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
_http://www.townsendletter.com/Oct2016/ruggiero1016.html
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.
