Literature Review_AmyJung

Inflammation linking Gut Microbiota, Circadian Rhythm, and Depression

Abstract

Increasing interest in the microbiota-gut-brain axis has revealed that this relationship may play a

role in neuropsychiatric disorders, such as depression. The gut microbiota affects brain function

in 3 main pathways: immunoregulatory pathway, neuroendocrine pathway, and vagus nerve

pathway. Each of these pathways seem to contribute to an increase in inflammation in the host.

Also, many studies have also associated insomnia and depressive disorder to disrupt biological

rhythms, immune system function, and nutrient metabolism. However, the emerging field of

microbiome-gut-brain axis suggests that the gut microbiome may not only affect the digestive,

metabolic, and immune system functions but also regulates host sleep and mental state. This

literature review serves to map out a potential relationship between physiological stress of sleep

disruption, the gut microbiome, and depression. Much of the literature suggests that lack of sleep

has been shown to increase pro-inflammatory gut bacteria, which may in turn increase gut

permeability and translocation of bacteria, leading to low-level chronic inflammation, a common

symptom of depression. In addition, this review also points out remedial properties of probiotics

on chronic inflammation and disorders of the metabolic and immune system, which make it a

potential treatment for depression.

Key words: ​gut microbiome, microbiota-gut-brain axis, depression, inflammation, sleep

Literature Review_AmyJung

Introduction

The emerging term “microbiota-gut-brain axis” describes the relationship between

gastrointestinal microbiota and the host.​1​ The term itself reflects the significant influence the gut

environment may have on brain health and disorders. Disturbances of the gut microbial

community can cause multiple host diseases, such as obesity, diabetes, and inflammation.​1

Furthermore, recent studies suggest that the microbiota-gut-brain axis may have a role in

neuropsychiatric disorders such as depression.​1​ Due to its complex nature, depression has

multiple different factors and symptoms, such as inflammation, that combine to result in its

clinical diagnosis.

In addition to a happy gut, good restful sleep and mood are also vital components of

health. Many studies have associated insomnia and depressive disorder with altering biological

rhythms, immune system function, and nutrient metabolism, although the exact underlying

mechanism is still unclear.​2​ However, the emerging field of microbiome-gut-brain axis suggests

that the gut microbiome may not only affect the digestive, metabolic, and immune system

functions, but also regulates host sleep and mental states.​2​ Even with the increasing interest in the

microbiota-gut-brain axis and its potential correlation to mental health, not many studies

consider lack of adequate sleep as a significant contributing factor. Therefore, this literature

review serves to map out the relationship between physiological stress of sleep disruption, the

gut microbiome, and depression, in addition to pointing out remedial properties of probiotics on

depression.
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Pathways of microbiota-gut-brain axis

Referring to the microorganisms that live in the gastrointestinal tract, the “gut

microbiome” has approximately a thousand different types of microbial bacteria present in the

adult intestinal tract.​2​ In healthy conditions, the composition of the intestinal microbiota

community fluctuates in dynamic equilibrium. But, if this delicate balance of microbiota is

broken, dysbacteriosis increases the host’s susceptibility to disease.​2

There are 3 main pathways the gut microbiota affect brain function in the

microbiome-gut-brain axis:

1. Immunoregulatory pathway

2. Neuroendocrine pathway

3. Vagus nerve pathway.

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In the immunoregulatory pathway, the gut microbiota affect immune cells by influencing

levels of cytokines, cytokinetic reaction factor, and prostaglandin E2, which in turn affect the

brain.​2​ The neuroendocrine pathway has more than 20 types of enteroendocrine cells in the gut,

resulting in the largest endocrine (hormone secreting) organ in the human body.​2​ It regulates

secretion of neurotransmitters, such as cortisol, tryptophan, and serotonin, to alter the

hypothalamic-pituitary-adrenal (HPA) axis and the central nervous system (CNS).​2​ The enteric

nervous system plays a major role in the vagus nerve pathway. Sensory neurons from the

intestinal myenteric plexus form synaptic contacts with motor neurons are exposed to gut

microbiota.​2​ These motor neurons in the intestine that regulate intestinal motility and gut

hormone secretion, functions that gut bacteria may affect through this nervous system.​2​ The gut

nervous system also forms synaptic connections with the vagus nerve, directly connecting the

intestine to the brain in a pathway described as the gut microbiota-enteric nervous system

