The Potential Benefits of Probiotic Ingestion in Psychiatric Disorders Such as Depression

Michael Douglass

NTR 507

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Introduction

The human gut contains trillions of living organisms, also called microbiota, which are

important for maintaining health. Gut microbiota have the ability to influence many roles

associated with human physiology including immune function, digestion, gut permeability,

neurotransmitter production and nutrient processing. Recent research has indicated that these

important gut microbiota may even have a role in the functioning of the central nervous system

(Foster & Neufeld, 2013). A direct link between the gut and the brain exists through the enteric

nervous system via the vagus nerve. This connection through the vagus nerve is thought to be a

direct route which allow gut microbiota to communicate with the brain and indicates that gut

microbiota may be able to influence emotional behavior (Kelly et al., 2015). The ability for

microbiota to influence behavior is supported by a study which examined behaviors of mice who

had underwent the removal of their vagus nerves. In this study, mice that were fed the probiotic

Lactobacillus ramnosus experienced a reduction in stress and anxiety behaviors. This reduction

in anxiety was not present in mice that underwent the removal of the vagus nerve, the connection

between the gut and brain, indicating brain functioning can be influenced by gut microbiota

(Dinan & Cryan, 2013)

. Major depressive disorder, also known just as depression, is a debilitating mental disorder

which affects a person’s mood. Individuals with depression can experience symptoms such as

anxiety, helplessness, sadness, loss of interest in previously enjoyable activities, diet changes,

and can even lead to suicide. Depression is a common mental illness with an estimated 350

million people currently affected worldwide and is the fourth leading cause of global burden

(Huang, Wang, & Hu, 2016). The treatment of depression with antidepressants can be effective

but these medications can lead to undesirable symptoms and in extreme cases can lead to an

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increase in suicidal thoughts. It’s estimated that 30-40% of major depressive disorder patients

medicated with antidepressants find the treatment ineffective (Jiang et al., 2015). The prevalence

of major depressive disorder, ineffectiveness of current medications and the symptoms related to

current antidepressants has increased the interest of discovering alternative treatments for the

illness (Huang et al., 2016).

Probiotics are live microorganisms that can when ingested in adequate quantities are beneficial

to the host’s health (Huang et al., 2016). Probiotic ingestion is associated with many health

benefits such as, development and maintenance of healthy gut microbiota, aiding digestion, and

supporting immune function through decreasing intestinal permeability. The relationship

between gut microbiota and brain function has inspired interest in the idea that probiotics,

through their ability to alter gut microbiota, may have the ability to influence symptoms of

mental illnesses such as depression. Emerging evidence in research that suggests a relationship

between probiotics and mental health has inspired a new term “psychobiotic”. A psychobiotic is

considered a live organisms that are beneficial to the host in regards to symptoms of

psychological disorders when ingested (Kelly et al., 2015). This review was conducted in order

to summarize the relationship between probiotics and major depressive disorder and to identify if

probiotics can be used as an effective treatment for reducing symptoms of depression (Huang et

al., 2016).

Probiotics and Brain Activity

Evidence continues to emerge that support the association between alterations in gut

microbiota and emotional behavior. Probiotics role of influencing gut microbiota indicate that

probiotic induced microbiota alterations have the ability to influence behavior. The results from a

recent study support the hypothesis that probiotic administration can influence brain activity.

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This study investigated the effect of a fermented milk product containing probiotics on brain

activity. A group of healthy women consumed a fermented milk product containing probiotics

twice daily for 4 weeks and their brain activity was measured using magnetic resonance imaging.

The fermented milk product contained 1.25 x 1010 units of Bifidobacterium animalis subsp

lactis per cup, and 1.25 x 109 units per cup of Streptococcus thermophiles, Lactobacillus

bulgaricus, and Lactococcus lactis subsp lactis. A non-fermented milk product without

probiotics was consumed by a control group which was matched to the test product for texture

and taste. An emotional faces attention task was performed before and after probiotic

intervention and brain activity was measured using magnetic resonance imaging. An emotional

faces attention task engages multiple regions of the brain and is suited for measuring changes in

emotional regulation. The results of the study showed a 49% decrease (P= .004) in activity from

pre to post-intervention in the functioning of the interoceptive, somatosensory and

periaqueductal gray regions of the brain. The results indicate that probiotics have the ability to

effect brain functioning in regions known to be responsible for processing emotion and sensation

(Tillisch et al., 2013).

Stress and Microbiota

Intestinal Permeability

One of the most promising pathways in which probiotics may influence mood disorders

is through maintenance of gut integrity. Major depressive disorder is associated with stress and

inflammation. The association between stress and depression is supported by the frequency of

irritable bowel syndrome sufferers who also suffer from depression. Irritable bowel syndrome is

a stress related disorder associated with increased intestinal permeability and altered microbiota.

