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
Wow, very interesting topic. I have never heard of the relationship between gut microbiome and mental health, but I am not surprised, as I have read many articles about how important the gut microbiome is proving to be and how specific gut microbiomes can predispose people to certain diseases, such as obesity. I am very curious about the idea of taking probiotics to help regulate gut microbiomes and in turn help people with mental disorders. This would be a very interesting pharmaceutical intervention to pursue as it would potentially eliminate the mood-numbing side effects people feel when taking certain medications to help their mental health. Because of my interest, I researched further into the benefits of probiotics for people affected by mental illness, and it appears to be an up and coming research topic. I found one pilot study that found that anxiety symptoms associated with Chronic Fatigue Syndrome were much less common in people taking probiotics compared to control subjects. Again, very interesting topic and good job!
ReplyDeleteRao, A.V., Bested, A.C., Beaulne, T.M. et al. A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathog 1, 6 (2009) doi:10.1186/1757-4749-1-6
This post is very interesting to understand how the gut-brain axis is involved in many physiological effects. It has been known that gut is a “second brain” and from resent studies it is event that the interaction between gut to brain is very crucial. It is interesting to see the correlation between how ADHD and gut-brain axis is correlated. There is ongoing research on how gut microbiota are viewed as important regulators in the cross-talk between gut-brain axis. It is known that ADHD is the most prevalent neuro-disorder effecting children. There seems to be countless diagnosis, treatments, and challenges with ADHD.
ReplyDeleteA study by Cenit et al, examined how dietary components that modulate gut microbiota influence ADHD development or symptoms (1). It seems that many environmental factors are playing a key role in risk of developing ADHD has been suggested to be associated with risk factors, gestational age, feeding, maternal health, and life stressors (1). The perinatal period is an important time for infant to get the initial microbiota and influences the brain development via gut microbiota modulation (1). During development the maternal gut microbiota pass through the placenta and the fetal gets exposed to the microbiota (1). This in turn effects the brain development and from gestational age to early childhood; thus having long-term consequence that contribute to ADHD development or its manifestation (1).
It’s now becoming more event that the gut microbiota influences brain functions and effects behavior as well. The gut-brain axis has becoming quite an interesting and critical therapeutic target to understand disorders such as ADHD. The evidence is growing to understand how diet, microbiota, and development all play a role in behavior development such as ADHD. It is very interesting to see how the exact routes and means of development, not only ADHD, but other behavior disorders occur in the gut-brain axis. It is important for scientists and the science community to correlate and work together to attain better understandings of the mechanisms of the gut-brain axis.
1. Cenit, María, Carmen Nuevo, Isabel Codoñer-Franch, Campillo Dinan, and Pilar Sanz. "Gut Microbiota and Attention Deficit Hyperactivity Disorder: New Perspectives for a Challenging Condition." European Child & Adolescent Psychiatry 26.9 (2017): 1081-092. Web.
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ReplyDeleteThe gut microbiome is also responsible for countless other symptoms of non-mental illnesses such as cancer and its symptoms of fatigue and diarrhea we must ask ourselves is the medications symptoms better than the actual condition. It has been shown that chemotherapy disrupts the intestinal microbiota homeostasis and further the incidence of diarrhea. For example, the mechanism of irinotecan induced diarrhea has been studied extensively in rodent models. These models suggest that even slight microbiota changes during chemo and pathology of the gut due to the treatment being CPT-11 or irinotecan (3). This specific involvement is linked to Iri metabolism in vivo, when it is converted into active SN38 it goes under glucuronidation hepatically and is then secreted into the bile as SN38G which is inactive. Gut bacterial Beta-glucuronidases deconjugate SN38G, this exposes SN38 to gut epithelia increasing gut toxicity. “specific bacterial organisms translocate from the intestine of CPT-11 treated animals and cause systemic infection and sepsis. Prophylaxis with antibiotics reduced SN-38 concentration and/or diarrhea both in animal models and patients” (3). Altering the gut microbiome is also most beneficial at an earlier age for most of these effects to attain its max benefit.
ReplyDelete(3)Lin, Xiaoxi B., et al. “Irinotecan (CPT-11) Chemotherapy Alters Intestinal Microbiota in Tumour Bearing Rats.” PLoS ONE, vol. 7, no. 7, 2012, doi:10.1371/journal.pone.0039764.
