1.1 Description of the condition
When an individual perceives that demands from society, work and study tax, or exceed his or her adaptive capacity, psychological stress unavoidably occurs. For the human being, psychological stress is more than a subjectively negative experience. Generally, stress response is important for enhancing adaptability and coping with threatening situations. However, excessive psychological stress is negative, not only increases the risk of diseases, included hypertension, cardiovascular diseases, digestive system diseases, and most neuropsychiatric disorders[8,9], but also may cause reduced happiness in life, job burnout, unhealthy lifestyles,[12,13] and other consequences. Statistics showed that in the UK, at least one-third of work-related diseases are caused by stress, resulting in a large loss of working time. Therefore, finding an effective means to prevent stress, relieve stress, and reduce the adverse effects of stress on individuals, families, and society has become a hot issue in the present research, especially in the medical field.
1.2 Description of intervention
A large number of diverse intestinal microbes are planted in the human gut, which are symbiotic with the host and participates extensively in the life activities of the host.[15,16] Studies have found that[17–19] intestinal microbes can regulate the mood, cognition, and nervous system function of the host through various means such as nerve, immunity, and endocrine (ie, brain-gut axis). Stress is an important factor in the intestinal micro-ecological disorders, and may cause more health problems.
Probiotics are active micro-organisms. When applied in sufficient quantities, probiotics can play a beneficial role by improving the intestinal tract for ecological balance. Animal and human studies have confirmed that in some cases, probiotics can increase or decrease the synthesis of certain neurotransmitters and biologically active factors such as serotonin, brain-derived neurotrophic factor, cortisol, thereby alleviating the subjective stress level of the participants, as well as related mental symptoms such as anxiety and depression. Because probiotics have a positive role in mood, cognition, and other psychological processes, probiotics are also known as “psychobiotics”[24,25] and may be a potential therapy or auxiliary means for stress-related mental disorders.
1.3 Why this systematic review is needed
So far, a large number of clinical studies on the application of probiotic supplements to intervene in stress response have been carried out worldwide. However, the Cochrane Database of Systematic Reviews, Embase, and MEDLINE databases were searched, and evidenced reviews or protocols on “whether probiotics have effects on relieving psychological stress in healthy participants” were not found. Therefore, this systematic review is urgently needed.
2.1 Study registration
The protocol has been registered in PROSPERO, the International Prospective Register of Systematic Reviews with registration number CRD42019122930 on February 21, 2019.
2.2 Ethics and dissemination
Ethical approval is not necessary as this paper is a reanalysis of the original study, which does not involve participations’ privacy issues. The results of this study will provide information on the effectiveness and safety of probiotics supplements to alleviate psychological stress in healthy populations. This protocol will be disseminated by a peer-reviewed journal, thus providing evidences for clinical practice.
The healthy participants with no known major health issues, regardless of age, gender, ethnicity, and region will be included. Pregnant women will be excluded in the selection criteria for this study due to potential adverse effects.
2.4 Interventions and comparisons
Studies that use oral probiotic supplements as interventions will be included. The probiotics can be in the form of tablets, powders, capsules, soft capsules, fermented milk, or fortified foods containing probiotics. Studies in which probiotics do not survive, (eg, after heat-killed) or use prebiotics as intervention alone will be excluded.
Trials will be included if they use placebo as a control. If compared with the control group, the effect of probiotics alone can be used in the treatment group, for example using probiotic yogurt and normal yogurt as comparison, will also be eligible.
2.5 Types of studies
All randomized controlled trials that reporting subjective stress level of participants will be included. If mean deviation and standard deviation of the study results cannot be obtained, then the study will be excluded. If the results of a study are reported multiple times, we will combine these reports and consider them as 1 study.
2.6 Outcome measures
2.6.1 Primary outcomes
- (1) Subjective stress level: measured using the Perceived Stress Scale, Berocca Stress Index, Personal Strain Questionnaire of the Occupational Stress Inventory-Revised, or Visual Analog Scales, and so on.
- (2) General mild psychiatric symptoms: measured using the General Health Questionnaire, Psychological General Well-Being Schedule, State/Energy Visual Analogue Scales, Hospital Anxiety and Depression Scale, Hamilton Anxiety Rating Scale, Depression Anxiety Stress Scale, Visual Analog Scales, Geriatric Depression Scale, or Hopkins Symptom Checklist-90, and so on.
2.6.2 Secondary outcomes
- (1) Cortisol level (saliva, plasma or serum, and so on);
- (2) Adverse effects likely to be related to treatment.
2.7 Search strategy
Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO, and Cumulative Index to Nursing and Allied Health Literature will be searched, and the references to relevant publications will also be retrieved to identify additional studies. The searches will be re-run before the final analyses. The detailed search strategy is seen in Tables 1 to 5.
