The influence of probiotic supplementation on brain function of the host system.
Probiotics were reported for several physical and psychological health benefits. Probiotics can positively alter the gut microbiome and nourish the commensal microbial load. Recent studies revealed that the cognitive functions (anxiety and depression) of human beings are meticulously associated with their genetic makeup, food habits, and gut microbiome. The gut microbiome may communicate with the brain through neural and humoral pathways, while involving several neurotransmitters and signaling molecules. The immune response, especially inflammatory system, plays a critical role in the microbiome and in mental health. Thus, many studies were conducted to explore the beneficial effect of probiotic, single and multistrain, formulations. Fruitful results were observed, but the underlying mechanism of probiotic-mediated improvement of mental health is not fully illustrated, even though some studies explained that the production of neurotransmitter-like metabolites by the probiotic strain could be the possible mediator of gut-brain axis. The present chapter summarizes the outcome of probiotic-based treatment for the improvement of stress and depression with respect to microbiome change, inflammation, and stress pathway.
According to FAO/WHO, probiotics are living bacteria that, which when administered in suitable amounts, confer a health benefit to the host.
The brain is a vital organ involved in leading and coordinating the homeostasis of the body. The changes or defect in the brain functions are closely associated with the development of serious physiological and emotional impairment [4, 5]. The cognitive impairment is not only associated with a decline in brain function but also linked to the immune system and the changes in microbiome. The new finding and complexity of the network provide new perceptions into cognitive dysfunctions .
The microbes residing in the gastrointestinal tract of human have been referred as gut microbiota or gut microbiome. The commensal microbial population was closely associated with the host system, and they have a complex connective ecosystem, which influences the physical and functionality of the host. Bacteroides, Prevotella, and Ruminococcus families are three most abundant bacterial communities in the gastrointestinal tract. Recent studies demonstrated how the commensal microbes modify them according to the environment and the availability of nutrition .
Inflammation is one of the body processes of protecting against harmful stimuli or any antigens. Even though inflammation is a part of the immune system, the chronic inflammation may lead to the development of malignancy. The alteration in microbiome and release of endogenous microbial debris induce chronic inflammation. More significantly, the microbiome may play an imperative role in modulating behavior by linking the immune systems and neuroendocrine via cytokines and the nerve system .
The stress and immune-induced pathways, for example, kynurenine pathway (PK), are involved in several neurodegenerative diseases and psychiatric disorders. Manipulating the gut microbiome may diminish the effect of stress-induced neurological damages. Studies on the link between the gut microbiome and brain provide significant information about the role of the microbiome in brain function and development . The metabolites of gut microbiome act as neurotransmitters, which regulate the brain function . The role of the gut microbiome and probiotic supplementation on the improvement of memory has been reported . The infection-mediated induction of cytokines altered the neuronal system and leads to the development of behavioral abnormalities .
Recently, probiotics were studied for their involvement in neurology, neurobehaviors, brain function, and cognition. Several preliminary studies revealed the importance of probiotics in neuroscience and cognition [12, 13]. The present chapter compiles the information about the probiotic-based improvement of brain health with respect to the cognitive function and discusses the microbiome changes upon probiotic supplementation.
2. Gut microbiome, inflammation, and brain function
The microbial load in the human gastrointestinal tract is about 1014 cells; on the other hand, studies suggested that the ratio of microbial and human cells is 3:1. The diversity and richness of the microbial community are varied during the developmental stage of the host, and two-thirds of microbes are unique to every human being. This unique microbial community is responsible for the host individuality in terms of immunity, physical activity, and overall health status. The mislead in the symbiotic relationship between host and microbes cause some unwanted health conditions like diabetes, obesity, and inflammatory bowel diseases [14, 15].
The mutual communication between brain and gut is documented, and the information exchange has been carried out via several immunes, neuroendocrine pathways, and enteric nerve systems [16, 17]. About 500 million nerve endings, mostly enteric nerve system, and high concentrations of immune cells are present in the gastrointestinal tract (GI), so most of the bidirectional interaction between the gut and brain mainly occurs in the GI tract. The afferent neurons of the enteric nervous system communicate with the GI tract and brain through the vagus nerve .
Several biochemical and neuronal signaling pathways are established and involved in the GI tract and central nerve system (CNS), and the signaling network is known as gut-brain-axis. The malfunction of the gut-brain axis may cause pathophysiological events and is linked to inflammation, chronic abdominal pain, eating disorders, and stress [16, 17]. The vagus nerve system, cell wall components (pathogen-associated molecular patterns, e.g., lipopolysaccharide, peptidoglycan monomers, and lipoteichoic acids), fatty acids, metabolites, neurotransmitters and neuropeptides-like gamma-aminobutyric acid (GABA), serotonin, and brain-derived neurotrophic factors are the key players of the gut-brain axis .
