|Coping with Stress related effects on the Brain – Role of Neuro-nutraceuticals and Gut microbes
Pathak, S1, Suhanya, P1, Sushmitha, S1, Murugesan, R1, Fang He2, Marotta, F3, Banerjee, A1*
Department of Allied Health Sciences, Chettinad Hospital & Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai-603103, India.
Department of Nutrition and Food Hygiene, West China School of Public Health, Sichuan University, China
ReGenera R&D International for Aging Intervention, Milano, Italy and San Babila Clinic, Healthy Aging Unit by Genomics and Biotechnology, Milano, Italy.
*Corresponding Author: Antara Banerjee, Chettinad Hospital & Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai-603103, India, E-mail: email@example.com, Contact: +91 9566072596.
Francesco Marotta, ReGenera R&D International for Aging Intervention, Milano, Italy and San Babila Clinic, Healthy Aging Unit by Genomics and Biotechnology, Milano, Italy
Number of pages in manuscript: 20
Number of figures: (Black and white): 4
Number of tables: 1
Keywords: Brain development, depression, gut microbes, hippocampus, nutraceuticals, stress
Running title: Role of nutraceuticals in brain
Human brain is the control system of body which helps in coordinating the function of every organ and maintaining homeostasis. A functioning brain receives information from the body and interprets information guiding the body’s response to it. There is found to be an interaction between the brain and the intestinal flora of the body. Apart from known benefits of microbes such as digestion and host defense, the gut microbiome also impacts mental health. Stress is being the major cause of occurrence of various mental health problems. Neuroinflammation and neurodegeneration are the pathophysiological implications of stress as it disturbs the generation of neurons. Gut microbes have been found to help ease the effects of stress such as anxiety, depression but there is a negative consequence of their composition being altered in case of chronic stress or emotional trauma. Specific food supplements maintain the gut population as well as protects the brain from stress induced debilitating effects. Nutraceuticals synthesized to nutrify the microbiome and influence cognitive functions and development of brain can be referred as neuro-nutraceuticals. This review aims to highlight the multi-targeted action of nutraceuticals and gut-microbiota upon brain during stress and their specific effects on normal brain functioning and development.
Every individual being is host to a diverse population of microbial organisms, with varying complexity. About a 100 trillion (1014) microbes is present which is equivalent to 1011-1012 cells/g colonic content with a biomass of >1 kg. This includes close to over 500 different species (Eckburg et al., 2005). These microbes are in a symbiotic relationship of mutualism with the host and maintain a state of homeostasis with the host’s immune system. The gut microbe is distinct for each individual depending on age, geographic location, diet, medication, host related factors. They are also found to differ within the same individual according to the body niche. Predominantly, anaerobes make up the population of microbes in the host. The oral cavity contains a complex population of anaerobes such as Bifidobacteria, Bacteroides, Leptotrichia, Propionibacteria, Fusobacteria, Veillonella, and Peptostreptococci. Anaerobes like Propionibacteria along with aerobes such as Staphylococci and Coryne bacteria reside on the skin. The stomach region has gram positive aerobes like Lactobacillus, Helicobacter pylori, and Streptococci. Likewise, the composition varies for the intestinal regions and vagina. The microflora acquire nutrients like dietary fibres, starch, oligosaccharides, sugars, lipids, proteins from the host intestinal tract and endogenous mucins, sloughed epithelial, enterocyte tissues, bile acids, and cholesterol. Experimental studies using germ-free mice have demonstrated the relevance of commensal microbial organisms in normal physiological and metabolic activities. Deregulation in the gut microbial communities has resulted in various health implications. Human gut microbiome is the focal point of research, impacting the functional aspects of the human body and can be exploited for their potential therapeutic effects (Ravinder Nagpal et al.,2014).Change in the diet can bring about a major transformation in the gut microbiota. The various other disruptive factors which impact the host’s normal flora include use of antibiotics, immune suppression, stress, pathological condition, and surgery (Figure 1).
The functions performed by the microbiota are referred to as microflora associated characteristics (MAC) by various researchers (Collinder et al., 1998). Among several functions, the important ones include digestion of metabolite substrates, vitamin K and B production, drug metabolism, mucosal cell development, stimulation of immune system, protection against pathogenic organisms where it has been found to induce antimicrobial proteins such as cathelicidins, C-type lectins, and (pro) defensins. The microbial gene products impact the metabolism and health status of the host. Recent research findings on the interaction of gut microbiome and the brain have paved the way for more in-depth studies on understanding the impact of these simple microbes on the complex distant organ the brain, thereby transforming neurosciences, opening frontiers for therapeutic strategies for neurodevelopment disorders.
