MOOD AND GUT FEELINGS - CRAAQ · 2015-11-05 · depression (29 active- MDD and 17 responded-MDD) and 30 healthy controls, as well as increased bacterial diversity in the active depression

MOOD AND GUT

FEELINGS

VH Taylor MD PhD FRCPC

Psychiatrist-in-Chief, and Senior Scientist

Woman’s College Hospital

Chief, Adult Health Systems, CAMH

Associate Professor, University of Toronto

Disclosure

• Proctor and Gamble

What was old is new again

‘The control of man’s diet is readily accomplished, but mastery over his intestinal bacterial flora is not…the innumerable examples of autointoxication that one sees in his daily walks in life is proof thereof. They are the cases that present…malaise, total lack of ambition so that every effort in life is a burden, mental depression often bordering upon melancholia, frequent attacks of indefinite abdominal pains due to flatulency, sudden attacks of acute diarrhea alternating with periods of constipation…A battle royal must be fought and when this first great struggle ends in victory for the Bacillus bulgaricus it must be kept on the field of battle forever at guard…’

Bond Stow, M.D., on autointoxication and Lactobacillus bulgaricus – Medical Record Journal of Medicine and Surgery, 1914

Summer 2012 Workshop in Biology and Multimedia for High School Teachers

A gut-brain history

• A leading proponent of autointoxication was Metchnikoff, who hypothesized that intestinal toxins shortened lifespan.

• The toxic process, however, was reversed by the consumption of lactic acid-producing bacteria that changed the colonic microflora and prevented proteolysis.

• The next logical step in treatment followed in the early 20th century when surgeons, chief among them Sir W. Arbuthnot Lane, performed colectomy to cure intestinal autointoxication

Surgery for Schizophrenia

Bidirectional Communication between gut microbes and the brain

Dinan et al Journal of Psychiatric Research 2015 63, 1-9

Strategies used to investigate the role of the Microbiota gut-brain-access in disease

What neurotransmitters can be produced by microbes?

• Norepinephrine: Escherichia, Bacillus, andSaaccharomyces

• Serotonin: Candida, Streptococcus, Escherichia, and Enterococcus

• Dopamine: Bacillus and Serratia

• Acetylcholine: Lactobacillus

Lyte M, Bioessays 2011;33:574-81, Lyte M PLoS Patyhog 2013;9. Wikoff WR et al. PNAS;2009:106:3698-703

What neurotransmitters can be modulated by bacteria?

• Lactobacillus acidophilus strain modulates expression of cannabinoid receptors in the

gut epithelium

• Bif. Infantis increases plasma tryptophan levels and thereby modulates 5HT

• Lactobacillus rhamnosus and Bifidobacteriumalters central GABA receptor expression

Rousseaux C. Nat Med. 200;13:35-7.

Functional Overlap Between Neurotransmitter Systems: Features of

Depression

Adapted from Stahl SM, Stahl’s Essential Psychopharmacology, Third Edition, Cambridge University Press, 2008.

Role of Serotonin

• Improved mood and reduced anxiety

• Attention, drive regulation, reduces distractibility

• Modulates pain, sleep and appetite

Altered CNS Serotenergic Function

Clarke et al, 2013, Mol Psychiatry;18:666-73, Desbonnet, 2008)

- No altered expression of Tph2 gene

- No alteration in the serotonin transportergene or other serotoningenes studied

An earlier study reported increases in tryptophan levels inrats treated with B. infantis 35624. (Desbonnet 2008 )

Microbes and neurotransmission

Sakata K.Austin J Pharmacol Ther. 2014;2(1): 1006

Role of BDNF

BDNF

• Sudo et al 2004 GF mice have decreased BDNF in the hippocampus and cortex

• Neufeld et al showed a down regulation in BDNF mRNA in the hippocampus of GF mice

Sudo et al, 2004;J of Physiology:558;263-275, Neufeld et al, 2011. NeurogastroenterolMotil;23:255-64. Clarke et al 2013. Mol Psychiatry18:666-73.

Decreased BDNF and Exaggerated Stress response

Clarke et al, 2013

BDNF

O’sullivan, 2011. Bercik, 2011)

- The probiotic B.breve 6330 increased BDNF total variants, and decreased BDNF splice variant IV in the hippocampus

- Oral administration of antimicrobials to mice increased hippocampal BDNF

- The probiotic bacterium longumnormalized the changes in behavior and BDNF mRNA produced by an intestinal parasite

Cognition

Gareau et al used a novel object recognition test and exploration of at maze to examine dorsal hippocampal function in GF mice.

-GF animals displayed an absence of non-spatial and working memory accompanied by a decrease in hippocampal BDNF.

- Compare with colonized animals GF mice display significant cognitive deficits. Mélanie G Gareau et al. Gut 2011;60:307-317

Cognition

Kang S. Molecular Degeneration. 2014;9:36

Cognition

Kang S. Molecular Degeneration. 2014;9:36

What does this mean clinically?

