Research has been showing that the gut microbiota can strongly influence our overall health and disease, including our brain’s health, as well as our mood and behavior. This article in the brain-gut axis series aims to explain how the brain and the gut interact, which means they have to communicate, and what research has uncovered so far.

Being such an immense ecosystem with which we live in a healthy symbiosis, it seems obvious that there has to be a way for gut microbiota to interact with our brain to let it know if everything is all right. Because we do need our gut’s microbes just as much as they need us.

The enteric nervous system

The gut actually has a nervous system of its own – the enteric nervous system (ENS). The ENS controls the functions of the gastrointestinal tract, pancreas, and gallbladder.

The human ENS is estimated to have around 100 million neurons, maybe more than the entire spinal cord. It contains local sensory and motor neurons, as well as interneurons establishing local connections. The enteric motor neurons control the smooth muscle of the gut, local blood vessels, and secretion by the mucosa. The ENS also responds to changes in the gut and sends information to the spinal cord about the gut’s environment such as pressure or stretch, ischemia, or the presence of irritating chemicals, for example. This information is then conveyed to the brain.

Given the size and complexity of the enteric nervous system, it does seem odd that its only functions would be to manage sensory input and motor control and to signal it to the brain. Indeed, information arising from the gut serves two main functions: it provides input to local reflexes that modulate motor activity, and it informs the brain of more complex settings that may represent potentially threatening conditions that may require a coordinated motor, neuroendocrine, and behavioral reaction.

ENS-CNS communication

There are hundreds of million of neurons connecting the central nervous system (CNS) and the ENS. But despite this extensive communication network, the ENS is actually able to operate somewhat independently, without input from the CNS, through its own reflexes: Many gut functions can continue without supervision from the brain, such as peristalsis, the wave-like muscle contractions that move food through the digestive tract.

But reflexes aside, most operations of the ENS are indeed controlled by the brain. Our brain and gut are connected by an extensive communication system operating not only through neurons, but also through blood-borne chemicals and hormones that signal hunger, stress and the presence of pathogens, for example. The neuroendocrine system, specifically through the hypothalamus, the pituitary gland and the adrenal glands, regulates many processes through the action of hormones, such as immune responses, mood, emotions, reactions to stress, and also digestion.

The CNS also communicates with the viscera through the autonomic nervous system, our involuntary nervous system responsible for controlling physiological functions such as heart rate, breathing, and digestion. The autonomic nervous system, through its sympathetic and parasympathetic divisions, acts on the digestive system to control food movement and secretions throughout the digestive tract. Secretions in the gut are paramount to the survival of the gut’s microbiota.

The vagus nerve is a major player in this brain-gut connection. The gastrointestinal tract is densely innervated by the vagus nerve, which plays a crucial role food intake, digestion, and intestinal barrier functions. It contains sensory and motor fibres contributing to a bidirectional communication between the gut and the brain. 80-90% of the nerve fibers in the vagus nerve are dedicated to communicating the state of the viscera up to the brain. Interestingly, the vagus nerve is also closely associated with stress and anxiety responses, and is responsible for the heart rate and breathing pattern, for example.

If a change occurs in the gut that somehow affects the survival of our microbiota, the brain will most likely be readily informed. And the extent of this connection is pretty amazing. Data suggest that the gut microbiota may be a key player in the communication between the immune and neuroendocrine systems. Recent data has been showing that our buddies in the gut may even influence our perception of the world and alter our behavior via the CNS; however, the mechanisms by which such influence occurs are still poorly understood. But given the massive research interest that the brain-gut-microbiota axis has been gathering, information is coming in.

Mechanisms of microbiota-brain communication

One of the possible mechanisms of communication between gut microbes and the brain is the release of biologically active molecules. These molecules are released packed into nanoparticles known as outer membrane vesicles. These vesicles can enter the systemic circulation and be delivered to different organs including the brain, eliciting a variety of immunological and metabolic responses.

Numerous small molecules are already known to be produced by the human microbiota. Some have been show to affect immune modulation and signaling, which has the potential to influence mood and behavior; they can even regulate the production or the metabolism of neuromodulators and neurotransmitters such as serotonin, dopamine and GABA, all of which are well known to strongly influence mood and other brain functions.

In fact, at least two types of intestinal bacterium have been shown to produce the neurotransmitter GABA. But most of these molecules are still unstudied and it is possible that they may have surprising effects.

The blood-brain barrier is the doorway to the brain; it controls the passage of molecules and nutrients in and out of the brain. Studies on germ-free mice have shown that the lack of microbes can increase the permeability of the blood-brain barrier, thereby revealing another mechanism by which the gut microbiota can influence the brain.

On the other hand, the CNS can influence composition of the gut microbiota both directly and indirectly. Direct alterations can be exerted by neurotransmitters and other molecules released in the gut. Indirectly, changes may occur through altered secretion and nutrient delivery in the gut; by changing the local environment, the brain can affect the survival and the composition of the gut microbiome.

It’s a two-way street. Neurotransmitters, hormones, and other chemical messengers convey information both ways. The brain not only senses the gut, but it is also able impact its environment. They are in almost constant communication, sending signals back and forth. Just as it signals pathogens, the enteric nervous system can also receive information from the state of our gut’s thriving ecosystem and send them messages about the state of our brain.

In Part 3 of this article series, I’ll talk about some of the recent findings on the impact of the gut microbiota in health and disease.

References

Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Tóth M, Korecka A, Bakocevic N, Ng LG, Kundu P, Gulyás B, Halldin C, Hultenby K, Nilsson H, Hebert H, Volpe BT, Diamond B, & Pettersson S (2014). The gut microbiota influences blood-brain barrier permeability in mice. Science translational medicine, 6 (263) PMID: 25411471

Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, Bienenstock J, & Cryan JF (2011). Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proceedings of the National Academy of Sciences of the United States of America, 108 (38), 16050-5 PMID: 21876150

Carabotti M, Scirocco A, Maselli MA, & Severi C (2015). The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Annals of gastroenterology : quarterly publication of the Hellenic Society of Gastroenterology, 28 (2), 203-209 PMID: 25830558

Donia MS, & Fischbach MA (2015). HUMAN MICROBIOTA. Small molecules from the human microbiota. Science (New York, N.Y.), 349 (6246) PMID: 26206939

El Aidy S, Dinan TG, & Cryan JF (2015). Gut Microbiota: The Conductor in the Orchestra of Immune-Neuroendocrine Communication. Clinical therapeutics, 37 (5), 954-67 PMID: 25846319

McCusker RH, & Kelley KW (2013). Immune-neural connections: how the immune system’s response to infectious agents influences behavior. The Journal of experimental biology, 216 (Pt 1), 84-98 PMID: 23225871

Muraca M, Putignani L, Fierabracci A, Teti A, & Perilongo G (2015). Gut microbiota-derived outer membrane vesicles: under-recognized major players in health and disease? Discovery medicine, 19 (106), 343-8 PMID: 26105697

O’Mahony SM, Clarke G, Borre YE, Dinan TG, & Cryan JF (2015). Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behavioural brain research, 277, 32-48 PMID: 25078296

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