2.8 Data collection and analysis
2.8.1 Study selection
The retrieved literature will be imported into EndnoteX7 and the duplicate data will be removed. Preliminary screening of the literature will be conducted by 2 authors independently through reading the title and abstract. The full text of these potentially eligible studies will be retrieved and independently assessed for eligibility by those 2 authors. Any disagreement between them over the eligibility of particular studies will be resolved through discussion with a third reviewer. The specific process of the selection procedure is presented in a preferred reporting items for systematic reviews and meta-analyses flow chart (Fig. 1).
2.8.2 Data extraction
A standardized, pre-piloted form will be used to extract data from the included studies for assessment of applicability of the data extraction form. Extracted information will include: study design, study population and participant demographics and baseline characteristics, details of the intervention and control conditions, study methodology, recruitment and study completion rates, measurement methods, measurement times and results for each outcome measure included, as well as information for assessment of the risk of bias. Two review authors will extract data independently, and discrepancies will be identified and resolved through discussion (with a third author when necessary).
2.8.3 Risk of bias assessment
Review Manager V5.3.5 software will be used for all bias risk assessments. The risk of bias in the included study will be assessed by considering the following characteristics:
- (1) Random sequence generation (selection bias);
- (2) Allocation concealment (selection bias);
- (3) Blinding of participants and personnel (performance bias);
- (4) Blinding of outcome assessment (detection bias);
- (5) Incomplete outcome data (attrition bias);
- (6) Selective reporting (reporting bias);
- (7) Other bias.
Disagreements between the review authors over the risk of bias in particular studies will be resolved by discussion, with involvement of a third review author when necessary.
2.8.4 Measures of treatment effect
For continuous variable, if the measurement tool is same, we will use the mean difference with 95% confidence intervals (CIs) to analyze the treatment effect. If the measurement tool is different, we will use standardized mean difference to eliminate the effects of different measurement units of the multiple studies. For dichotomous variable, we will use the relative risk with 95% CIs to analyze the effects of treatment.
2.8.5 Dealing with missing data
If the research report cannot provide all data in the data extraction form, we will try to contact the corresponding author or first author to obtain the data by e-mail. If the data cannot be obtained, the available data will be analyzed.
2.8.6 Assessment of heterogeneity
We will use tests for heterogeneity to assess the heterogeneity of the statistics of multiple studies. If I2 value is less than 50% and P value is >.10, it is considered that the heterogeneity between multiple studies is acceptable. A range of 0% to 40% of I2 indicates the heterogeneity might not be important; a range of 30% to 60% indicates possible moderate heterogeneity among multiple studies; a range of 50% to 90% indicates substantial heterogeneity; a range of 75% to 100% indicates considerable heterogeneity. We will select models based on the heterogeneity between studies. If heterogeneity exists between multiple studies, we will perform sensitivity analysis and subgroup analysis to process heterogeneity and analyze heterogeneity sources.
2.8.7 Subgroup analysis
It should be noted that this is a qualitative synthesis and while subgroup analyses may be undertaken. It is not possible to specify the groups in advance. If the necessary data are available, subgroup analyses might be done according to the age of participants, length of intervention, or the type of probiotics (including single-strain probiotics formulation and multi-strain probiotics formulation).
2.8.8 Sensitivity analysis
We will eliminate the studies with more than 1 risk of high bias, or 2 or more risks of unknown bias by item. It will be observed that whether the quality of the study will affect the results of the study.
2.8.9 Assessment of reporting biases
If more than 10 studies are included, we will use Review Manager V5.3.5 software to assess potential reporting bias. If there is a clear reporting bias, we will assess the impact of bias on the outcome.
As we are concerned, excessive stress is threatening our physical and mental health and triggering more and more public health problems.[26,27] As an important type of “spiritual microbes,” probiotics show good prospects in relieving stress and preventing stress-related health problems. Although many animal experiments and clinical studies have been conducted, the efficacy of probiotic supplements for relieving stress has not been scientifically and systematically evaluated. The purpose of this systematic review is to assess the effectiveness and safety of probiotics in relieving stress in healthy populations, and we hope that this study will provide additional evidence. Through preliminary search, we found that there are still many clinical studies underway. These studies are very important for the conclusion, so we consider updating the systematic review after 5 years.
Conceptualization: Ning Zhang, Weiguang Wang, Shuangqing Zhai.
Data curation: Ning Zhang, Yanan Zhang, Menglin Li.
Formal analysis: Xing Liao, Yanan Zhang, Menglin Li.
Investigation: Yanan Zhang, Menglin Li.
