990. Rapid and simultaneous determination of lactulose and mannitol in urine, by HPLC with pulsed amperometric detection, for use in studies of intestinal permeability. Clinical chemistry, 36(5), pp.797-799.

 

Grimoud, J., Durand, H., De Souza, S., Monsan, P., Ouarné, F., Theodorou, V. and Roques, C., 2010. In vitro screening of probiotics and synbiotics according to anti-inflammatory and anti-proliferative effects. International journal of food microbiology, 144(1), pp.42-50.

 

Groeger, D., O’Mahony, L., Murphy, E.F., Bourke, J.F., Dinan, T.G., Kiely, B., Shanahan, F. and Quigley, E.M., 2013. Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut microbes, 4(4), pp.325-339.

 

Laetitia, R., Paul, A., Marinescu, D., Shao, W. and Prakash, S., 2013. Effect of probiotics Lactobacillus and Bifidobacterium on gut-derived lipopolysaccharides and inflammatory cytokines: an in vitro study using a human colonic microbiota model. Journal of microbiology and biotechnology, 23(4), pp.518-526.

 

Larson, S.D., Li, J., Chung, D.H. and Evers, B.M., 2007. Molecular mechanisms contributing to glutamine-mediated intestinal cell survival. American Journal of Physiology-Gastrointestinal and Liver Physiology, 293(6), pp.G1262-G1271.

 

Leblhuber, F., Geisler, S., Steiner, K., Fuchs, D. and Schütz, B., 2015. Elevated fecal calprotectin in patients with Alzheimer’s dementia indicates leaky gut. Journal of Neural Transmission, 122(9), pp.1319-1322.

 

Liu, Y., Chen, F., Odle, J., Lin, X., Jacobi, S.K., Zhu, H., Wu, Z. and Hou, Y., 2012. Fish oil enhances intestinal integrity and inhibits TLR4 and NOD2 signaling pathways in weaned pigs after LPS challenge. The Journal of nutrition, 142(11), pp.2017-2024.

 

Mo, C., Wang, L., Zhang, J., Numazawa, S., Tang, H., Tang, X., Han, X., Li, J., Yang, M., Wang, Z. and Wei, D., 2014. The crosstalk between Nrf2 and AMPK signal pathways is important for the anti-inflammatory effect of berberine in LPS-stimulated macrophages and endotoxin-shocked mice. Antioxidants & redox signaling, 20(4), pp.574-588.

 

Moro, C., Palacios, I., Lozano, M., D’Arrigo, M., Guillamón, E., Villares, A., Martínez, J.A. and García-Lafuente, A., 2012. Anti-inflammatory activity of methanolic extracts from edible mushrooms in LPS activated RAW 264.7 macrophages. Food Chemistry, 130(2), pp.350-355.

 

Paterson, B.M., Lammers, K.M., Arrieta, M.C., Fasano, A. and Meddings, J.B., 2007. The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT‐1001 in coeliac disease subjects: a proof of concept study. Alimentary pharmacology & therapeutics, 26(5), pp.757-766.

 

Skardelly, M., Armbruster, F.P., Meixensberger, J. and Hilbig, H., 2009. Expression of zonulin, c-kit, and glial fibrillary acidic protein in human gliomas. Translational oncology, 2(3), pp.117-120.

 

Sturgeon, C. and Fasano, A., 2016. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers, p.e1251384.

 

Thomas, C.M. and Versalovic, J., 2010. Probiotics-host communication: Modulation of signaling pathways in the intestine. Gut microbes, 1(3), pp.148-163.

 

Trent, M.S., Stead, C.M., Tran, A.X. and Hankins, J.V., 2006. Invited review: diversity of endotoxin and its impact on pathogenesis. Journal of endotoxin research, 12(4), pp.205-223.

 

Wu, Y.H., Chuang, S.Y., Hong, W.C., Lai, Y.J., Chang, G.J. and Pang, J.S., 2012. Berberine reduces leukocyte adhesion to LPS-stimulated endothelial cells and VCAM-1 expression both in vivo and in vitro. International journal of immunopathology and pharmacology, 25(3), pp.741-750.

