Microflora and psyche
How bacteria living in the gut affect brain cells and our behavior
The behavior of animals (including humans) is influenced by sensory and molecular data obtained from the environment. With sensory, it is more or less clear: visual receptors record visible light, skin receptors — touch and temperature, the auditory system — acoustic signals. And what about the molecular data? Molecules of volatile substances are perceived by olfactory chemoreceptors of the epithelium of the nasal cavity. But the most important place of influence of environmental molecules on us, mammals, is the gastrointestinal tract (gastrointestinal tract). And the most important part of it in this regard is the intestine, where food components are chemically transformed by the microbiota, after which the resulting metabolites spread throughout the body, including the brain, and affect a variety of aspects of our life, including behavior and mental state.
Studies of the last decade have consistently linked the composition of the intestinal microbiota with autism spectrum disorders (ASD), anxiety, schizophrenia, neurodegenerative diseases. Moreover, experiments on mice have shown that by manipulating the microbial community of the intestine, neurological and neurodegenerative conditions can be influenced, either weakening or aggravating their symptoms. But how exactly and why does it work? The mechanisms of this relationship have remained unclear for a long time.
Trying to understand the causes of gastrointestinal problems that often occur in people suffering from ASD, doctors examined their feces and blood and drew attention to the fact that certain chemical compounds in the samples obtained from these patients are many times more than in people from control groups. One of these substances turned out to be 4-ethylphenyl sulfate (4EPS), a product of the vital activity of some bacteria. In the samples taken from 231 children with ASD, it turned out to be, on average, seven times more than in neurotypical children. It is noteworthy that later — in a study on mice — scientists found elevated levels of the same substance in mice with atypical neurodevelopment.
Such information prompted researchers from the California Institute of Technology (Caltech), from the laboratory of Professor Sarkis K. Mazmanian, to test, first on mice, the relationship between the presence of 4EPS-producing organisms in the intestinal microbiota and behavior, and also try to figure out the mechanism of this interaction. A publication about the study was published recently in the journal Nature (Needham et al., A gut-derived metabolite alters brain activity and anxiety behavior in mice).
Since the brain is primarily responsible for behavior, scientists first created bioengineered bacteria that can be part of the intestinal microbiome of mice and at the same time produce a lot of 4-ethylphenyl sulfate, and then studied the effect of this metabolite on brain cultures ex vivo. These experiments revealed that 4EPS alters the function of oligodendrocytes, special cells of the central nervous system whose main task is to help the axons of neurons by creating a myelin sheath around them. The 4-ethylphenyl sulfate produced by bacteria, as it turned out, interferes with the interaction of oligodendrocytes with neurons.
Then the experimenters planted modified bacteria in the intestinal microbiota of mice and began to observe the latter. As expected, mice colonized by 4-ethylphenyl sulfate-producing organisms exhibited abnormally anxious behavior. But when mice were given drugs that promote the differentiation of oligodendrocytes from stem cells, the behavioral effects of increased levels of 4EPS were overcome.
Further investigation showed that animals with modified microorganisms in the intestinal biota, which produced abnormally high levels of 4-ethylphenyl sulfate, decreased myelination of neuronal axons, and 4EPS is found in various tissues, including directly in the brain.
This is an important result: it showed that the molecule that disrupts the function of brain cells and affects complex behavior, apparently, has a bacterial-intestinal origin, and also allowed us to conduct a small clinical study - already in humans. Scientists from the same Caltech, from the same laboratory, tested an oral adsorbent (AB-2004) on thirty adolescents with ASD, the effect of which is limited to the gastrointestinal tract and which adsorbs mostly small phenolic molecules, including the same microbial metabolite 4EPS, the increased content of which in feces and blood has recently been linked with behavioral disorders. As a result of treatment, some observed behavioral parameters improved in adolescents, with the best results related to anxiety and irritability associated with ASD. Also, for eight weeks after treatment, the study participants did not have gastrointestinal problems characteristic of their disorders.
To confirm, consolidate and develop the results obtained, of course, more research is needed, but the way to understand the mechanism and cure (or, at least, alleviate the symptoms) of a number of behavioral disorders seems to be becoming more obvious.
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