The Effects of Probiotics on

Neuropsychiatric Disorders
Rob Fancher, NDTR, FSP
Dietetic Intern – Sodexo, New Bedford
August 26, 2018
The Effects of Probiotics on Neuropsychiatric Disorders R. Fancher 8/26/18

The human gut microbiome is home to a complex and diverse agglomeration of

microorganisms that are responsible for an immense array of metabolic functions. In particular,

the commensal and symbiotic bacteria that live in the gut are being studied for their beneficial

role not only in gastrointestinal function, but brain function as well. Consumption of probiotic

foods and supplements may enhance the positive effects of the gut microbiome and help to

improve symptoms of or even prevent some neuropsychiatric disorders.

The microbiota play a major role in maintaining the integrity of the gut barrier. Factors

that contribute to the composition of gut flora include age, diet, use of antibiotics, probiotics, and

synbiotics- a combination of prebiotics and probiotics. Gut flora contribute to macro- and

micronutrient metabolism in a number of ways. They mostly thrive on dietary carbohydrates,

which are in turn synthesized into short chain fatty acids (SCFAs) via bacterial fermentation.

SCFAs such as butyrate prevent the accumulation of lactic acid in the colon, which contributes to

metabolic acidosis when concentrations are high[4]. SCFAs are absorbed directly through the

portal vein, are able to cross the blood-brain barrier, where they can stimulate the release of

serotonin[9]. Gut flora also enhance lipid metabolism by suppressing the inhibition of lipoprotein

lipase activity in adipocytes and promoting the expression of other lipid digesting enzymes.

Bacterial proteinases and peptidases transport amino acids from the intestine into the bacterial

cell, where they are then converted into cell signaling molecules and antimicrobial bacteriocins;

these actions make protein metabolism more efficient. Gut flora also play a role in micronutrient

synthesis of vitamin K and most B vitamins. Polyphenols such as flavanols, isoflavones, tannins,

and lignans, among others, which are found in plant-based foods, are inactive until the associated

sugar moiety is consumed by the microbiota. These active compounds are absorbed into the

portal vein where they go on to have antimicrobial effects in other tissues and organs. Xenobiotic

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environmental compounds as well as drugs and their metabolites are also metabolized by the gut

microbiome[4]. All of these factors contribute to the direct link the gut has with the brain and

related disorders.

The gut-brain axis is a term used to describe the bi-directional communication link of the

central nervous system (CNS), autonomic nervous system (ANS), enteric nervous system (ENS),

and the hypothalamic pituitary adrenal (HPA) axis. This link involves neural, endocrine,

immune, and humoral signals sent back-and-forth largely along the vagus nerve. The HPA axis

responds to internal and external environmental stressors by sending signals for the release of

pro-inflammatory cytokines, cortisol, and other stress hormones. Stress-related health conditions,

such as depression and anxiety, are often co-morbid with gastrointestinal distresses such as IBS

or IBD[9, 10].

Microbiota may have an impact on stress-related and neuropsychiatric disorders via the

gut-brain axis and other pathways. Various mechanisms may account for the relationship

between the gut and depression. For instance, it has been shown that gut bacteria produce gamma

aminobutyric acid (GABA), which is a primary regulatory neurotransmitter that can modulate

feelings of anxiety[10]. Microbiota can also produce other neurotransmitters, such as serotonin,

dopamine, and more importantly, their precursors. While serotonin produced in the gut will stay

there, tryptophan can cross the blood-brain barrier and increase serotonin levels in the brain[9].

Furthermore, it is possible that depressive symptoms may be caused by increased intestinal

permeability, and certain probiotics have been found to decrease intestinal permeability by

improving the epithelial barrier[8].

Fermented foods have been consumed by humans for thousands of years. Many of these

foods were discovered by accident, such as yogurt. Probiotic cultures are found naturally in these

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foods, but may also be added in processing for additional benefits, such as the number of colony-

forming units (CFUs) or more bacterial strains. There are many different varieties of foods that

are probiotic in nature, such as the traditional Korean kimchi and German sauerkraut, both

fermented cabbage dishes. Kefir is a fermented milk drink, while kombucha, also a beverage,

consists of fermented tea inoculated with a symbiotic culture of bacteria and yeast, or SCOBY.

