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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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Marco RuggieroIntroduction
Marco Ruggiero was born in Firenze (Florence), Italy, in 1956. There he graduated from the School of Medicine in 1980. He has a PhD in molecular biology and a specialization in diagnostic radiology. He served in the army as lieutenant medical officer. From 1984 to 1986 he worked at the Laboratory of Cellular and Molecular Biology of Burroughs Wellcome, where he published a paper sponsored by Nobel laureate Sir John Vane. He subsequently worked at the National Cancer Institute of the National Institutes of Health (Bethesda, Maryland, US), where he performed research on oncogenes and signal transduction. He returned to Italy as professor of molecular biology at the University of Firenze until his retirement in 2014. In his 36-year scientific career, he published more than 150 peer-reviewed articles and was invited to participate in hundreds of congresses and conferences. As senior author, in 2011, he published a seminal paper on HIV infection and AIDS together with Prof. Peter Duesberg of Berkeley and Prof. Henry Bauer. Currently, his main research interests are in the fields of oncology, neurosciences, and immunotherapy, cooperating closely with the National Autism Conference and Autism One. Together with his wife, Dr. Stefania Pacini, he is the inventor of the probiotic yogurt "Bravo" and of powerful stimulants of the immune system based on macrophage-activating factors.
Jacques Fernandez de Santos: As reflected in your book, recently published with Peter and Drew Greenlow, Your Third Brain, there are three brains: the one inside the head, one in the GI tract, and the microbiome, an "organ" within organs disseminated throughout the gut and different parts of the body. How would you schematically define those three brains in lay terms?
Marco Ruggiero: When we wrote the book, we postulated the existence of three brains: two of these brains are "human"; that is, made by human neurons and glial cells in the brain inside our heads and embedded in the layers of the GI tract. These two human brains are interconnected and the flow of information is bidirectional; in lay terms, the brain inside our head influences the working of our GI tract and vice versa: the neurons in the GI tract influence the working of the brain inside the skull. The "third brain" was an intuition of mine, as explained in the book, and with this term I indicated the microbiome that is mainly, but not uniquely, located in the gut. In fact, the commensal microbes that constitute the microbiome produce substances, neurotransmitters, that influence both the neurons inside the skull and the neurons in the GI tract. There is a huge amount of scientific literature describing the interactions between the microbes and the function of the brain in health and disease. Thus, scientists now openly talk about "melancholic microbes" or "voices from within," referring to the alterations of the microbiome in psychiatric disorders such as depression or anxiety. Other scientists propose the development of "psychobiotics," which are sort of probiotics aimed at restoring the function of the third brain so as to rebalance our neurologic and psychological functions. It is also well assessed that experimental changes in the composition of the microbiome in the gut lead to changes in behavior that can be reversed by reconstituting the original microbiome. In sum, there is ample evidence for the existence of such a nonhuman "third brain," even if, as far as I know, we´ve been the first to use such a term to describe the role of the microbiome in influencing our neurological, cognitive, and psychological functions. In the past few months, however, after the publication of our commentary in Frontiers in Neuroscience (2015 Dec 22;9:485), I realized that there is indeed a "fourth brain." The fourth brain is nothing other than the brain microbiome; that is, the array of microbes that live in symbiosis with our neurons and glial cells inside our heads. This is a completely novel concept that had never been described thus far. The idea for such a fourth brain derives from a paper that was published a few years ago by Canadian researchers looking for microbes in the brains of HIV/AIDS patients (PLoS One. 2013;8[1]:e54673). I guess that it was a surprise for them to find out that "in an organ widely assumed to be free of infectious agents in the absence of a specific disease process, autopsied and surgically-derived human brain specimens showed a restricted but distinct bacterial population in the present studies, which was composed of bacterial classes chiefly recognized in the physical environment, i.e., soil and water." In other words, in the brains of healthy people, there are the same microbes that are found in the environment and, consequently, the gut. It is interesting to notice that, according to the authors, the microbes travel to the brain carried by cells of the immune system that include macrophages. In fact, they write, "The brain is constantly surveyed by trafficking leukocytes (activated lymphocytes and macrophages), which provide a Trojan horse mechanism for microbial entry into the nervous system across the blood brain barrier." And, quite obviously, the presence of the microbes in the brain has an enormous influence on the functioning of the neurons and the glial cells up to the point that the authors are compelled to write, in a rather poetic fashion, "Since bacteria express multiple molecules … their capacity for influencing brain function is immense" – "immense" being an absolute superlative.
