Probiotics and the MGBA

Part of the MGBA Series

What are Probiotics?
The second half of our psychobiotic treatment approach to anxiety is probiotics. 

The term probiotics refers to living microorganisms that confer health benefits when consumed. For a microorganism to qualify as a true probiotic, it needs to meet a few criteria:

1. It must withstand the digestive process and actually reach your intestines.
2. It has to be able to grow and survive once established within the gastrointestinal (GI) tract.
3. It needs to contribute to the well-being of the individual consuming it. 

Importantly, probiotics should not pose any health risks upon ingestion. Although our GI tract is inhabited by various microorganisms, encompassing bacteria, viruses, protozoa, archaea, and fungi, only specific types are classified as probiotics.

When you consume probiotics, you don’t actually digest them and break them down; instead, these microorganisms make their way to the gut and start to grow there. Probiotics confer a benefit from their continued growth in your gut.

There are four main types of bacteria in your gut: Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. Each of these broader categories contains thousands of types of bacteria; we are going to zoom in on two specific types: Lactobacillus and Bifidobacterium. These two types of bacteria are common probiotics found in fermented foods and probiotic supplements. They are often referred to as psychobiotics because of their associated mental health benefits.

Lactobacillus is a type of lactic acid bacteria (LAB), labeled as such because it is able to produce lactic acid. The presence of lactobacillus is key to maintaining a healthy gut; it helps to maintain intestinal lining integrity, protect the intestine from damaging molecules and inflammation, and outcompete bad bacteria for real estate. Lactobacillus also produces GABA, which is a neurotransmitter in the brain—a key signaling molecule that helps to decrease excitement in the brain. Through its role in producing GABA, the presence of (or lack of) Lactobacillus can impact an individual’s mood. 

Bifidobacteria are bacteria from the Actinobacteria phylum. They have numerous demonstrated health benefits throughout the body, including improving bone health, regulating the immune system, and protecting the body from pathogens. Most important to anxiety, Bifidobacteria, like Lactobacillus, are also able to produce GABA and impact individuals’ moods.

Lactobacillus and Bifidobacteria are the microbes that actually make fermented foods fermented. The use of microbes to ferment foods like kimchi and certain yogurts makes these foods a healthy and tasty source of probiotics.

What Do Probiotics Do?
The main benefit of probiotics comes from how they interact with our existing gut microbiome. When probiotics are consumed, they travel to our GI tracts and start to live and grow there. Once the probiotic bacteria have become established in the GI tract, they begin to clean up their new home in three main ways:

1. Probiotics compete with harmful bacteria for resources: There is limited available real estate within the gut where microbes can grow. Probiotic consumption allows for a continuous source of good bacteria to enter the body and look for a home in the gut. As more and more good bacteria establish themselves within the gut, there is simply less room for the bad bacteria that harm our bodies. 
2. Probiotics create an environment that is hostile for harmful bacteria: Microbes produce a variety of products once they are established in the gut, including substances like short-chain fatty acids (SCFAs) and other metabolites that alter the gut’s pH and create a less optimal environment for harmful bacteria. Probiotics also produce substances called bacteriocins and biosurfactants that kill other microbes. 
3. Probiotics directly heal our intestines: Once living in the gut, probiotic microbes interact with the cells that line our intestines, helping them produce a thick layer of mucus that protects our intestines and keeps the intestinal lining tightly sealed. Microbes interact with the immune system via the gut, which helps protect us from inflammation and pathogens.

The effectiveness of probiotics is dependent upon their establishment and growth within the GI tract. In order to be beneficial, probiotics have to be consumed in quantities known as “colony-forming units” (CFUs). CFUs contain sufficient amounts of microbes to effectively establish and cultivate microbes within the GI tract. Consuming enough CFUs is an essential factor for probiotic efficacy, and determining appropriate CFUs is currently a large component of probiotic research.

Digging into the Research
Research has shown that consuming probiotics can improve the composition of the gut microbiome and, in turn, improve mental health. Let’s dive into the details of the research.

What Have We Found in Animal Studies?
In the study of the gut microbiome, researchers often use germ-free animal models. “Germ-free” models are animals raised in an environment devoid of microorganisms, so they lack a natural gut microbiome. This makes them ideal subjects for testing and manipulating an entirely artificial and controlled gut microbiome. Germ-free models have been instrumental in laying the foundation for probiotic research and offer promising avenues for translating findings into clinical trials involving human subjects.

