The human microbiome encompasses all sites on and within the human body inhabited by microorganisms. This includes the nasal cavities, skin, urogenital tract and the gut. Colonization of an initially sterile gut begins at birth when the foetus is colonized mainly by the bifidobacterium species. The source of this colonization is unclear, however Mueller et al (2014) believe it’s Maternal to offspring exchange of microbiota. Disrupting this transmission by undergoing birth methods such as C-section and taking prenatal antibiotics could increase the risk of asthma, coeliac disease, type 1 diabetes and obesity. It was originally believed that the intrauterine environment was free of microbes but Han et al (2006) and Bearfield (2002) found microbes in umbilical cord blood, foetal membranes and the placenta. So how is the gut microbiome related to the brain?
This relationship between the brain and the gut is known as the gut-brain axis and it describes how the brain affects the gut and vice versa. This is known as a bi directional communication system. Santos et al in 2001 supported this gut brain link saying that cognitive stress disrupted the gut epithelial lining and activated mast cells which would release histamine and increase inflammation and leakiness of the gut epithelium. Childhood stress, emulated by maternal seperation studies done on mice, increase corticosterone levels and change the fecal and gut microbes by releasing the hormone noradrenalline. Noradrenalline, Dopamine and its precursor L-Dopa are all present in abnormal amounts during stress and in physiactric disorders. When they are present in these abnormal amounts they also increase the growth of gut microbes Clostridium Jejuni, E-coli, and Yersinia Enterocolitica.
The gut microbiota is heavily influenced by diet and certain foods even affect behaviour and neural activity, (think of high sugar levels causing hyperactivity in children). 10¹² microorganisms in the gut are close to enteric nerves, so changes in gut microflora could be detected by the enteric nerves and relayed to the CNS. Li, Dowd and Surlock et al (2008) fed 5 week old mice either a pellet powder diet, chow mix or beef supplemented diet for 3 weeks and observed their behaviour over time. Using an ARISA test to see the composition of the microbiota in the gut they found that the beef fed mice had a higher gut microbe diversity and even had 12 bacteria species completely unique to the beef diet compared to the pellet diet with only 3 unique species. So diet and nutrient intake does affect composition. They also tested the mice working memory and reference memory for 1 week and found that the beef fed mice performed better in memory tasks than the pellet fed mice, so, according to this study, higher gut microbe diversity can improve cognition.
One interesting way to study the gut microbiota is to compare normal mice to germ free mice. These are mice that are not naturally colonized by microbes at birth, generally they are born by c-section. Mark lyte et al ((1998) gave a small dose, not enough to produce an immune response, of Campylobacter Jejuni to germ free lab mice. They were then introduced to a maze set up and they became more anxious than normally colonized mice about going into exposed areas of the maze. In 2013, Desbonnet et al tested germ free mice, with no commensal bacteria, sociability skills and they showed characteristic autism and schizoprenic like tendencies, such as repetition and social anxiety. He saw this behaviour in a test with a 3 chamber set up, 1 empty, 1 with a cage and 1 with a caged mouse. Normal mice spent time with the caged mouse but germ free mice preferred the empty chambers. When the germ free mice were colonised with bacteria they switched to becoming social with the caged mouse. So according to this study, gut microbe composition does affect social behaviour, at least in mice. But how is this related to cognitive disorders?
Premature delivery could be one of the major risk factors for children developing schizophrenia. Robinson (2011) found that premature children born 2-3 weeks before term in china and brazil and by c-section had social withdrawal in early years and early onset of schizophrenia. They had low bifidobacterium and bacteriodes but high clostridium difficil compared to vaginally born babies. C difficil is commonly associated with bad side effects when it is in an abnormally high amount. Schizophrenia has been associated with high C-diff and high amounts of the phenylalanine it makes. Germ free animals have been seen to have less Brain derived Neurotropic Factor (BDNF) used for brain plasticity and memory. This is also seen in schizophrenics, so the imbalance in the gut microbiota could be causing certain schizophrenic symptoms. Lack of gut microbiota also triggers lymphocyte accumulation in the gut and affects the balance of pro inflammatory cytokine IL-8 and IL-1 and anti inflammatory cytokines IL-10 and TGF-Beta. This lack of microbes and elevated pro inflammatory cytokines is commonly seen in schizophrenia. Schizophrenics also commonly suffer more from metabolic syndromes and anti0psychotics often lead to weight gain. This could be due to changes within the gut microbiome, such as the firmicutes bacteria increasing and good bacteriodes decreasing. They also have more antibodies against their own commensal Saccharomyces Cerevisiae and bacterial translocation and intestinal inflammation is increased in schizophrenia as is food antigen sensitivity. However the structure of the microbiome in a schizophrenic patient is not fully known.