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Interesting, it’s estimated that around 50% of IBS sufferers are also diagnosed with a mental

disorders such as depression (Dinan & Cryan, 2013).A major role of gut microbiota is the

development and maintenance of the intestinal barrier. The intestinal barrier is responsible for the

prevention of pathogenic and toxic substances from entering the bloodstream which initiates an

immune response. An immune response resulting from weakened intestinal permeability leads to

an increase in stress and a pro-inflammatory state for the host which can affect the CNS via the

vagus nerve. Stress is known to increase intestinal permeability indicating that preexisting stress

and stress induced by altered intestinal permeability can develop a cycle of inflammation and a

chronic inflammatory state in the host. Chronic inflammation is also associated with sufferers of

major depression disorder. Probiotics can be used to treat increased intestinal permeability by

repopulating gut microbiota and by reestablishing tight junction integrity of the gut. The ability

of probiotics to decrease intestinal permeability, decreasing stress and inflammation, supports the

hypothesis that probiotics may be used as a treatment for mood disorders such as depression

(Kelly et al., 2015).

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Figure 1: A disrupted intestinal barrier results in an immune response increasing stress and inflammation (Kelly

et al., 2015)

HPA axis and Behavior

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 Another stress related pathway where probiotics may influence behavior is through the

hypothalamic pituitary adrenal axis. The hypothalamic pituitary adrenal (HPA) axis is a process

which is responsible for how animals and humans respond to stress. The HPA axis is a stress

response system between the pituitary gland, hypothalamus, and the adrenals which regulates the

release of glucocorticoids during stressful situations. A hyperactive HPA axis is associated with

major depressive disorder and is associated with altered gut microbiota (Kelly et al., 2015). Early

animal studies have discovered that mice with sterile GI tracts experience an increase in anxiety

and stress. The increase in stress and anxiety is believed to be as result from the development of

a hyperactive HPA axis due to lack gut microbiota. The hyperactive response of the HPA axis

was reversed with the administration of the probiotic Bifidobacterium infantis. The reversal of

anxiety symptoms in rats with the introduction of probiotics indicates a link between probiotic

intervention and behavior (Dinan & Cryan, 2013).

In a more recent animal study, rats were administered a probiotic solution containing two

strains of probiotic for two weeks and their ability to cope with stress was observed. The

probiotic group was compared to a control group of rats with no probiotic administration. The

two strains of probiotic administered to the rats were Lactobacillus helveticus R0052 and

Bifidobacterium longum R0175. The rats were subjected to an electric shock and their behaviors

were screened by a trained observer using the defensive burying test to evaluate the level of

stress and anxiety the rats experienced. The results of the defensive burying test showed that the

rats that were administered the probiotic formula scored 47.50 and experienced significantly less

stress, with a p-value of 0.001, compared to the untreated rats which scored 62.25 on the test.

The reduction of stress experienced by the rats after administration of a probiotic formula

correlate with similar studies which indicate that probiotic intervention can influence behavior

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through stress related pathways. Animal studies are important for research; however, results

from animal studies are not always reliable for human comparison (Messaoudi et al., 2011).

Probiotic Human Studies

The suggested beneficial effects of probiotics on their role in influencing symptoms of

depression is still a new topic with few human studies existing. However; the evidenced from the

limited human studies support the hypothesis that probiotics have the ability to reduce symptoms

of psychological disorders such as depression. In one double-blind experiment, human subjects

were given a probiotic formula containing 3 x 109 units of Lactobacillus helveticus R0052 and

Bifidobacterium longum R0175 for 30 days and their psychological stress was evaluated using

the self-assessment questionaires Hospital Anxiety and Depression scale (HADS) and Hopkins

Symptom Checklist-90 (HSCL-90). The subjects that received the probiotic intervention

experienced significant (P < 0.05) change between baseline and follow-up in their HSCL-90

scores compared to the control group. In particular, the results from the HSCL-90 showed

improvements in the subscales somatization, depression, and anger-hostility in the probiotic

treated subjects. The results from the HADS scale were also promising indicating a significant

(p=0.03) reduction of psychological stress from baseline to follow-up. The results indicate that

probiotic ingestion has the ability to reduce general symptoms of anxiety and depression and

improve mood in individuals (Messaoudi et al., 2011).

Metabolic Response to Probiotic Administration

Major depressive disorder is associated with increased inflammation and oxidative stress

and can cause physiological changes in the human body. The increase in stress seen in depression

sufferers increases inflammation indicated by increased C- reactive protein levels and insulin

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resistance seen in patients diagnosed with major depressive disorder. C-reactive proteins are

inflammation indicators known to affect mood. A recent randomized, double-blind, placebo-

controlled trial was conducted in order to assess the effectiveness of probiotic supplementation

on symptoms of depression and to examine if probiotic ingestion can influence inflammation and

insulin regulation. A group of patients diagnosed with major depressive disorder were randomly

chosen to receive a probiotic supplement or a placebo for eight weeks. The probiotic group

received one capsule containing 2 x 109 units per gram of Lactobacillus acidophilus,

Lactobacillus casei, and Bifidobacterium bifidum daily. The patient’s level of depression was

measured using the Beck Depression Inventory (BDI) questionnaire at the beginning and after 8

weeks of administration. Blood samples were also collected to measure serum insulin and

various biomarkers for inflammation. The group that received the probiotic supplement had

significantly (P=0.001) decreased BDI scores compared to the placebo group. The probiotic

group also had a significant (P=0.03) decrease in the serum C-reactive protein and insulin. The

results indicate that probiotic intervention benefitted depressed patients by decreasing

inflammation indicated by the decreased levels of C-reactive protein and serum insulin

(Akkasheh et al., 2016).

