The idea that implanting the intestines with Lactobacillus strains may improve quality of life and mental health is not a new one. Dr. George Porter Phillips first reported in 1910 that although Lactobacillus tablets and powder were ineffective, a gelatin-whey formula with live lactic acid bacteria improved depressive symptoms in adults with melancholia [15]. In a series of case reports, separate researchers concluded in 1923 that ‘the administration of acidophilus milk is recommended in the treatment of psychoses as a means to physical betterment’ [16]. In this pilot study we found that the oral administration of Lactobacillus casei strain Shirota (LcS, Yakult Honsha, Tokyo, Japan) caused a significant rise in fecal Bifidobacteria spp. and Lactobacillus spp. The rise in Lactobacilli was an expected finding, although the concomitant rise in Bifidobacteria suggests that there may be far reaching effects of oral probiotics on other microbial residents of the gastrointestinal tract. This finding supports previous research showing that the oral administration of Lactobacillus plantarum 299 V caused a significant rise in fecal Bifidobacteria levels [17]. In this case the elevation of Bifidobacteria levels should be considered a positive finding, particularly when considering that Bifidobacteria levels may be low in CFS. Also of relevance is a recent experimental study which has shown that a specific strain of Bifidobacteria can boost plasma tryptophan levels and alter serotonin and dopamine turnover in areas of the brain associated with depression and anxiety [12]. We also found a significant reduction in anxiety scores among those CFS patients consuming the LcS bacteria. The group differences in anxiety are noteworthy since anxiety is a frequent mental health symptom reported by CFS patients.

In recent years the interface between neuropsychiatry and gastroenterology has converged into a new discipline referred to as enteric neuroscience. Emerging studies have shown that intestinal bacteria may directly communicate with the central nervous system by way of the vagal sensory nerve fibers and the peripheral immune system. Indeed, experimental studies have shown that even minute doses of microbes within the gastrointestinal tract, levels that do not trigger an immune response, are capable of influencing neurotransmission in the paraventricular hypothalamus, the central nucleus of the amygdala, and the bed nucleus of the stria terminalis [8]. All three of these regions are involved in the processing of emotions related to anxiety and mood. It is also true that quantitative alterations in the make-up of gastrointestinal microbes are a consequence of states of stress and fear, and alterations in the gut microflora have recently been associated with impaired glucose control and obesity [18, 19].

More hints of a connection between intestinal microflora and brain function come from studies in the autistic spectrum. Research has shown marked alterations of the gastrointestinal microflora in autism, with specific elevations in various Clostridium spp. [20]. Some researchers speculate that low-grade chronic intestinal inflammation induced by elevations in bacteria such as potentially pathogenic Clostridium spp may be directly influencing brain centers. Experimental studies show that indeed chronic gut inflammation leads to activation of areas of the brain associated with mental health and behavioral disorders, including the hypothalamus, amygdala and cortical centers [21]. While we did not look specifically at Clostridium spp. in this pilot investigation, it has been noted that Lactobacillus can competitively displace Clostridium and other potentially pathogenic gut bacteria [22]. Propionic acid is a short chain fatty acid produced primarily by Clostridium and Bacteroides spp.; emerging research suggests that this acid may be involved in anxiety. Elevated production of propionic acid in the gut has been shown to increase behaviors associated with anxiety and aggression in animals [23]. It has also been shown recently that when propionic acid gains access to the brain it can impair the social behavior of animals. Changes to the animal behavior include decreased playful behavior, increasing social isolation, and an increase in repetitive behaviors that may indicate anxiety [24]. While human data is lacking, a study in animals did show that the LcS as used in our study can lower cecal propionate levels [25].

Some researchers have stated that the so-called ‘hygiene hypothesis’ extends into the realm of mental health disorders as well. The hygiene hypothesis is the proposition that the documented rise in chronic inflammatory disorders (allergies, autoimmunity, and inflammatory bowel disease) within developed countries is driven by a changing microbial environment, an absence of beneficial bacteria that has in turn altered the immuno-regulatory circuits which normally keep inflammatory responses in check [26]. Many mental health conditions, and so-called functional somatic disorders such as CFS, have been well-documented to have elevations in inflammatory cytokines, and these inflammatory cytokines at even low levels can produce symptoms of anxiety and depression in otherwise healthy adults [26]. Therefore, since orally administered probiotics can decrease inflammatory cytokines in humans, it has been postulated that bacteria may be used to positively influence mood in patient populations where both emotional symptoms and inflammatory immune chemicals are elevated [10]. It is becoming increasingly clear that anxiety and stress itself may lower levels of fecal lactic acid bacteria, and this, in turn, may compromise various aspects of health [27].

Overall the results suggest that specific strains of probiotic bacteria may have a role to play in mediating some of the emotional symptoms of CFS and other related conditions. However, it is important to note that this is a small pilot study and broad conclusions cannot be drawn at this time. Since we did not evaluate bowel function during the study, it is entirely possible that the decreased anxiety was a consequence of improved bowel function. In an unexplained medical condition such as CFS, where over 70% of patients meet the criteria for IBS, it is possible that regulation of bowel movements made a difference in mental state. Indeed LcS has been shown to regulate bowel function and decrease constipation in a controlled trial [28]. It is also true that LcS has been shown to reduce small intestinal bacterial overgrowth and the subjective reporting of the passage of gas in patients with IBS [29]. This is of significance because SIBO and intestinal permeability often overlap, and patients with chronic fatigue syndrome are known to have both increased intestinal permeability and SIBO. Indeed, correction of SIBO and intestinal permeability has been shown to improve symptoms in CFS and depressive disorders [30, 31]. Therefore, it is entirely possible that our results are an artifact of improved gut structure and function via the LcS restoration of a healthy intestinal biofilm. However, a recent study using the same LcS strain in healthy adults suggests that there may be a more direct microbial influence on emotional state. In healthy adults who were reported to be more depressed/less elated in daily functioning at baseline, there was significant improvement in mood scores after taking the probiotic. In that controlled trial the improvements in mood were not related to changes in bowel function [11].

This preliminary research raises many questions regarding possible mechanisms whereby probiotics might influence anxiety and depression. The results of the present study should be viewed simply as a stimulus for further research. Follow-up studies with probiotics should further examine specific gut microbes, intestinal structure and function as well as physiological markers associated with anxiety and depression. These may include inflammatory cytokines and other immune chemicals, blood tryptophan levels and urinary metabolites of neurotransmitters.