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

08/12/2014 |

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
Collins, S.M. and Bercik, P. (2013)  Intestinal bacteria influence brain activity in healthy humans.  Nature Reviews Gastroenterology & Herpetology 10, 326-327.
Cryan, J.F. and Dinan, T.G. (2012)  Mind-altering micro-organisms; the impact of the gut microbiota on brain and behaviour.  Nature Reviews Neuroscience 13, 701-712.
David, L.A. et al. (2014)  Diet rapidly and reproducibly alters the gut microbiome.  Nature 505, 559-566.
Diamond, B. et al. (2011)  It takes guts to grow a brain.  Bioessays 33, 588-591.
Faith, J.J. et al. (2011)  Predicting a human gut microbiota's response to diet in gnotobiotic mice.  Science 333, 101-104.
Forsythe, P. et al. (2010)  Mood and gut feelings.  Brain, Behaviour and Immunity 24, 9-16.
Frank, D.N. and Pace, N.R. (2008)  Gastrointestinal microbiology enters the metagenomics era.  Current Opinion in Gastroenterology 24, 4-10.
Heijtz, R.D. et al. (2011)  Normal gut microbiota modulates brain development and behaviour.  Proceedings of the National Academy of Sciences, USA 108, 3047–3052.
Jahan-Mihan, A. (2011)  Dietary proteins as determinants of metabolic and physiologic functions of the gastrointestinal tract.  Nutrients 3, 574-603.
Kurokawa. K. et al. (2007)  Comparative metagenomics reveals commonly enriched gene sets in human gut microbiomes.  DNA Research 14, 169-181.
Lee, W.J. and Brey, P.T. (2013)  How microbes influence metazoan development: insights from history and Drosophila modelling of gut-microbe interactions.  Annual Review of Cell and Developmental Biology 29, 571-592.
Lee, W.J. and Hase, K. (2014)  Gut microbiota-generated metabolites in animal health and disease.  Nature Chemical Biology 10, 416-424.
Lyer, L.M. et al. (2004)  Evolution of cell-cell signalling in animals: did late horizontal gene transfer from bacteria have a role?  Trends in Genetics 20, 292-299.
Messaoudi, M.et al. (2011)  Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.  British Journal of Nutrition 105,755-764.
Montiel-Castro, A.J. et al. (2013)  The microbiota-gut-brain axis: neurobehavioural correlates, health and sociality.  Frontiers in Integrative Neuroscience 7, article 70.
O’Hara, A.M. and Shanahan, F. (2006)  The gut flora as a forgotten organ.  EMBO Reports 7, 688-693.
Randal Bollinger, R. et al. (2007)  Biofilms in the large bowel suggest an apparent function of the human vermiform appendix.  Journal of Theoretical Biology 249, 826-831.
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Riddles in code; is there a gene for language?

07/09/2014 |

‘I have…’

Words are like genes; on their own they are not very powerful.  But apply them with others in the right phrase, at the right time and with the right emphasis, and they can change everything.

‘I have a dream…’

Genes are coded information.  They are like the words of a language, and can be combined into a story which tells us who we are.

The stories we choose to tell are powerful; they can change who we become, and also change the people with whom we share them.

‘I have a dream today!’

Language is a means for coding and passing on information, but it is cultural, and definitely non-genetic.  Nevertheless, for our speech capacity to have evolved, our ancestors must have had a body equipped to make speech sounds, along with the mental capacity to generate and process this language ‘behaviour’.  Our body’s development is orchestrated through the actions of relevant genes.  If the physical aspects of language ultimately have a genetic basis, this implies that speech must derive, at least in part, from the actions of our genes.

The hunt for genes involved with language led researchers at the University of Oxford to investigate an extended family (known as family KE).  Some family members had problems with their speech.  The pattern of their symptoms suggested that they inherited these difficulties as a ‘dominant’ character, and through a single gene locus.