Microbiota metabolites modulate the T helper 17 to regulatory T cell (Th17/Treg) imbalance promoting resilience to stress-induced anxiety- and depressive-like behaviors
The Details: In 2021, a study conducted by researchers at the Icahn School of Medicine at Mount Sinai and published in Brain, Behavior, and Immunity explored the impact of synbiotic supplementation on stress, anxiety, and depression in male mice. The synbiotic supplement included probiotics (Lactobacillus plantarum and Bifidobacterium longum) and prebiotics, fiber that feeds microorganisms in the gut. During a 28-day period, the mice were divided into three groups of 16: one received the synbiotic supplement, another received only the probiotics, and the third group received a biologically inert placebo. The synbiotic treatment reduced anxiety-like behavior in the mice, while the probiotic treatment alone did not have the same effect. Both the synbiotic and probiotic treatments, however, were effective in reducing stress-related behaviors in the animals. The researchers discovered that synbiotic treatment increased the production of serotonin, a compound involved in signaling within the brain; low serotonin levels are frequently associated with mood disorders. Additionally, both the synbiotic and probiotic treatments were successful in reducing inflammation in the brain and lowering the levels of kynurenine, a neurotoxic chemical. 
The Takeaway: Mice that consumed synbiotics (a combination of Lactobacillus, Bifidobacterium, and prebiotics) showed reduced anxiety and stress based on behavioral metrics. This may have been due to reduced inflammation and increased serotonin production associated with synbiotics.

Chronic Stress-Induced Depression and Anxiety Priming Modulated by Gut-Brain-Axis Immunity
The Details: The above results were further confirmed in a subsequent study from the same group of researchers, published in 2021 in Frontiers Immunology. In this study, the researchers used 42 mice to model chronic and recurrent stress, which led to a significant decrease in the diversity of microorganisms in the gut. The stressed mice also exhibited significant inflammation in both the intestine and the brain. To address these effects, the mice received a daily synbiotic supplement consisting of Lactobacillus plantarum, Bifidobacterium longum, and prebiotics for  28 days. The synbiotic supplement was highly effective in reducing chronic and recurrent stress symptoms in the animals. The researchers observed that the synbiotic supplement could alter the composition of the gut microbiome and reverse the gut imbalance caused by stress. Furthermore, the synbiotic supplementation reduced inflammation both in the brain and the intestine, effectively reversing the harmful effects of stress on both the body and the gut. Overall, the authors concluded that synbiotic supplementation yielded more consistent and robust results compared to probiotic or prebiotic supplementation alone.
The Takeaway: Mice that consumed synbiotics (Lactobacillus, Bifidobacterium, and prebiotics) had reduced chronic stress, improved gut health, and reduced inflammation throughout the body.

The role of microbiota-gut-brain axis in neuropsychiatric and neurological disorders
The Details: In 2021, a paper authored by researchers from the Medical University of Lodz in Poland and published in Pharmacological Research conducted a comprehensive review of existing research on probiotic supplementation in animal models. Their analysis encompassed 30 animal studies, and their findings were quite consistent. Chronic stress was shown to have a detrimental impact on the balance of the gut microbiome, resulting in a gut imbalance. However, when Lactobacillus and Bifidobacterium bacteria were administered together, these probiotics consistently produced beneficial effects.² The studies showed that probiotic supplementation reduced anxiety-like behaviors in the animals. Probiotic supplementation led to higher levels of serotonin and dopamine in the brain; these natural chemicals play essential roles in regulating mood and emotional well-being. Probiotics helped lower the levels of stress-related hormones in the animal – a crucial step in managing the effects of stress on the body – and reduced inflammation throughout the body. These findings provide valuable insights into the potential benefits of probiotics for managing stress and anxiety.
The Takeaway: Animal studies showed that stress caused imbalances in gut microbes. Supplementing with probiotics Lactobacillus and Bifidobacterium reduced anxiety-like behaviors, increased serotonin and dopamine in the brain, and reduced stress hormones in the body.

Does It Translate to Humans?
While animal studies have provided valuable insights into the potential benefits of probiotic use for managing anxiety and stress, it is essential to translate these findings to human clinical trials in order to understand how probiotics might help individuals with both clinical and/or subclinical anxiety and stress. 

Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects
The Details: In a 2010 study conducted by researchers from Cambridge University and published in the British Journal of Nutrition, the impacts of probiotic supplementation were examined in humans. The study involved 26 adult participants of varying ages and genders who were provided with a supplement containing Lactobacillus helveticus and Bifidobacterium longum at a concentration of three billion CFUs daily for 30 days. Their anxiety levels were assessed using several surveys, including the Hopkins Symptoms Checklist, the Hospital Anxiety and Depression Scale, the Perceived Stress Scale, and the Coping Checklist. These surveys collectively evaluated participants’ experiences of anxiety, depression, stress, and their responses to adverse events, with questions covering day-to-day emotions and experiences (e.g., “Do you suddenly feel scared for no reason?” and “Do you blame yourself for things?”). The study also measured levels of cortisol, often referred to as the “stress hormone,” in the participants’ urine. After 30 days of probiotic supplementation,  results indicated significant decreases in anxiety, stress, depression, and hostile feelings as reported in survey responses. Participants also reported improved coping strategies based on the Coping Checklist. Importantly, there was a statistically significant decrease in urinary cortisol levels following probiotic supplementation, suggesting a reduction in circulating cortisol levels within the body. The authors concluded that probiotic supplementation showed promise in human participants for alleviating symptoms of anxiety, depression, and stress.
The Takeaway: Consuming Lactobacillus and Bifidobacterim led to decreases in self-reported anxiety, stress, depression, and hostile feelings, as well as a decrease in cortisol. 

Prebiotics and probiotics for depression and anxiety: A systematic review and meta-analysis of controlled clinical trials
The Details: A 2019 review conducted by the Alpert School of Medicine at Brown University and published in  Neuroscience Behavioral Review, revealed that treatment with Lactobacillus alone was not sufficient to produce significant benefits for symptoms of depression or anxiety. However, when a combination of Lactobacillus and Bifidobacterium was used, small but consistent benefits were observed for individuals experiencing symptoms of depression and anxiety in clinical trials. Probiotic treatments also appeared to be more effective in individuals with more severe anxiety and depression, with the most robust results observed in populations diagnosed with clinical mood disorders.
The Takeaway: Consuming Lactobacillus and Bifidobacterium leads to decreases in symptoms of anxiety and depression; consumption of Lactobacillus alone is not sufficient to benefit anxiety or depression. Probiotic treatment is most effective in individuals with clinically diagnosed mood disorders.

Efficacy and safety of Lacticaseibacillus paracasei Lpc-37® in students facing examination stress: A randomized, triple-blind, placebo-controlled clinical trial (the ChillEx study)
The Details: A more recent clinical trial conducted in 2023 by IFF Health & Biosciences in Finland and published in Brain, Behavior, and Immunity investigated the effects of probiotics on chronic stress in university students. The study involved 190 students who were given a supplement containing 15.6 billion colony-forming units of Lacticaseibacillus paracasei (another lactic acid bacteria) over a 10-week period. Anxiety and stress were assessed using the State Trait Anxiety Inventory (STAI), and the researchers analyzed the participants’ gut microbiomes. Surprisingly, the study found that probiotic administration had no impact on gut microbiome composition or STAI scores in the students. These results underscore the importance of considering the specific types of probiotics used, as not all probiotics may have the same impact on mental well-being. The combination of Lactobacillus and Bifidobacterium strains appeared to be more consistently beneficial in addressing symptoms of depression and anxiety in previous clinical trials.
The Takeaway: Not all probiotics are beneficial for anxiety; Lacticaseibacillus showed no effect on gut health, self-reported anxiety, or self-reported stress.