From Bowel to Behavior

Cryan J Neurogastroenterol Motil (2011) 23, 187–192

Gut–brain axis: how the microbiome

influences anxiety and depression

Foster J, Neufeld KA , Volume 36, Issue 5, 2013, 305–312

Animal Models of Neurodevelopmental Illness

Desbonnet et al. Mol Psychiatry, 19 (2014), pp. 146–148Dinan TG Journal of Psychiatric Research 2015. 63;1-9. 63,

Animal Models of Neurodevelopmental Illness

Reviewed in Dinan TG Journal of Psychiatric Research 2015. 63;1-9. 63,

Reversed with B. Fragilis

.

Dinan TG, et al. Biological Psychiatry, Volume 74, Issue 10, 2013, 720–726

How do probiotics alter stress related behavior?

Probiotics and Stress

• Treatment with the probiotic B. infantisnormalized stress-related behavior but did not reduce corticosterone in a maternal separation model (Desbonnet, 2008)

• Lactobacillus spp. reduced corticosterone levels in maternal stress model ( Gareau, 2011)

• a non-anxious phenotype can be induced with a microbiota transplant from an animal with a similar phenotype (Collins,2013)

Can probiotic ingestion impact brain function

Tillisch et al, Gastroenterology 2013

Intake of FMPP associated with decreased connectivity of an extensive brain network including somato-and viscerosensory

regions in response to tasks

Tillisch et al. Gastroenterology. 2013 ;144(7):1394-401

Minocycline and Psychiatric symptoms

• Minocycline has broad spectrum activity against both gram positive and gram negative organisms

• Novel therapeutic targets in depression:

minocycline as a candidate treatment

• Successful use of add on minocycline for treatment of persistent negative symptoms in schizophrenia

Soczynskajk JK Behav Brain Res. 2012 1;235(2):302-17. Jhamnani K, Neuropsychiatry Clin Neurosci. 2013 ;25(1):E06-7

Faecal Microbiota Transplantation

• Parkinson Disease

• Multiple Sclerosis

• Autism

• Chronic Fatigue

Fremont, M., et al (2013). High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgicencephalomyelitis/chronic fatigue syndrome patients. Anaerobe, 22, 50-56. Aroniadis, O. C., & Brandt, L. J. (2013). Fecal microbiotatransplantation: past, present and future. Curr Opin Gastroenterol, 29(1), 79-84. Ananthaswamy, A. (2011). Faecal transplant eases symptoms of Parkinson's disease. New Scientist, 209(2796), 8-9. Borody TJ et al (2011). Fecal microbiota transplantation (FMT) in multiple sclerosis (MS) Am J Gastroenterol., 106, S352.

Faecal Microbiota Transplantation• Recent work has identified a significant correlation

between the gut microbiota and depression in 37 patients with depression and 18 non-depressed patients

• There was also a significant association between depression and the gut microbiome in 46 patients with depression (29 active- MDD and 17 responded-MDD) and 30 healthy controls, as well as increased bacterial diversity in the active depression group but not in the remitted depressed group

Naseribafrouei, A et al . (2014). Correlation between the human fecal microbiota and depression. Neurogastroenterol Motil, 26(8), 1155-1162. Jiang, H. et al (2015). Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun, 48, 186-194.

Clinical Evidence

• Unsuccessful probiotic clinical trial for schizophrenia

• Unsuccessful probiotic clinical trial for MDD

• Ongoing clinical trial for Bipolar

• Unsuccessful FMT trial for depression/anxiety in clients with UC

• SO WHERE DOES THIS LEAVE US?

Dickerson, F. B et al. (2014). Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: a randomized, placebo-controlled trial. Prim Care Companion CNS Disord, 16(1).Anglin R., et al (2015). Fecal MicrobiotaTransplantation does not Improve Anxiety or Depression in Patients with Ulcerative Colitis in a Randomized Controlled Trial. Submitted for Publication. Romijn, A. R., et al (In press). A double blind, randomised, placebo-controlled trial of a probiotic formulation for the symptoms of depression. Brain, Behavior and Immunity.

Probiotics

• There is important evidence that psychobiotics can alter mental processes and reduce stress responses.

• Resilience to environmental stress seems to be heavily influenced by microbial composition.

• This effect is most likely dependent on alterations of the HPA axis, and can be positively influenced by certain probiotic bacterial species.

• In support of this suggestion is the recent finding that prebiotic treatment, which is known to increase probiotic levels in the gut, alters the cortisol awaking response and emotional reaction in healthy subjects ( Schmidt et al., 2014).

Impact of the gut microbiota on the gut-brain axis in health and disease

Cryan J, Dinan T. Nature Reviews Neuroscience 2012: 13, 701-712

Dinan Nature Neuroscience Reviews

"our bodies are ……a complex ecosystem in which human cells represent a paltry 10% of the population. But beyond the sheer numbers, we now know about the profound diversity of this ecosystem and striking individual differences. How these differences in our microbial world influence the development of brain and behavior will be one of the great frontiers of clinical neuroscience in the next decade"

Thomas Insel, NIMH Review