The FoxP2 gene encodes for the ‘Forkhead-Box Protein-2’; a transcription factor. This is a type of protein that interacts with DNA (shown here as a pair of brown spiral ladders), and influences which genes are turned on in the cell, and which remain silent. This diagram shows two Forkhead box proteins, which associate with each other when active. This bends the DNA strand and makes critical areas of the genetic code more accessible (Image: Wikimedia Commons)

The FOXP2 gene encodes for the ‘Forkhead-Box Protein-2’; a transcription factor. This is a type of protein that interacts with DNA (shown here as a pair of brown spiral ladders), and influences which genes are turne... mored on in the cell, and which remain silent. This diagram shows two Forkhead box proteins, which associate with each other when active. This bends the DNA strand and makes critical areas of the genetic code more accessible (Image: Wikimedia Commons)

Discovery of another unrelated patient with the same symptoms confirmed that the condition was linked to a gene known as FOXP2  (short for ‘Forkhead Box Protein-2’).  This locus encodes a ‘transcription factor’; a protein that influences the activation of many other genes.  FOXP2 was subsequently dubbed ‘the gene for language’.  Is that correct?

Not really.  FOXP2 affects a range of processes, not just speech.  The mutation which inactivates the gene causes difficulties in controlling muscles of the face and tongue, problems with compiling words into sentences, and a reduced understanding of language.  Neuroimaging studies showed that these patients have reduced nerve activity in the basal ganglia  region of the brain.  Their symptoms are similar to some of the problems seen in patients with debilitating diseases such as Parkinson’s and Broca’s Aphasia; these conditions also show impairment of the basal ganglia.

Genes code for proteins by using a 3-letter alphabet of adenine, thymine, guanine and cytosine (abbreviated to A, T, G and C). These nucletodes are knwn as ‘bases’ (are alkaline in solution) and make matched pairs which form the ‘rungs of the ladder’ of the DNA helix. Substituting one base for another (as happens in many mutations) can change the amino acid sequence of the protein a gene encodes. Changes may make no impact on survival, allowing the DNA sequence to alter over time. Changes that affect critical sections of the protein (e.g. an enzyme’s active site), or critical proteins like FoxP2, are rare (Image: Wikimedia Commons)

Genes code for proteins by using a 3-letter alphabet of adenine, thymine, guanine and cytosine (abbreviated to A, T, G and C). These nucletodes are knwn as ‘bases’ (are alkaline in solution) and make matched pairs w... morehich form the ‘rungs of the ladder’ of the DNA helix. Substituting one base for another (as happens in many mutations) can change the amino acid sequence of the protein a gene encodes. Changes may make no impact on survival, allowing the DNA sequence to alter over time. Changes that affect critical sections of the protein (e.g. an enzyme’s active site), or critical proteins like FOXP2, are rare (Image: Wikimedia Commons)

Genes provide the code to build proteins.  Proteins are assembled from this coding template (the famous triplets) as a sequence of amino acids, strung together initially like the carriages of a train and then folded into their finished form.  The amino acid sequences of the FOXP2 protein show very few differences across all vertebrate groups.  This strong conservation of sequence suggests that this protein fulfils critical roles for these organisms.  In mice, chimpanzees and birds, FOXP2 has been shown to be required for the healthy development of the brain and lungs.  Reduced levels of the protein affect motor skills learning in mice and vocal imitation in song birds.

The human and chimpanzee forms of FOXP2 protein differ by only two amino acids. We also share one of these changes with bats.  Not only that, but there is only one amino acid difference between FOXP2 from chimpanzees and mice.  These differences might look trivial but they are probably significant.  FOXP2 has evolved faster in bats than any other mammal, hinting at a possible role for this protein in echolocation.