There is increasing evidence of the critical role played by gut microflora in neuro and immune modulatory functions during development and adulthood. The normal microbiota is responsible for synaptogenesis to occur and its absence denotes behavioral and histopathological abnormalities (Cryan et al., 2012). A homeostatic communication is maintained between the brain and the gut intraluminal milieu through various signals including neural, hormonal, and immunological. A more recent observation has been the pathogenesis of several Central nervous system disorders correlated with a perturbed gut-microbiota population (Catanzaro R et al.,2015).During infancy, there are innumerable synaptic connections which provide the essential substrate for functional brain activities such as cognition, perception, and action. A study shows that the commensal microbiota is necessary for the development of brain (Heijtz et al., 2011). The authors hypothesized that gut microbiota modulates synaptogenesis. Intestinal microorganisms are also critical for activation of systemic immunity. They regulate the function of macrophages that reside in the lamina propria of the intestine. The pathways that link the intestinal flora to the brain are (1) Via the activation of the vagus nerve from mature enteric nervous system (ENS) to central nervous system (CNS) (Forsythe et al., 2014). (2) Through circulatory system, various metabolites pass through intestine barriers and then across the blood brain barrier to regulate neurological function. (3) Via immune cells- Microbe associated molecular pattern (MAMP/PAMPs) such as bacterial lipoprotein, lipopolysaccharide, and polysaccharide A. Signals are sent to brain through cytokines like dendritic cells, macrophages, T cells, and B cells.
Microbiota mediated alterations in behaviour and mood
The intestinal microbes send signals affecting the hypothalamic-pituitary-adrenal axis (HPA) which reveals a bidirectional communication system between the host gut and brain (Figure 2). There are a high proportion of neurotransmitters in the gut which have the potential to modulate activity of vagus nerve which is the primary nerve connecting enteric nervous system to CNS and subsequently influence brain function (Bravo et al., 2011). During fetal development, the microbiota plays a crucial role in programming the phenotype, they influence the levels of serotonin (5-HT, 5 hydroxy tryptamine), BDNF (Brain derived neurotropic factor) in regions of Amygdala and Hippocampus. These factors play a regulatory role in neurogenesis and synaptic plasticity.
BDNF is a protein encoded by BDNF gene important for long term memory, helps support survival of existing neurons and encourage growth and differentiation of new neurons, generation of synapses. The symbiotic organisms residing in the GI tract largely affect the production and regulation of its function. Reduced levels of BDNF are seen in neurological conditions like schizophrenia, depression, Alzheimer’s, mood disorders like anxiety and epilepsy (Foster et al., 2013).
Serotonin is a monoamine neurotransmitter acquired from the amino acid tryptophan. It is responsible for the well-being, regulation of mood, sleep and cognitive functions. Deficit of serotonin causes depression. 5-HT synthesis requires tryptophan and this is generated by the intestinal microbiota which can cross the blood brain barrier for the synthesis. Neurophysiology can be changed by actions of the microbiome such as by altering the permeability of blood brain barrier, allowing flux of metabolites into and out of the brain (Bercik et al., 2014). In absence of microbes, there is a decreased level of neurotransmitters such as dopamine and GABA. Specific intestinal bacteria produce small molecules such as serotonin, dopamine, epinephrine, and norepinephrine (Wall et al., 2014, Lyte et al., 2013).
Mechanism of action
The microbes send signals to enterochromaffin cells which produce neurotransmitters and enteric neurons, glia. The decarboxylation of the amino acid tryptophan by neurotransmitter tryptamine is initiated by specific microbes residing in the namely Clostridium sporogenes and Ruminococccus gnavus (Williams et al., 2014). In the brain tryptamine, a monoamine alkaloid is a non-selective serotonin receptor agonist which plays an inhibitory role in the response to serotonin and modulate mood and appetite (Zucchi et al., 2006) while in the gut tryptamine can also induce enterochromaffin cells to release 5-HT. The gut microbiota is also responsible for release of another neuromodulator tyramine, which has higher affinity for TAAR1 receptor found in the brain. Lactic acid bacteria such as L.brevis and enterococcus species act locally via vagus nerve / via the periphery (Barett et al., 2012)
Studies have shown that microbiota derived signals can induce non-inflammatory cytokine pathways. For instance, the plasma G-CSF can cross the blood brain barrier and acts to stimulate neurogenesis in the brain (Zhao et al., 2007). Through G-CSF production, the microbiota influences the rate of neurogenesis.