(ENS)-vagus-brain axis.​2​ Through this, neurotoxic metabolites, such as D-lactic acid and

ammonia produced by the intestinal microbiome, are able to pass through the vagus nerve and

into the CNS to affect brain function, stress response and sleep patterns.​2​ Vice-versa, the CNS is

also able to regulate the composition of the gut microbiota through these 3 pathways.​2​ However,

it should be noted that there may be other pathways involved in the gut microbiota-brain function

and that these pathways may interact with one another, introducing confounding variables.
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The gut microbiota and circadian rhythm

The gut microbiota seems to have circadian

rhythm for both its bacteria population

structure and functional activity. The main

bacteria that make up about 60% of the gut

microbiota, ​Clostridiales​, ​Lactobacillales​,

and ​Bacteroidales​, are observed to exhibit

diurnal fluctuations throughout the day that

refer to specific bacterial configurations.​2

The rhythmic fluctuations within the gut

microbial positioning and localization cause

the intestinal lining (epithelium) cells to be

exposed to different bacteria and their respective metabolites throughout the day.​2​ This projects

significant impacts on the transcription of host’s circadian clock genes and affects transcriptional

modifications and oscillations of metabolites.​3 ​Thus, there must be a link between the gut

microbiota and host circadian clock.

Impacted sleep and changes in the gut microbiota

Lack of sleep or disturbed sleep may cause changes in the gut microbial community. A

recent study by Benedict et al., points out the impact that short sleep has on the human gut
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microbiota.​4​ The ratio of ​Firmicutes​ to ​Bacteroidetes​ was significantly affected by the loss of

sleep.​4

Animal studies on chronic sleep fragmentation (SF) have shown that SF temporarily

induces coordinated changes in gut microbial communities, changing their processing properties.

Mice subjected to this condition showed an increase in ​Lachnospiraceae​ and ​Ruminococcaceae,

but decrease in ​Lactobacillaceae​.5​​ Although a relatively minor shift in microbial function, SF

can induce a significant overall effect on the gut microbiota structure. These microbial changes

caused systemic and visceral white adipose tissue inflammation, possibly due to disruption of the

gut epithelial barrier.​5

The link between gut microbiota and depression: inflammation

Many animal studies indicate that inflammation may be the result of disturbed sleep on

the gut microbiota. These studies show that when there is an increase of pro-inflammatory gut

bacteria, adverse metabolic effects occur, promoting an increase in gut permeability and

therefore subsequent translocation of bacteria across the intestinal epithelium.​2​ This translocation

exposes metabolically active tissues, such as adipose tissue, the liver, muscle, and pancreas, to

low-level chronic inflammation.​2​ A characteristic feature of this metabolic dysfunction may arise

from an increase in epithelial barrier permeability, which is primarily caused by an increase in

lipopolysaccharide (LPS) in the body followed by bacterial translocation.​2

According to Berk et al., depression is linked to chronic, low-grade inflammation and

activation of both the cell-mediated immunity and the compensatory anti-inflammatory reflex

system.​6​ This low-level chronic inflammation that causes depression can be attributed primarily
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to oxidative and nitrosative stress (O&NS), with various factors, such as psychosocial stressors

and altered gut permeability, that seem to increase risks of depressive symptoms.​6

Emerging studies indicate a new pathway of increased immune response due to

lipopolysaccharides (LPS) of different commensal, gram negative bacteria from the gut.​6​ Clinical

depression has been shown to be accompanied by an increase in plasma levels of

immunoglobulin (Ig) A and/or IgM, that are directed towards a number of specific gram negative

bacteria, such as ​Hafnia alvei​, ​Pseudomonas aeruginosa​, ​Morganella​ ​morganii​, ​Proteus

mirabilis​, ​Pseudomonas putida​, ​Citrobacter koseri​ and ​Klebsiella pneumoniae​, which all belong

to the gut flora.​6​ This suggests that there is an IgA- and IgM-mediated immune response against

LPS from the bacterial cell wall. By binding to CD14-Toll-Like receptor-4 (TLR4), LPS may

activate immune cells, which in turn may activate a cascading effect producing pro-inflammatory

cytokines like TNF𝛼, IL-1 and cyclooxygenase-2 (COX-2).​6​ IgA- and IgM-mediated immune

response against LPS also induce the O&NS pathway by increasing the expression of inducible

nitric oxide (iNOS) and therefore nitric oxide (NO).​7

Bacterial translocation may play a role in the inflammation and O&NS pathophysiology

of clinical depression as presented by the systemic IgM-mediated immune response against LPS.

