The Microbiome and Mental Health

Table of Contents

Key Takeaways

  • At the end of this lecture, you should be able to:
  • Understand the connection between gut health and mental health
  • Name the major pathways that connect the gut to the brain
  • Understand that inflammation can induce depression
  • Understand how the HPA axis is affected by the presence of the microbiome
  • Explain how SCFA may impact neurological diseases
  • Understand how the vagus nerve relays information to and from the gut at a high level
  • Explain how serotonin biology is implicated in depression

Gut Biology Key Terms

Gut is your Second Brain

  • Called the enteric nervous system

  • Two thin layers of more than 100 million nerves

  • More neurons than a cat’s true brain

  • Controls digestion from swallowing, to the release of enzymes, to blood flow, to elimination of waste

  • For years doctor’s assumed anxiety and depression contributed to diarrhea, bloating, upset stomach, etc but we now know that this is a bi-directional pathway involving the microbiome

    Not just your thoughts and emotions impacting your gut, but your gut impacting your thoughts and emotions

Why so important?

  • The lifetime prevalence of major depressive disorder (MDD) is more than 10%
  • Lifetime anxiety disorders is approaching 30+%
  • The World Health Organization predicted that by 2020 only heart disease will outrank depression for global disease burden

Gut Brain Immune Connection

  • During infection, immune cells release cytokines that cause loss of appetite, low mood, loss of motivation, fatigue and social withdrawal
  • Many of those descriptions fit the description of depression as well
  • Depression, bipolar disorder, and schizophrenia have consistently been shown to correlate with increased (though low grade) inflammatory markers
  • Depression can be triggered by administration of exogenous cytokines

1) Inflammation

  • “Leaky gut” or the microbial translocation of bacterial products across the gastrointestinal epithelium is one major theory

    • Depression, autism and Alzheimer’s disease all report increase elevated levels of a key inflammatory bacterial product called LPS

  • Chronic stress is also known to increase intestinal permeability through the production of cortisol and catecholamines

  • Notably, rat models of depression are reversed by the administration of B. infantis through reductions in inflammation

  • The same probiotic normalizes inflammation in patients with IBS as well

  • Germ free mice have significant reductions in a brain specific immune cell called microglia microglia are like macrophages in the brain

  • A full, diverse spread of bacteria are needed for the maturation of these cells

  • The mechanism appears to be the critical production of short chain fatty acids such as butyrate, acetate and propionate

2) The HPA axis – hypothalmus-pituitary-adrenal gland

  • The HPA axis is best known for regulating the stress response
    • Stress causes the production of corticotropin releasing hormone (CRH)
    • CRH drives the production of adrenocorticotropic hormone (ACTH) by the pituitary
    • ACTH drives the production of cortisol by the adrenal glands
  • Evidence for a connection to the gut
    • Germ free mice express higher levels of ACTH and cortisol release in a stress test

      • Completely reversed by the presence of a single bacteria, Bifidobacterium infantis

      • This reversal was time dependent, if you wait too long, the effect is permanent

      • Further research implicates microbial modulation of serotonin, glutamate, and other key neurotransmitters

        This stress response is set for life after an early age

3) Short chain fatty acids [Short Chain Fatty Acids]

  • The digestion of various forms of fiber by the microbiome generate metabolites that are used for multiple functions

  • The byproduct of resistant start are the short chain fatty acids butyrate, acetate and propionate

  • Locally, the SCFA influence the neuroendocrine system through inducing the release of PYY (satiety hormone) and serotonin

    Most serotonin in your body is in your gut, not your brain

  • However, the SCFA can also travel through the rest of the body influencing a significant number of other processes

Butyrate has shown preclinical (mice) beneficial effects for:

  • Depression
  • Autism
  • Huntington’s disease
  • Parkinson’s
  • Alzheimer’s

4) Microbial production of neurotransmitters

  • The gut bacteria have the ability to produce multiple neurotransmitters • GABA • Noradrenaline • Serotonin • Dopamine • Acetylcholine Not proven to effect the nervous system but highly correlated

  • Of course, the quantities are much smaller and the impact on the overall function of the brain remains unclear

Vagus Nerve

  • The major parasympathetic nerve in the body
  • Plays a key part in regulating heart rate, bronchial constriction, and gut motility, etc.
  • Stimulation of this parasympathetic pathway has an anti-inflammatory effect
  • The vagus nerve is an appears to respond to, and relay information about, changes in gut bacteria
    • Responds to bacterial signals through bacterial metabolites and through interaction with gut enteroendocrine cells
  • Probiotic benefits on anxiety (previously mentioned) are dependent upon the vagus nerve
    • Severing the nerve eliminates the benefit of Lactobacillus rhamnonsus on anxiety

5) Tryptophan and Serotonin biology

  • 90% of the serotonin in the body exists in the gut
  • The pathway involves the conversion of

tryptophan -> 5-HT -> serotonin Germ free mice have way less 5-HT than regular

  • Germ free mice have significantly LESS 5-HT than normal mice
    • Bacteria induce expression of key enzymes for production
  • In the brain, tryptophan is converted via the Kynurenine pathway
    • Immune activation through, something like leaky gut induces heightened expression of molecules that suppress this pathway
    • The microbiome also impacts this pathway through modulating

tryptophan levels

Summary

  • The microbiome is a key component of the gut–brain axis
  • Communication with the brain occurs via the HPA axis, the immune system, serotonin/tryptophan metabolism, and the production of various neurotransmitters
    • The Vagus nerve appears critical for this process
  • Patients with a wide variety of neurological diseases have distinct microbiomes
  • Certain probiotics have demonstrated the ability to improve anxiety and cognition

Supplimentary Video

Bacteria can change how we live

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