Control they nonetheless raise the possibility that the

Control of Brain Development, Function, and Behavior by the Microbiome

Animals share a life-long partnership with a numerous number of microbial species, also referred to as the microbiota. Interacting microbes have been proven to regulate nutrition and metabolism. Microbes are also important for the development and function of the immune system. Recently, studies have shown that gut bacteria can influence neurological outcomes, such as altering behavior and even potentially affecting the start of severe nervous system disorders.

Introduction

It’s only recently that we began to appreciate the connection between microbes and mammals. Research describes how gut bacteria (microbiota) influence critical aspects of our physiology. In the last decade, research has shed a light on various complex interactions between the microbiota and the immune and metabolic systems. Many of these systems have a significant meaning on human health. The concept of microbes influencing such a complex organ as the brain had already been established. Specific microbes could influence the behavior and neurological function of their host.  There are also numerous parasitic microbes, which are capable of altering the locomotive behavior and environmental preferences of their host to benefit the microbe.

While these alterations represent pathogenic and/or parasitic relationships, they nonetheless raise the possibility that the internal microbes, which are constantly in interaction with their human and animal hosts, could influence the behavior and neurological function during the development or within health and disease states. That psychiatric and neurological illness are often co-morbid with gastrointestinal pathology, is now becoming increasingly more recognized. Furthermore, observations have indicated that intestinal microbiota indeed alters aspects of their hosts’ neurological function, which leads to having an effect on the mood and behavior of the host. However, the intestinal microbiota is well-established to have had a serious impact in the shaping of their host’ immune system, which itself may influence the host’s behavior and might indirectly have effects on neurodegeneration and repair during the progress of aging, neurological trauma, and disease. But the precise mechanisms of the impact of intestinal microbes on neurological function and behavior remains mostly unknown, but are likely to be very complex.

Interactions between a host and its microbiota are very complicated. Intestinal microbes influence a variety of aspects of metabolism. They produce metabolic precursors to neurotransmitters and hormones or they directly produce the active metabolites themselves. Symbiotic bacteria are additionally able to influence the condition of the systemic immune system, which may alter how the immune system later will interact with the nervous system. Moreover, the enteric nervous system (ENS) is directly connected through the vagus nerve to the central nervous system (CNS), which provides a direct neurochemical pathway for microbial-promoted signals in the GI tract to proliferate to the brain.

Role of the microbiota in mood and individual behaviors

One of the original studies on the influence of the microbiota on neurological functions observed germ-free (GF) mice. These mice showed an elevated response to restraint stress. When microbiota isn’t present, mice have considerably higher concentrations of corticosterone, a stress hormone in the hypothalamus, and they also have reduced levels of brain-derived neurotrophic factor (BDNF). This progress can partially be turned around by re-colonization with a variety of microbiota in adulthood, which suggests that active signals of the microbiota play a significant part in brain development. As a matter of fact, colonization with specific bacterial species restores these defects and stimulate normal behavior. Showing that microbiota affects the hypothalamic-pituitary-adrenal axis (HPA axis), revealed a two-way communication between the gut and the brain, which has a serious effect on the host’s behavior. But some strains of GF mice show reduced anxiety-like behavior which is similar compared to specific pathogen free (SPF) mice, which are colonized with numerous microbial populations. The behavioral effects of these mice can be restored by recolonizing the GF mice with the microbiota of the SPF mice. The effects, however, aren’t automatically consistent with all strains of mice.  

Research showed that when microbiota relocates between strains of mice, the behavior of the parent strain is transferred, which means that signals derived from the microbiota can change behaviors within the host. Now there is an increasing amount of observations that show the effect of probiotic species on the host’s behavior.

Other studies show that microbial signals that are directed by the vagus nerve can alter CNS outputs (for instance behavior). This would suggest that these microbiota signals have an active role in interfering neurological functions. Yet other studies suggest that the functionality of the gut microbiota influence anxiety-like behavior. These studies all support the hypothesis that active modulation of the intestinal microbiota can have drastic effects on behavior.

However, anxiety isn’t the only behavior that is modulated by symbiotic bacteria. Studies have been done to examine depression-like behavior in rats, which showed a decrease of depression after treatment with specific symbiotic bacteria. These findings further suggest that the function and/or structure of the microbiota actively alter the behavior in adult animals.

Interestingly a probiotic complement is noticed to have an impact on both depressive and anxious behavior in mice, as well as on their memory and learning abilities. While some studies have shown that a specific diet can alter the content of the microbiome and that they have an effect on behaviors, but whether their microbial content itself is a cause for the depressive behavior and loss of learning ability is not clear. Most observations of these studies are there to understand the role that the content and function of microbes may pay in shaping the mood and behavior of the host.

There is also work being done to understand if microbiota has similar roles in shaping the human neurological functions. A few recent human studies have suggested that the microbiota can actively alter some of the functional aspects of the mood in humans. Another study examined if probiotic consumption could influence anxiety. These studies together showed that the microbiota influences neurological functions in humans and eventually affect the mood and behavior.  But to validate this, it requires further research.

Research observed that in both humans and mice probiotic complements don’t inevitably alter the content of the gut microbiome. Instead, the metabolic activity and/or transcriptional state of the microbiota are altered. Extended study on how the presence of a specific species of bacteria impacts physiology but doesn’t alter the complete population of gut microbes, will be necessary to understand the function of the microbiota.