The association of microbiome and immune system has been studied using germ-free mice. The supplementation of specific microbes, either pathogenic or commensal, to germ-free mice and the study of the changes in the behavior and immune system help to understand the role of particular microbes in host immune system and cognition. The results of studies using germ-free model revealed the importance of gut microbiome. The immune system of gut protects the system from pathogenic infection and supports the growth of commensal microbes . The immune system of the antibiotic-treated mice was diminished during flu virus exposure compared to untreated mice, which revealed the importance of beneficial gut microbes, especially
A balanced communication between host immune system and gut microbiome is necessary to establish the homeostasis, which protects the system during adverse conditions. The weakening of gut-brain signaling is linked with the development of inflammation. If there is any alteration in the neuroendocrine system, for example, cortisol level, the barrier function of the gut is amended and the permeability increased, which in turn induces the release of cytokines by immune cells .
The lipopolysaccharide (LPS) injection is employed to induce a strong immune response, which increases the level of pro-inflammatory cytokines and glucocorticoids. The LPS challenging mimic as pathogenic infection and the elucidated immune response can weaken the development of the physiological system . LPS can induce the release of pro-inflammatory cytokines, interferons, IL-1β, IL-2, IL-6, and TNF-α that can act on the brain, and initiates the acute-phase responses like fever, reduced food intake, and boosted pain response [21, 22]. The responses, both physiological and behavioral, to pathogen-associated molecular pattern (like LPS, lipoteichoic acid, and flagellin) are comparable to the physiological and behavioral changes in neurological disorders like anxiety, depression, and autism. It is evidenced that gut-brain axis, microbiome, and immune system are related to each other [21, 22, 23].
3. Stress, microbiome, and immune system
Psychological disorders like anxiety and depression display consequences on the gastrointestinal function that links to the brain. The brain can communicate with the gut via the hypothalamic-pituitary-adrenal (HPA) axis, autonomic, and the enteric nervous system. Stress may be responsible for the dysregulation of gut-brain axis and cause gastrointestinal consequences . The corticotrophin-releasing factor (CRF), a group of peptides of the central nervous system, is one of the regulators of immune, endocrine, and behavioral response to stress. The CRFs can alter the gut-brain interaction, which can alter the gastrointestinal motility, gastrointestinal secretion, intestinal permeability, intestinal microbiota, and visceral perception.
The pituitary gland releases the adrenocorticotropic hormone that stimulates the adrenal glands to produce cortisol, a stress hormone. All the processes were initiated by the release of CRF in the hypothalamus, which in turn activates the hypothalamic pituitary adrenal axis . The crosstalk between gut-brain axis, the gut microbiome, and the immune system has a crucial role in the inflection of the stress response of the gut in terms of the development of gut disorders and diseases. The stress changes the microbial flora, which may have a reflective effect on the gut-brain axis and may alter the permeability, motility, and visceral sensitivity .
The microbiome of normal and depressed humans has been analyzed and the results revealed that there were no significant changes in the microbial group, but the amount of specific bacterial groups was altered (increase in Bacteroidetes species and decrease in Lachnospiraceae) among the depressed people. Especially, Oscillibacter (can produce GABA like neurotransmitter) and Alistipes were more abundant in depressed individuals. Alistipes was reported to be associated with stressed mice, chronic fatigue syndrome, and irritable bowel syndrome [27, 28, 29, 30]. Jiang et al. reported that major depressive people have high amounts of Bacteroidetes, Actinobacteria, and Proteobacteria, while Firmicutes content was very low .
The stress brings the changes in inflammatory cytokines and neurotransmitter levels that could disturb the microbiota either directly or indirectly. The increase in norepinephrine alters the virulence of commensal bacteria like
Stress can induce the tryptophan metabolic pathways, also known as kynurenine pathway (KP). KP is known to be involved in several neurological regulations and neurodegenerative diseases [35, 36]. The connections between kynurenine pathway, stress, microbiota, and gut-brain axis are not fully elucidated. The involvement of KP in stress and neuropsychiatric disorder has been reported .