In 2013, however, the existence of another immunological pathway leading to an even closer interconnection between the brain and the immune system, and hence the microbes that are carried by immune cells, was unknown, and only in 2015 it became evident that the brain has a classical lymphatic system like any other organ. Thus, as we describe in our paper in Frontiers in Neuroscience, there is an even stricter relationship between the function of the immune system and the function of the brain inside our heads: in fact, cells of the immune system carrying microbes to and from the brain may travel through these newly discovered lymphatic vessels bypassing the blood–brain barrier. The identification of the fourth brain bears unimaginable consequences: we have to consider the microbes as cells of the central nervous system with a dignity equal to that of neurons and glial cells, but with two important differences. First of all, they are nonhuman and the information in their DNA is microbial and not human; this means that they are looking after their interest that may or may not be coincident with the human interest. Second, they change continuously as we interact with the environment and, most important, with food, quite at variance with neurons and glial cells. In simpler words, as a sort of a slogan, we could say that "the microbes that you have in your brain are the microbes that you have in your gut … and you want to have good microbes in your gut!" In addition, we may want to add that "you want to have a functioning brain lymphatic system .. . and active macrophages" that recirculate and balance the microbial populations in the brain and in the gut. Thus, now we have four brains: two human brains, one inside our head and one in the walls of the GI tract, and two nonhuman brains, again, one inside our heads and one in the mucosa of our GI tract. Most likely, as we keep on studying the brain microbiome, or the fourth brain, we shall come to the conclusion that, in essence, we have only one integrated brain that is composed by human and nonhuman cells distributed in the gut and inside our heads. However, since we need to classify things in order to study and comprehend them, I feel that this, probably artificial, subdivision in four brains may help us in coping with the complexity of this system.
JFS: Is that third brain a moving organ located in different parts of the body even though an important part of it is lodged in the gut?

If we assume that the third brain is constituted by the microbes composing the human microbiome, then we have to conclude that it is scattered throughout the body, even if the greatest mass of the microbiome is located in the mucosa of the GI tract, from the mouth to the anus. At variance with the human neurons and glial cells that constitute the first and the second brain, the microbes constituting the third brain, just like the microbes inside our skull constituting the fourth brain, are much more variable and do not have a fixed location. In other words, the composition of our microbial third and fourth brains is highly dynamic and reflects our interactions with the environment, mainly but not uniquely through the consumption of food. Therefore, the third and the fourth brains are constantly changing in response to the changes in the environment and to our relationship with the environment itself. And, consequently, the influence of the microbial third and fourth brains on the human first and second brains is constantly changing. This rapid adaptation to the changes of the environment is instrumental in giving our integrated human/microbial brains the flexibility that they need to adapt and survive in the most diverse environments. However, this variability and flexibility of the microbial brains are not limitless; there appears to be a core microbiome, both in the gut and in the brain, that is fairly constant; and the study of such a core microbiome, and how to restore it in case of unbalances, is a major challenge in the field of microbiome and neuroscience research.
In addition, the emergence of the concept of an integrated human/microbial brain gives us the opportunity to reconsider the role of the immune system in determining our neurological or psychological activities. For example, if the immune system cells that carry the microbes to the brain inside our head are not functioning to the best of their capabilities, the microbiome inside the brain suffers alterations that influence the working of neurons and glial cells. Or, if the newly discovered brain lymphatic system is clogged by inflammation in the deep cervical nodes where the lymph from the brain drains, the recirculation of lymph in the brain is hampered, and therefore the immunological surveillance of the brain is impaired. This may lead to unbalances in the composition of the brain microbiome because pathogenic microbes from the gut or the environment cannot be controlled by the combined action of the healthy microbes of the brain microbiome and immune system cells.