One confirmed the physiological function of the microbiota is generating essential nutrients for the host. The results of a small study in humans offered a basis for the hypothesis that symbiotic microbes may be capable of modulating their host’s appetite.

Microbiota shape social behaviors

The host’s social behavior is also altered by the composition, function, and presence of the microbiota. GF mice are somewhat socially dysfunctional compared to the SPF mice, which are colonized by microbiota. This suggests that microbiota influence these social behaviors. But the social dysfunction of the GF mice could be restored by recolonizing adult mice with microbiota. Gut bacteria could eventually form lifelong behavioral traits.

There have also been studies of social behavior in hyenas. These studies support the assumption that symbiotic bacteria affect how hosts interact in a social environment. If gut bacteria adjust their host’s neurological function to choose a specific mate, then microbiome may play an important role in influencing the evolution of their hosts. Microbiota could eventually be an important factor in the evolution of metazoan species, by influencing how individuals experience genetic transfer and how they interact.

The link between gut bacteria and disorders involving social impairment

Autism spectrum disorder (ASD) consist of a few complicated neurodevelopmental disabilities defined by a shortage of social interaction and repetitive behaviors. ASD children, as well as ASD mice, have an altered content of the intestinal microbiome. And while treatment with a specific probiotic didn’t restore the microbial population, it did save some behavioral defects.

One study showed that molecules of the microbiome can influence behavior inside mammals. And yet another study showed that ASD mice also display an increased intestinal inflammation. These studies together suggest that particular neurodevelopmental disorders may have a microbial anatomy, but this hypothesis will need further research to get more validation. The outcome of one study even suggests that genetics alone cannot explain many diseases and that there must be another factor that is involved, the microbiome.  

Microbiome-mediated alterations to neurophysiology

In some cases, there is proof that microbiota mostly occurs during a specific time frame of development or disperse signals, to have some effect on the neurological function of the host. One study showed that the host’s molecules couldn’t be rebuilt after the re-colonization of the microbiome in adult mice, which implies that particular phenotypes are almost surely programmed by the microbiota in their adolescence or during their critical development.

While changes to the function or population of microbiome may result in the production of metabolites, it’s unknown if they can alter the neurological function of their host.

Regulation of neurotransmitter levels by the gut microbiota

While it has been noticed that the microbiome can be resolved in changes of the neurophysiology, but how this exactly works is still unclear. One way to alter the neurological function could be through controlling the concentration of the neurotransmitters in the brain. In the absence of gut microbiota, the number of neurotransmitters decreases. But how the gut bacteria change the amount of neurotransmitters that are produced still has to be determined. While neurotransmitter production may be controlled by signals from the microbiota to the neurotransmitter-producing cells, gut bacteria also produce small molecules that could act as neurotransmitters, which could impact neurological function sooner or later.

It is known that certain gut bacteria are able to produce small molecules, but it is still unknown of these molecules can act as neurotransmitters. A recent study showed that human gut microbes are able to produce neurotransmitters. This study also showed that there is a chance that neurotransmitters produced by gut microbiota could alter the neurological function of the host. Another study observed that gut bacteria may have an effect on the brain. It also observed that the neuroregulation of gut bacteria may possibly adjust the activity of the vagus nerve, which could later impact brain function.

Microbial control of neurological function by the immune system

The interactions between microbiota and the nervous system may be implied. Now data indicates that the immune system can impact the behavior and the neurological function of the hosts. Actually, some neurological disorders are caused or allowed by signals of the immune system.

One study observed that given the role of microbiota have in changing behaviors, radiation may restore behavioral function, by resetting the immune system and/or changing the content of the microbiome. This study also provides proof for the link between social and behavioral disorders and immune dysfunction. The results of another study showed that microbiota may be able to impact the amount of neurogenesis, which couldn’t only impact the neurodevelopmental progress, but also the injuries and neurodegenerative diseases. This could be a way to enhance the microbiome to alter the outcome of neurodegenerative diseases and may have, in the future, a microbiota based therapy to cure neurodegenerative diseases.

Future directions and conclusions

This article proves there is a clear link between the microbiome and neurophysiological and behavioral disease. Several reports show that animals that don’t have microbiota have different behavior and brain development compared to animals that do have them. When we’re able to identify microbes that change these systems, we will be able to identify the way that the neurophysiological function is controlled. The study of the genetics and genomics of newly discovered organisms may give an insight on how microbial molecules alter their host’s neurophysiology. It will be important to know whether the impact of the microbiome on a host is active or developmental in nature and if it can be changed in later life-stages.

One of the most important areas in this research is understanding the consequences of altering the population of microbiome that correspond with certain diseases. By lack of a strong genetic part, environmental factors are said to have an important role in many neurological diseases. Further study may show that microbiome is the environmental factor, that could have consequences on neurological diseases. Furthermore, knowing how the microbiota changes immune responses may lead to an understanding of how we can alter gut bacteria to control immune anatomy in the brain.

Only recently we began to appreciate the scale on which microbes could affect the neurological function in mammals. Nowadays, neurodevelopmental, psychiatric and neurodegenerative disorders are serious medical problems and new findings are desperately needed to explain many neurological conditions. This may be accomplished through the exploration of the human microbiome.