Gut feelings; are microbes in your intestines dictating your mood?

A cat hears a scuffling sound amongst the garbage.  She stands in shadow, all senses poised.

A few moments pass; the rat emerges.  In this alleyway, a light breeze carries her scent towards him.  He sniffs the air, and looks in her direction.  Two eyes blink, and then fixate upon him.

But he does not heed the warnings.  A parasite in his brain, picked up from cat faeces, has immobilised his fear response.  He scuttles out across the floor…


We are mostly bacteria.  The microbes living on our skin, on the inner surfaces of our lung linings and through our gut outnumber our body cells ten to one.  In fact, bacteria and other micro-organisms live in and around all multicellular life forms – from plants to people.  This ‘microbiome’ is

an essential part of our biology and our health, and even influences how we (and all other animals) behave.

Microbes begin to colonise our gut from the moment of our birth.  They help to pre-digest our food, making nutrients soluble and hence available for absorption  through the gut wall.  But the helpfulness of these bacteria doesn’t stop here.

The many small fatty acids and amino acids produced by bacterial fermentation act as signals inside our bodies.  They initiate the development of the network of nerves in the gut wall; our ‘enteric nervous system’ (also known as our ‘second brain’).  These nerves control the rhythmical contractions of the digestive canal, which operate independently of the central nervous system.  Bacterial products also initiate, nourish and maintain the cells lining our gut.

A thin section of the small intestine wall, stained for CK20 protein (found in the mucosal lining).   The lining of our intestines is a vast sensory surface, whose cells are nourished by fatty acids, vitamins and other compounds produced by bacterial fermentation.  The finger-like projections (called villi) visible in this section, form our main absorptive surface for nutrients, and sense the presence of both friendly bacteria and harmful pathogens (Image: Wikimedia Commons)

A thin section of the small intestine wall, stained for CK20 protein (found in the mucosal lining).The lining of our intestines is a vast sensory surface, whose cells are nourished by fatty acids, vitamins and other com... morepounds produced by bacterial fermentation. The finger-like projections (called villi) visible in this section, form our main absorptive surface for nutrients, and sense the presence of both friendly bacteria and harmful pathogens (Image: Wikimedia Commons)

However the role of this microbial community goes beyond digestion.

– They out-compete harmful bacteria, ‘policing’ the gut and maintaining its pH.

– They present antigen signals (bacterial surface proteins) to our immune system, training us to recognise ‘friend’ from ‘foe’.

– They produce neurotransmitters and hormones, which are used directly and indirectly by the body. These include the cytokines and chemokines needed by immune cells to induce inflammation  and fever responses and to target white blood cells into infected tissues. Bacteria produce precursors for 95% of our body’s serotonin (the ‘feel good’ brain chemical), and 50% of our dopamine.

Bacterial products affect the formation of connections between neurons (the synapses).

The enteric nervous system interacts with the central nervous system via the vagus nerve (the parasympathetic system) and the prevertebral ganglia (sympathetic nervous system).  However if these nerve connections are severed, the enteric system will continue to function, integrating and resolving signals from the body and the environment.  For this reason the gut is sometimes known as our ‘second brain’.  This network uses around 30 neurotransmitters, most of which are also found in the brain, and which include acetylcholine, dopamine and serotonin (Image: Wikimedia Commons)

The enteric nervous system interacts with the central nervous system via the vagus nerve (the parasympathetic system) and the prevertebral ganglia (sympathetic nervous system). However if these nerve connections are sev... moreered, the enteric system will continue to function, integrating and resolving signals from the body and the environment.  This network uses around 30 neurotransmitters, most of which are also found in the brain, and which include acetylcholine, dopamine and serotonin (Image: Wikimedia Commons)

Our ‘gut-brain axis’ is linked indirectly by chemicals the bacteria produce, which activate the immune system.  Our mind and gut is also linked  directly via the vagus nerve.

The vagus or ‘wandering’ nerve, our 10th cranial nerve, forms part of the parasympathetic (involuntary) nervous system.  It is a ‘mixed nerve’, meaning it carries both sensory information about our body state back to the brain, including from the gut to the brain stem, and relaying messages from the brainstem and emotional centres to the body.

This information highway operates the  ‘vagal reflex’, which relaxes the muscles around the stomach wall making space for our food, and also integrates the digestive process with our blood circulation, hormone system and emotional state.

This conversation between the digestive, immune, hormonal and nervous systems is essential for our healthy development.  Mice raised under sterile conditions (so that their guts are free of bacteria) develop fewer connections between neurons, which results in retarded brain growth.