JFS: Neurons and interstitial cells are in the brain, the GI tract, and apparently also in the heart. What do those facts mean in terms of a total new vision of the human body, and ways of carrying the information at all levels inside the body?

MR: With the identification of the microbial third and fourth brain, our vision of the flow of information in the human body drastically changes. First of all, it becomes difficult to define as "human" a body that contains 10 times more microbial cells than human cells and more than 100 times more microbial genes than human genes. The very definition of being "human" has to change, and we have begun to perceive ourselves as a complex ecosystem wherein the information is continuously and dynamically exchanged between the very many different living entities that constitute what we call our body; a body, however, that belongs as well to the myriads of microbes that contribute to all its functions.
In biology, the basic level of information from which all other types of information derive is located in the DNA under the form of genes. If we consider that our microbiome contains 100 times more genes than our human genome, we easily understand that the human information is rather marginal. If we assume that our behavior somehow depends on the information contained in the DNA, it is clear that our behavior then mostly depends on the microbial rather than the human information; or, if you prefer, the microbial "will" rather than the human will.
In fact, the most primeval form of behavior, common to all living things, essential for life itself and from which all other forms of behaviors derive, is the eating behavior. A recent peer-reviewed paper clearly states that our microbes "manipulate host eating behavior to increase their fitness, sometimes at the expense of host fitness" (Bioessays. 2014 Oct;36(10):940–949). In other words, our most basic behavior is only marginally based on our supposed human free will, and it is the microbes that tell us what to eat so that they can increase their fitness. If we can reach an agreement and their fitness coincides with our human fitness, then we are in a state that is defined "health"; otherwise, our human part of the body is "sick" even though the microbial part of our body could indeed flourish. As in most things in this universe, when harmony prevails and interests coincide, there exists a "win–win" situation. Vice versa we end up in a state of continuous fight wherein only one part, the microbial, is bound to win. Although it may represent a serious blow to our human esteem, the fact is that when we die, it is only the human part of our body that dies, whereas the microbial part with all its information remains alive and well.
JFS: Is our memory actually located just in our first brain, or is it somehow disseminated in different parts such as organs like the heart? Is memory located throughout our body's cells and organisms of the microbiome?

MR: I began studying the molecular mechanisms of learning and memory in 1987 when, together with my good friend and colleague Renato Corradetti, we published three seminal papers on the molecular bases of memory (Brain Res. 1987 May 12;411[1]:196–199; EMBO J. 1987 Jun;6[6]:1595–1598; Neurochem Int. 1989;14[1]:1–9). In those days, researchers were convinced that the hippocampus was involved in the consolidation of information from short-term to long-term memory. Now, almost 30 years later and with the novel notions of a third and a fourth brain, we can safely assume that what we call memory is actually scattered throughout our body and resides both in our human neurons, as commonly accepted, and our microbial cells. In fact, it is now well established that the process of learning and memory involves changes in the DNA, in the process called expression that often goes under the name of epigenome. Therefore, since the changes in the epigenome occur both in our human neuronal cells and microbial cells, it is possible to say that our memory is dispersed and there is not an anatomical seat of the memory, something like the hard disk of a computer.
It is true that certain areas of the brain are dedicated to some specific functions that are related to learning and memory, but it is also true that, in certain cases, such areas can be removed and neurological functions can be maintained. If we wish to deal with metaphysics, we may even deduce that, although our human memory dies with the death of our human cells, our microbial memory persists after the death of our human body, and this concept bears an incredible number of implications that deal with matters such as life after death, the persistence of memory and consciousness after death, and so on.