These and other probiotic foods are gaining traction with the public, and have become widely

available in grocery stores in a multitude of styles and flavors. However, those with severely

compromised immune systems such as HIV/AIDS and cancer patients receiving chemo or

radiation treatment should avoid live and active bacterial cultures due to the risk of potential

infection[7]. Probiotics have been studied extensively for their positive effects on gastrointestinal

health, so it would seem a shift in focus towards studying other ways they may be helpful is the

next logical step. The direct connection of the gut and the brain is an interesting and important

subject to study for these reasons.

In a study by Mohammadi et al, the researchers were interested in learning more about

the effects of probiotics on mental health in relation to the HPA axis. Specifically, they targeted

their research to petrochemical workers who are exposed to aromatic compounds on a daily

basis, as well as being a high-stress job, and the effect probiotics may have on mood and

biochemical markers of depression, anxiety, and overall mental health. The study took place in

Iran with 70 subjects, 36 male, 34 female, aged 20-60. The study excluded those who were using

insulin or vitamins or other supplements, or antibiotics, those with renal, hepatic, thyroid,

intestinal, or other chronic or acute inflammatory disease, allergies, or pregnant.

During this 6 week, randomized, double-blind, placebo-controlled trial, participants were

assigned to one of three groups. The first group received 100g/day of probiotic yogurt

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(containing additional bacterial strains of Lactobacillus acidophilus and Bifidobacterium lactis)

and one placebo capsule. The second group received 100g/day of conventional yogurt and one

probiotic capsule (containing seven different bacterial species). The third group received

100g/day of conventional yogurt and one placebo capsule. The participants were instructed to not

change their usual intake and to not consume any other probiotic or synbiotic products. Three

dietary and physical activity records were provided to confirm compliance. Anthropometric

measurements and blood samples were obtained at baseline and after the 6 week intervention.

Primary outcomes were measured using two psychiatric screening tools. The general

health questionnaire (GHQ) consists of 28 self-reported scales on somatic symptoms, anxiety

and insomnia, social dysfunction, and severe depression. The depression, anxiety, and stress

scale (DASS) consists of 14 self-reported scales measuring depression, anxiety, and stress.

Secondary outcomes included several biochemical measurements related to the HPA axis,

notably tryptophan and cortisol. Mean anthropometric measurements showed no significant

change after the 6 week trial. A significant improvement of GHQ and DASS scores were

observed in both the probiotic yogurt and probiotic capsule groups (GHQ p = 0.007, 0.001,

respectively, DASS p = 0.02, 0.006), and no significant changes were observed in the

conventional yogurt and placebo capsule group. No significant effects were noted in any group

with HPA axis markers[5]. Overall, this study showed a positive effect of probiotics on the mental

health of generally healthy petrochemical workers.

In another study by Steenbergen et al, researchers were looking to test the effects of

probiotics on cognitive reactivity to sad mood. Similar to Mohammadi et al, this study was

interested in the microbiota’s role in producing neuroactive substances and their precursors such

as tryptophan. The study took place in the Netherlands with 40 subjects, 8 male and 32 female,

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with no psychiatric or neurological disorders, and no personal or family history of depression or

migraines. Exclusion criteria consisted of those with cardiac, renal, or hepatic disease, allergies

or intolerance to lactose or gluten, prescribed medication or drug use, and consumption of more

than 3-5 alcoholic drinks per week.

The participants were randomly assigned to either a probiotic or placebo group. The

probiotic group received a 2g/day supply of freeze-dried probiotic powder, and the placebo

group received a 2g/day supply of powder containing maize starch and maltodextrins, also found

in the probiotic powder. Each group was instructed to mix the powder with water or lukewarm

milk and to drink before bed. Compliance was assisted via text message reminders each evening,

but not confirmed in any manner. This study was randomized, triple-blinded, and placebo-

controlled, and took place over 4 weeks.

For this study, outcomes were measured by the LEIDS-r, Beck Depression Inventory II

(BDI-II, and Beck Anxiety Inventory (BAI) questionnaires which assess the existence and

severity of depressive and anxiety symptoms. Results showed the probiotic group experienced

significantly reduced overall cognitive reactivity to depression (p = <0.001), as well as reduced

aggressive (p = <0.01) and ruminating thoughts (p = <0.001) as measured by the LEIDS-r scale.

