In recent years the prevalence of mental illness continues to rapidly increase, affecting nearly one in five adults in the United States (1). These disorders present as an especially challenging medical burden with lower rates of treatment and recovery than any other disease, as the complexity of human psychiatry is still poorly understood.
Psychiatric disorders are generally thought of as originating solely within the brain, but recent studies are shifting the paradigm. With the increasing awareness that the human being is a superorganism, it has become apparent that the microbiota-gut-brain axis likely plays a major role in mental health.
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Figure 1. The increasing medical burden of mental and neurological
disorders. (A,B): Disability-adjusted life years (DALYs) of disorders. (C,D):
DALYs for different respective diseases in 1990, 2006, and 2016 (2).
The human gut is the largest endocrine organ of the body
with 90-95% of its total cell count shockingly consisting of microorganisms. It also possesses its own nervous system. The
gut microbiota develops simultaneously with the brain, impacting both its
structure, i.e., rate of myelination and synaptic connectivity and its function
by altering cognition (3). The
developmental mirroring of the gut and brain intuitively suggests a very
intimate physiological dichotomy between the two. Beyond development, the
microbiome of the gut has been demonstrated to play a significant role in one’s
cognition and behavior, although this role is still poorly understood and
usually ignored.
Some functions that the microbiome have been shown to
regulate are perception and response to pain (4,5), cognitive
abilities (i.e., learning and memory) (6,7) and of particular interest, mood and emotion (4,5).
Figure 2.
Developmental patterns illustrating the similarity and
intimacy of the gut-brain axis (3)
A recent study that exemplifies this dichotomy showed that
changes in the fecal metabolome, which are indicative of an altered gut
microbiome, were significantly associated with depressive-like phenotypes in
rats subjected to chronic unpredictable mild stress (8). More
specifically, changes in the fecal abundance of multiple essential amino acids
were correlated with changes in the plasma metabolomes of the rats that
exhibited depressive-like behavior in response to stress. Depressive disorders
have commonly been correlated with disturbed amino acid synthesis and metabolism,
which is the paramount duty of the brain attributed to the gut microbiome, and
the key mechanism for mediating the communication between the two. These
results suggest that the gut microbiota, and more specifically its associated
metabolites, may play a crucial role in the pathogenesis of depressive-like
mammalian behaviors.
Another recent study has investigated the influence of the
gut microbiome on neural reward pathways in attention-deficit/hyperactivity disorder
(ADHD) (9). ADHD is a highly prevalent mental disorder
characterized by chronic patterns of inattention and impulsivity that can
impede normal cognitive function or development. Though ADHD is poorly
understood, it is thought to potentially be associated with lower levels of the
neurotransmitter dopamine in the basal ganglia of the brain, which contributes
to the brain’s “reward system.” Using 16S rRNA gene sequencing and fMRI, gut
bacterial identities and neural responses to reward anticipation were evaluated
in 28 human subjects who were either diagnosed with ADHD or were healthy
controls. The resulting data revealed that the genus Bifidobacterium was
present at significantly higher levels in ADHD patients than the controls and
correlated with decreased ventral striatal fMRI responses during reward
anticipation. This bacterium is crucially involved in the synthesis of
phenylalanine – an essential amino acid, and a precursor molecule to dopamine.
Although the mechanism of ADHD pathology associated with this bacterium isn’t
clear, the disturbance in its normal levels of gut colonization were
nevertheless correlated with clinical signs of mental disorder.
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Figure 3.
Potential pathways of basic microbiome influence on brain
function (9).
To conclude, the relationship between the gut and brain
plays a unique and inseparable role to our mental health. Further understanding of the gut-brain axis
could reveal novel pharmacological interventions and therapies as a solution to
a multitude of mental illnesses. With regards to our limited current understanding, some
theoretical solutions that could be imagined are: individualized probiotic
supplements to properly recolonize patient microflora; immunotherapies to
target and control unwanted overabundance of specific bacterial taxa; exogenous
supplementation with the specific enzymatic byproducts of bacterial metabolism;
or even genetic modification via technologies such as CRISPR of human host cells
that are the environmental framework supporting these bacteria and their
activity.
References:
1. “Mental Illness.” (2017). National Institute of
Mental Health, U.S. Department of Health and Human Services, https://www.nimh.nih.gov/health/statistics/mental-illness.shtml.
2. GBD 2015 DALYs and HALE Collaborators. “Global, regional,
and national disability-adjusted life-years (DALYs) for 315 diseases and
injuries and healthy life expectancy (HALE), 1990-2015: a systematic analysis
for the Global Burden of Disease Study 2015.” Lancet (London,
England) vol. 388,10053 (2016): 1603-1658.
doi:10.1016/S0140-6736(16)31460-X
3. Liang, Shan et al. “Gut-Brain Psychology: Rethinking Psychology From the Microbiota-Gut-Brain Axis.” Frontiers in integrative neuroscience vol. 12 33. 11 Sep. 2018, doi:10.3389/fnint.2018.00033
4. Luczynski P.,
McVey Neufeld K. A., Oriach C. S., Clarke G., Dinan T. G., Cryan J. F. (2016). Growing up in a bubble: using germ-free animals to assess
the influence of the gut microbiota on brain and behavior. Int. J. Neuropsychopharmacol. 19:pyw020. 10.1093/ijnp/pyw020
5. Vuong H. E., Yano J. M., Fung T. C., Hsiao E. Y.
(2017). The microbiome and host behavior. Ann. Rev. Neurosci. 40 21–49.
10.1146/annurev-neuro-072116-031347
6. Gareau M. G.
(2016). Cognitive function and the
microbiome. Int. Rev. Neurobiol. 131 227–246. 10.1016/bs.irn.2016.08.001
7. Manderino
L., Carroll I., Azcarate-Peril M. A., Rochette A., Heinberg L., Peat C., et al.
(2017). Preliminary evidence for an association between the composition of
the gut microbiome and cognitive function in neurologically healthy older
adults. J. Int. Neuropsychol. Soc. 23 700–705.
10.1017/S1355617717000492
8. Jianguo, Li et al. “Altered gut metabolome contributes to
depression-like behaviors in rats exposed to chronic unpredictable mild
stress.” Translational psychiatry vol. 9,1 40. 29 Jan. 2019,
doi:10.1038/s41398-019-0391-z
9. Aarts, Esther et al. “Gut
microbiome in ADHD and its relation to neural reward anticipation.” PloS
one vol. 12,9 e0183509. 1 Sep. 2017, doi:10.1371/journal.pone.0183509