With the knowledge of the important role played by microbes in neurological activities, research studies and findings progress towards maintaining this rich microbiota and stimulating them to contribute to the host a positive effect. Dietary macronutrients have a great effect on the gut microbiome. Bacteroidetes, Firmicutes, Actinobacteria are 3 major phyla that inhabit the large intestine. The diet can significantly change the composition of the microbiota. From birth, the diet is involved in the development of microbial communities in GI tract.
Stress and its effects on brain
Human beings are susceptible to stress factors at some point of time, irrespective of age, gender, economic status. As a matter of fact, all organisms have some form of exposure to stress. It weakens the physiological functioning of the entire body and fails to maintain homeostasis. Stress has been known to cause many unfavorable effects in the body, the first among them equals derangement of gut mucosa permeability and compromised intestinal morphology, which indirectly impacts the brain leading to increased inflammation in conditions like depression. A symbiotic composition of Saccharomyces boulardii lysate has been investigated to impede the stress induced gut hyper-permeability and other related parameters were monitored (Takadanohara H et al., 2012). It also triggers a chemical change in the brain that modifies the synapses thereby disturbing the neuronal connectivity. During the period of exposure to stress there is elevated levels of cortisol, commonly referred to as “stress hormone”, is the body’s natural response to stress. Response to stress is an essential part of survival. However, while enabling the body to manage the effects of stress, this hormone has devastating effects on the brain. The high levels of glucocorticoid activity are associated with reduced neurogenic activity (Gould et al., 1997a, 1999b, Lagace DC et al., 2010). The hypothalamic-pituitary-adrenal axis (HPA) is considered as the central response system in the body, it reticulates the central nervous system and endocrine system and coordinates a defective response to stress factors. HPA axis is responsible for the prominent increase in behaviour altering chemicals including glucocorticoids, catecholamines, and mineralocorticoids. Its activity is regulated by afferent nerve fibres of the parasympathetic system such as vagus nerves, oculomotor nerves, limbic system which includes hippocampus, amygdala, basal ganglia and sympathetic systems.
The hippocampus is a horse shaped region near to the amygdala in the midbrain. Our experiences, emotions, memory retention rely entirely on the hippocampus to function correctly. Neuroscientists have confirmed that chronic stress can damage the brain severely and have a long-term effect involving changes in brain structure such as shrinking the hippocampus volume, loss of memory retention, neuroinflammation, suppressing the neural activity and increasing the size of amygdala which heightens flight/fight response. The maintenance of stability in the brain is disturbed due to continual exposure of stress. Raised levels of cortisol is involved in the synthesis of neurotransmitter glutamate which is a chemical used to transmit signals to other nerve cells. This excitatory neurotransmitter when released in high amounts has neurotoxic effects by generating free radicals. Cortisol also damages the receptors of the neurotransmitters serotonin and dopamine which are regulators of mood, pleasure, happiness and motivation. Prolonged stress is known to alter the blood brain barrier permitting the entry of pathogens, heavy metal, toxins which damage the brain cells (Figure 3). There is an immense loss of neurons and brain cells due to inhibitory action of cortisol on the brain derived neurotropic factor (BDNF) which is a protein used to maintain healthy brain cells and for synthesis of new cells in the brain.
Role of nutraceuticals
The term “nutraceutical” was coined by Stephen L. Defelice in 1979. According to Defelice, it is defined as food or parts of food that dispense medical/health benefits including prevention and treatment. It is a composite of nutrition and pharmaceutical which helps to maintain the physiological functions of the body. These nutrient factors provide sufficient nutrients to meet the fundamental nutritional requirements for quality living, balance and growth (Maddi et al., 2007). They are also referred to as medical foods, and designer foods. These products are derived from food sources with additional health benefits besides providing the basic nutritional value in foods (Rishi et al., 2006). Nutraceutical compounds specifically targeting the neurodevelopment processes are referred to “neuro-nutraceuticals”, a term that has been recently introduced. These supplements are chemically identified molecules that beneficially affect the brain at molecular level. Their actions are directed to aid in improvement of cognition, improve memory, positively impact the production of neurotransmitters, reduce inflammations and ageing of brain, management of neurodegenerative and neuropsychiatric disorders (Malik et al., 2008). In line with the subject, they also are known to enhance the gut microbes and influence their activities. A healthy gut impacts the brain development and signalling mechanisms. It helps to lower the stress levels and maintain a good mood. Foods can infuse our brains with energy to make us think faster and better. Nutraceuticals range from isolated nutrients such as vitamins, minerals, fatty acids, probiotics, prebiotics, antioxidants, polyaminoacids, polysaccharides, herbal products, genetically engineered foods and phytochemicals which include (Carotenoids- fruits, vegetables and egg yolk. Flavonoid polyphenolics- berries, fruits, vegetables, legumes, are potent antioxidants Non-flavonoid polyphenolics- dark grapes, raisins, berries, peanuts, turmeric roots).