This indicates that individuals who were in a sad mood were less distracted by aggressive and

ruminative thoughts after probiotic supplementation. However, the study did not control for

consumption of additional probiotic foods[8].

A study by Pärtty et al greatly differed in approach, and tested early probiotic

intervention in infants to investigate the risk of developing neuropsychiatric disorders later in

childhood. Specifically, the researchers looked at the prevalence of ADHD and Asperger’s

syndrome (AS) at age 13 after probiotic supplementation during the first six months of life.

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Interestingly, the original aim of the cohort was to test the effects of probiotics on development

of eczema, but several types of data were collected including the results of this study; 159

mothers in Finland were randomized into a probiotic group receiving capsule supplementation

for 4 weeks before birth, or a placebo group. After birth, the mother kept taking the capsule if

breastfeeding, or the capsule contents were given to the children that were formula-fed for 6

months. 75 of the 159 children finished the study, 40 males and 35 females. Fecal samples were

taken at 3 weeks, 3, 6, 12, 18, 24 months, and 13 years.

In this randomized, double-blind, placebo controlled, prospective cohort study, at the 13

year follow-up, the children were analyzed by child psychiatrists or neurologists who made a

diagnosis of ADHD or AS based on the international classification of diseases (ICD-10) criteria.

Out of the probiotic group, none of the children were diagnosed with either disorder, whereas the

placebo group had 6 diagnoses, notably all male (p = 0.008). Differences in fecal bacterial

composition were also assessed, showing significantly lower median numbers of certain bacteria

in the children diagnosed with the disorders at 3, 6, 18, and 24 months. However, at age 13, no

statistically significant differences in gut microbiota composition were found between those with

neuropsychiatric disorders and those without[6]. This study is not without its faults, such as a

large number of dropouts and no control over diet after 6 months of age, but shows that early

probiotic supplementation may have an effect on the neural pathways of the gut-brain axis and

possible preventive effects of the development of neuropsychiatric disorders later in childhood.

In direct contrast to Steenbergen et al, a study by Akkasheh et al looked at the effects of

probiotics on patients already diagnosed with major depressive disorder (MDD). The researchers

cited Mohammadi et al in their interest of how probiotics may affect those already with

neuropsychiatric disorders. This 8 week clinical trial also utilized the BDI questionnaire.

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Secondary measures included serum CRP, markers of oxidative stress and metabolic status. 40

individuals, 34 women and 6 men were randomized into probiotic capsule or placebo groups.

The participants were asked to not change their normal intake or physical activity habits, and to

not consume any other supplements or medications that might affect the results; diet and physical

activity records were provided to confirm compliance.

This randomized, double-blind, placebo-controlled study took place in Iran. After the

intervention, the probiotic group showed a significantly improved BDI score (p = 0.001),

significantly decreased serum insulin levels, HOMA-IR (a measure of insulin resistance), and

high sensitivity CRP concentrations (p = 0.03), but no significant differences were seen in FPG,

HOMA-B (beta-cell function), or lipid profiles. Additionally, there was a significant increase in

antioxidant glutathione concentrations (p = 0.02), but no significant difference in total

antioxidant capacity (TAC).

This study indicated there may be a positive effect on probiotic supplementation for

patients with MDD, and showed a reduction in symptoms of depression. The researchers

hypothesize that probiotics increase plasma tryptophan levels and decrease the metabolism of

serotonin and dopamine through bacterial fermentation[1]. Limitations include the length of the

study and sample size.

Lastly, and similarly to Akkasheh et al, a study by Dickerson et al also wanted to observe

the effects of probiotics on those already with a neuropsychiatric disorder. This study took it a

step further by looking at individuals diagnosed with schizophrenia or schizoaffective disorder.

The researchers of this randomized, double-blind, placebo-controlled, 14 week intervention

wanted to study the microbiome’s influence on symptoms of schizophrenia and associated

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inflammatory response and GI function in conjunction with antipsychotic medications, which

can cause severe constipation.

