In the guts of the mind

Nazareth Castellanos

In The Guts Of The Mind

40 trillion bacteria live in our body. With a weight of more than 2kg, they have 150 times more genes than the human organism and treble its number of cells. What connection does this complex ecosystem have with our own organism and our behaviour?

The object of studying neuroscience is the biology which sustains cognition and behaviour. It is usually focused in the brain, its structure, functions, chemistry and electromagnetic activity. However, in the last decade, a representation which is more complex and networked is being made; the brain-centred over-simplifying is shaky. The discovery of the interaction between the brain and the heart has been one of the epicentres of the earthquake that is shaking neuroscience (see article in the same blog: “the heart of the mind”). Another epicentre exists that is far-reaching: the relationship between the intestine and the brain.

To speak of the intestine is to speak of its microbiota. Our bodies are inhabited by millions and millions of bacteria situated in the mouth, pharynx, respiratory system, skin surface, urogenital tract, stomach, and above all, in the intestine, mainly in the colon. The microorganisms which live in the body are known as microbiota. Until very recently, it was thought they were parasites which had little to do with us. Today we know that they are not only involved in diverse processes in the digestive, immune and nervous systems, but also they transmit genes which have helped our evolution.

When, 20 years ago, the human genome sequence deciphered that there was a percentage of genes with bacterial origin, it was thought to be a technical error and the result was rejected. Today, it is more than demonstrated that there is a horizontal genetic transfer (the vertical is the one that comes from our parents) between microbiota and the human being. Intestinal microbiota weighs more than 2kg, they have 150 times the genes of the human genome, there are 10 times more bacteria than cells in our body, and although they are 10 times smaller than cells, there are nearly enough to go around the world 3 times. A bacterial universe inhabits us.

These discoveries should make us reconsider the concept of the human body as independent and self-sufficient. One of the most beautiful theories in biology is the theory of hologenomic evolution, by Eugene Rosenberg (Rosenberg,2014), which developed studying the dynamics of the deep-sea corals: There exists a dynamic symbiotic relationship between coral and its bacterial community. Microbiota and its beings which it lives in, interact forming a whole called a holobiont. The interaction between the genome of the host and its microbiota is known as hologenome. In other words, a symbiotic interaction exists between the host (the human body) and the microbiota, of a form where they evolve together. The human being is a holobiont.

How do bacteria interact with us? It has been known for some time that microbiota are involved in the digestion and absorption of nutrients, which form a barrier against invaders, and that they produce and free the enzymes needed for the synthesis of vitamins K & D (for a revision see Pelaez and Requena,2017). But very recently it has been seen that they influence in the development and reaction of the immune, endocrine and nervous systems.

The already known relation between intestinal microbiota and the immune system (Forsythe,P and Bienenstock,2010,Duerkop et al,2009) has potential implications for medicine. For example, it is known that microbiota stimulate the production of cytokines, proteins which are involved in the function and communication between cells, and regulate the mechanisms of inflammation. To know the routes of anti-inflammatories of the body has a special relevance in the prevention and treatment of dementia, which would allow control of the process of neuro-inflammation associated with the illness of Alzheimer´s, and therefore, its affect on the cerebral function (Alkasir et al,2017). Pilot studies published recently place the intestinal microbiota as one of the major targets in the prevention of dementia.

Another potential mechanism of interaction between intestinal microbiota and the brain is its role in the generation of neurotransmitters. Neurotransmitters, also known as “the chemical bases of thinking”, are the molecules which measure communication between neurons. The radical alteration of certain neurotransmitters is crucial for psychiatric and psychological alterations. Recent studies have shown that bacteria have the capacity to generate many of the most important neurotransmitters (Lyte,2011;Matury Eraslan,2012;Barret et al,2012).

For example, Lactobacillus and Bifidobacterium species produce GABA, dopamine and acetylcholine, mediators in the motor function, vision, addictive processes and the sensation of pleasure, regulation of the waking-sleeping and memory consolidation. Escherichia, Bacillus and Saccharomyces species produce noradrenalin, involved in motivation, depression and anxiety. Candida, Streptococcus, Escherichia and Enterococcus produce serotonin, also known as the hormone of happiness because of its strong influence on the state of mood.

If the bacteria that compose our microbiota are capable of regulating the generation of transmitters which measure the interaction between neurons, we can say that the intestinal microbiota directly influence our conduct and cognition. Experiments on animals and people have demonstrated that altering the bacterial composition can modify the neuronal response. The group led by Kirsten Tillisch in Los Angeles University were pioneer in the study in the role of microbiota in emotional regulation. Their experiments proved that the ingestion of probiotics altered the cerebral activity responsible for the process of facial expression (Tillisch et al,2013, Tillisch,2014).