Effects of nutrients on gut and brain
The diverse composition of gut microbiota in humans depends on dietary habits. The key mechanisms to maintain gut health are considered to increase the intake of high fibre diet, polysaccharides, polyunsaturated fatty acids, antioxidants, and phytochemicals. High-fibre rich foods stimulate fermentation which proliferates the bacteria and increase biomass. Fermentation causes carbohydrates to undergo chemical changes which result in organic acids that provide energy for the microbes. Short chain fatty acids (SCFA) are the end products of carbohydrate fermentation which help to inhibit the growth of pathogenic microorganisms. The intake of short-chain non-digestible carbohydrates which include inulin-type fructans, fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) are source of prebiotics that typically target growth of bacterial groups such as Bifidobacterium and Lactobacillus. These prebiotic fibres help to ease anxiety, depression, restore healthy sleep patterns and protect beneficial gut bacteria. Dietary saturated fats may increase the number of existing pro-inflammatory gut microbes by stimulating formation of taurine conjugated bile acids that promotes growth of these microbes (Devkota et al., 2012). Polyphenol containing berries metabolized by resident microbiota results in bioactive products which impacts the health (Duthie et al., 2003). Any gut malfunction has a negative impact on human health, therefore it is highly essential to incorporate foods that enhance the microflora of the gut. Artichokes have a strong probiotic potential, the high content of inulin which is insoluble fibre ferments into healthy microflora (Gibson et al., 1995). Adequate administration of probiotics is recognized to have balanced immunoregulatory activities. Investigations on a particular probiotic strain Lactobacillus Pentosus has been shown to enhance the cytokine production especially IL-10 which is responsible for maintaining the host immunity by normalizing the T regulatory cells (M. Kimura et al.,2017). Lately, a fascinating finding has been that cocoa or chocolate the most craved food across the globe may modulate the gut commensal population. They are found to contain flavonoids including procyanidins, like catechin and epicatechin oligomers which enhance the action of the neurotransmitters in the brain. A. Homayouni Rad and his colleagues formulated chocolate as a potential carrier of probiotic culture strains including lactobacillus.casei and paracasei , positively sustaining the intestinal microbiota population and also releasing stress busting endorphins. Another notable strain is the lactic acid bacteria Streptococcus thermophilus, widely used in the commercial production of fermented dairy products. Because of its inability to survive in the healthy gastric pH of the stomach, it has not been suggested as a ideal probiotic candidate. Nonetheless Xiaohong Kangaan and colleagues conducted an intriguing study on the health promoting effects of milk fermented by Streptococcus thermophilus in mice, the fermented milk was found to have an enhanced cell-mediated response and positive immunostimulatory effects (M. Kimura et al.,2017). Bananas restore health of the bacterial community and reduce inflammation. It is found to maintain harmony between the different phyla present in the gut. Polenta is a corn-based complex carbohydrate which has fermentable components that fosters healthy microbiota because of its high fiber (Anderson et al., 2009). Broccoli, kale, cauliflower, cabbage consist of sulfur containing metabolites namely glucosinolates, which are fragmented by the microbes to release substances that reduce inflammation (Li et al., 2008).