Very intriguing topic! I never would have thought that the gut microbiome could affect the mental conditions of an individual. It does make sense, however. With health issues such as obesity and eating disorders there are changes associated with the mental state. Depression also causes a drastic change in diet and so there must be link with diet affecting the brain’s state as well. Since this is the case, then there is potential in finding cures for mental illnesses through change of a better diet.
ReplyDeleteI researched on this topic a bit further and found that about 95% of serotonin is made by the gut which affects the mood and GI tract in an individual. It is said that even the slightest stress can alter the gut bacteria causing further changes within the body. Basically, it is like a yin-yang effect between the brain and the gut that can be cured by maintaining a healthy diet and stress-free environment.
Carpenter, Siri. “That Gut Feeling.” Monitor on Psychology, American Psychological Association, Sept. 2012, www.apa.org/monitor/2012/09/gut-feeling.
Great post Titus, so informative! The recent studies on the microbiota and its wide-reaching effects on the human body are so fascinating. Mental disorder effects such as the ones you describe remind me slightly of parasites that control the host's actions such as the flatworms that infect snails. The parasite finds its home in the snail's eyes and once there, the snail will act against instinct by finding high ground which puts them at a higher risk for predation by birds. The flatworm induces this action in the snail because it's only able to reproduce in the gi tract of birds so the ingestion of their host snail is their goal. In the case of depression, the microbiota isn't directly controlling the host's movements however, it is indirectly controlling some behaviors as a symptom of the depression. Ideas such as this spark the question in myself of how much of what we believe to be inherently us, are actually our microbiota influencing our actions.
ReplyDelete“Crazy Eyes and Mind Control – the Power of Parasites.” Smithsonian Insider, 16 Mar. 2016, https://insider.si.edu/2014/11/crazy-eyes-mind-control-power-parasites/.
Prior to this course I never considered the microbiota as a factor in disease management. The fact that we have this city of bacteria that could be communicating with other parts of our bodies is fascinating. This concept falls back on the idea of homeostasis and the affects that arise when there is a disturbance. In many of these studies that assess the role of the gut microbiota in disease incidence, I find myself questioning what the ideal microbiome would be. No human follows the exact same diet, though some similar. Just because you see an increase of a single bacterium, does that mean that disease is imminent? Do other bacterial fluctuations cause the same response as the single bacterium? The evolution of this concept is quite intriguing and I look forward to seeing the developments in the future.
ReplyDeleteJen Eccleston
This was a great read, Titus! I am fascinated by the research revolving around exploring the relationship between microbiota and diseases. Mental health is often overlooked due to the stigma and fear associated with it so I appreciate you bring this to light. You mentioned Bifidobacterium being present at higher levels in ADHD patients which is interesting. I read a study conducted by Sivan et al. (2016) where they investigated the relationship between Bifidobacterium and its impact on the efficacy of anti-PD-L1. They found Bifidobacterium in the fecal samples of mice who showed reduced growth of the tumor while promoting the tumor-specific response by the T-cells. These results showed that Bifidobacterium can dictate spontaneous antitumor immunity along with displaying better response to PD-1 therapy (1). It's intriguing that in one case this bacteria is beneficial but in other cases, such as the one you wrote about, it could play a role in ADHD.
ReplyDelete1. Sivan, Ayelet et al. “Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.” Science (New York, N.Y.) vol. 350,6264 (2015): 1084-9. doi:10.1126/science.aac4255
It is so interesting that the microbiota could have a relationship with our mental health. Your blog post made me wonder if there had been any correlations made between a mother who consumed a poor diet while pregnant that resulted in her child developing mental health problems. After doing some research, I found a study that examined this exact idea. As we learned in class, a multitude of things a mother does while she is pregnant can have lifelong impacts on her developing baby. A study found that maternal and postnatal dietary factors could contribute to subsequent risks of behavioral and emotional problems in children. An increased intake of unhealthy foods and a decreased intake of nutrient-rich foods in early childhood were related to higher internalizing and externalizing behaviors in young children. The internalizing and externalizing behaviors indicated early markers of mental health problems that developed as the child grew older. This study suggests that the impact of inadequate nutrition during pregnancy and early childhood can have effects on the child’s mental health later in life (Jacka et al 2013). Overall, this really puts it into perspective just how important our nutrition is. This really needs to be taken into account when a mother is pregnant because her nutritional decisions can have long-lasting impacts on her offspring. These impacts include but are not limited to the child’s mental health, emotional, and behavioral developments throughout the length of their life. Your blog was very well written and extremely insightful!
