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From the Townsend Letter
October 2016

An Interview with Prof. Marco Ruggiero:
Understanding the GI and Brain Microbiome and the Role of GcMAF in Harmonizing the Immune System with the Microbiome Populations
by Jacques Fernandez de Santos
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JFS: Hundred of years ago we did not have the same type of diseases that we have today; for instance, autism affects 1 in 68 children today versus 1 in 10,000 in 1990. Why in the case of autism is this happening: is it vaccines and poor nutrition combined that harm the original microbiome and therefore the immune system?

MR: Although the cause of autism remains unknown to this date, I think that with the publication of our paper in Frontiers in Neuroscience, we have at least elucidated some important aspects of its pathogenesis; that is, the mechanisms that lead to the onset and progression of the symptoms. Changes in the nutritional properties of food, increased exposure to chemicals and other toxicants including electromagnetic radiations or radioactivity, excessive exposure to antibiotics and other drugs – all these factors may contribute to the observed increase in the incidence of autism spectrum disorders. In addition, a different way to diagnose and classify disorders of the development may also contribute to such an observed increase. There is, however, a point that is rarely taken into consideration and may prove rather relevant: the effects of low-intensity electromagnetic fields on the human microbiome and hence on the third and fourth brains. We elaborated on this point in a chapter that we wrote for the prestigious Encyclopedia of Cancer. In fact, even though the low-intensity electromagnetic fields to which we are constantly exposed appear to be fairly safe for our human cells, they appear to be detrimental for our microbial counterpart. In our chapter, we write:

The effects of electromagnetic fields on the human microbiome open a new perspective in assessing the risks for health and in preventing them. So far, most of the research was concentrated on assessing the effects of electromagnetic fields on those areas of the body that were exposed to their energies. In other words, all the effects of electromagnetic fields on human health were ascribed to their interaction with the human cells of our bodies. However, since we have learned that electromagnetic fields, even of minimal intensity such as the endogenous electromagnetic fields, modify the human microbiome, their effects might be much more complex and far ranging. In fact, microbes and the microbiome may amplify or mitigate carcinogenesis, responsiveness to cancer therapeutics, and cancer-associated complication (Garrett 2015) and, therefore, electromagnetic fields modifying the microbiome may interfere with all such cancer-related responses. It is foreseeable that the development of functional foods containing probiotics for the prevention and treatment of cancer will have to take into account the effects of endogenous as well as exogenous electromagnetic fields on the human microbiome.

Quite obviously, all these considerations apply even more to the development of the brain (or at least of the human first brain inside our head).
JFS: It is currently proven that there is no good health without a healthy microbiome, or third brain. You and your team have been able after years of research to create a super food that stimulates strongly the immune system through the stimulation of macrophages and natural killer cells. The key component of this super food, amongst others, is the protein GcMAF (Gc protein-derived macrophage activating factor), which could be described simplistically as carrier for the vitamin D. How would you define the main properties and characteristics of this protein as well as the super food you have created as a whole?

We began working on this "super food" that comes in the form of a fermented milk and colostrum product, a sort of a yogurt, about 5 years ago, when we were interested in developing a nutrition-based immunotherapeutic protocol. After hundreds of trials and errors, we eventually found the exact formula that is now in production, under the commercial name "Bravo." This product shows two features that render it unique: it contains the live microbial strains that reconstitute the healthy human microbiome, and it contains about 200 natural, newly formed molecules that contribute to health maintenance in a wide variety of ways.
The live microbial strains contained in Bravo are known to activate the immune system, stimulate macrophages, fight cancer, and help neurological and psychological processes; all these features contribute to the observed health effects of Bravo that have been published in a number of peer-reviewed papers (see, for example, Anticancer Res. 2014 Jul;34[7]:3569–3578).
The newly formed molecules, naturally occurring during the fermentation of colostrum and milk, exert a number of biological functions that may contribute to health. Such biologically active molecules are not present in milk or colostrum but are formed during the process of fermentation, thanks to the enzymes produced and released by the microbes that we carefully selected for such a purpose. Among these molecules, there are peptides that help control blood pressure, others that stimulate the immune system, others that show antimicrobial properties, others that show antithrombotic properties, others that favor the absorption of minerals, others that have antioxidant activity, and others that influence mood and perception. There is, however, one particular molecule that gained great attention in the recent past and that is naturally produced (in other words, it is not added to the product) in Bravo: GcMAF. This powerful stimulator of the immune system shows a number of interesting healthful properties and has proved effective in a variety of pathologic conditions even independently of its main action of stimulating the immune system.
JFS: This super food and its main component, GcMAF, have shown at the beginning of your studies years ago amazing results in pathologies such as AIDS or cancer proliferation. Can you please expand, before going to other pathologies, on the results observed on those important diseases?

