Gut Microbiome Presentation

Advances in understanding of the

Gut Microbiome and its Relation

To Psychiatric Disorders of the Brain

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Aims and objectives

• To give an overview of the Gut Microbiome• Discuss the Gut/Brain axis and how Gut

microbes affect CNS function and development

• Discuss Gut microbiota links to several cognitive diseases

• Discuss current and potential treatment aimed at the gut microbiome for mental disorders

What is the Gut Microbiome

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The infant gut is dominated by Bifidobacteria, a fermentative class of Actinobacteria, and doesn’t reach adult like composition until the age of 3.

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 Tract”(MetaHIT).

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 microbiota composition.

• 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 and Escherichia-Coli

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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 more fermentable carbohydrates in the diet cause the gut microbes to increase their fermentative metabolism and increase fatty acids and lactic acids in the gut which led to anxiety and aggression in the rat.

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Germ Free Studies in Mice

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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 caged mouse.

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?

Schizophrenia

• 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.

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Depression

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• Figure 6 represents the bi-directional gut-brain 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 microbiome composition.

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Autism

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This diagram shows that increased virulence producing bacteria in the gut that overwhelms the commensal bacteria can lead to inflammatory immune responses. 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 children.

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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

• 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.

References• 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, Molecular

Psychiatry.• 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

05/02/2015)• 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 06/02/2015)• Figure 11- Gut and Psychology Syndrome book, (2014), www.amazon.co.uk• Finegold, SM. (2011), Desulfovibrio species are potentially important in regressive autism, Medical

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

References• Han, YW. et al (2006) Fusobacterium nucleatum induces premature and term

stillbirths in pregnant mice: implication of oral bacteria in preterm birth, Infectious Immunity, 72, 2272

• Li, W., Dowd, SE., Scurlock, B., Acosta-Martinez, V. and Lyte, M. (2008) Memory and Learning behaviour in mice is termporarally associated with diet-induced alterations in gut bacteria, Gastroenterology, 96, 557-567

• Lyte, M. and Ernst, S. (1992) Catecholamine induced growth of gram negative bacteria, Life Sciences, 50, 203-212

• Mueller, NT., Bakacs, E., Combellick,J., Grigoryan, Z. and Dominquez-Bello, MG. (2014) The infant Microbiome development: Mom matters, Trends in Molecular Medicine, 14, 1471-4914

• Neufeld, KM., Kang, N., Bienenstock, J. and Foster, JA. (2010) Reduced anxiety-like behaviour and central neurochemical change in germ-free mice, Neurogastroenterology and Motility, 3, 255

• O, Mahony, SM., Marchesi, JR., Scully, P., Codling, C., Ceolho, AM., Quigley, EMM., Cryan, JF. And Dinan, TG. (2009) Early life stress alters behaviour, immunity and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses, Biological Psychiatry, 65, 263-267

• O, Mahony, SM., Hyland, NP., Dinan, TG., Cryan, JF., (2011) Maternal Seperation as a model of brain-gut axis dysfunction, Psychopharmacology, 214, 71-88

References• Park, AJ., Collins, J., Blennerhassett, PA. et al (2013) Altered colonic function and

microbiota profile in a mouse model of chronic depression, Neurogastroenterol motility

• Robinson, EB., Munir, K., Munafo, MR., Hughes,M., McCormick, MC. and Koenen, KC. (2011) Stability of autistic traits in the general population: further evidence for a continuum of impairment, Journal of the American Academy of Child and Adolescent Psychiatry, 50, 376-384

• Santos, J., Yang, PC., Derholm, JD., Benjamin, M. and Perdue, MH. (2001) Role of mast cells in chronic stress induced colonic epithelial barrier dysfunction in the rat, Gut, 48,630

• Severance, EG., Alaedini, A., Yang, S., Halling, M., Gressitt, KL., Stallings, CR. et al (2012) Gastrointestinal inflammation and associated immune activation in schizophrenia, Schizophrenia Research, 138, 48-53

• Song, X., Fan, X., Song, J., Zhang, W., Zhang, X., et al (2013) Elevated levels of adiponectin and other cytokines in drug naiive first episode schizophrenia patients with normal weight, Schizophrenia, 150, 269-273

• Sudo, N., Chida, Y., Aiba, Y., Sonoda, J., Oyama, N., Yu, XN., et al (2004) Postnatal microbial colonization programmes the hypothalamic-pituitary-adrenal system for stress response in mice, Journal of Physiology, 558, 263-275