Benefits of berry fruit polyphenols
Oxidative stress is a serious threat, triggering widespread increase in the occurrence of major diseases such as Alzheimer’s, Parkinson’s, other neurodegenerative disorders and ageing. Foods rich in antioxidant activity help to prevent age-related changes (Figure 4). Berry fruit polyphenols can neutralize the negative effects of free-radicals, the harmful by-products of cellular metabolism which contribute to age related diseases. They also possess a multiplicity of actions aside from antioxidant activity. They stimulate brain activity, neuronal communication, cognitive skills, calcium buffering ability, improve movement control and prevent memory loss. Supplements derived from berry fruits like blueberry, cranberry, strawberry have been reported to be effective in reversing motor and behavioral deficits and control sensory inputs. These tiny fruits laden with healing properties are referred to as brain protective fruits, berries are rich in bioflavonoids such as anthocyanins and proanthocyanins, both of which are scavengers of free radicals. Active phytochemicals present in the blueberry confer the benefit of being able to cross the blood-brain-barrier. Anthocyanins have been shown to penetrate the brain and their concentrations correspond to appropriate cognitive performances (Lacueva et al., 2005). They upregulate TNF α, IL-1β, NF-κB and consequently suppress ageing and improve blood flow to the brain. Blueberries are responsible for reducing expression of stress signals and results in increasing protective signals and impact cell signalling molecule expression (Shukitt-Hale et al., 2008). The anthocyanins elevate the level of BDNF (Brain derived neurotropic factor) which is crucial to boost neuronal communication influencing cognitive function. Heat shock proteins are known to fight free radicals and inflammation inducing agents to support healthy brain tissues. The ability to generate heat shock proteins declines with age dramatically. However, researchers have found that consumption of blueberries could restore heat shock protein response and help protect against neurodegeneration processes associated with ageing. Blueberries play an essential role in reducing the toxicity of kainic acid on hippocampal cells. Kainic acid is an amino acid which is naturally abundant in seaweeds and can be neurotoxic because of its potent ability to stimulate neurons by activating receptors for glutamate. This aminoacid can be induced in laboratory animal models to study various neurodegenerative disorders.
Polyunsaturated fatty acids (PUFAs) are critical components of neuronal cell membranes and are involved in neurotransmitter communication within the neural networks. They are responsible for maintaining membrane fluidity essential synaptic vesicle fusion and serve as precursors for lipid messengers which participate in signalling processes to promote neuronal protection (Bazan et al., 2005). Flaxseeds, fish, soybeans, walnuts, are rich in PUFA specifically omega- 6 fatty acid linoleic acid, omega-3 α linolenic acid.
Intake of PUFA supplements for improve cognitive function
In most neurological conditions, inflammation manifests in the nervous tissue, and this inflammation is a therapeutic target by the pharmaceutical industries. During high levels of stress, the body cannot regulate an inflammatory response which leads to a greater risk of development of other diseases. Anti-inflammatory agents containing nutraceuticals is the focus of development. Oxymatrine derived from the root of a Chinese herb Sophora flavescens has been reported to have anti-inflammatory actions and decreases damage observed after hypoxic- ischaemic brain injury in neonatal rat models (Zhao et al., 2015). Apocynin obtained from the root of Picrorhiza kurroa is also believed to have anti-inflammatory properties, and attenuate the cholesterol oxidation product induced apoptosis in neuronal cells by preventing production of reactive oxygen species (Simonyi et al., 2012). Quercetin known to be found in vegetables, fruits have antioxidant effects, regulate proteins, transcription factors and kinase dependent signalling pathways. Nutraceutical additive actions of quercetin expedite optimal delivery and improve brain activity. Naturally occurring 7, 8-dihydroxyflavone rescues cognition deficits and serve as a novel treatment for autism and schizophrenia. Trans-resveratrol and pterostilbene are plant derived synergistic phytonutrients improving brain health and having diverse actions against oxidative stress (Poulose et al., 2015). Creatine is a natural substance when taken as supplements in recommended dose is beneficial to enhance brain function and improve cognitive function (Wallimann 2008) (Table 1).