MR: Probiotic yogurts had been known for years as very effective tools in the fight against HIV/AIDS or cancer, thanks to the combined action of the microbes and the products of their metabolism. In 2010, a Canadian research team led by Dr. Reid demonstrated that a probiotic yogurt very similar to Bravo increased CD4 cells in African HIV/AIDS patients and ameliorated their clinical situation in a manner quite comparable to that of conventional antiretroviral drugs without the side effects of the latter (J Clin Gastroenterol. 2010 Oct;44[9]:e201–e205). Two years later, the same research group demonstrated that such an effect on HIV/AIDS patients was not limited to those living in impoverished countries and presumably suffering from malnutrition, but was observed in Canadian patients as well (Gut Microbes. 2012 Sep–Oct;3[5]:414–419). Interestingly, the same research group observed that one African patient in the probiotic group experienced seronegativization; that is, while consuming the probiotics, she tested HIV negative after having been confirmed HIV positive before being assigned to the probiotic group, whereas no patients in the placebo group experienced such an occurrence (Gut Microbes. 2011;2[2]:80–85).
It is interesting to notice that all the papers mentioned above were published at about the same time that we were presenting our results at the Sixth International Aids Society Conference on HIV pathogenesis, treatment, and prevention, in Rome in 2011; at that conference, we observed that consumption of "our" yogurt brought about very similar results in terms of stimulation of the immune system. When almost identical results are independently produced by different research groups that report observations spanning from Africa to Italy and Canada, the probability that such results are not the product of serendipity are very high.
Nowadays it is well accepted that probiotics are one of the pillars of the nutritional immunotherapy of HIV and AIDS, since they not only strengthen the individual's immunity but also help reduce the systemic inflammation and improve the prognosis of HIV-infected individuals (PLoS One. 2015 Sep 16;10[9]:e0137200). The effects of probiotic yogurts such as Bravo on cancer patients are even more striking. For example, a recent review describes the effects of probiotic yogurt on the immune system and in cancer (Endocr Metab Immune Disord Drug Targets. 2015;15[1]:37–45), while another paper states that probiotic yogurt prevents cancer (J Agric Food Chem. 2015 Nov 4;63[43]:9381). When our Bravo yogurt was administered to advanced cancer patients in the context of a natural, nutrition-based, immunotherapeutic protocol, we observed significant results that were published in peer-reviewed journals, with one notable case wherein we even observed the reversal of a genetic marker of cancer (Anticancer Res. 2014 Jul;34[7]:3569–3578; Anticancer Res. 2015 Oct;35[10):5525–5532). In other words, a cancer-causing gene (also known as oncogene HER2) that was highly represented before the nutrition-based approach was no longer present after the implementation of the protocol.
JFS: Also, later on, you and your team started studying the effects of this super food on autism in children and different neurodegenerative adult diseases, with very encouraging positive results. Why does it work, and to what extent have you observed net improvements in specific cases of autism independently of its etiology?

MR: Although we may have contributed to the understanding of the pathogenesis of autism, I am convinced that the etiology, that is, the cause(s), may be multiple and different in each individual. The results of supplementation with Bravo yogurt in the context of an integrated, nutrition-based immunotherapeutic protocol in autism have been widely described in a number of conferences and congresses, and there is ample scientific consensus that probiotics help heal the symptoms of autism. According to some authors, alterations of the gut microbiome could actually be the cause for autism (Drug Metab Dispos. 2015 Oct;43[10]:1557–1771), and therefore it is logical that restoration of the microbiome helps improve the symptoms. However, I think that the dramatic improvements which we observe in children consuming the Bravo yogurt in the context of an individualized protocol are due to the combination of at least two factors: the reconstitution of the microbiome in the gut and in the brain (the third and fourth brain) and the stimulation of the immune system, notably the macrophages, that is in charge of balancing the two microbial populations between the gut and the brain. Whatever the case, we are witnessing significant improvements that are being independently confirmed by doctors from all over the world.
JFS: The lymphatic system of the brain is a new and amazing revolutionary discovery, announced not even a year ago, that explains many of the discoveries made by your team regarding immune therapy in the last few years. What are the implications of this new discovery for your work, and therefore for all of us?

MR: The implications are enormous, particularly if we consider that the newly discovered brain lymphatic system now has to be associated with the very novel concept of the brain microbiome. The presence of commensal microbes inside the brain and their role as cells of the central (and probably also of the peripheral) nervous system calls for a complete reassessment of all the notions of neurobiology and neurology. As we describe in our paper in Frontiers in Neuroscience, the direct connection between the brain and the immune system may explain a number of observations that could not be explained before. For example, in 2002 a Brazilian researcher, Matarrazzo, described two cases of children who at first developed normally, but before age 3 developed autistic symptoms following the reactivation of a chronic otorhinolaryngologic infection; that is, an infection of the nose and throat. He then proceeded to administer adrenocorticotropic hormone as a means to reduce inflammation; and, in one case where the drug was prescribed in the first months of the disease, the child was completely cured. The other patient, who was 2 years old when autistic symptoms appeared and was treated only 6 years later, showed a partial but definitive improvement with the treatment (World J Biol Psychiatry. 2002 Jul;3[3]:162–166). In 2002 no one could explain such wonderful results, but now we can interpret them in light of our publication in Frontiers in Neuroscience.
Chronic inflammation in the nose and throat clogs the deep cervical nodes, the nodes where the lymph drains from the brain. Therefore, the lymph cannot recirculate and toxins or toxicants accumulate in the brain, an occurrence that can be severely detrimental to the developing brain. In addition, the obstacle to of the lymph flow leads to accumulation of fluid inside the brain, and such an accumulation in a closed cavity (the skull) leads to the disruption of the connections between the neurons. Finally, such an impairment of the lymphatic drainage causes a relative immunodeficiency inside the brain, since the cells of the immune system, mainly the macrophages, cannot recirculate. Such an immunodeficiency may lead to an imbalance of the brain microbial population and to the chronic inflammatory status of the brain and the meninges that has been widely described in autism. As Matarrazzo demonstrated in 2002, if the inflammation in the nodes is fought at the early stages of autism progression, all these events do not occur or are rapidly reversed, and the symptoms of autism disappear. Most likely a similar mechanism is at work in a number of neurological conditions ranging from Alzheimer's disease to multiple sclerosis, wherein the involvement of the immune system is well assessed.
JFS: With your recent discoveries the excellent results observed in patients with autism and neurodegenerative diseases treated with therapeutic nutritional approaches can now be explained. Recirculation of the lymph in the brain through the lymphatic vessels could be the key. Is this observation on its way to be fully proved?

