Related to the differences in traditional versus contemporary Westernized dietary patterns and mental health is the role of the intestinal microbiota. A decade ago, prior to the scientific hypotheses of Logan et al.[73, 74], the notion that the intentional manipulation of the intestinal microbiota could provide therapeutic value to human depressive and fatigue states was, at the very least, outlandish. However, in the ensuing years, many of the mechanisms first proposed by Logan and colleagues (as listed, adapted from [73, 74]) whereby beneficial microbes could influence mood or fatigue, have been examined experimentally.

Direct protection of the intestinal barrier;

Influence on local and systemic antioxidant status, reduction in lipid peroxidation;

Direct, microbial-produced neurochemical production, for example, gamma-aminobutyric acid (GABA);

Indirect influence on neurotransmitter or neuropeptide production;

Prevention of stress-induced alterations to overall intestinal microbiota;

Direct activation of neural pathways between gut and brain;

Limitation of inflammatory cytokine production;

Modulation of neurotrophic chemicals, including brain-derived neurotrophic factor;

Limitation of carbohydrate malabsorption;

Improvement of nutritional status, for example, omega-3 fatty acids, minerals, dietary phytochemicals;

Limitation of small intestinal bacterial overgrowth;

Reduction of amine or uremic toxin burden;

Limitation of gastric or intestinal pathogens (for example, Helicobacter pylori );

Analgesic properties.

Moreover, preliminary placebo-controlled human studies have shown that oral probiotic microbes can decrease anxiety, diminish perceptions of stress, and improve mental outlook [75]. In the context of our later discussion of fermented foods and their intersection with the gut-brain-microbiota connection, a brief summary of this microbiota-brain research is necessary. For interested readers, more detailed reviews specific to the scientific advances exploring direct and indirect relationships between intestinal microbes and anxiety or depression have recently been published [76, 77].

Viewed strictly from the nutritional perspective, experimental studies have shown that the administration of probiotic bacteria to laboratory chow can increase peripheral tryptophan levels, and alter dopamine and serotonin turnover in the frontal cortex and limbic system [78]. In addition, probiotic-fortified laboratory chow increases the tissue levels of omega-3 fatty acids [79], and the omega-3 fatty acids play a critical role in communication in and between nerve cells. The consumption of omega-3 fatty acids, eicosapentaenoic acid in particular, has been linked to positive mental outlook and reduction in mental distress in human beings [80]. Levels of other anti-inflammatory fatty acids, such as gamma-linolenic acid, also increase in the human plasma when co-administered with probiotics [81]. It is also becoming increasingly clear that the extent to which phytochemical absorption can provide systemic antioxidant and anti-inflammatory activity is controlled, at least to some degree, by resident intestinal microbiota [82–84]. Finally, probiotics and the overall profile of the intestinal microbiota can influence tissue levels of mood-regulating minerals, such as magnesium and zinc [85, 86].

As mentioned, intestinal microbiota may also have far-reaching effects related to glycemic control; our commensal gut microbes may contribute to healthy glucose tolerance. Indeed, the oral administration of Bifidobacterium lactis, and, in separate research, the combination of Lactobacillus curvatus and Lactobacillus plantarum, can improve fasting insulin levels and glucose turnover rates, even in the presence of a high-fat diet [87, 88]. Again, the minimization of the detrimental LPS burden by beneficial microbes appears to be a central mechanism in the promotion of normal glycemic control [89]. For example, bifidobacteria and other beneficial microbes can prevent the efflux of LPS into systemic circulation, while in human beings, the administration of probiotics may diminish systemic access of gut-derived LPS and also reduce reactivity to the endotoxin [90].

Beyond direct nutritional and glycemic effects, there are other intriguing ways in which probiotics and the intestinal microbiota have been connected to the brain. When a strain of Lactobacillus rhamnosus is administered to healthy animals under stress, there is a reduction in anxiety and depression-like behaviors in experimental models, such as the elevated plus maze and forced swim tests. These behavioral changes were associated with alterations in the GABA system of the brain in the probiotic group, matching the known effects of antidepressant or anxiolytic chemical agents (for example, anxiolytic agents such as benzodiazepines work at GABA receptors) [91]. Importantly, the changes in behavior and brain chemistry were largely extinguished with vagotomy, suggesting direct lines of communication from gut to brain [90]. Additional research shows that Lactobacillus helveticus and Bifidobacterium longum added to animal drinking water can increase nerve cell resiliency and reduce apoptosis during conditions of experimental physiological stress [92]. Moreover, oral Mycobacterium vaccae, a soil-based microorganism widely distributed in nature, which can easily find its way onto edible plants, has been shown in experimental models to improve cognitive function and diminish anxiety-like behavior among animals [93].