Depression is a disorder with many co-morbidities, such as Irritable Bowel Syndrome (an example of the importance of the gut). As the diagram shows the bi-directional communication between the gut and the brain involves more ACTH and impaired negative feedback to the Adrenal cortex. This then enlarges and leads to more pro inflammatory cytokines disrupting the gut epithelium permeability and gut microbe composition. Depressed patients have overactive Hypothalamic-pituitary-adrenal systems (HPA) wit hmore cortisol in plasma. Sudo et al (2004) demonstrated that germ free mice have overactive HPA systems in response to stress. This is reversed if Bifidobacterium infantis, normally in the infant gut, is introduced. Park et al in 2013 tried to prove the gut-brain link by showing that mice who had olfactory bulbs removed had altered gut microbiota leading to depression symptoms and endocrine changes. They acted differently as opposed to sham operated mice and exhibited prolonged immobility in a tail suspension test and behavioural despair. The test is based on the premise that mice subjected to short term inescapable stress with eventually develop an immobile posture and give up. Bulbectomised and sham operated mice had only 49% similarity in gut microbe composition and this was due to changes in proportions of certain species rather than dissapearance of numbers. So redistribution, not disapearance, of gut microbes could be related to depression.
Autism spectrum disorders are neurodevelopmental disorders with behavioural symptoms such as communication defects, dependency on routine, sensitivity to environment changes and inappropriate focus on items. Finegold in 2011 published findings showing increased desulfovibrio and bacteriodes Vulgates in autistic cildren compared to controls. Vulgatis is a known producer of Proprionic acid which has been shown to produce pathologic changes in the brains of rats. These bacteriodes that produce the acid cause symptoms characteristic of Autism. Anouther study by Finegold showed that Bifidobacterium levels were decreased in autistic people and when its introduced to the bacteriodes Vulgatis and Desulfovibrio normally found in autism cases it inhibited them. So the decrease of Bifidobacterium could be the catalyst for autism onset. As we have seen gut microbes have a systemic effect on the whole body so changes in the gut microbiome can lead to regressive autism by changing gut permeability via inflammatory cytokines. Under normal conditions gut permeability is small enough to reduce proprionic acid from entering the blood and brain from the gut. But in autism the increased inflammation cause gut permeability which allows the pro inflammatory cytokines to pass the blood brain barrier and inflame the brain causing symptoms of autism. This is shown in the diagram where its demonstrated that increased virulent bacteria lead to immune responses. If this becomes chronic, gut epithelium becomes leaky, allowing bacteria into the blood. They then release proprionic acid and inflammatory cytokines into the blood. The cytokine infiltration into the brain develops slowly and takes time to accumulate due to the large size of the brain and limited diffusion through tight junctions. In autism IL-1 beta builds up, however if the gut microbe composition is returned to normal, IL-1 beta returns to healthy amount. A study in 2014 by Dr Natasha Mcbride notice that autistic people commonly had GI problems such as leaky gut and IBD’s. Her gut physiology syndrome nutritional programme aims to stop gut flora entering the blood and the brain.
Gut Microbiome Presentation
Fig 1- genomicenterprise.com-
Aims and objectives
• To give an overview of the Gut Microbiome
• Discuss the Gut/Brain axis and how Gut
microbes affect CNS function and
• Discuss Gut microbiota links to several
• Discuss current and potential treatment aimed
at the gut microbiome for mental disorders
What is the Gut Microbiome
Fig 2- www.broadinstitute .org
The infant gut is dominated by
Bifidobacteria, a fermentative class
of Actinobacteria, and doesn’t reach
adult like composition until the age
The Gut microorganisms were once considered to merely commensals, but we now
know they play an important role in early development and predisposition to
disease. The recognition that Human Gut Microbes function as Mutualists spawned
two major projects; one in the US called the “Human Microbiome Project” and one
supported by Europe called “Metagenomics of the Human Intestinal
The Gut-Brain Axis
• How does the Brain affect the Gut Microbiome?
• This relationship is bi-directional, gut microbiota
can affect the brain and the brain affects gut
• Cognitive stress affects mucous secretion in the
GI tract by the release of Noradrenaline which
may stimulate growth of specific Microbes,
changing the gut microbiome.