The human appendix is surrounded by copious amounts of immune tissue which particularly nurture and protect this sub-sample of our gut bacterial community. This creates a ‘safe house’ for a sample of our gut microflora.  After an infection has triggered a diarrhoea response which expels the intestinal contents, the guts are recolonized by bacteria from this reservoir in the appendix.  Charles Darwin first suggested that the human appendix is a relic of our evolution; a ‘vestige’ of a much larger mammalian caecum. (A caecum is a larger area of gut, containing bacteria, adapted in herbivores to digest large amounts of plant material).  However this explanation doesn’t fit the facts.  The appendix has evolved at least twice, arising independently in marsupials and placental mammals; an example of evolutionary convergence.  This suggests that it has a current and selectable function (Image: Amended from Wikimedia Commons)

The human appendix is surrounded by copious amounts of immune tissue which particularly nurture and protect this sub-sample of our gut bacterial community. This creates a ‘safe house’ for a sample of our gut microfl... moreora.  After an infection has triggered a diarrhoea response which expels the intestinal contents, the guts are recolonized by bacteria from this reservoir in the appendix. Charles Darwin first suggested that the human appendix is a relic of our evolution; a ‘vestige’ of a much larger mammalian caecum. (A caecum is a larger area of gut, containing bacteria, adapted in herbivores to digest large amounts of plant material). However this explanation doesn’t fit the facts. The appendix has evolved at least twice, arising independently in marsupials and placental mammals; an example of evolutionary convergence. This suggests that it has a current and selectable function (Image: Amended from Wikimedia Commons)

Gut microbes also influence our mood and emotions, affecting our behaviour.  If intestinal bacteria from timid mice are used to populate the guts of a normally inquisitive mouse strain, these more adventurous mice become timid.  Likewise, timid mice become adventurous when given the microflora from inquisitive mice.

Behavioural effects are also visible in humans.  One of the first studies, conducted in France by Michaël Messaoudi and co-workers, found that drinking milk fermented with probiotic bacteria (versus non-fermented milk) lifted the mood of healthy human volunteers, reduced their blood cortisol levels (a hormone which increases during stress) and gave them a greater resilience against stimuli provoking symptoms of depression and anxiety.

Just as gut bacteria influence our health and mood, experiences that change our mood and behaviour in turn affect the composition of this microbial community.  This shows that our gut microbiota are not autonomous, but act like a fully integrated body organ.  This microbiotic organ monitors and responds to the food we eat, influences how we respond to our world, and connects with our body using messages sent in a common chemical ‘language’ .  We speak about our ‘gut feelings’, usually unaware that this is much more than a metaphor.

It seems then, that our thoughts, feelings and behavioural choices affect our gut microbiome.  As we ‘tell them’ how we feel (through the parasympathetic nervous system, immune system and hormones), they align their metabolic responses with this information.  Their biochemical cues reinforce the body’s signal by releasing neurologically active chemicals that affect our mood.  If our enteric nervous system really does deserve its title of the ‘second brain’, then the bacteria in our gut are mediating a connection that integrates the ‘thoughts of our guts’ with those of our mind.

Lab mouse, strain mg 3204.  Laboratory mice are usually derived from the house mouse (Mus musculus).  Mice are useful as a system to study many aspects of human health, thanks to having a high similarity with our genetic code, as well as the ability to thrive in a human-influenced environment.  As with humans, many aspects of their development and behaviour are dependent upon a healthy community of gut microflora (Image: Wikimedia Commons)

Lab mouse, strain mg 3204. Laboratory mice are usually derived from the house mouse (Mus musculus). Mice are useful as a system to study many aspects of human health, thanks to having a high similarity with our genetic ... morecode, as well as the ability to thrive in a human-influenced environment. As with humans, many aspects of their development and behaviour are dependent upon a healthy community of gut microflora (Image: Wikimedia Commons)

 

Since we and all other animals  are intimately associated with our gut bacterial ‘organ’, this raises interesting questions at the cellular level about where our physical boundaries really are.

Text copyright © 2015 Mags Leighton. All rights reserved.

References
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Blind evolution gives eyeless fish sleepless nights

As the bats chatter above you in the cavern roof, their droppings rain down into the pool below.  The floor is silky with bacteria.  It’s cold and still.  A musty tang lingers in the air.  

You are completely blind.  You rely on hairs in your skin to feel for movement in the water. 

You are hungry.  Something is disturbing the mud; you can smell it!   You follow the scent trail and grab at it.  It feels like a shrimp. 