The implication of probiotics in social conduct and emotional regulation (Sarkar et al., 2016, Benton et al., 2007; Messaoudi et al., 2011) has a long hoped-for implication for the treatment of the autism spectrum, as has been demonstrated in animal models and in pilot studies in children and adolescents (Wang et al., 2011. Finegold et al., 2010, Cryan and Dinan, 2012). The group led by John Cryan of the Irish University of Cork are pioneers in what has been christened “the psychology of the brain-intestinal microbiota axis”. Their experiments are based on a cognitive and gastric neuroscience with dramatic implications for psychological therapies (Allen et al, 2017).

Investigations on the influence of certain bacteria on the generation of specific neurotransmitters or its influence on the immune system in one of the most important subjects today. However, also, it is where the most contradictory results can be found. The majority of the studies based on the ingestion of pro or prebiotics are, up to now, pilot studies where the most relevant result is perhaps to show the influence of microbiota on the cerebral function more than to establish prescriptions or directives on the benefits of certain diets. Nevertheless, one could also consider that equally we must recognise nature interdependency of the human being and their microbiota, we must conceive the microbiota as a network of independencies in itself.

The different groups of bacteria of which the microbiota is consisted is in constant interaction. The relationship can go from parasitism, where some bacteria benefit from others, threatening, where the benefit of one supposes the prejudice of the other, commensalism where some benefit from others without altering them. The microbiota is a complex network in itself. Faced with such complexity, we can suppose that to alter the abundance of a bacterial population supposes the reorganisation of the whole network, and it is therefore difficult to speak of specific effects of one component of the microbiota. To study the interaction network of micro-organisms that inhabit us and how they relate to the human body in one of the subjects of most relevance in science today (Faust and Raes, 2012).

The scientific acceptance of the intestine as a “second brain” (Gershon, 2005) has been accompanied by the strongest pieces of biological evidence already shown, as much as the pharmacological implications could have. However, the evidence of interaction between the electric cerebral field and the intestine has been adopted by the scientific community more discreetly. Catherine Tallon-Baudry´s group, which has now demonstrated the electrical relationship between the heart and the brain, (Park et al,2014) has published a study recently on the subject of the alpha brain cycle rhythms and the gastric oscillations (Richer et al,2017). The most surprising, shown during a statistical analysis of the cause that the modulation goes from the intestine to the brain and not the other way around.

Just as the relation between the heart and the brain has not reached a critical mass yet in scientific publications (in spite of being published in primary magazines), studies on the intestine-brain axis have multiplied exponentially in the last few years. This could be due to that work in the wake of the enormous technological advances that have taken place in the field of genetics, now that to determine the bacterial composition, it is necessary to have an analysis of the genes present in the stool. The Human Genome project was born with the hope of decoding the factors that “determine” to develop certain illnesses or conduct – expectations that are not covered. Currently, universities in the USA and Europe have joined forces to characterise our microbiota (https://hmpdacc.org/), with a similar objective as the Human Genome project.

Sometimes, the feeling is that the microbiota will be the next “thing to blame” to pass off on our behaviour. The scientific philosopher, Phippe Meyer, said that biology understands little about human freedom. This scientific determinist vision rules the human being with a passive pole dictated by inheritance or influence of external agents. Fortunately, things are more complex.

We have said that microbiota interact with the human body modulating the immune and nervous systems, but also through the endocrine system. Microbiota are seen to be affected by stress and lifestyle. The physiological impact of stress is measured through the liberation of a substance known as cortisol, which affects the intestine directly (Messaoudi et al., 2011). The influence of cognitive therapies, from stress reduction (Allen et al, 2016) based on mindfulness (Whitebird et al, 2013) and the education on lifestyle (Miller et al,2015, Bressa et al, 2017) are key factors in the regulation of microbiota, and therefore for the cerebral function, closing the environment-body-mind cycle. These experiments must provoke a scientific and humanist rethinking about the role of subjectivity and interpersonal variability, intention and attention, and the relationship environment-body-mind.

Science is found between the unmanageable challenge of studying complex systems that interact in a complex form between what is difficult and adorns things. But, as individuals, this complexity invites humility and wonder. The paradox is that, the more “we know”, the greater the problem.

Cover illustration: Painting of Oliver Indri.

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Dialogue & Discussion