Moving from preclinical to clinical evidence, probiotics have been proven to have some success in ameliorating mood in a number of clinical studies
[58,59][57][58]. The combination of
L. helveticus R0052 and
B. longum R0175 are probably among the best investigated and although there are some conflicting results, studies indicate that the combination can reduce stress and anxiety
[3]. Improvements in mood scores were observed in elderly participants following administration with a milk drink containing
Lacticaseibacillus casei, proving most beneficial in the participants that reported the lowest mood scores at baseline
[60][59]. A multi-species combination of
Streptococcus thermophilus,
Lactobacillus delbrueckii subsp.
bulgaricus,
Lactococcus lactis,
Lactobacillus acidophilus,
L. plantarum,
Bifidobacterium animalis subsp.
lactis and
Limosilactobacillus reuteri administered to healthy participants elicited anxiolytic effects
[61][60], whereas another multi-species combination (nine strains, including
Lactobacillus (
sensu lato),
Lactococcus, and
Bifidobacterium) ameliorated cognitive reactivity to sad mood in healthy participants
[62][61]. Of note, one later study using the same combination demonstrated that the neurocognitive benefits of this multi-species probiotic became evident only when the participants were stressed, highlighting the need to carefully characterize study populations
[63][62]. A multi-species combination (containing
L. fermentum LF16,
Lacticaseibacillus rhamnosus LR06,
L. plantarum LP01, and
B. longum BL04) induced significant improvements in mood, with a reduction in depressive mood state, anger, and fatigue, and an improvement in sleep quality in healthy volunteers
[64][63].
L. plantarum DR7 administration to stressed adults alleviated stress and anxiety, as well as improving several aspects of memory and cognition, enhanced serotonergic signaling, and decreased plasma cortisol and proinflammatory cytokines
[65][64]. Intake of
L. plantarum HEAL9 also led to a significant decrease in the plasma levels of two inflammatory markers (soluble fractalkine and CD163) following exposure to an acute stress test
[66][65]. A 12-week intervention with
Lactobacillus gasseri and
B. longum also resulted in positive changes in stress and salivary cortisol measurements and concomitant improvements in immune response in healthy participants
[67][66]. Four-week consumption of
B. longum 1714 attenuated cortisol output and subjective anxiety in response to the cold pressor test
[4]. Similarly,
L. paracasei Lpc-37 reduced self‐reported perceived stress in healthy males compared to the placebo after five-week consumption
[5]. Healthy medical students undergoing university examinations had reduced levels of stress following the consumption of a fermented milk containing the probiotic
L. casei Shirota
[68][67]. Furthermore, increases in salivary cortisol reported during an exam stress period were also reduced in a healthy student population supplemented with
L. plantarum 299v
[69][68]. A multi-species probiotic administered to healthy college students was found to improve panic anxiety, neurophysiological anxiety, negative affect, worry, and increase negative mood regulation
[70][69]. Further, supplementation with
L. casei Shirota
[71][70] and
Bifidobacterium bifidum R0071
[72][71] reduced the physical symptoms of exam stress, including the onset of stress-induced gastrointestinal symptoms and colds. Finally, an open-label study conducted in highly stressed information technology specialists found that administration of
L. plantarum PS128 improved several self-reported and objective measures of mood, anxiety, stress, and sleep
[73][72].
Taken together, these examples highlight significant results and describe an intriguing role of probiotics in mood, anxiety, stress, and related behaviors such as sleep. A recent meta-analysis demonstrated that probiotic consumption could result in a reduction of subjective stress levels in healthy volunteers and may alleviate stress-related subthreshold anxiety and depression levels
[58][57]. However, further clinical studies are required to provide a deeper understanding of the strain specificity and mechanisms of action of probiotics to help fully realize their role in stress management and the relief of the symptoms of anxiety.
3.2. Depression and Probiotics
Major Depressive Disorder (MDD) is a common psychiatric disorder characterized by depressed mood or significantly reduced pleasure or interest in all activities and is currently a leading cause of disability worldwide. Emerging evidence shows that the dysfunction of the gut–brain axis may be implicated in the etiology of depression. In support of this, the gut microbiota are impacted by MDD and associated with changes to gut epithelial permeability and increased systemic inflammation with elevated levels of C-reactive protein, IL-1β, IL-6, and TNFα in depressed patients compared with healthy controls
[74][73]. Furthermore, the “leaky gut” phenomenon resulting from disrupted gut barrier function is proposed to contribute to MDD. In this context, MDD patients show elevated serum concentrations of immunoglobulin (Ig)-M and IgA against lipopolysaccharides of Gram-negative bacteria compared to healthy controls
[75][74], suggesting an increase in bacterial translocation from the gut and subsequent inflammatory response, potentially contributing to an MDD phenotype.