What is the Selfish Brain Theory?

According to the Selfish Brain theory our brain has a series of (hierarchically ordered) mechanisms in place to maintain constant supply of energy at a certain concentration.

Despite weighing only ~2% of body weight, the brain consumes a disproportionate high amount of energy: ~20%. Knowing that, it should come as no surprise that many physical symptoms linked with poor metabolism (incl. muscular fatigue, obesity, taxed liver function possibly due to alcoholism) are linked with compromised brain function (i.e. migraines, forgetfulness, irritability).

The Selfish Brain theory was put forward by scientist at University of Luebeck in Germany in 2004 and is likely to bring a swift in the way we understand and treat metabolic & personality disorders in the future. [ The theory has its roots in some earlier research in 1997 on addiction (DuPont RL 1997) ]

In clinical practice I consider 3 qualitative markers as a sign of good health: Energy, Mood & Appetite (EMA). When all 3 in are balance the body is 95% of the time thriving. The Selfish Brain theory offers a “simple” model of their intimate relationship.

1. The brain’s unique role in energy management

How the human body manages energy supply to different organs is key for treating chronic illness including: obesity, PCOS, cardiovascular disease & cancer. Energy metabolism is dependent on:
i. energy supply
ii. energy allocation

The brain plays a key role in this process. What gives the brain a unique role in body’s metabolism?

i. It carries important functions for the rest of the body.
Together with the heart the brain is responsible for processes that run on an ongoing basis. Shortage of energy supply to these 2 organs can be life threatening.

ii. It consumes a lot of energy.
Despite its small weight (~2% of total body weight), it consumes a disproportionate high amount of energy ~20%, partly due to the energy needs of neurotransmitter transmission (Attwell D and Laughlin S 2001).

iii. It has low energy storage capacity.
In contrast to most other organs it depends almost entirely on glucose for energy but has limited capacity to store glucose. The liver and (to a lesser extent) the muscles are the body’s main glucose reserves (in the form of glycogen).

iv. It’s access to the blood supply is controlled.
The brain comes in contact with the blood (cardiovascular system) in 2 areas only: the Blood Brain Barrier (BBB) where astrocytes (neuron cells) serve as a filter wall and the Hypothalamus. Due to the high amounts of toxins and pathogens circulating in the blood there may be an evolutionary benefit in this physical protection of the brain.

v. It is able to monitor other organs and affect their function.
Through the Peripheral Nervous System (PNS) the brain is able to record information from other organs as well as control their function.

Accounting for the above idiosyncratic functions, the Selfish Brain theory suggests that the brain:

i. Prioritises its own energy supply before other organs by using the stress system when there is an energy deficit (Allocation)

ii. It subsequently alters appetite to alleviate stress and return to balance (Appetite -> Food intake)

The model has the shape of a fishbone to illustrate the hierarchically structure of the pathway.

2. How does the brain sense if it has enough energy?

Cells in the brain as well as skeletal muscles (Lazdunski M. 1994) sense the levels of energy intracellularly through: ATP-sensitive potassium (Katp) channels. ATP & ADP (the body’s energy currencies) bind on these channels and this way signal availability or lack of energy. In an excitatory neutron adequate levels of ATP (by binding on Katp channels) will trigger the release of glutamate or brain-derived neurotrophic factor (BDNF) while elevated ADP will silence it.

A key feature of the Selfish Brain theory is that the brain has 2 types of Katp channels: high & low affinity. When a cell has relatively low ATP concentrations, high affinity Katp channels are still occupied. On the other hand low affinity Katp channels require high ATP concentration to get occupied. The high affinity Katp channels are found mostly in excitatory neurones (releasing glutamate & Brain-Derived Neurotrophic Factor (BDNF)) while low affinity ones are in inhibitory neurones (releasing γ-amino-butyric acid / GABA) (Ohno-Shosaku T et al., 1993). Both types of are found in the human neocortex (Jiang C et al., 1997).

