Probiotic milk impacts stress response, gene expression in human trial

Students who drank probiotic milk before taking exams showed fewer signs of stress than students drinking standard milk, according to a 47 person trial published in Applied and Environmental Microbiology. Researchers from the Yakult Central Institute in Japan measured physiological and psychological stress responses, with a strong difference between the groups observed in the expression of 179 stress-related genes.


Dr. Emeran Mayer, Director, Oppenheimer Center for Neurobiology of Stress, David Geffen School of Medicine, UCLA (webpage):

Expertise: Brain gut interactions in health and disease. 

“It’s an interesting study which adds much needed  human data to the field of gut microbiota brain interactions, and the effect of probiotics on these interactions.  Most of the available evidence comes from animal studies and some low quality human studies.  The authors have to be congratulated on a well-designed study which includes both behavioral and biological read outs, but I would not take it as definitive.  One problem is that 13 of the coauthors were employees of Yakult, the sponsor of the study.

“Another question is how generalizable some of the findings are, given the small sample size. This is particularly true for the behavioral readouts. Normally, when you do randomized controlled trials with probiotics you need hundreds of patients to demonstrate clinical effects. And since symptoms are more variable than biological markers, you need a large sample to show a significant effect on symptoms.

“In the study there was really no significant effect on anxiety and feelings of stress, and small  changes in other factors like abdominal symptoms between the probiotic group and the placebo group. There were some changes in the composition of the microbiota, but they were small changes in number and abundance of species. One thing that does look interesting is the gene expression profile: one day before there was this big difference between the probiotic group and the placebo group.

“There is pretty good evidence from human studies that acute and chronic stress is associated with change in gene expression profiles of circulating immune cells. There are preclinical studies showing clear effects of probiotics on gene expression in the brain, but there are no human studies looking at stress induced gene expression profiles in peripheral immune cells that involve a probiotic intervention.

“It’s remarkable when you think about it that a probiotic intake might have such a profound effect on the immune system. Hopefully other people will come out with similar reports with larger sample sizes that confirm these intriguing findings.”


Dr. Jennifer Mulle, Assistant Professor, Department of Epidemiology, Emory University (webpage):

Expertise: Psychiatric genetics; genetic epidemiology; microbiome research.

“This study advances the body of work showing that administration of probiotics can influence emotional state and response to stress.  Prior studies in animal models have shown that Lactobacillus rhamnosus diminishes the stress response in mice.  A small study in human female volunteers who ingested a probiotic mixture revealed changes in an emotional attention task, as measured by fMRI.  The latest study by Kato-Kataoka et al continues this effort, showing that human volunteers who ingested Lactobacillus casei strain Shirota reported diminished response to stress, and had blunted physiological stress responses, as measured by commonly used stress biomarkers such as salivary cortisol.

“One strength of this study is the choice of study population.  Humans exhibit vast heterogeneity and experiences a multitude of stressful experiences in daily life. Designing a study to evaluate stress in a human samples in a controlled, coordinated way is a substantial challenge. These authors addressed this in a unique way, by ascertaining human volunteers from 4th year medical students in Japan, two months prior to taking a nationwide exam required for advancement in their training. Thus all individuals in the study had a common stressor to be applied in the same way at the same time. While this may limit the generalizability of these findings, their wise selection of study sample likely allowed the authors to see an effect in a relatively small sample size. This study should be replicated in additional populations.  Future studies should also explore other types and strains of probiotics.

“In addition to well-known biomarkers, the authors also examined gene expression changes in peripheral blood. A limitation of the study is that their gene expression analysis was limited to males only; it is not clear why females were excluded.  Additional studies should investigate expression changes in females alongside males.  While more work is required, this study adds to the tantalizing possibilities that have already been hinted at for the role of probiotics in human health.”


Declared interests (see GENeS register of interests policy):

Dr. Emeran Mayer: “I am on the advisory board for another probiotic company not involved in the study.”

No further interests declared.



‘Fermented milk containing Lactobacillus casei strain Shirota 2 preserves the diversity of the gut microbiota and relieves abdominal 3 dysfunction in healthy medical students exposed to academic stress’ by Kato-Kataoka et al, published in Applied and Environmental Microbiology on Friday, May 6, 2016.

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