Effects of Microbiota Imbalance in Anxiety and Eating Disorders: Probiotics as Novel Therapeutic Approaches
The Details: A 2021 paper published in the International Journal of Molecular Science, conducted by the Childhood and Environment Research Group (GRIE) in Spain,reviewed 14 studies of probiotics and synbiotics in human participants. One of the key findings was that patients diagnosed with Generalized Anxiety Disorder (GAD) consistently exhibited gut imbalances. Patients with GAD consistently had higher levels of Bacteroides and Escherichia-Shigella, which are harmful microbes that are normally present in very small amounts in your gut microbiome and are associated with inflammation. The authors also observed lower overall microbial diversity in the participants’ guts, which can cause damage to the intestinal barrier, a complication that has been linked to anxiety. Using a combination of Lactobacillus and Bifidobacterium strains had the best results in reducing existing anxiety and stress in patients with GAD. Probiotic supplementation was effective in restoring the gut microbiome in GAD patients and reducing the hyperreactivity of their hormonal pathways. While reaffirming that probiotic treatment was most effective in patients with severe, diagnosed anxiety, the study also reported that probiotic supplementation with Lactobacillus and Bifidobacterium strains could prevent anxiety and stress from developing in the first place among healthy individuals.
The Takeaway: Generalized Anxiety Disorder (GAD) is associated with gut microbiome imbalances. A combination of Lactobacillus and Bifidobacterium reduces self-reported anxiety and stress in individuals with GAD. Probiotic supplementation in healthy individuals can protect against stress.

Feed your microbes to deal with stress: a psychobiotic diet impacts microbial stability and perceived stress in a healthy adult population
The Details: In a 2023 study published in Molecular Psychiatry, researchers from APC Microbiome Ireland conducted a clinical trial to assess the effects of a three-week “psychobiotic diet” among  45 adult participants. The diet was rich in whole grains, prebiotic fruits and vegetables, fermented foods, and legumes, and participants were discouraged from consuming “unhealthy” foods like sweets, fast food, or sugary drinks. The study monitored participants’ dietary intake using weekly food records.Stress levels before and after the dietary intervention were measured using Cohen’s perceived stress scale, which includes questions like “In the last month, how often have you been upset because of something that happened unexpectedly?” Additionally, the researchers assessed GI health using a GI symptom scale and the Bristol stool assessment. Following the three-week psychobiotic diet, the participants reported significantly reduced stress levels, and their microbiome compositions were also significantly altered, indicating changes in their gut bacteria. Furthermore, participants reported higher levels of satisfaction with bowel movements.  Greater improvement in both GI and stress symptoms was associated with stricter dietary adherence – participants who reported consuming more fermented foods, fiber, and whole fruits and vegetables felt less stressed and had less gastrointestinal discomfort. Most previous studies have focused on the use of supplemental probiotics, but this research highlights the potential benefits of adopting a dietary approach that incorporates probiotic-rich foods and emphasizes overall dietary patterns for managing stress and GI health.
The Takeaway: A psychobiotic diet (high in unprocessed prebiotics and probiotics and low in processed foods) reduced gut discomfort, altered the gut microbiome substantially, and reduced self-reported stress. 

Not all studies have reported success with probiotic supplementation, and some have shown no significant impact on mood disorders. 

Probiotics as a treatment for prenatal maternal anxiety and depression: a double-blind randomized pilot trial
The Details: In a 2021 clinical trial conducted by the Donders Institute for Brain, Cognition, and Behavior in the Netherlands and published in Scientific Reports, researchers investigated the effects of probiotic supplementation on 40 women with prior mood disorder diagnoses who were in the second or third trimester of low-risk pregnancies. The participants were given a daily supplement containing multiple probiotic strains at a dosage of 2.5 billion colony-forming units for eight weeks. The probiotic supplement included Bifidobacterium bifidum, Bifidobacterium lactis, Bifidobacterium lactis, Lactobacillus acidophilus, Lactobacillus brevis, Lactobacillus casei, Lactobacillus salivarius, Lactococcus lactis, and Lactococcus lactis. Anxiety, stress, and depression were assessed using various questionnaires, including the Pregnancy-Related Anxiety Questionnaire-Revised, the STAI, the Pregnancy Experience Scale, and the Everyday Problems List. The researchers did not observe any significant impact of probiotic supplementation on stress, anxiety, or depression in the study participants. 
The Takeaway: Supplementation with a variety of probiotics (including Lactobacillus and Bifidobacterium) showed no significant impact on self-reported stress, anxiety, or depression.

