Microbiota-gut-brain axis and role of probiotics

The idea of connection between gut-microbiota and onset of mental illness based on ‘autointoxication’ and ‘intestinal toxemia’ theory and toxemia were used to describe a process where toxins influence systemic health [173]. Later on, brilliant work of British surgeon Sir Arbuthnot Lane and Nobel-Prize-winning microbiologist Ilya Metchnikoff added great explanation for mental health disorders, which development could be connected to autointoxication, when systemic toxin load would influence nervous system function [174]. A New Jersey physician, Henry Cotton, believed that gut infections are the initiator of all forms of behavioral and mood disorders, and psychosis as well [175]. In 1926, Kopeloff proposed to use the Lactobacillus acidophilus as a potential treatment for different health conditions, because “...acidophilus, the twin brother of Bulgarian bacillus, is much more desirable” [176]. Great proposal made by a brilliant scientist Elie Metchnikoff, that orally consumed lactic acid bacteria could combat the dangers of autointoxication, could slow the aging via to slowing arteriosclerosis and improve the quality of life [177,178]. This great work was also supported by Albert Abrams [179], Frederick Forchheimer [180] and was carried out through the early 1930s. In 1945 Danish scientists found that older adults with dementia had the highest level of clostridia species [181]. The first practical suggestion to use probiotics for treatment of mental illness was proposed by Scottish physician Hubert J. Norman [182], but it took over 70 years to combine these ideas with research results. However, for any firm conclusions, properly powered studies are required before using probiotics in treatment of depression [183].

Now, the evidence of the gut-microbiota influence on behavior and brain chemistry is well documented [67,184]. It is also known, that normal healthy microbiota influences the development and function of CNS, via behavioral and molecular changes [68]. It is known that cerebral dopamine (DA) synthesis is induced by DA-producing enzymes, inhibited by stimulation of intestinal microbiota through the “microbiota-gut-brain axis” (MGB). The oral treatment of rats with Lactobacillus reuteriwhich activated calcium dependent potassium channels in enteric neurons in the colonic myenteric plexus, proves that that gut microbiota may affect brain via autonomic nervous system [185,186]. Anxiety and depression are common in patients with chronic GI disorders [187]. Recent research supporting a role for the microbiota in maintaining normal brain function offers the intriguing possibility that the therapeutic targeting of the gut microbiome might be a viable strategy in the treatment of CNS disorders [84]. Around 4 million people in USA are suffering from chronic fatigue syndrome, which is a result of prolong IBS which is characterized by neuropsychological and cognitive problems, as well memory loss, lack of concentration, bad sleep, moodiness, anxiety and depression [188, 189]. The results of a recent study which demonstrated beneficial psychological effects in healthy human volunteers following administration of a combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 [190]. Bifidobacterium infantis 35624 treatment, for example, was shown to normalize immune responses, reverse behavioral deficits in the forced swim test, and restore basal noradrenaline concentrations in the brainstem of adult rats subjected to the early life stress of maternal separation, an animal model of brain–gut axis dysfunction [60,191]. Lactobacillus paracasei NCC2461 administration has also shown efficacy in reducing visceral hypersensitivity in a mouse preclinical model of IBS [192]. Furthermore, a preclinical study using the same probiotic found that CRD-induced visceral pain behaviors were significantly reduced in the viscerally hypersensitive Wistar-Kyoto rat strain [165,193]. These reports raise the possibility that therapeutic targeting of the microbiome might be an effective treatment strategy for specific disorders of the CNS. In this context, supporting gut health through microbiota supplementation with a view toward positively influencing mental status represents a putative preventative strategy worth following [194]. In addition to consideration of the microbiome as a therapeutic target, we also need to direct more efforts toward mining its metabolites for putative drugs, a strategy that has already paid some dividends [195].

The probiotic Bifidobacterium longum (Bl NCC3001) normalizes behavior and CNS biochemistry in mice with mild colitis, an effect also mediated via the vagus nerve. Bl NCC3001 produces an anxiolytic effect in two different models of anxiety-like behavior as assessed by light/dark preference and step-down tests [184,196,197]. Evidence that microbiota are linked to brain chemistry and behavior is well documented, an interestingly abnormal behavior was displayed before there was any significant immune response gut microbiota change, indicating that this behavior was not a consequence of cytokine-induced reactions, but a interaction between the gut microbiota and the neural system. Infestation of mouse with H. pylori infection has been shown to lead to change in behavioral pattern and changes in neural biochemistry accompanied with following dyspepsia [198]. Using of probiotics, for example administration of Bifidobacterium longum to DSS-treated mice reversed their altered behavior without affecting gut inflammation with possible effect ofBifidobacterium longum on enhancement of exploratory behavior [184]

In contrast, the effect of Lactobacillus rhamnosus (Lr JB-1) varies considerably depending on the experimental paradigmused, an anxiolytic-like effect observed in open field and elevated plus maze tests vs. an anxiogenic effect reported in the fear-conditioning model (increased emotional learning is an anxiety-like behavior) with no significant effect observed against stress-induced hyperthermia [61,199].