Stress occurs when the normal homeostasis of an organism is disrupted because of an actual or perceived threat and can be categorized as either acute or chronic. Acute stress activates the HPA axis, causing an immediate release in cortisol to respond appropriately to the stressor, which can induce anti-inflammatory responses, thereby preparing the individual for defense against the presented threat. Over time, chronic stress leads to dysregulation of the HPA axis, increasing the risk of consequent side effects, such as mood and stress-related disorders, cancer [
38], cardiorespiratory, metabolic, and immune system problems (reviewed in [
39]). Today, chronic stress is a rapidly growing global societal challenge [
40].
Stress can alter the gut–brain axis and has been shown to have a direct impact on the gut microbiota across numerous different animal models, including rodents [
41,
42,
43] and non-human primates [
44,
45] (also reviewed in [
46,
47]). Cortisol, the primary stress hormone, has a direct influence on the ENS and vagus nerve, resulting in alterations in the gut microbiota composition [
24]. In this field of research, a pioneering preclinical study conducted in germ-free (GF) mice found an exaggerated HPA axis response to stress, which could be normalized by subsequent colonization with
B. infantis [
48]. Acute stress has been shown to influence the microbiota community profile in mice by causing alterations in the relative proportions of the main microbiota phyla [
49]. Chronic stress is linked to decreased fecal lactobacilli in rhesus macaques experiencing maternal separation early in life, concomitant with an increase in offspring stress-related behaviors [
44]. Furthermore, the transfer of maternal vaginal microbiota from stressed dams to non-stressed pups resulted in an alternation in their response to stress later in life [
50]. In humans, infants of mothers with high cumulative stress levels during pregnancy had an altered gut microbiota composition with lower levels of lactobacilli and bifidobacteria, higher levels of potentially pathogenic bacterial taxa, and an increase in maternally reported adverse health symptoms [
51].
There is growing evidence to suggest that manipulating the gut microbiota through probiotics could modulate stress-related behavior and HPA axis activity [
46]. To date, the focus has been on bifidobacteria and lactobacilli, with both preclinical and clinical studies demonstrating promising effects on stress and psychiatric disorders such as anxiety and depression [
24,
47,
52]. In this regard, preclinical models have shown beneficial effects of bifidobacteria and lactobacilli to ameliorate stress-induced behavioral alterations across the lifespan, indicative of a link between the gut microbiota and the stress response. For example,
Companilactobacillus farciminis prevented the hyperactivation of the HPA axis elicited by acute stress, which the authors hypothesized was a result of the prevention of excessive gut permeability associated with acute stress [
53]. Sprague Dawley rats exposed to chronic restraint stress also showed improved anxiety- and depression-like behavior and improved cognitive function following administration of
Lactobacillus helveticus MCC1848 [
54].
Lactiplantibacillus plantarum supplementation alleviated heightened stress responses as a result of both chronic unpredictable stress and sleep deprivation stress [
55]. Supplementation with
Bifidobacterium spp. has also been reported to alleviate stress-induced behavioral alterations in preclinical models [
56,
57]. Likewise,
L. paracasei Lpc-37 attenuated anxiety‐ and depression‐related behavior in mice following chronic stress and reduced corticosterone
[2].
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]. 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]. 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], whereas another multi-species combination (nine strains, including
Lactobacillus (
sensu lato),
Lactococcus, and
Bifidobacterium) ameliorated cognitive reactivity to sad mood in healthy participants [
62]. 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]. 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].
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]. 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]. 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]. 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]. 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]. 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]. Further, supplementation with
L. casei Shirota [
71] and
Bifidobacterium bifidum R0071 [
72] 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].