The traditional view has been that microorganisms are not of particular importance in the development and function of the central nervous system (CNS), nor in the physiology and regulation of mood. Although gut-brain connections have been studied for decades—providing extensive research insight and information about the axis connecting the gut-associated immune system, enteric nervous system, and gut-based endocrine system1—these findings have yet to gain broader acceptance by the conventional psychiatric and neurological research communities. Despite this, a compelling body of evidence demonstrates an ability by microbiota of the gut to influence mood-related behaviors and even cognitive reactivity to sad mood, specifically.2-7

Research in animals

As early as 1998, oral administration of a single, unique bacterium in the gut (Campylobacter jejuni) to rats was found to lead to stress-like behavior, without an accompanying immune response.8 Later, research confirmed that introduction of C. jejuni caused stress-like behavior in mice, with concomitant activation of neuronal regions in the brain that were dependent on information received from the gut via the vagus nerve.9 Around the same time, Sudo and colleagues showed that administering commensal Bifidobacterium species could reverse exaggerated hypothalamic–pituitary–adrenal (HPA) axis responses to restraint stress.10 This revolutionary observation motivated other research groups to investigate the role of the host gut microbiota on CNS function.

Animal research supports the theory that there are several possible gut-brain signaling pathways influenced by the gut microbiota and capable of modulating the brain and behavior. For example, gene expression changes in brain regions of germ-free mice have been documented, including hippocampal expression of brain-derived neurotrophic factor (BDNF), a key protein involved in neuronal plasticity and cognition.11 Moreover, administration with the commensal bacterium Lactobacillus rhamnosus demonstrated beneficial BDNF expression, serotonin signaling, and metabolism in zebrafish.12

Behavioral and biochemical parameters have also been significantly modulated by recolonizing the gut with probiotics. Of the probiotics investigated thus far, Bifidobacterium and Lactobacillus species have the most extensive data sets supporting beneficial effects on mood and behavior.13 In one study, 40 male rats were randomized to either a control or high-fat diet for 10 weeks. After five weeks, the rats were randomized to receive either placebo or a multi-strain probiotic combination (Ecologic BARRIER, Winclove, Amsterdam containing Lactobacillus casei W56, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactococcus lactis ssp. lactis W58, Bifidobacterium animalis ssp. lactis W52, Lactococcus lactis ssp. lactis W19, Lactobacillus salivarius W24, Bifidobacterium bifidum W23, and Bifidobacterium lactis W51). Forced swim test results demonstrated significantly improved mood (34%, P<0.001) in the probiotic-treated animals, independent of diet.† In addition, the probiotic group showed decreased levels of inflammatory cytokines and increased indole-3-propionic acid, a potential neuroprotective agent.†14

Clinical evidence

Although most of the research linking mood and the microbiota has come from animal models, clinical trials validating these concepts have begun to emerge, and with these trials, a new class of probiotics has emerged as well, so-called psychobiotics, or psychomicrobiotics.15,16 Recent clinical findings for select psychobiotic formulations are reviewed below.

At the end of the study, an overall 40.7% reduction in stress was noted (P<.001).†  It demonstrates the ability of a well-formulated probiotic to influence sad mood.

In a six-month pre- and postintervention assessment of adults experiencing emotional stress, 42 participants consumed a probiotic multivitamin preparation consisting of L. acidophilus, B. bifidum, and B. longum daily with breakfast. A questionnaire was used to assess mood and mental status. At the end of the study, an overall 40.7% reduction in stress was noted (P<.001).†  In addition, a 91% decrease in GI discomfort, an established indicator of emotional stress, was recorded. The majority of participants (73%) rated the outcomes of the intervention as “good” or very good.17

In a more recent randomized, triple-blind, placebo-controlled trial of 40 adults, participants received a multi-strain probiotic formula (Ecologic BARRIER, Winclove, Amsterdam) at a dose of 5 billion CFU per day. Over the four-week period, this multispecies probiotic demonstrated significant improvements in cognitive reactivity to sad mood as evidenced by a reduction in aggressive and ruminative thoughts (LEIDS-R scale).†7 What is particularly noteworthy in this trial, is the use of a probiotic as a first-line clinical support for mental well-being. It demonstrates the ability of a well-formulated probiotic to influence sad mood.

A 2017 systematic 10-study review by Wallace and Milev assessed the impact of probiotics on mood, stress, and cognition.18 Of the studies, most found positive results on all measures of mood; however, the studies were heterogeneous in terms of the strain of probiotic used, the dosing, and duration of treatment. The authors concluded that further randomized controlled clinical trials are warranted to validate the efficacy of probiotic intervention.

As neuroscientist, Jane Foster, PhD of McMaster University states, “It might be time to start thinking about treating [sad mood] from the bottom up instead of the top down. The evidence is there that the brain is responding to the gut. Let’s make that the therapeutic pathway.”19