There are more neurons in the human gut than in an entire mouse or rat brain possibly communicating information from and to the kilograms of microbes in the gut.  This may hold the keys to some mental health disorders.  

The Gut-Brain Axis.

Over the last several years, interest in what is known as the “gut-brain axis” has rapidly grown both within scientific endeavor and in the mainstream media. This  has been based on the realisation that the gut, and the microbiome living within it, send out a complex array of neural, hormonal and immunological messages which have the capacity to influence, not only other parts of the body, but also the brain. Furthermore, dysfunction of these signalling pathways is thought to potentially underpin multiple disorders, including obesity and inflammatory disease, as well as several brain-based disorders. But what do we actually know to date? Is our gut really a suitable clinical target for treating human disorders such as depression and autism or are the effects merely correlational or epiphenomenal rather than causal?

See related post The Frustration of Treating Depression

The human as a superorganism.

Historically, research into the gut has focused on how the brain controlled the more obvious functions of the gut such as regulating digestion and satiety. However, these days it is the bidirectional nature of this axis which is of particular interest, especially once you consider that the enteric nervous system alone is composed of over 100 million neurons (plus many millions more glia) which are located mainly within the myenteric and submucosal plexuses embedded in the lining of the gut. This is more neurons than is found in the entire mouse brain and about equivalent to the number of neurons in the rat brain.  This is why the gut is sometimes called our “second brain”. What’s more, people have realised the importance of our natural microbiome – consisting of billions of bacteria, archaea, fungi, viruses, and protozoa – which coexists with every one of us and has led some people to consider humans as “superorganisms” to reflect the fact that at any one time we may be carrying around thousands of different types of microorganisms on our external and internal surfaces. For example, some estimates suggest that there are around 1-2kg of microorganisms in our gut – a similar weight to the human brain that can communicate to the brain via the enteric nervous system.

Experience-dependent gut microbiota

The stability and composition of our gut microbiota is something that can change across our lifetime, especially during early development, and as an adult is heavily dependent on our medical status, experience, diet and lifestyle choices (see here for a review on the global diversity of the human microbiome). For example changes to diet, taking particular medications or having an infection can all temporarily disrupt the gut’s microbiota. In addition, stress is also thought to alter gut function and microbiota as well as the opposite – changes to the microbiota can influence the body’s stress response. For example, a seminal study in 2004 showed that germ free mice had an exaggerated hypothalamic-pituitary-adrenal (HPA) axis response to stress. What was particularly striking at the time was that these changes could be reversed by colonization with a specific Bifidobacteria species. Results from subsequent animal studies have continued to support a connection between gut microbiota and stress, suggesting that chronic stress exposure early in life or in adulthood can change an organism’s microbiota composition (see here for a recent review). It has been suggested that this association with the HPA system may underpin the proposed link between the gut-brain axis and some stress-based mental-health disorders such as a depression.

Functional understanding of gut microbiota disruption.

In addition to depression, disruption of the gut microbiota has been also implicated in a variety of other conditions including autism, schizophrenia and Parkinson’s disease (see here for a recent review). However, there is still considerable debate as to whether all of these disturbances are central to the pathophysiology of such conditions in humans or if they are merely epiphenomenal.

One difficulty is that there is a still a relatively poor understanding at a mechanistic level about how changes in the gut microbiota may actually translate into changes in brain function and behaviour because of the complexity of the interactions. For example, the main pathway between the gut and brain is via the vagus nerve which connects the enteric nervous system (made up or sensory, motor, interneurons and glial cells) with the central nervous systems.

From Bonaz et al 2018 Communication between the central nervous system and the microbiota through the vagus nerve (VN). VN afferent fibers can be stimulated by microbiota components either directly or indirectly via gut endocrine cells (GEC). VN afferent fibers exert stimuli on the central nervous system via the central autonomic network (CAN). VN afferent fibers are able to stimulate efferent fibers through the inflammatory reflex. VN efferent fibers can reduce digestive inflammation and reduce intestinal permeability by tight junction reinforcement. These actions of vagal efferent fibers can indirectly modulate microbiota composition. Alongside with brain-VN-microbiota axis exists bi-directional communication by various ways.

 

This signalling pathway can be modulated by a whole host of metabolites from the gut microbiota (e.g short chain fatty acids) and from the breakdown of food, as well as many different peptides released from specialized enteroendocrine cells. In addition, bacteria in the gut can produce neurotransmitters such as GABA serotonin, norepinephrine which can directly and indirectly regulate activity in the enteric nervous system and vagus nerve. On top of this, the gut forms a significant portion of the body’s immune system and direct and indirect interactions between the gut contents and microbiota and the body’s immune response is another method of gut-brain axis regulation (see here for a recent review)  For example, damage to the lining of the gut (e.g. caused by factors such as stress) causes a condition called “leaky gut” where the microorganisms can pass into the bloodstream potentially causing an immunological reaction.

Mice not humans.

Another difficulty is that the majority of the evidence for how changes in gut microbiota can influence brain function and behaviour, and potentially mental health, comes from mouse and rat models rather than from human research. These murine models have been bred to be artificially “germ free” or have been given large doses of antibiotics to remove or disrupt their gut microbiome, and so do not reflect ecologically valid representations of human neurobiology, function and behavior. (See From Mouse Brain to Human Brain). Although some studies in humans have been conducted, such as those which analyze faecal samples in depressed patients (e.g. see here), there is still limited evidence to date showing a causal link between changes in the gut microbiome and psychiatric disorders in humans.

A more embodied approach.

In sum, studies on the gut microbiota reinforce the idea that psychiatric disorders are not just confined to the brain, but also interact with other body systems. A more embodied approach to mental health disorders potentially offers new routes for determining clinical etiology and developing novel treatments. But only once more comprehensive research is conducted with human subjects – both healthy and clinical – can we start to gauge the size of the opportunity that the gut microbiome offers.

see related post Beyond the Brain: Embodied Cognition