The efficacy of probiotics and/or n-3 long-chain polyunsaturated fatty acids intervention on maternal prenatal and postnatal depressive and anxiety symptoms among overweight and obese women
The Details: A 2021 study by the University of Turku in Finland and published in the Journal of Affective Disorders involved 439 pregnant women with a pre-pregnancy BMI greater than 25. Participants were administered either a probiotic supplement containing Lactobacillus rhamnosus and Bifidobacterium animalis at a dosage of 100 billion colony-forming units alone or a combination supplement of probiotics (Lactobacillus rhamnosus and Bifidobacterium animalis) and fish oil for more than a year. Anxiety was assessed using the SCL-90/anxiety questionnaire, which measures feelings of terror, nervousness, tension, and panic. There was no significant difference in anxiety scores over the course of pregnancy and postpartum for either treatment group. The researchers recommended further research to explore dietary interventions and probiotics for managing stress, anxiety, and depression in pregnant women and new mothers. 
The Takeaway: Pregnant women who were overweight based on BMI prior to pregnancy took probiotics for a year and had no significant reductions in self-reported anxiety.

These studies highlight the complexity of probiotic interventions and suggest that their effects may vary depending on factors such as the specific probiotic strains used, the population being studied, and the duration of supplementation. While some studies have shown promising results, others have not observed significant benefits in terms of mood disorders. Further research is needed to better understand the factors influencing the efficacy of probiotic supplementation in managing stress, anxiety, and depression.

Efficacy of probiotics on stress in healthy volunteers: A systematic review and meta-analysis based on randomized controlled trials
The Details: A 2020 review conducted by the School of Traditional Chinese Medicine at Beijing University and published in Brain and Behavior investigated the effects of probiotic supplementation in individuals with no previous history of mood disorders to determine whether probiotics could be beneficial in alleviating day-to-day stress and anxiety. The review included seven studies involving human participants and assessed subjective stress levels, anxiety and depression levels, and cortisol levels. These studies were divided into two categories: single-strain probiotic studies (studies involving supplementation with only Lactobacillus microorganisms) and multi-strain probiotic studies (studies involving supplementation with both Lactobacillus and Bifidobacterium microorganisms). Multi-strain probiotic studies administered the probiotics either as supplements, in tablet or powder form, or as part of a yogurt. The review indicated that both single-strain probiotics and multi-strain probiotics reduced the day-to-day stress experienced by participants. However, there were no significant changes in the levels of anxiety or depression reported by the participants, regardless of the type of supplement used. Furthermore, probiotic administration did not have a discernible impact on cortisol levels, a measure often associated with stress. These results suggest that probiotic supplementation could be effective in reducing day-to-day stress levels in individuals without prior mood disorders.
The Takeaway: Taking probiotic supplements reduced self-reported day-to-day stress for healthy individuals but did not impact physiological metrics of stress or self-reported anxiety and depression.