Management of stress
Nutrient supplements have the potential to overcome the debilitating effects of stress. They act as prophylactic and therapeutic agents and are more efficient and safe in comparison to pharmaceutical drugs (Pandey et al., 2010). Botanically derived ingredients are used to treat mild depression, anxiety, improve sleep patterns and maintain good health. Since a persistent level of cortisol in circulation is the chief cause of depression and stress, naturally derived products target this hormone to annihilate the stress factors and boost mental health and cognition. Researchers have studied the effects of probiotics against stress in a zebrafish model by introducing the bacterial strain Lactobacillus plantarum into the tank (Davis et al., 2016). The objective is to bring the body back to homeostasis, maintaining a balanced level of cortisol. The actions of gut microbes and nutraceuticals work interdependently to help reduce the dangerous outcomes of stress upon the body. Experiments with germ free mice have been used to probe the role of microbiota in adult hippocampal neurogenesis. Also, disruptions of gut microbiome induced mice behaviour resulted in anxiety, depression and even autism. Gut microbes are the key modulators of brain plasticity, cognitive functions and help to optimize the body’s response to stress by regulating their synthesis of neurotransmitters like serotonin to lower the cortisol level. Studies have shown that during stress there is an increased population of certain bacterial strains in the gut such as Enterobacteriaceae, Proteobacteria, Actinobacteria and this can be controlled by increasing the administration of probiotics containing Lactobacillus and Bifidobacterium species. Experiments have been conducted with Bifidobacterium longum and results showed that this strain was able to reverse hippocampal, and BDNF abnormalities.
In today ‘s ambitious world, so much importance is being given to performance, perfection, competition that it leads to an insidious increase in stress, depression, anxiety. Stress is a psychological issue which predisposes a person to various other ailments. It is inevitable in the life of any individual but the duration and intensity differs. According to Hans Selye, who coined the term stress in 1936, it is the non- specific response of the body to any demand for change. Stress levels are rising worldwide; it is a top health concern. The damages that can be caused by stress are often underestimated. It primarily affects the nervous system, but prolonged exposure leads to cardiovascular, musculoskeletal diseases and even affects the reproductive system. Claude Bernard (1865-1961) observed that the maintenance of life is essentially dependent on keeping our internal milieu constant in the face of a changing environment. Thus, sustaining a state of homeostasis is vital for a healthy life. Workplace stress and depression is on the rise, it is the health epidemic of 21st century, a frequently reported problem. According to WHO, depression is among the leading causes of disability globally. There is a compelling need to confront the ameliorating and deleterious effects of stress inflicted on an individual. These health risks can be prevented or managed. A multi targeted approach is required to tackle a problem as severe as stress. It can be controlled in the healthy way by nourishing and stimulating the gut microbes in our body to act on the brain, which increases the release of neurotransmitters to help relieve the effects of stress. Nutrient supplements referred to as nutraceuticals has been introduced to influence the brain activity and protect it from the negative impact of stress hormones. These nutraceuticals help to enhance the quality of life by modulating the gut health. They prevent the alteration of microbiome during stress. Extensive research has been conducted in the field of gut microbes and nutraceuticals and their efficacy towards alleviating stress has been proved. We are moving towards the direction of exploring psych biotics as a mode of treatment for anxiety, depression and various psychiatric issues. However, it is a recently introduced term and research and is still on-going whether it has proven benefits or not. Dietary interventions with food supplements designed to modulate responses to stress that can be administered effectively. Managing stress in the natural way is proven to be the most favorable method.
The authors are thankful to Chettinad Academy of Research and Education (CARE) for the support.
Conflicts of interest
We declare no conflict of interest. All co-authors have agreed to transfer the copyright to the publisher if it is accepted for publication. This study was partially financially supported by Chettinad Hospital & Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai-603103, India.
Anderson, J.W, Baird, P., Davis, R.H., Ferreri, S., Knutdson, M., Koraym, A., Waters, V., Williams, C.L. (2009). Health benefits of dietary fibre. Nutrition Reviews 67:188-205.
Andres, R.H., Ducray, A.D., Schlattner, U., Wallimann, T., Widmer, H.R. (2008). Functions and effects of creatine in the central nervous system. Brain Research Bulletin 76(4):329-43.
Andres-Lacueva, C., Shukitt-Hale, B., Galli, R.L., Jauregui, O., Lamuela-Raventos, R.M., Joseph, J.A. (2005). Anthocyanins in aged blueberry-fed rats are found centrally and may enhance memory. Nutritional Neuroscience 8(2):111-20.
Andres-Lacueva, C., Shukitt-Hale, B., Galli, R.L., Jauregui, O., Lamuela-Raventos, R.M., Joseph, J.A. (2005). Anthocyanins in aged-blueberry fed rats are found centrally and may enhance memory. Nutritional Neuroscience 8(2): 111-20.
Barrett, E., Ross, R.P., O'Toole, P.W., Fitzgerald, G.F., Stanton, C. (2012). gamma-Aminobutyric acid production by culturable bacteria from the human intestine. Journal of applied microbiology 113:411–417.