Cognitive Reactivity and Depression

Cognitive reactivity is believed to play an important role in the development and relapse

of major depressive disorder. Cognitive reactivity refers to negative thinking patterns activated

by mood changes in an individual and is considered a reliable predictive marker for depression.

The association between cognitive reactivity in the development of depression is supported by a

study that found that individuals who scored high in tests measuring cognitive reactive were

more likely to develop major depressive disorder within the next two years. Therefore, a

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treatment which attempts to control cognitive reactivity may offer an effective preventative

treatment for depression. A recent randomized controlled trail evaluated the effectiveness of

probiotic administration on cognitive reactivity. A group of healthy individuals were randomly

chosen to receive either probiotics or a placebo for four weeks and their level of cognitive

reactivity was measured before and after intervention. The freeze dried probiotic mixture

contained 2.5 x 109 units per gram of Bifidobacterium bifidum W23, Bifidobacterium lactis

W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, L. casei W56, Lactobacillus

salivarius W24, and Lactococcus lactis W19 and W58. The LEID-r, a self-report questionnaire,

was used to measure cognitive reactivity by assessing the level of negative thoughts activated

while in a state of sad mood. The results showed that the participants who received the probiotic

intervention scored significantly lower (p < 0.001) post intervention compared to the control

group. The greatest reductions of cognitive reactivity were observed in the subscales of

aggression and rumination. Studies have shown that rumination and aggression are particularly

important markers of depression. The tendency to ruminate while in a sad mood increases the

chances of developing depression and increases the difficultly of recovery. The occurrence of

aggressive thoughts while in a sad mood is also important because of its association with

increased risk suicide. The results indicate that probiotic intervention can positively influence

cognitive reactivity which is a strong determinate for the development of depression and

recovery (Steenbergen, Sellaro, Hemert, Bosch, & Colzato, 2015).

Probiotics and Neurochemistry

The exact mechanism for how probiotics influence brain activity and reduce symptoms of

depression are not completely understood. Evidence indicates that probiotic intake has the ability

to reduce symptoms of depression through maintaining gut integrity and by the reversal of

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hyperactive HPA axis activity (Kelly et al., 2015). Other possible pathways that probiotics can

influence mood and behavior exist but have less evidence to support them. One possible pathway

probiotics may influence behavior is through the production of the inhibitory neurotransmitter

Gamma-Amino Butyric acid (GABA). The ability of the probiotic strains Lactobacillus and

Bifidobacterium to metabolize GABA support the idea that probiotics may influence behavior

through this pathway. Altered GABA expression in brain regions associated with stress have

also been seen in animal studies after administered the probiotic L. rhamnosus further supporting

this possible pathway. The association between GABA and probiotic strains is interesting but

further research is needed on this mechanism in order to better understand the process (Foster &

Neufeld, 2013).

Another possible pathway for probiotic induced behavior change is through serotonin

signaling. Serotonin is a neurotransmitter found in abundance in the GI tract and is involved in

many physiological processes. Evidence suggests that gut microbiota may influence the

serotonergic system. It is also suggested that serotonin may influence intestinal permeability. The

relationship between serotonin and gut microbiota is promising but more research needs to be

conducted in order for any conclusions to be made about the possible pathway in regards to

influence on behavior change (Kelly et al., 2015).

Conclusion

The association between gut microbiota and brain function has increased interest in the

hypothesis that alterations in gut microbiota may be influential in mood disorders such as

depression. Since probiotics have the ability to alter gut microbiota, it has been suggested that

probiotic ingestion can be used as a treatment for depression. Recent studies indicate that

probiotics can influence behavior and reduce symptoms of depression (Kelly et al., 2015). In

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animal studies, probiotics are associated with reversing overactive HPA axis activity and

reducing stress in mice (Messaoudi et al., 2011). The results from human studies involving

probiotic intervention have been promising. Results from human studies show reduced scores in

multiple measuring tools for depression and a decrease in inflammation in the subjects (Huang et

al., 2016). The exact mechanism probiotics use to influence behavior is unknown; however,

probiotics role in reducing intestinal permeability is believed to be one important pathway which

gut microbiota can influence behavior (Kelly et al., 2015). Due to the large variety of existing

probiotic species, it is difficult to known what strains will be most effective for mood disorder

treatment. More research needs to be done on the effectiveness of probiotic intervention in order

to conclude that their consumption is an effective treatment for depression. Daily ingestion of

probiotics does seem to benefit mood without any negative symptoms but at this time specific

recommendations for probiotic consumption in order to gain these benefits cannot be made.

However; the specific strains and doses of probiotic intervention used in the studies mentioned in

this review indicate probiotic consumption is capable of behavior changes and support the

hypothesis that probiotic ingestion may be useful as a treatment for the symptoms of depression

(Huang et al., 2016).

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