Bacterial translocation is often called a “leaky gut” or an increase in permeability of the gut wall

by the loosening of tight junction barriers.​6​ In normal conditions, the immune cells are separated

from gram negative bacteria in the gut, but an increase in permeability of the gut wall allows

invasive gram negative bacteria to translocate into the mesenteric lymph nodes and occasionally

into the systemic circulation via blood.​6​ The IgM and IgA responses are tagged onto the LPS of

the translocated bacteria, and once primed, the immune cells may produce pro-inflammatory
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cytokines, stimulating the O&NS pathways.​6​ Therefore, it can be said that bacterial translocation

may drive inflammatory and O&NS symptoms in depression.

Other links that may separately connect gut microbiota and circadian clock to depression

Noted, there are other pathways of interaction, aside from inflammation, between the gut

microbiome and the body’s circadian clock that could result in depressive symptoms. One is host

metabolism. The gut microbiota is observed to increase host metabolism by affecting the

circadian transcription factor NFIL3, causing a significant correlation of metabolic syndrome in

shift workers and people who often experience jet lag.​8​ Likewise, patients with depression often

times have disrupted rhythms of clock gene expression, expressing clinical symptoms similar to

jet lag.​9​ Another potential cause of depression is the direct correlation of circadian clock genes.

Dopamine is a molecule closely related to depression and CLOCK protein knockout mice show

an increase risk of depressive symptoms and changes in dopamine-related gene expression in the

ventral tegmental area of the brain.​10​ However, due to the complex nature of depression, it is

more likely that there are multiple ways and factors that contribute to symptoms characterized by

this particular mental disorder.

Potential cure: probiotic intervention

Physiological stress, such as affected sleep, alter gut microbiota composition that causes

pro-inflammatory bacterial translocation, which in turn may affect the function of the immune

system to induce depression-like symptoms. But, some probiotics like ​Lactobacillus​,

Bifidobacterium​, and ​Enterococcus​, may trigger changes in different parts of the brain through

the gut microbiota-ENS-vagus-brain pathway and immune system, thereby remediating a portion

of the initial physiological stress.​2

Literature Review_AmyJung

Other studies have shown

that probiotic intervention

helped decrease stress-induced

corticosterone while also

having antidepressant-like

effects on mice exposed to

chronic stress.​2​ High levels of

cortisol contribute to an

increase in depressive-like

behavior.​12​ The absence of gut

bacteria disrupts the

interaction between gut

microbiota and intestinal

epithelial cells that control

diurnal variations in the

secretion of corticosteroids in

mice, leading to hypertriglyceridemia, hyperglycemia and insulin resistance.​11​ Gut bacteria help

mediate inflammation through the microbiota-ENS-vagus-brain pathway, the immune system

and secretion of glucocorticoids, and an increase in specific bacteria via probiotics present a

promising remedial supplement for depressive symptoms.

Literature Review_AmyJung

Conclusion

With 322 million people worldwide living with depression according to the Anxiety and

Depression Association of America, depression is an epidemic that still does not have a cure.

Due to its complex nature, there are multiple different factors and symptoms that combine to

manifest as depression—inflammation being one of them. Physiological stress, such as lack of

sleep, has been shown to increase pro-inflammatory gut bacteria, which in turn increase gut

permeability and translocation of bacteria, causing low-level chronic inflammation, a symptom

of depression. However, recent studies provide potential remediations of this inflammation. One

possible route is the supplementation of probiotics in order to combat the inflammation by

focusing on the root cause of the inflammation--which is at the gut.