ReplyDeleteJacka, F. N., Ystrom, E., Brantsaeter, A. L., Karevold, E., Roth, C., Haugen, M., … Berk, M. (2013, October). Maternal and early postnatal nutrition and mental health of offspring by age 5 years: a prospective cohort study. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24074470.
This is a great topic! It is of particular interest to anyone concerned with mental health, and stress disorders. Many of our mental health disorders are poorly understood, but I find it intriguing there is a correlate with ADHD and Dopamine; as ADHD is associated with lower levels of dopamine in the basal ganglia of the brain. This in turn contributes to the brain’s reward system. The study that was referenced provides more questions than answers for me. If there were higher levels of Bifidobacterium present in the gut, presumably would not that correlate with higher levels of Dopamine? Given that Bifidobacterium is crucially involved in the synthesis of phenylalanine, a dopamine precursor. L-Phenylalanine is biologically converted into L-tyrosine. L-tyrosine in turn is converted into L-DOPA, which is further converted into dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). I would have the curiosity to investigate whether the individuals with ADHD had lower circulating levels of these converting enzymes. Where in the path from Phenylalanine to Dopamine are there deficits in these converting enzymes, or is there merely a disconnect between the gut microbiome and the basal ganglia? I suspect that is only one small piece of the puzzle, and more work will need to be done.
ReplyDeleteHey Titus, thanks for the recap of some of the recent findings on the relationship between the gut microbiome and mental health. I am personally not sure about the efficacy and reliability of microbiome research for several reasons, not the least of which is that the field feels more than a little hype driven. That is to say that this booming field of study is very new, hot-button, and they findings of studies are often over stated. As in an editorial published by one MD/PhD, there are several flaws inherent to most microbiome studies as they pertain to mental wellness. The first major flaw is that the exact workings and importance of microbial components of the microbiome is not well understood. Because of this lack of understanding, many of the findings overstate the importance of one variety of bacteria over another. Tangentially, there is no definition of a good or bad microbiome beyond the net degree of variation, with greater variation being considered better for overall health. At the same time, many of the models commonly used for microbiome research such as germ free mice do not tolerate research well and it is difficult to gauge the extent to which the introduction of novel bacterium can influence a change in behavior given the wide range of physiological changes that occur and could also cause behavioral alterations.
ReplyDeleteAside from this, mental health is an incredibly and profoundly complex issue that is both informed by genetics, the environment, and other possibly unknown factors. It is known, however, that long term mental health problems permanently alter the state of the brain and make a return to true physiological and anatomical normalcy unlikely. So, it is difficult to convince many scientists that the microbiome could inform such a large multiple system change in the mood phenotype. That said, it is not impossible that this is the case and it may be that the microbiome is more influential than I currently believe. There is, after all, a diverse and growing collection of data to support the possibility that the microbiome could be just this powerful.
Foster, J. A. (2017). Targeting the Microbiome for Mental Health: Hype or Hope? Biological Psychiatry, 82(7), 456–457. doi: 10.1016/j.biopsych.2017.08.002
This was a very interesting read! As someone who suffers from mental illness, this blog post was very easy to relate to. I especially enjoyed the information on the changes in the fecal abundance of essential amino acids relating to rats' depressive-like behavior in response to stress. I am aware at how little is actually known about mental illness and maybe that is in part due to focusing solely on the brain as the issue. The body should be viewed as a whole with all parts considered. Speaking from personal experience, I find that I am most content mentally or "firing on all cylinders" per say when I am eating proper amounts of nutrients, working out regularly, and taking my anti-anxiety medication. Without this combination, I react to stress very negatively. This could be just me, but this article poses the idea that it relates in a very scientific way.
ReplyDelete-Alivia Larkin
This is a fantastic blog post, great work!! Mental health has become such a prevalent topic in our society, it is very important that resources are being put towards the understanding of how they develop in each person. It is very interesting how the relationship between mental health and gut microbiome shows significant correlation. After class recently and reading the blog post, I had begun to think about how our microbiomes develop. There are a few hypotheses going around right now, two main ones are the old friends hypothesis and the hygiene hypothesis. They are essentially the same thing, discussing that we as a population are too clean and it is affecting our microbiomes. Being exposed to a vast number of microbes is very important for our body’s health, and I am curious to see if there is an overall increase in the prevalence of mental health disorders as we as a species get cleaner. I found an article discussing this phenomenon; however, it is locked behind a paywall. The abstract does a great job of providing some insight, so I will link it below.