The discovery of the brain lymphatic system brings about what is termed a paradigm shift; thus, now that a direct connection between the brain and the immune system has been established, the pathogenesis of many brain-based disorders is being revisited. We played our role in defining the importance of inflammation in the deep cervical nodes in autism, but other authors are proposing that a similar mechanism is at work in other neuropathologies such as Alzheimer's disease. Just a few months ago, researchers from the US, France, and Sweden described "the clearance systems of the brain as they relate to proteins implicated in Alzheimer disease pathology" with particular reference to the newly discovered lymphatic drainage (Nat Rev Neurol. 2015 Aug;11[8]:457–470). Only a few days ago, in 2016, based on the discovery of the brain lymphatic system, other researchers reevaluated the entire corpus of knowledge concerning brain immunology and went so far to title their academic paper "Get It Through Your Thick Head: Emerging Principles in Neuroimmunology and Neurovirology Redefine Central Nervous System 'Immune Privilege'" (Nat Rev Neurol. 2015 Aug;11[8]:457–470). However, as odd as it may seem, I and my team have been the only ones so far to merge the two observations of the brain lymphatic system and the presence of microbes in the normal brain into a single unitary concept: the brain microbiome, or the fourth brain. Such a concept is too novel to have been accepted by academia; however, there are some hints that other researchers share this intuition. For example, at the beginning of 2016, Irish researchers wrote a scientific paper with a rather unusual title that is fully consistent with all the notions that I have described so far: "The Brain's Geppetto-Microbes As Puppeteers of Neural Function and Behaviour?" (J Neurovirol. 2016 Feb;22[1]:14–21). In this paper, they write that "there is a growing literature showing active behavioural manipulation in favour of the microbe," and they conclude that "novel experimental approaches and theoretical concepts, such as the hologenome theory, are necessary to incorporate transgenerational epigenetic inheritance of the microbiome into evolutionary theories."
Your Third Brain, you write extensively on the importance of correctly feeding the second brain (the GI tract) and the third brain or the microbiome: the second brain with healthful food, including a diet based on 60% high-quality protein, 20% carbohydrates, and 20% fatty acids, and the third brain with what you call "the dessert cup" – the probiotic product with GcMAF that you and your team have been studying for years. How do both healthful alimentation and your team's probiotic interact?
MR: The nutritional plan that I describe in the book is known under a plethora of different names: ketogenic diet, Paleo diet, caveman diet and so on. All these names refer to the fact that primitive people, before the age of agriculture, ate very little carbohydrates (carbs) and relatively high proteins and fats. Since this type of diet induces the accumulation of ketone bodies, it is also called ketogenic. Such a nutritional approach is recognized as effective in the complementary treatment of a variety of chronic conditions ranging from cancer to neurological disease including autism (Eur J Clin Invest. 2016 Mar;46[3]:285–298). For example, as far as cancer is concerned, this approach is consistent with the 90-year-old observation of Prof. Otto Warburg, who demonstrated how cancer cells depend solely on carbs, whereas normal cells could use also ketone bodies for their survival. Consistent with this approach, our research group has been working for about 30 years on the role of glycolysis (the metabolism of carbs) in carcinogenesis and other human diseases and we have published 13 peer-reviewed papers on the role of a byproduct of glycolysis (diacylglycerol) in cancer as well as in chronic conditions such as neurodegenerative diseases, chronic kidney disease, and cardiovascular disease. We observed that the low-carb-high fat/protein nutrition improves the response to the natural immunotherapy based on Bravo, as well as to all the specific therapeutic approaches for each individual neoplasia, since it makes cancer cells more susceptible to ionizing radiations, chemotherapy or immunotherapy, as we demonstrated several years ago (Biochem Mol Biol Int. 1995 Sep;37[1]:81–88). We designed our nutritional approach around Bravo yogurt in order to exploit its main features that stimulate the immune system and reconstitute the human microbiome in addition to containing healthful fats and proteins with excellent nutritional value.

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