References

1. Mörkl S, Butler MI, Holl A, Cryan JF, Dinan TG. Probiotics and the Microbiota-Gut-Brain Axis: Focus on Psychiatry [published correction appears in Curr Nutr Rep. 2020 Jun 5;:]. Curr Nutr Rep. 2020;9(3):171-182. doi:10.1007/s13668-020-00313-5
2. Sasso JM, Ammar RM, Tenchov R, et al. Gut Microbiome-Brain Alliance: A Landscape View into Mental and Gastrointestinal Health and Disorders. ACS Chem Neurosci. 2023;14(10):1717-1763. doi:10.1021/acschemneuro.3c00127
3. O’Callaghan A, van Sinderen D. Bifidobacteria and Their Role as Members of the Human Gut Microbiota. Front Microbiol. 2016;7:925. Published 2016 Jun 15. doi:10.3389/fmicb.2016.00925
4. Chen J, Chen X, Ho CL. Recent Development of Probiotic Bifidobacteria for Treating Human Diseases. Front Bioeng Biotechnol. 2021;9:770248. Published 2021 Dec 22. doi:10.3389/fbioe.2021.770248
5. Dempsey E, Corr SC. Lactobacillus spp. for Gastrointestinal Health: Current and Future Perspectives. Front Immunol. 2022;13:840245. Published 2022 Apr 6. doi:10.3389/fimmu.2022.840245
6. Gamma-Aminobutyric Acid (GABA). Cleveland Clinic. Updated April 25, 2020. Accessed January 27 2024. https://my.clevelandclinic.org/health/articles/22857-gamma-aminobutyric-acid-gaba
7. Chen J, Chen X, Ho CL. Recent Development of Probiotic Bifidobacteria for Treating Human Diseases. Front Bioeng Biotechnol. 2021;9:770248. Published 2021 Dec 22. doi:10.3389/fbioe.2021.770248
8. Butel MJ. Probiotics, gut microbiota and health. Med Mal Infect. 2014;44(1):1-8. doi:10.1016/j.medmal.2013.10.002
9. Katarzyna Socała, Urszula Doboszewska, Aleksandra Szopa, Anna Serefko, Marcin Włodarczyk, Anna Zielińska, Ewa Poleszak, Jakub Fichna, Piotr Wlaź. The role of microbiota-gut-brain axis in neuropsychiatric and neurological disorders. Pharmacological Research. 2021; 172. Volume 172. doi:10.1016/j.phrs.2021.105840.
10. Westfall S, Caracci F, Zhao D, et al. Microbiota metabolites modulate the T helper 17 to regulatory T cell (Th17/Treg) imbalance promoting resilience to stress-induced anxiety- and depressive-like behaviors. Brain Behav Immun. 2021;91:350-368. doi:10.1016/j.bbi.2020.10.013 (39)
11. Westfall S, Caracci F, Estill M, Frolinger T, Shen L, Pasinetti GM. Chronic Stress-Induced Depression and Anxiety Priming Modulated by Gut-Brain-Axis Immunity. Front Immunol. 2021;12:670500. Published 2021 Jun 24. doi:10.3389/fimmu.2021.670500
12. Messaoudi M, Lalonde R, Violle N, et al. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr. 2011;105(5):755-764. doi:10.1017/S0007114510004319
13. Derogatis LR, Lipman RS, Rickels K, Uhlenhuth EH, Covi L. The Hopkins Symptom Checklist (HSCL): a self-report symptom inventory. Behav Sci. 1974;19(1):1-15. doi:10.1002/bs.3830190102
14. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361-370. doi:10.1111/j.1600-0447.1983.tb09716.x (43)
15. Liu RT, Walsh RFL, Sheehan AE. Prebiotics and probiotics for depression and anxiety: A systematic review and meta-analysis of controlled clinical trials. Neurosci Biobehav Rev. 2019;102:13-23. doi:10.1016/j.neubiorev.2019.03.023
16. Mäkelä SM, Griffin SM, Reimari J, et al. Efficacy and safety of Lacticaseibacillus paracasei Lpc-37® in students facing examination stress: A randomized, triple-blind, placebo-controlled clinical trial (the ChillEx study). Brain Behav Immun Health. 2023;32:100673. Published 2023 Aug 1. doi:10.1016/j.bbih.2023.100673
17. Navarro-Tapia E, Almeida-Toledano L, Sebastiani G, Serra-Delgado M, García-Algar Ó, Andreu-Fernández V. Effects of Microbiota Imbalance in Anxiety and Eating Disorders: Probiotics as Novel Therapeutic Approaches. Int J Mol Sci. 2021;22(5):2351. Published 2021 Feb 26. doi:10.3390/ijms22052351
18. Berding K, Bastiaanssen TFS, Moloney GM, et al. Feed your microbes to deal with stress: a psychobiotic diet impacts microbial stability and perceived stress in a healthy adult population. Mol Psychiatry. 2023;28(2):601-610. doi:10.1038/s41380-022-01817-y
19. Browne PD, Bolte AC, Besseling-van der Vaart I, Claassen E, de Weerth C. Probiotics as a treatment for prenatal maternal anxiety and depression: a double-blind randomized pilot trial. Sci Rep. 2021;11(1):3051. Published 2021 Feb 4. doi:10.1038/s41598-021-81204-9
20. P. Hulkkonen, E.-L. Kataja, T. Vahlberg, E. Koivuniemi, N. Houttu, O. Pellonperä, K. Mokkala, H. Karlsson, K. Laitinen. The efficacy of probiotics and/or n-3 long-chain polyunsaturated fatty acids intervention on maternal prenatal and postnatal depressive and anxiety symptoms among overweight and obese women. Journal of Affective Disorders. 2021;289:21-30. doi:10.1016/j.jad.2021.04.006.
21. Zhang, N,  Zhang, Y,  Li, M, et al.  Efficacy of probiotics on stress in healthy volunteers: A systematic review and meta-analysis based on randomized controlled trials. Brain Behav.  2020; 10:e01699. https://doi.org/10.1002/brb3.1699