• Santos et al (2001) looked at maternal separation
in mice in order to study childhood stress and
found that the early stress changed faecal
microbiota and gut microbiota composition by
the release of Noradrenaline. It produced an
increase in the gut microbes; Clostridium Jejuni
How Gut Microbiota affect CNS
function and Neurodevelopment
• Gut microbiota
composition is largely
influenced by dietary
factors, and these can
affect neuron activity
in the CNS.
• Rat studies show that
carbohydrates in the
diet cause the gut
microbes to increase
increase fatty acids and
lactic acids in the gut
which led to anxiety
and aggression in the
Germ Free Studies in Mice
Desbonnet et al (2013) conducted a
study on the sociability of mice raised in
bacteria free environments. They showed
behaviour similar to autism
characteristics such as social anxiety.
Germ free mice raised in bacteria free
environments preferred the empty
chamber in this three maze set up,
whereas normal mice colonized by
normal microbiota spent time with the
When the germ free mice were exposed
to and colonized with commensal
bacteria they became more social with
the caged mouse.
So How Are Gut Microbiota Related
To Social And Cognitive Disorders?
• Lack of microbiota and elevated pro-
inflammatory cytokines is seen in
schizophrenic patients compared to controls.
(Francesconi et al., 2011, and Song et al., 2013)
• Side effects associated with Schizophrenia
such as metabolic syndrome and autoimmune
disorders could be attributed to changes in
microbiota. However no theories are proven.
Fig 6- www.deviantart.com
• Figure 6 represents the bi-
communication axis, showing
increased ACTH, which is often seen
in abnormal levels in depression.
• It also shows impaired negative
feedback to the adrenal cortex so
this enlarges and produces more
cortisol, leading to pro-
inflammatory cytokines which then
disrupt the GI tract and alters
This diagram shows that increased virulence
producing bacteria in the gut that overwhelms the
commensal bacteria can lead to inflammatory
This then makes the gut epithelium permeable and
allows pro-inflammatory cytokines to permeate the
blood-brain barrier and accumulate in the brain.
This sequence of events is seen often in autistic
Dr McBride conducted a
large study on autistic
people in 2014 and found
that they commonly had
unusually permeable gut
epithelia and imbalances
in gut microbes.
Where is research heading in the
• Future research aims to understand exactly how the Microbiome
exerts its affects on the brain.
• Also the aim is to find out whether cognitive disorders can be
treated by therapies that are aimed primarily at the gut
microbiome. This could get passed the problem of getting drugs
past the blood brain barrier.
• To target the newborns microbiome, babies born by c-section in
Europe and Canada are currently being given vaginal lavages so
they get a dose of the mothers microbiome.
• Heat killed bacteria treatments for stress and depression are
currently being developed by the department of Integrative
physiology in the university of the colarado boulder.
• Very early studies are currently being investigated in germ free mice
and Alzheimers diseases and Parkinson’s.
• Bearfield, C. et al (2002) Possible association between amniotic fluid microorganism infection and
Microflora in the mouth, BJOG, 109, 527
• Borthwick, L. (2015) Can Microbes in the Gut influence the Brain, The Kavli Foundation
• Desbonnet, L. et al (2013) Cognition and Behaviour: Bacteria make germ free mice social,
• Figure 1, The Human Microbiom Project, (2012), www.ondineblog.com (accessed on 27/01/2015)
• Figure 2, What’s in your Gut?, (2013), www.broadinstitute.org (accessed on 25/01/2015)
• Figure 3, Eat yourself smart, (2013), changinghabits.com (accessed on 03/02/2015)
• Figure 4, Lacto Bacto, (2014), lactobacto.com (accessed on 11/03/2015)
• Figure 5, Germ free mice and social behaviour, (2013), sfari.org (accessed on 03/02/2015)
• Figure 6, Schizophrenia, (2007), www.deviantart.com (accessed on 11/03/2015)
• Figure 7, Causes of Schizophrenia, (2015), www.hindustanlink.com (accessed on 04/02/2015)
• Figure 8, Bi-directional gut-brain communication, (2013), onlinelibrary.wiley.com (accessed on
• Figure 9, Mouse suspension test, (2013), www.bioseb.com (accessed on 03/02/2015)
• Figure 10, Gut microbiom upset and autism,(2014), www.sciencedirect.com (accessed on
• Figure 11- Gut and Psychology Syndrome book, (2014), www.amazon.co.uk
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Hypotheses, 77, 270
• Francesconi, LP., Cereser, KM., Mascarenhas, R., Stertz, L., Ganna, CS., Belmonte-de-abreu, P.
(2011) Increased annexin-v and decreased TNF alpha serum levels in chronic-medicated patients
with Schizophrenia, Neuroscience, 3, 143-146
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