Mouse brain slice, showing neurons from the somatosensory cortex (20X magnification) producing green fluorescent protein (GFP). Projections (dendrites) extend upwards towards the pial surface from the teardrop-shaped cell bodies. Humanised Foxp2 in mice causes longer dendrites to form on specific brain nerve cells, lengthens the recovery time needed by some neurons after firing, and increases the readiness of these neurons to make new connections with other nerves (synaptic plasticity). The degree of synaptic plasticity indicates how efficiently neurons code and process information (Image: Wikimedia Commons)

Mouse brain slice, showing neurons from the somatosensory cortex (20X magnification) producing green fluorescent protein (GFP). Projections (dendrites) extend upwards towards the pial surface from the teardrop-shaped ce... morell bodies. Humanised Foxp2 in mice causes longer dendrites to form on specific brain nerve cells, lengthens the recovery time needed by some neurons after firing, and increases the readiness of these neurons to make new connections with other nerves (synaptic plasticity). The degree of synaptic plasticity indicates how efficiently neurons code and process information (Image: Wikimedia Commons)

Changing the form of mouse FOXP2 to include these two human-associated amino acids alters the pitch of these animals’ ultrasonic calls, and affects their degree of inquisitive behaviour.  Differences also appear in their neural anatomy.  Altering the number of working copies (the genetic ‘dose’) of FOXP2 in mice and birds affects the development of their basal ganglia.

Mice with ‘humanised’ FOXP2 protein show changes in their cortico-basal ganglia circuits along with altered exploratory behaviour and reduced levels of dopamine (a neurotransmitter  that affects our emotional responses).  So too, human patients with damage to the basal ganglia show reduced levels of initiative and motivation for tasks.

This suggests that FOXP2 is part of a general mechanism that affects our thinking, particularly around our initiative and mental flexibility.  These are critical components of human creativity, and are as it happens, essential for our speech.

Basal ganglia circuits process and organise signals from other parts of the brain into sequences.  Speaking involves coordinating a complex sequence of muscle actions in the mouth and throat, and synchronising these with the out-breath.  We use these same muscles and anatomical structures to breathe, chew and swallow;  our ability to coordinate them affects our speech, although this is not their primary role.

Family KE’s condition, caused by a dominant mutation in the FoxP2 gene, follows an autosomal (not sex-linked) pattern of inheritance, as shown here. Dominant mutations are visible when only one gene copy is present. In contrast a recessive trait is not seen in the organism unless both chromosomes of the pair carry the mutant form of the gene. The FoxP2 transcription factor protein is required in precise amounts for normal function of the brain. The loss of one working FoxP2 gene copy reduces this ‘dose’ which is enough to cause the problems that emerged as family KE’s symptoms (Image: Annotated from Wikimedia Commons)

Family KE’s condition, caused by a dominant mutation in the FOXP2 gene, follows an autosomal (not sex-linked) pattern of inheritance, as shown here.Dominant mutations are visible when only one gene copy is present. In... more contrast a recessive trait is not seen in the organism unless both chromosomes of the pair carry the mutant form of the gene. The FOXP2 transcription factor protein is required in precise amounts for normal function of the brain. The loss of one working FOXP2 gene copy reduces this ‘dose’ which is enough to cause the problems that emerged as family KE’s symptoms (Image: Annotated from Wikimedia Commons)

In practice, very few of our 25,000 genes are individually responsible for noticeable characteristics.  Most genetically inherited diseases result from the effects of multiple gene loci.  FOXP2 is unusual because of its ‘dominant’ genetic character.  It does not give us our language abilities, but it is involved in the neural basis of our mental flexibility and agility at controlling the muscles of our mouths, throats and fingers.

In addition, genes are only part of the story of our development.  The way we think and subsequently behave alters our emotional state.  Feeling stressed or calm affects which circuits are active in our brain.  This alters the biochemical state of body organs and tissues, particularly of the immune system, modifying which genes they are using.

The dance between the code stored in our genes and the consequences of our thoughts builds us into what we are mentally, physically and socially.  This story is ours to tell.  By our experience, and with this genetic vocabulary, we create what we become.

Text copyright © 2015 Mags Leighton. All rights reserved.

References
Chial H (2008)  ‘Rare genetic disorders: Learning about genetic disease through gene mapping, SNPs, and microarray data’ Nature Education 1(1):192  http://www.nature.com/scitable/topicpage/rare-genetic-disorders-learning-about-genetic-disease-979
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