ReplyDeletehttps://link.springer.com/article/10.1007/s40572-016-0100-5
Wow! This was an awesome post! Especially since I am reading this right after our class lecture on the microbiota. This subject has made me curious about current probiotics on the market. These products have been found to be fairly unregulated, but have never been seen as much of a health threat to the public since it is considered to be a ‘supplement’. In return, this has created an industry that is marketing untested microbes to society. Especially since we are not completely aware of some of the true side effects of some of these microbe strains. Similar to what you’re stating in your research, that it could potentially make an issue worse or have serious side effects. While it is a bit frightening that these are so freely available to individuals, I do think that this field could have some major benefits if used correctly! For instance, how researchers have found microbes that will allow a treatment to work better on a patient! It’ll be really cool to see the future of probiotics.
ReplyDeletede Simone, C. (2018). The unregulated probiotic market. Clinical Gastroenterology and Hepatology.
It’s amazing how interconnected our body systems are! I had no idea that there was any connection between psychological disorders and gut microbiota, even though I myself have been treated for anxiety and depression. It just shows that there are always new developments in our understanding of human disease, especially when it comes to diseases of the mind. I just read this article about the reverse relationship: how our stress levels can affect our digestive health. The gut-churning feeling you get when anxious can actually make a negative difference in your GI tract. Additionally, psychological dysfunctions can even make you more responsive to physical pain. In the future, I think there will have to be more than a systems-based approach for treating disease. We are learning more and more about the interrelated nature of these systems, so that the body will have to be treated as a whole unit, rather than several separate parts that don’t affect one another.
ReplyDeleteHarvard Health Publishing. “The Gut-Brain Connection.” Harvard Health, https://www.health.harvard.edu/diseases-and-conditions/the-gut-brain-connection.
Titus this was a really interesting post! The human microbiome is composed of over one million genes compared to the human genome, which is made up of roughly 23,000 genes. This emphasizes the importance of our microbiome and its effect on our overall health. Cells of the human microbiome outnumber other body cells almost 10:1 and they account for 1-3% of our entire body mass, which is a lot of cells. Psychiatric disorders like depression, anxiety, and PTSD are usually treated with several pharmaceutic agents. These drugs can often make conditions like depression worse. For instance, popular antidepressant medications like SSRIs commonly cause weight gain, which for many people can worsen their depression. Therefore, I believe that new, more targeted, and effective interventions are necessary, and our microbiome seems like a perfect target for pharmaceutical research.
ReplyDeleteNiamh Costello
Estus, S. (2019). Gut-Brain Axis: Microbiome. Integrated Biomedical Sciences 606: Physiological Communications. University of Kentucky, Lexington.
I love this post about the gut microbiome! There is so much emerging research about how widespread microbiome affects can be within animal and human bodies, from simple digestion disorders to full blown dementia. I had no idea about the involvement of the gut-brain-axis in ADHD, but I have seen and heard of a lot of emerging research that implicates a role of the gut-brain-axis in the pathogenesis of Alzheimer's disease (AD). In fact, one study was able to identify "numerous microbial taxa...that act as predictors of AD dementia in comparison to elders without dementia or with other dementia types." As of yet, there seems to be very little known about exact mechanisms involved in the gut-brain-axis interaction, but I am very excited for the future of this research direction. I think understanding the gut microbiome could be the key to improving health outcomes in a multitude of disease and ailments that have not seen updated treatment methods in years, if ever.
ReplyDeleteHaran, John P., et al. “Alzheimer’s Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Glycoprotein Pathway.” MBio, vol. 10, no. 3, 2019, doi:10.1128/mbio.00632-19.
DeleteTo be completely honest I had no idea that there was a gut-brain axis. I knew the gut had immunological properties and worked as a defense mechanism, but never would I have thought to connect psychiatric disorders and microbiota. So with this information regarding depression and gut microbiota, could there be a future in depression treatment with some sort of fecal transplant? Or taking probiotics that can enhance a general microbiota that diminishes depression? This topic is very knew to me and the fact that possible psychiatry and psychology can be altered due to bacteria, fungi and viruses is incredible.
ReplyDeleteThis is really cool to read and learn about. I hope that this leads to more "explanations" and treatments for depression and psychiatric issues. It seems like microbiome is a integral part of whole body and mind health that needs more research.
ReplyDelete