4. Impact of probiotic supplementation on brain function, immunity, and microbiome
The mice (germ-free and specific pathogen-free) were supplemented with
The female Wister rats were supplemented with
The male BALB/c mice supplemented with
The anxiolytic-like activity of probiotic preparation comprising of
The communication between gut-brain, inflammatory response, and function of probiotic were interconnected and also associated with diet and genetic makeup of individuals.
Due to the changes in brain function, inflammatory disease patients may have sickness behaviors. The supplementation of VSL#3 (a mixture of 1.7 billion cells of
The rats were supplemented with 0.5–1.0% of
4.2. Clinical trails
The mood and cognition of the healthy human volunteers were measured at baseline, during and after the intervention of
The impact of probiotic supplementation on stress-induced gastrointestinal consequences was studied. The stressed people were treated with probiotic preparation, which contains 3 × 109 CFU of
The patients with chronic fatigue syndrome (CFS) were supplemented with
The intervention of probiotic preparation containing 3 billion CFU of
The children with the autism spectrum disorder were supplemented with
The fermented milk with probiotics (FMP) consisting of 1.25 × 1010 CFU of
Acute psychological stress is linked to the onset of flu/cold. The supplementation of
The healthy volunteers were consumed the multispecies probiotic preparation containing
Kato-Kataoka et al. conducted a double-blind, placebo-controlled study on the impact of probiotic supplementation (
The healthy petrochemical workers were randomized and supplemented with probiotic yogurt containing
Depression and stress are associated with several inflammatory consequences and dysregulation of gut microbiota. The brain function, microbiome, and immune system were interconnected. The childhood experiences like diet habit, stress, and immune activation can affect the development of specific microbiome and cognition in the later age of life. The supplementation of probiotic, especially multispecies formulation, can positively regulate the gut microbiota, brain function, and helps to maintain the typical immune state of the host (Table 1). The beneficial effects of probiotic are closely associated with diet, genetic makeup, and commensal microbiota of the host. The secretion of neurotransmitters-like molecules and promoting the growth of beneficial commensal microbes are the possible ways by which probiotics confer the mental health benefits. How the microbiome is influencing the cognition and brain function and its mechanisms are scope for further investigation.
|1||Male BALB/c mice||28 days||Modulation of the GABAergic system. Reduced the depression and anxiety|||
|2||Germfree, specific pathogen-free, and gnotobiotic BALB/c mice||—||Normalized the inflated stress response|||
|3||Female Wistar rats||15 days||Reduced the partial restraint stress|||
|4||Male AKR mice||10 days||Normalized the anxiety behavior|||
|5||Dextran sodium sulfate treated mice||7 days||Normalized the anxiety behavior, but not myeloperoxidase activity|||
|6||Wistar rats||14 days||Reduced the anxiety-like behavior|||
|7||Mice||21 days||Decreased anxiety-like behavior|||
|8||Mice||VSL#3 (||10 days||Reduced the inflammation-associated sickness behavior|||
|9||Rats||—||Improved the brain intracellular signaling|||
|10||Male C57BL/6 mice||28 days||Protected from stress-induced behaviors|||
|Clinical trials with human subjects|
|11||Healthy human||Probiotic yogurt containing ||21 days||Improved the mood|||
|12||Stressed human volunteers||21 days||Reduced the stress-induced gastrointestinal problems|||
|13||Chronic fatigue syndrome patients||60 days||Reduced the symptoms of anxiety|||
|14||Healthy human||30 days||Reduced the psychological distress|||
|15||Healthy human||—||Reduced the cortisol level and improved the anxiety and depression. Not affecting the learning and memory|||
|16||Autism spectrum disorder patients||60 days||Reduced the level of D-arabinitol, and D-/L-arabinitol ratio. Improved the responsiveness to the orders|||
|17||Healthy women||28 days||Modulate the sensitivity of brain network in healthy women|||
|18||Academically stressed students||42 days||Prevented the onset of stress-related cold/flu|||
|19||Healthy volunteers||28 days||Reduced the negative thoughts|||
|20||Healthy medical students||56 days||Prevent the stress-related physical symptoms|||
|21||Healthy petrochemical workers||42 days||Improved the general health, and reduce the stress and depression|||
|22||Healthy medical students||Fermented milk with ||56 days||Reduced the cortisol level, and reduced the symptoms of stress|||
We gratefully acknowledge Upper Northern Research Administration Network, Office of the Higher Education Commission, Thailand and the Chiang Mai University grant (CMU-grant) for their support. BSS wishes to acknowledge the CMU Post-Doctoral Fellowship, Chiang Mai University, Chiang Mai, Thailand.
Conflict of interest
The authors declare that there is no conflict of interests.