There are also a number of studies involving mice reared in germ-free environments, the results of which seem to demonstrate a direct role of intestinal microbiota on behavior. Compared withconventional animals raised with the normal range of intestinal microbiota, these animals display the murine equivalent of what might be decreased anxiety [94–96]. Meanwhile, supplementation with Bifidobacterium appears to attenuate an exaggerated stress response and maintain adequate levels of the neuropeptide brain-derived neurotrophic factor (BDNF), levels of which are known to be low in depression [97]. It is also noteworthy that even mild chronic inflammation of the gastrointestinal tract can provoke anxiety and diminish BDNF production in animals [98]. Furthermore, supplementation with Bifidobacterium also provides systemic protection against lipid peroxidation and decreases brain monoamine oxidase activity, thereby potentially increasing intersynaptic neurotransmitter levels [99].

Rodent studies have provided compelling insights; however, they have countless shortcomings as a reflection of human microbiota, human dietary patterns, and the ultimate intertwining of these variables with complex mental health disorders. Far more convincing research, albeit very preliminary at this juncture, comes from published human studies involving probiotic administration. The first formal investigation of a probiotic and human mental outlook involved 132 otherwise healthy adults consuming Lactobacillus casei fermented beverage for three weeks; vs. placebo, significant improvement in mood scores were noted upon the among those with the higher baseline depressive symptoms [100]. A separate placebo-controlled pilot study, one using the same Lactobacillus casei probiotic (powder form), involved 39 chronic fatigue syndrome patients. After two months, depression scores remained unchanged between the groups, however Beck Anxiety Inventory scores showed significant improvements in anxiety versus placebo [101].

Michaël Messaoudi and colleagues from France evaluated a Lactobacillus helveticus and Bifidobacterium longum combination probiotic, which was orally administered for one month (n?=?55) in a placebo-controlled study[102]. Among the otherwise healthy adults, significant improvements in depression, anger, anxiety, and lower levels of the stress hormone cortisol versus placebo were noted. A concurrent experimental arm of the study also confirmed that the probiotic added to the dietary of rodents was effective in reducing behaviors indicative of anxiety. Messaoudi’s group performed a secondary analysis, looking specifically at those with the lowest baseline urinary free cortisol (n?=?25). Indeed, the results once again showed improvement with Lactobacillus helveticus and Bifidobacterium longum versus controls (particularly in somatization, depression and anger-hostility), and among this low cortisol sub-group the overall benefits in anxiety and depression were pronounced over time [103]. In addition, a study involving 44 patients with irritable bowel syndrome showed thatoral consumption of a prebiotic fiber (trans-galactooligosaccharide) significantly reduced anxiety in conjunction with marked elevations in fecal bifidobacteria levels [104].

Finally, a small placebo-controlled study involving functional magnetic resonance imaging (fMRI) has demonstrated that the one-month consumption of a fermented food containing Bifidobacterium animalis subsp lactis, Streptococcus thermophilus, Lactobacillus bulgaricus, and Lactococcus lactis subsp lactis can influence brain activity versus baseline [105]. Specifically, the researchers reported that the group who received the fermented dairy product, versus unfermented counterpart and the no-intervention controls, affected activity of brain regions that control central processing of emotion and sensation. Enthusiasm concerning this study runs high, with editorials in mainstream journals claiming that this fMRI study, ‘provides the first objective evidence that gut commensal and/or probiotic bacteria influence brain activity in healthy humans’,[106]. The study, of course, did not provide any such objective evidence concerning ingested bacteria; it was a study involving a transformed milk product, not an isolated probiotic powder. Despite attempts to keep caloric and macronutrient content equal, a fermented milk product is not the same as an unfermented milk product in only its microbiota. Within the study, there was no evidence of a change in gut microbiota profile via consumption of the fermented product; however, more importantly, the fermentation of milk significantly alters bioactive peptides and other chemicals that are well capable of influencing central nervous system function [107–110]. In short, objective evidence that ingested probiotic bacteria alone (or diet-induced shifts in commensal bacteria) can influence human brain activity has yet to be published.