65 participants, 42 male, 23 female, in an outpatient psychiatric rehab facility in

Baltimore, Maryland were assigned to a probiotic tablet or placebo group. Individuals included

also displayed moderately severe residual psychotic symptoms measured by the Positive and

Negative Syndrome Scale (PANSS), which was the primary measure for this study, taken every

2 weeks. In relation to GI symptoms, the researchers particularly looked at the drug clozapine’s

influence, but patients across the groups were on several types of antipsychotics. Their findings

showed no significant improvement in total PANSS scores, but the probiotic group showed that

they were less likely to report difficulty moving their bowels (p = 0.003). However, the two

groups did not show a significant difference in the use of laxatives or incidence of diarrhea[3].

This study shows that probiotics may not have an effect on more severe neuropsychiatric

disorders. Nonetheless, the beneficial GI effects attributed to probiotic use were present in this

study. However, this study’s limitations include a small sample size, short duration, and no

mention of whether usual diet, physical activity, or use of other probiotics were enforced.

To conclude, more research on the subject is required. Not all of these studies mentioned

use of antibiotics during intervention, which could be a very important and impactful factor on

the results. Overall, probiotic supplementation is generally regarded as safe, and shows many

potential benefits. Although current research may benefit from larger sample sizes and tighter

control of confounding variables, these preliminary results do show that probiotic use may have

a positive impact on, or may even help prevent, mild-to-moderate neuropsychiatric symptoms.

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References
1
Akkasheh, G., Kashani-Poor, Z., Tajabadi-Ebrahimi, M., Jafari, P., Akbari, H., Taghizadeh, M., . . .
Esmaillzadeh, A. (2016). Clinical and metabolic response to probiotic administration in patients
with major depressive disorder: A randomized, double-blind, placebo-controlled
trial. Nutrition,32(3), 315-320. doi:10.1016/j.nut.2015.09.003

2
Carabotti, M., Scirocco, A., Maselli, M. A., & Severi, C. (2015, April). The gut-brain axis:
Interactions between enteric microbiota, central and enteric nervous systems. Retrieved from
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367209/

3
Dickerson, F. B., Stallings, C., Origoni, A., Katsafanas, E., Savage, C. L., Schweinfurth, L. A., . . .
Yolken, R. H. (2014). Effect of Probiotic Supplementation on Schizophrenia Symptoms and
Association With Gastrointestinal Functioning: A Randomized, Placebo-Controlled Trial. The
Primary Care Companion For CNS Disorders,16(1). doi:10.4088/pcc.13m01579

4
Jandhyala, S. M., Talukdar, R., Subramanyam, C., Vuyyuru, H., Sasikala, M., & Reddy, D. N.
(2015, August 07). Role of the normal gut microbiota. Retrieved from
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4528021/

5
Mohammadi, A. A., Jazayeri, S., Khosravi-Darani, K., Solati, Z., Mohammadpour, N., Asemi, Z., .
. . Eghtesadi, S. (2015). The effects of probiotics on mental health and hypothalamic–pituitary–
adrenal axis: A randomized, double-blind, placebo-controlled trial in petrochemical
workers. Nutritional Neuroscience,19(9), 387-395. doi:10.1179/1476830515y.0000000023

6
Pärtty, A., Kalliomäki, M., Wacklin, P., Salminen, S., & Isolauri, E. (2015). A possible link
between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood:
A randomized trial. Pediatric Research,77(6), 823-828. doi:10.1038/pr.2015.51

7
Regulatory Oversight and Safety of Probiotic Use - Volume 16, Number 11-November 2010 -
Emerging Infectious Diseases journal - CDC. (2011, March 08). Retrieved from
https://wwwnc.cdc.gov/eid/article/16/11/10-0574_article

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8
Steenbergen, L., Sellaro, R., Hemert, S. V., Bosch, J. A., & Colzato, L. S. (2015). A randomized
controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad
mood. Brain, Behavior, and Immunity,48, 258-264. doi:10.1016/j.bbi.2015.04.003

9
Tengeler, A. C., Kozicz, T., & Kiliaan, A. J. (2018). Relationship between diet, the gut microbiota,
and brain function. Nutrition Reviews,76(8), 603-617. doi:10.1093/nutrit/nuy016

10
Vlainic, J. V., Š Uran, J., Vlaini|, T., & Vukorep, A. L. (2016). Probiotics as an Adjuvant Therapy
in Major Depressive Disorder. Current Neuropharmacology,14(8), 952-958.
doi:10.2174/1570159x14666160526120928

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