Preclinical models of depression, such as the maternal separation model
[76][75] and the Flinders-sensitive rat model
[77][76], have demonstrated alterations in the gut microbiota composition and inflammation. In humans, many studies have examined alterations in the gut microbiota in MDD patients compared to healthy controls
[78,79,80,81][77][78][79][80]. Specifically, MDD patients are reported to have an altered gut microbial compositional profile relative to healthy controls
[80,81,82][79][80][81]. Patients with MDD have been reported to have reduced abundances of Bacteroidetes, Firmicutes, and Actinobacteria with a concomitant outgrowth of Proteobacteria
[81[80][81],
82], and increased abundance levels of
Alistipes spp.
[80][79]. The Flemish Gut Flora project provided further associations between the gut microbiota profile in a depressive cohort by highlighting the absence of
Coprococcus and
Dialister species in patients with depression
[83][82]. However, several variations have been reported across these studies, which may be due to the small sample sizes or the effects of adjunct medications
[47][46].
The use of probiotics for the reduction of symptom severity in MDD has gained attention in recent years, indicated by increasing numbers of preclinical and clinical studies that have supported the anti-depressive efficacy of probiotics. Accumulating preclinical evidence indicates that single-strain or multi-species preparations may be effective in improving the behaviors related to depression (reviewed in
[47][46]). In a recent study, a multi-species probiotic combination of
L. plantarum LP3,
L. rhamnosus LR5,
B. lactis BL3,
B. breve BR3 and
Pediococcus pentosaceus PP1 alleviated depressive-like behaviors and decreased corticosterone levels in mice subjected to restraint stress
[84][83]. Similarly,
L. plantarum WLPL04 alleviated anxiety- and depressive-like behaviors and chronic stress-induced cognitive dysfunction in mice, while also reversing abnormal alterations in the composition of the gut microbiota
[85][84].
In humans, administration of
B. longum NCC3001 for six weeks to adults with irritable bowel syndrome (IBS) and mild to moderate anxiety and/or depression reduced depression scores and enhanced the participants’ quality of life, which was associated with alterations in brain activation patterns in the limbic system. No improvement in anxiety scores were observed in this cohort
[86][85]. Another study investigated the effect of
B. coagulans MTCC 5856 in patients experiencing co-morbid IBS symptoms with MDD and found that the probiotic significantly improved symptoms of both depression and IBS
[87][86]. Slykerman and colleagues found that
L. rhamnosus HN001 supplementation during pregnancy resulted in a significant reduction of postnatal depression and anxiety symptoms
[88][87]. An improvement in cognition was reported in a cohort of depressed patients receiving
L. plantarum 299v compared to the placebo group
[89][88]. MDD patients who were administered
L. acidophilus,
L. casei, and
B. bifidum for eight weeks also reported ameliorations in self-reported depression scores
[90][89]. In patients with MDD who were taking antidepressant drugs for three months or more, consumed the combination of
L. helveticus R0052 and
B. longum R0175. This resulted in significantly reduced depressive symptoms as measured using the Beck Depression Inventory (BDI), compared to the placebo group
[3]. Finally, an open-label study conducted in patients with treatment-resistant depression highlighted the potential of probiotics as an adjunct therapy with antidepressant drugs
[91][90].
Further evidence to support these clinical findings are reported in several systematic reviews
[92,93,94][91][92][93]. However, it is important to note that several intervention studies failed to demonstrate any beneficial effects on improving overall mood (reviewed in
[95,96,97][94][95][96]). It is evident from the preclinical research that specific bacterial strains play a role in ameliorating depressive-like behaviors, and certain clinical studies have demonstrated a role for probiotics towards alleviating symptoms of depression; however, the exact bacterial species and/or strains and mechanisms underpinning their beneficial effects remain unclear. Nevertheless, current research highlights the importance of a healthy microbiome for patients suffering from depression. Future studies into the strain-dependent nature of putative probiotics in patients with clinically diagnosed MDD are warranted to evaluate their therapeutic potential.
4. Conclusions
The promise of probiotic treatments for MDD is complicated by the heterogeneous nature of both the gut microbiota composition and depressive symptoms in the clinical setting, depression subtypes, and probiotic formulations. However, despite these obstacles, selected probiotics have been shown to improve symptom severity in mood disorders and so there is promise that early interventions with probiotics to restore the gut microbiota composition could reduce the risk of the development of mood disorders such as depression and anxiety in later life[1]. Further clinical investigations into the role of probiotics on mental and brain health and to investigate optimal probiotic composition, dosage and duration of supplementation, employing high quality randomized, double-blind, placebo controlled clinical trials in different populations, are essential and certainly warranted.