Things touch and nip you…  You are afraid of being eaten.  You move slowly, dozing for short periods, but don’t sleep. 

You have been here for…  How long?  Can you tell this without a sense of day and night?


The enhanced touch and taste senses of cave fish are also found in fish that hunt in murky waters, e.g. this channel catfish (Ictalurus punctatus).  These fish have touch sensitive ‘whiskers’ (barbels) and a high density of chemoreceptors (taste organs) over their bodies, making them into a ‘tactile, swimming tongue’.  These senses are more important to this fish than vision, hence their eyes are small (Image: Wikimedia Commons)

The enhanced touch and taste senses of cave fish are also found in fish that hunt in murky waters, e.g. this channel catfish (Ictalurus punctatus). These fish have touch sensitive ‘whiskers’ (barbels) and a high den... moresity of chemoreceptors (taste organs) over their bodies, making them into a ‘tactile, swimming tongue’. These senses are more important to this fish than vision, hence their eyes are small (Image: Wikimedia Commons)

Mexico’s blind cave fish show many of the adaptations found in animals from cave ecosystems across the world.  They have lost their eyes, and instead have chemoreceptors (‘taste buds’) scattered over their skin, allowing them to follow ‘pathways’ of chemical concentration (chemotaxis).  Touch-sensitive hairs around the mouth, along with a well-developed lateral line system, enable them to sense tiny water currents caused by prey and other fish.

In these caves, as in the deep sea, food is always in short supply.  To avoid being eaten by other fish they must remain vigilant, and so may ‘doze’ but do not sleep.  These fish have a low metabolic rate to conserve energy, and build up reserves of body fat .

Why do these fish and other cave dwellers go blind? One explanation is that eye loss is neutral to their survival.  When a characteristic is no longer essential to survival, mutations (mistakes in the DNA) that cause crucial genes to cease working are not selected against.  They are then passed to the next generation ‘at random’.

Random bead sampling experiments show how certain forms of a gene can become quickly widespread in a few generations in a small isolated population. This is known as ‘genetic drift’ (Image: Wikimedia Commons)

Random bead sampling experiments show how certain forms of a gene can become quickly widespread in a few generations in a small isolated population. This is known as ‘genetic drift’ (Image: Wikimedia Commons)

These small populations of cave fish were likely founded from only a few individuals.  We could anticipate that neutral mutations present in these founders would become widespread in the population by chance.  However these cave fish have evolved separately multiple times.  If the loss of eyes and skin pigment were a random, neutral process, we could expect some of these populations to have retained their sight and colour.  Also the PAX6 gene, used to build eyes in nearly all animals, is present and working in these fish.

Another possibility is energy conservation.  Eyes are costly to build and maintain, so disposing of them in this energy-poor environment seems a sensible option.  This however doesn’t fit the facts.  Eye cups are present in day-old embryos.  By day two, the lens cells are beginning to grow and divide, but in these cave fish a process of deliberate ‘cell death’ destroys them as they arise.  This strategy seems neither neutral nor particularly economic.

So what is really driving the evolution of these pale, sightless and sleepless fish?  Genetic studies are providing some alternative answers that shine light into how evolution really works.

Why do cave fish kill off their own eyes? 

A cross-section of a mouse eye showing the PAX6 protein, visible here in green thanks to a fluorescent  tag.   PAX6 is a transcription factor; a protein that controls the actions of many other genes.  Its biological role is to define which cells develop into eyes in all vertebrate embryos.   The PAX6 gene functions in the Mexican blind cave fish, but works at less intensity than in sighted fish.   Cave fish eyes develop normally for the first 2 days in the embryo, then stop growing, and the cells degenerate.  These fish appear eyeless because other tissues expand and cover what remains of the eye cups (Image: Wikimedia Commons)

A cross-section of a mouse eye showing the PAX6 protein, visible here in green thanks to a fluorescent tag. PAX6 is a transcription factor; a protein that controls the actions of many other genes. Its biological role is... more to define which cells develop into eyes in all vertebrate embryos. The PAX6 gene functions in the Mexican blind cave fish, but works at less intensity than in sighted fish. Cave fish eyes develop normally for the first 2 days in the embryo, then stop growing, and the cells degenerate. These fish appear eyeless because other tissues expand and cover what remains of the eye cups (Image: Wikimedia Commons)

The PAX gene plays a key role in the development of eyes in vertebrate embryos.  PAX6 action is reduced by increases in the activity of another gene, called HEDGEHOG whichdefines boundaries between cell types and promotes development of the fish’s lateral line, jaws, teeth and taste buds.  HEDGEHOG is more active in cave fish embryos than in their sighted sister species, causing the lateral line cell zone and the jaw to expand.  As it does so, this also switches off PAX6 and halts eye development.