Bazan, N.G. (2005). Lipid signaling in neural plasticity, brain repair, and neuroprotection. Molecular Neurobiology 32(1):89-103.
Bercik, P., Denou, E., Collins, J., Jackson, W., Lu, J., Jury, J., Deng, Y., Blennerhassett, P., Macri, J., McCoy, KD., Verdu, E.F., Collins, S.M. (2011). The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141:599-609.
Borre, Y.E., O'Keeffe, G.W., Clarke, G., Stanton, C., Dinan, T.G., Cryan, J.F. (2014). Microbiota and neurodevelopmental windows: implications for brain disorders. Trends in Molecular Medicine 20:509-518.
Bravo, J.A., Forsythe, P., Chew, M.V. (2011). Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proceedings of the National Academy of Sciences of the United States of America 108:16050-16055.
Brianna, B., Andrew, W.H., Benschoten, V., Cimermancic, P., Donia, M.S., Zimmermann, M., Taketani, M., Ishihara, A., Kashyap, P.C., Fraser, J.S., Fischbach, M.A. (2014). Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe 16(4):495–503.
Catanzaro R. , Anzalone M. G. , Calabrese F. , Milazzo M. , Capuana M. L. , Italia A. , Occhipinti S. , Marotta F.The gut microbiota and its correlations with the central nervous system disorders.Panminerva Medica 2015. 57(3):127-43
Collinder, E., Lindholm, A., Midtvedt, T., Norin, E. (1998). The usefulness of microbial-associated characteristics (MACs) for studies of microbial intestinal functions in different species. Microbial Ecology in Health and Disease 10:203–4.
Cryan, J.F., Dinan, T.G. (2012). Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nature Reviews Neuroscience 13:701–712.
Davis, D.J., Doerr, H.M., Grzelak, A.K., Busi, S.B., Jasarevic, E., Ericsson, A.C., Bryda, E.C. (2016). Lactobacillus plantarum attenuates anxiety-related behavior and protects against stress-induced dysbiosis in adult zebrafish. Scientific Reports 6:33726.
Devkota, S., Wang, Y., Musch, M.W., Leone, V., Fehlner-Peach, H., Nadimpalli, A., Antonopoulos, D.A., Jabri, B., Chang, E.B. (2012). Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice. Nature 487(7405):104-8.
Duthie, G.G., Gardner, P.T., Kyle, J.A.M. (2003). Plant polyphenols: are they the new magic bullet? Proceedings of the Nutrition Society 62:599-603.
Eckburg, P.B., Bik, E.M., Bernstein, C.N., Purdom, E., Dethlefsen, L., Sargent, M., Gill, S.R., Nelson, K.E., Relman, D.A. (2005). Diversity of the human intestinal microbial flora. Science 308:1635-1638.
Forsythe, P., Bienenstock, J., Kunze, W.A. (2014). Vagal pathways for microbiome-brain-gut axis communication. Advances in experimental medicine and biology 817:115-133.
Foster, J.A., Neufeld, K.A. (2013). Gut-brain axis: how the microbiome influences anxiety and depression. Trends in neurosciences 36:305-312.
Gibson, G.R., Roberfroid, M.B. (1995). Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. Journal of Nutrition 125:1401-1412.
Gould, E., McEwen, B.S., Tanapat, P., Galea, L.A., Fuchs, E. (1997). Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. Journal of Neurosciences 17:2492-2498.
Gould, E., Tanapat, P. (1999). Stress and hippocampal neurogenesis. Biological Psychiatry 46:1472–1479.
Homayouni Rad.A, Mehrban Roudbaneh. M, Ghasemnezhad Tabrizian.V, Javadi.M, Harati.N, Homayouni Rad.H and Kasaie.Z. Chocolate as a Probiotic carrier food – A Review.International Journal of Probiotics and Prebiotics 37-42, 2016.
Heijtz, D.R., Wang, S., Anuar, F., Qian, Y., Björkholm, B., Samuelsson, A., Hibberd, M.L., Forssberg, H., Pettersson, S. (2011). Normal gut microbiota modulates brain development and behavior. Proceedings of the National Academy of Sciences of the United States of America 108:3047-3052.
Kimura .M, Sirilun.S, Chaiyasut.S.Isolation of an efficient Lactobacillus pentosus strain capable of stimulating lymphoid cells to produce IL-10.International Journal of Probiotics and Prebiotics 12,77-82, 2017.