Although the microbiota-gut-brain axis has been gaining attention recently, much more

research is needed in order to clarify preliminary assumptions that probiotics may reverse mental

health disorders, such as depression. There have been many animal studies on this topic, but in

order to make probiotics a viable prescription for depression, more human trials and studies are

needed in addition to different studies on the confounding factors that may play a role in the gut

microbiome-brain axis, such as the immune system. It should also be noted that there are

multiple mechanisms of probiotic bacteria that can either affect the immune system, vagus nerve

activation, and microbial metabolites. Also, even though a probiotic may be able to impact the

psychology and mood of a patient, it is difficult to determine how the probiotic is interacting

with other microbes in the host. Therefore, caution must be taken when drawing comparisons

between germ-free rodents commonly used for gut microbe experiments and probiotic trials on

humans. An increase in human trials may include different experiments that test the effect of
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probiotics on the various microbiota-gut-brain axis pathways individually as well as collectively,

elucidating the mechanisms in which the pathways may interact with one another in order to

produce or inhibit the inflammatory response caused by inadequate sleep. Future research like

this may single out specific probiotic bacteria that perform assigned functions within the body in

order to become a potential prescription on the market.

References

1. Rieder, Ryan|Wiśniewski, Paul J.|Alderman, Brandon L.|Campbell, Sara C. "Microbes

and Mental Health: A Review." ​Brain, Behavior, and Immunity​ 66 (2017): 9-17.

MEDLINE. ​Web.

2. Li, Yuanyuan, et al. "The Role of Microbiome in Insomnia, Circadian Disturbance and

Depression." ​Frontiers in psychiatry​ 9 (2018): 669. ​PubMed. ​Web.

3. Thaiss, Christoph A., et al. "Microbiota Diurnal Rhythmicity Programs Host

Transcriptome Oscillations." ​Cell​ 167.6 (2016): 1510.e12. ​MEDLINE. ​Web.

4. Benedict, Christian|Vogel, Heike|Jonas, Wenke|Woting, Anni|Blaut, Michael|Schürmann,

Annette|Cedernaes, Jonathan. "Gut Microbiota and Glucometabolic Alterations in

Response to Recurrent Partial Sleep Deprivation in Normal-Weight Young Individuals."

Molecular Metabolism​ 5.12 (2016): 1175-86. ​MEDLINE. ​Web.

5. Poroyko, Valeriy A., et al. "Chronic Sleep Disruption Alters Gut Microbiota, Induces

Systemic and Adipose Tissue Inflammation and Insulin Resistance in Mice." ​Scientific

reports​ 6.1 (2016): 35405. ​MEDLINE. ​Web.

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6. Michael Berk, et al. "So Depression is an Inflammatory Disease, but Where does the

Inflammation Come from?" ​BMC Medicine​ 11.1 (2013): 200. ​Virology and AIDS

Abstracts. ​Web.

7. Maes, M., et al. "In Depression, Bacterial Translocation may Drive Inflammatory

Responses, Oxidative and Nitrosative Stress (O&NS), and Autoimmune Responses

Directed Against O&NS-damaged Neoepitopes." ​Acta Psychiatrica Scandinavica​ 127.5

(2013): 344-54. ​Technology Research Database. ​Web.

8. Wang Y, Kuang Z, Yu X, Ruhn KA, Kubo M, Hooper LV. The intestinal microbiota

regulates body composition through NFIL​3​ and the circadian clock. ​Science​.

2017;357(6354):912-916.

9. Germain A, Kupfer DJ. Circadian rhythm disturbances in depression. ​Hum

Psychopharmacol.​ 2008;23(7):571-85.

10. Mukherjee S, Coque L, Cao JL, et al. Knockdown of Clock in the ventral tegmental area

through RNA interference results in a mixed state of mania and depression-like behavior.

Biol Psychiatry​. 2010;68(6):503-11.

11. Hussain MM. Metabolism: gut microbiota modulates diurnal secretion of glucocorticoids.

Nat Rev Endocrinol​. 2013;9(8):444-6.

12. Johnson, Sarah A., Neil M. Fournier, and Lisa E. Kalynchuk. ​Effect of Different Doses of

Corticosterone on Depression-Like Behavior and HPA Axis Responses to a Novel

Stressor​. 168 Vol. , 2006. Web.