This trade-off between ‘touch and taste’ versus ‘sight’ enhances the very senses that the cave fish needs in its ever-dark world.  Eye shrinkage, which reduces the energy budget, is a secondary effect of selection for these other senses.  This subtle change in the key interaction of two developmental genes  at a critical stage can radically alter a gene’s effect and the body which results.

What does enhanced touch sensitivity provide for these fish?

Try stroking your eyebrow against the direction of hair growth. Now stroke your forehead. Which feels like a stronger movement?

A school of sardines shoaling together with precise coordination.   Fish have an awareness of space that is provided by their lateral line system.  This sensory mode is able to pick up changes in turbulence around rocks and other obstacles, and to detect the movements of other fish.  This is how shoals are able to swim together without colliding (Image: Wikimedia Commons)

A school of sardines shoaling together with precise coordination.Fish have an awareness of space that is provided by their lateral line system. This sensory mode is able to pick up changes in turbulence around rocks and... more other obstacles, and to detect the movements of other fish. This is how shoals are able to swim together without colliding (Image: Wikimedia Commons)

Hairs in our skin enable us to be more sensitive to touch.  The Mexican blind cave fish have a lateral line systemlike all fish.  All lateral line systems use tiny hair cells to detect changes in water movement, but in these cave dwellers it is unusually sensitive.

These fish also have a behaviour which seems counter-intuitive.  If introduced into a new environment, instead of slowing down and moving cautiously, they swim faster.  The reason is that more rapid movements increase the flow of information to the hair cells.  This expands their awareness, providing a larger ‘hydrodynamic image’ of their world.  Also at greater speeds, the water layer that clings to their skin is reduced, helping to make this image ‘sharper’.

Why are cave fish so pale?

Cave animals typically lose their colour and cease to develop eyes, like this Texas Blind Salamander (Eurycea rathbuni).   Cave ecosystems have limited air exchange with above ground.  Often the air is low in oxygen.   This film clip shows the salamander’s external gills, a juvenile characteristic retained here in the adult form in order to capture enough oxygen gas (Image: Wikimedia Commons)

Cave animals typically lose their colour and cease to develop eyes, like this Texas Blind Salamander (Eurycea rathbuni). Cave ecosystems have limited air exchange with above ground. Often the air is low in oxygen. This ... morefilm clip shows the salamander’s external gills, a juvenile characteristic retained here in the adult form in order to capture enough oxygen gas (Image: Wikimedia Commons)

The melanin-based pigments in our skin and those of other animals provide colour and pattern, but they have a more ancient evolutionary role: to  protect us from damage by ultraviolet light.  Without sunlight, cave animals typically are colourless.  In Mexican cave fish this is connected to a loss-of-function mutation (in the gene oca2), controlling the first step of pigment production.

Independently evolved populations of cave fish are colourless thanks to unique mutations in this same gene.  This is curious.  If pigment loss occurred by chance, we would expect that some populations would have shut down later stages of pigment production, as this would give the same effect.  This specific mutation suggests instead that pigment loss has been actively selected.

Pigment loss may conserve energy, and it is possible that mutating the genes controlling later biosynthetic stages may have other effects that reduce fitness.  However a more compelling explanation is that shutting down oca2 increases the availability of tyrosine, an amino acid.  What is so special about tyrosine?

Panellus stipticus is a fungus that grows on dead wood. The bioluminescent strain is nicknamed "glow wood" (Image: Wikimedia Commons)

Panellus stipticus is a fungus that grows on dead wood. The bioluminescent strain is nicknamed “glow wood” (Image: Wikimedia Commons)

Neurotransmitter production depends upon the tyrosine supply.  The fish produces the neurotransmitters dopamine and noradrenaline (norepinephrine), and the hormone adrenaline (epinephrine), from tyrosine.  Cavefish brains have higher concentrations of these chemicals than brains of sighted fish.  Noradrenaline and adrenaline provoke the ‘fight or flight response; in these fish they are linked to the minimal amounts of sleep and the ability to engage in unusually fast foraging.

Adaptation to life in caves has produced a range of animals with some remarkably similar characteristics.  It seems that Mexico’s cave fish have made an evolutionary trade-off.  Faster swimming and an enhanced sensitivity to touch and taste comes at the cost of eyes and skin colour.  And it keeps them awake in the dark.

Text copyright © 2015 Mags Leighton. All rights reserved.

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