JFS: In that sense, in the book
Your Third Brain, it is mentioned that in fact we could live and function with 90% of the brain missing, as some cases have been detected and published in important scientific reviews, notably one case in Marseille (France). Have other similar cases been discovered? How could such a replacement work and be explained?
The case that you are referring to was published in a prestigious medical journal, the Lancet, in 2007 (Jul 21;370[9583]:262). It described the case of a perfectly normal adult man from Marseille, a civil servant, married father of two children, who serendipitously discovered at age 44 that essentially 95% of his brain was absent and his skull filled with fluid that, unbeknownst to him, had accumulated since his childhood. This paper clearly demonstrated that we can live perfectly normal lives with only about 5% of our cerebral mass. Quite obviously, these results challenge all the notions of neuroanatomy, wherein even the most minute areas of the brain has an assigned function.
Interestingly, such a case is not isolated. Several years earlier, in 1992, authors from the Psychology Department of the Kalamazoo Regional Psychiatric Hospital in Michigan, US, had demonstrated that twins (homozygotic or heterozygotic) who had significantly different cerebral masses because one of the two had suffered from hydrocephalus, also had different intelligence. The oddity lies in the fact that those with drastically reduced cerebral mass had above-average intelligence! In other words, all the other variables being equal (as in the case of twins and particularly homozygotic twins), the size of the brain made the difference; however, contrary to common logic, the smaller the brain, the higher the degree of intelligence.
Quite curiously, these studies were not followed up, most likely because they challenge all the notions that we have about the functioning of the brain. However, since these studies are what in philosophy are called black swans (and here there are many black swans), we cannot escape the fact that our reductionist vision of localizing all neurological and psychological functions in the brain inside our head is, at best, very partial, if not completely wrong.
JFS: Mental states and decision-making, according to the book, are generated in the gut rather than in the first brain due to microbiota conditions; is that all? Is free will just generated in the gut, which could sound a bit reductionist, or do we still have a psychological margin independently from the microbiome or third brain?

At slight variance with what I wrote in the book about a year ago, I now postulate that mental states and decisions are generated both in the gut and inside our skull, but mainly by the microbial brains located there. The issue of free will as we knew it died when it was discovered that the microbiome contains a number of genes estimated to be between 2 and 8 million; that's more than 100 times the number of human genes in our DNA; about 20,000. In fact, if we consider for a moment only the human part of ourselves, all our mental states and decisions ultimately depend on the information contained in our human DNA. It is the information in the DNA that tells the neurons how to connect and form the neural web of interactions that are at the basis of our consciousness and thinking. In addition, the interaction with the environment, the processes of learning and memory, our experiences that determine our future decisions – all these events are embedded in the DNA of the neurons in the form of epigenetic variances that can be transmitted through the generations with the epigenetic inheritance.
These are some of the reasons why it is postulated that the information at the basis of our neurological and psychological functions ultimately resides in our DNA. If we now put into the equation the existence of an enormous amount of information that is present in the microbial DNA, it becomes evident that our behavior is actually "manipulated" by the microbes, as pointed out in the paper quoted above. When the authors write "manipulate," they use the true meaning of the verb. However, it would be equally reductionist to state that the human part of ourselves has no role and we are like puppets maneuvered by tiny microbes. The reality is that we are a complex society of different living beings in whom the behavior of each can be cooperative and altruistic or competitive and egotistic. In the first case, we live in a state of health; whereas in the second case, one class of living beings prevails and, as odd as it may seem, the human part is the most frail and impotent.
We may compare this complex society that is our body to the rhizome theory as proposed by the French philosophers Deleuze and Guattari. In conclusion, the concept of free will has to be extended to the "free will" of each individual microbe that is part of our body, since each individual microbe harbors genes that drive it to behave in the best way to guarantee its own fitness. If we accept this notion, then we can still maintain a concept of free will that is the algebraic sum of the free wills of all the beings living with us in this very moment.

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