Lagace, D.C., Donovan, M.H., DeCarolis, N.A., Farnbauch, L.A., Malhotra, S., Berton, O., Nestler, E.J., Krishnan, V., Eisch, A.J. (2010). Adult hippocampal neurogenesis is functionally important for stress-induced social avoidance. Proceedings of the National Academy of Sciences of the United States of America 107(9):4436-41.
Li, T.S.C. (2008). Vegetables and Fruits: Nutritional and Therapeutic Values, (Taylor and Francis Group, Boca Raton, Fla, USA) Vol. 169, 195, 198.
Lyte, M. (2013). Microbial endocrinology in the microbiome-gut-brain axis: how bacterial production and utilization of neurochemicals influence behaviour. PLoS pathogens 9: e1003726.
Maddi, V.S., Aragade, P.D., Digge, V.G., Nitaliker, M.N. (2007). Importance of nutraceuticals in health management. Pharmacognosy Reviews 1:377-379.
Malik, A. (2008). The potentials of Nutraceuticals, Pharmainfo.net 6.
Pandey, M., Verma, R.K., Saraf, S.A. (2010). Nutraceuticals: new era of medicine and health. Asian Journal of Pharmaceutical and Clinical Research 3:11-15.
Pepping, J. (1999). Omega-3 essential fatty acids. American Journal of Health-System Pharmacy 56:719-724.
Poulose, S.M., Thangthaeng, N., Miller, M.G., Shukitt-Hale, B. (2015). Effects of pterostilbene and resveratrol on brain and behavior. Neurochemistry International 89:227-233.
Ravinder Nagpal, Hariom Yadav, Francesco Marotta.Gut Microbiota: The Next-Gen Frontier in Preventive and Therapeutic Medicine? Front Med (Lausanne). 2014; 1: 15.
Rishi, R.K. (2006). Nutraceuticals: borderline between food and drug? Pharmacological Reviews pp. 51-53.
Shukitt-Hale, B., Lau, F.C., Carey, A.N., Galli, R.L., Spangler, E.L., Ingram, D.K., Joseph, J.A. (2008). Blueberry polyphenols attenuate kainic acid-induced decrements in cognition and alter inflammatory gene expression in rat hippocampus. Nutritional Neuroscience 11(4):172-82.
Simonyi, A., Serfozo, P., Lehmidi, T.M., Cui, J., Gu, Z., Lubahn, D.B., Sun, A.Y., Sun, G.Y. (2012). The neuroprotective effects of apocynin. Frontiers in Bioscience 4:2183-2193.
Wall, R., Cryan, J.F., Ross, R.P., Fitzgerald, G,F., Dinan, T.G., Stanton, C. (2014). Bacterial neuroactive compounds produced by psychobiotics. Advances in Experimental Medicine and Biology 817:221-39.
Takadanohara H, Catanzaro R, Chui de H, He F, Yadav H, Ganguli A, Sakata Y, Solimene U, Minelli E, Kobayashi R, Nagamachi Y, Marotta F.Beneficial effect of a symbiotic preparation with S. boulardii lysate in mild stress-induced gut hyper-permeability. Acta Biomed. 2012; 8 3(3):208-16.
Zhao, L.R., Navalitloha, Y., Singhal, S., Mehta, J., Piao, C.S., Guo, W.P., Kessler, J.A., Groothuis, D.R. (2007). Hematopoietic growth factors pass through the blood-brain barrier in intact rats. Experimental neurology 204:569–573.
Zhao, P., Zhou, R., Zhu, X.Y., Hao, Y.J., Li, N., Wang, J., Niu, Y., Sun, T., Li, Y.X., Yu, J.Q. (2015). Matrine attenuates focal cerebral ischemic injury by improving antioxidant activity and inhibiting apoptosis in mice. International Journal of Molecular Medicine 36(3):633-44.
Zucchi, R., Chiellini, G., Scanlan, T.S., Grandy, D.K. (2006). Trace amine associated receptors and their ligands. British Journal of Pharmacology 149:967–978.
Figure 1: Schematic representation of various factors that affect the intestinal gut microbes
Figure 2: Description of the bidirectional gut-brain communication
Figure 3: Schematic diagram displays the effect of chronic stress on the brain, characteristic of increased cortisol levels
Figure 4: Foods rich in antioxidants
Table 1: Herbal supplements and their applications
Popular herbal medicine, induce calmness, lower inflammation levels
Reduces moderate depression