Methodology: Xing Liao, Weiguang Wang.
Project administration: Shuangqing Zhai, Xing Liao.
Software: Ning Zhang.
Supervision: Shuangqing Zhai, Xing Liao.
Validation: Shuangqing Zhai, Xing Liao.
Visualization: Shuangqing Zhai, Ning Zhang.
Writing – original draft: Ning Zhang, Shuangqing Zhai, Yanan Zhang.
Writing – review and editing: Shuangqing Zhai, Xing Liao, Ning Zhang.
. Cohen S, Janicki-Deverts D, Miller GE. Psychological stress and disease. JAMA 2007;298:1685–7.
. Epel ES, Crosswell AD, Mayer SE, et al. More than a feeling: a unified view of stress measurement for population science. Front Neuroendocrinol 2018;49:146–69.
. McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 2007;87:873–904.
. Schneiderman N, Ironson G, Siegel SD. Stress and health: psychological, behavioral, and biological determinants. Annu Rev Clin Psychol 2005;1:607–28.
. Steptoe A, Kivimäki M, Lowe G, et al. Blood pressure and fibrinogen responses to mental stress as predictors of incident hypertension over an 8-year period. Ann Behav Med 2016;50:898–906.
. Esler M. Mental stress and human cardiovascular disease. Neurosci Biobehav Rev 2017;74:269–76.
. Murray CD, Flynn J, Ratcliffe L, et al. Effect of acute physical and psychological stress on gut autonomic innervation in irritable bowel syndrome. Gastroenterology 2004;127:1695–703.
. Bianchi R, Schonfeld IS, Laurent E. Burnout or depression: both individual and social issue. Lancet 2017;390:230.
. Conway CC, Starr LR, Espejo EP, et al. Stress responsivity and the structure of common mental disorders: transdiagnostic internalizing and externalizing dimensions are associated with contrasting stress appraisal biases. Abnorm Psychol 2016;125:1079–89.
. Teh HC, Archer JA, Chang W, et al. Mental well-being mediates the relationship between perceived stress and perceived health. Stress Health 2015;31:71–7.
. Iacovides A, Fountoulakis KN, Kaprinis S, et al. The relationship between job stress, burnout and clinical depression. J Affect Disord 2003;75:209–21.
. Spanagel R, Noori HR, Heilig M. Stress and alcohol interactions: animal studies and clinical significance. Trends Neurosci 2014;37:219–27.
. Lawless MH, Harrison KA, Grandits GA, et al. Perceived stress and smoking-related behaviors and symptomatology in male and female smokers. Addict Behav 2015;51:80–3.
. Despréaux T, Saint-Lary O, Danzin F, et al. Stress at work. BMJ 2017;357:j2489.
. Dinan TG, Cryan JF. Gut-brain axis in 2016: brain-gut-microbiota axis - mood, metabolism and behaviour. Nat Rev Gastroenterol Hepatol 2017;14:69–70.
. Mayer EA, Tillisch K, Gupta A. Gut/brain axis and the microbiota. J Clin Invest 2015;125:926–38.
. Mayer EA, Knight R, Mazmanian SK, et al. Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci 2014;34:15490–6.
. Borre YE, O’Keeffe GW, Clarke G, et al. Microbiota and neurodevelopmental windows: implications for brain disorders. Trends Mol Med 2014;20:509–18.
. Sandhu KV, Sherwin E, Schellekens H, et al. Feeding the microbiota-gut-brain axis: diet, microbiome, and neuropsychiatry. Transl Res 2017;179:223–44.
. Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr 1995;125:1401–12.
. Cao YN, Feng LJ, Liu YY, et al. Effect of Lactobacillus rhamnosus GG supernatant on serotonin transporter expression in rats with post-infectious irritable bowel syndrome. World J Gastroenterol 2018;24:338–50.
. Liang S, Wang T, Hu X, et al. Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress. Neuroscience 2015;310:561–77.
. Kato-Kataoka A, Nishida K, Takada M, et al. Fermented milk containing Lactobacillus casei strain Shirota preserves the diversity of the gut microbiota and relieves abdominal dysfunction in healthy medical students exposed to academic stress. Appl Environ Microbiol 2016;82:3649–58.
. Dinan TG, Stanton C, Cryan JF. Psychobiotics: a novel class of psychotropic. Biol Psychiatry 2013;74:720–6.
. Romijn AR, Rucklidge JJ. Systematic review
of evidence to support the theory of psychobiotics. Nutr Rev 2015;73:675–93.
. Jackson M. The stress of life: a modern complaint? Lancet 2014;383:300–1.
. Lupien SJ, McEwen BS, Gunnar MR, et al. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 2009;10:434–45.