With low ATP concentrations the glutamateric neurones are dominantly active while at high ATP concentrations the GABA-eric neurones predominate.

It is worth mentioning that at critically reduced ATP both excitatory & inhibitory neurones are inactive – a phenomenon referred to as “global silencing” (Mobbs CV et al., 2001).

3. How does the brain maintain a constant energy level?

The brain according to the Selfish Brain theory has 2 ways to maintain a set energy level. One via moderating the allocation on the currently available energy from the peripheral tissue to itself and a 2nd by demanding more energy from the environment by controlling eating behaviour.

3.1 Brain’s “energy on demand”

In order for the brain to access glucose (energy) available in the blood it needs to “open” the blood-brain barrier (BBB). Glutamate activates the glucose receptors (GLUT1 in the astrocytes) of the BBB and sequentially the glucose enters the brain (Magistretti PJ et al., 1999). GABA on the other hand does not have the same impact in the BBB (Chatton JY et al., 2003).

Glutamate* was also shown to activate the limbic-hypothalamic-pituitary-adrenal (LHPA) axis (Yousef KA et al., 1994). LHPA axis is commonly referred to as the stress or the flight or flight response. By activating the LHPA axis glutamate is able to restrict glucose supply to other organs and preserve it for the brain. The steps are as follows:

Glutamate signals the limbic system that the body is in a stressful state. The limbic system stimulates the sympathetic nervous system (NS) through the Ventromedial part of the Hypothalamus (VMH) resulting in the release of CRH & vasopressin hormones. In this way it tells the pituitary to release ACTH hormone. ACTH is released in the blood and stimulates the production of cortisol from the adrenals. Cortisol finally inhibits the production of insulin from pancreatic β cells and thus the uptake of glucose for certain organs making it available for the brain (Jansen AS et al., 1997). In the Selfish Brain model the allocation of energy takes place in the VMH.

In a state of high energy GABA (a calming neurotransmitter) is also released counteracting glutamate’s excitatory effects. The sympathetic system is not activated and the junctions in the BBB remain tightly closed.

In summary the brain can moderate the allocation on the currently available energy from the peripheral tissue to itself as follows:

When there is low energy in brain, glutamate is released in relatively higher levels than GABA causing 2 effects:
1. the BBB opes and increases the intake of glucose from the blood stream to the brain
2. the Limbic Hypothalamic Pituitary Adrenal (LHPA) axis is activated restricting the supply of glucose in peripheral tissue.

3.2 Requesting energy from the environment

Lateral Hypothalamus (LH) is a key area of the brain where appetite is controlled (Anand BK, Brobeck JR. 1951), although not the only one. Glutamate can stimulate the LH to increase appetite [13]. With the increase of food intake, energy from the environment is enters the body (Stanley BG et al., 1993)

According to the Selfish Brain theory the Neocortex acts at the primary regulatory system for energy and the LHPA axis functions as a secondary. xxx Many more hormones (i.e. Leptin hormone signals the hypothalamus that energy has been stored in the fat tissue (Spanswick D et al., 1997)) can be added to the graph without affecting its hierarchy.

The Selfish Brain theory demonstrates how the brain manipulates the stress response mechanism to moderate energy supply. That’s worth keeping in mind when dealing with mental or eating disorders.

 

 

 

* in particular through glutamate receptors of N-methyl-D-aspartate (NMDA) subtype (Molina PE, Abumrad NN 2001).

 

 

 

References

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Spanswick D, Smith MA, Groppi VE, Logan SD, Ashford ML. Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature 1997;390(6659):521–5.

Stanley BG, Ha LH, Spears LC, Dee MG. Lateral hypothalamic injections of glutamate, kainic acid, D,L-alpha- amino-3-hydroxy- 5-methyl-isoxazole propionic acid or N-methyl-D-aspartic acid rapidly elicit intense transient eating in rats. Brain Res 1993; 613(1):88–95.

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