Elsevier

Brain, Behavior, and Immunity

Volume 90, November 2020, Pages 403-419
Brain, Behavior, and Immunity

Review Article
Nutraceuticals and probiotics in the management of psychiatric and neurological disorders: A focus on microbiota-gut-brain-immune axis

https://doi.org/10.1016/j.bbi.2020.08.027Get rights and content

Highlights

  • Nutrition has a major role in shaping the human microbiota composition and function.

  • Nutraceuticals and probiotics are evidenced to benefit psychiatric and neurological disorders.

  • Vitamins, fish oils and probiotic supplementation are effective in treatment of neuropsychiatric disorders.

  • Vitamins, fish oils and probiotics have complex interaction with gut microbes.

  • These supplements exert benefits to the host via regulating the microbiome-brain-immune axis.

Introduction

The human body harbours trillions of microorganisms; especially in the intestinal lumen, forming a stable microenvironment relating to health at all times (Arumugam et al., 2011, Sommer and Bäckhed, 2013). This microenvironment usually termed, as gut microbiota comprises of commensal, symbiotic, and pathogenic microbiota, which balance the health status of the host depending on their stability, composition, and recoverability (Dave et al., 2012, Lozupone et al., 2012). A healthy microbiome intricately governs several biological processes and influences neurobiology of the host via bi-directional communication with the central nervous system (CNS) generally termed the ‘microbiota-gut-brain axis’, involving the vagus nerve, the immune system, the hypothalamic–pituitaryadrenal (HPA) axis and the bacteria-derived metabolites directly or indirectly (Breen et al., 2019, Cryan et al., 2019, Honda and Littman, 2016, Mayer et al., 2015, Neuman et al., 2015, Stevens et al., 2018). The dysfunction of interaction between the gut microbiota and the brain or a compositional alteration of microbiota has been associated or featured with the pathogenesis of metabolic disorders, CNS and neurological diseases, cancer and other diseases (Foster and McVey Neufeld, 2013, Ma et al., 2019, Ni et al., 2017, Roy and Trinchieri, 2017, Torres-Fuentes et al., 2017). Furthermore, crosstalk between this axis and the immune system (microbiota-gut-brain-immune axis) has gained more attention as it plays a vital role in the pathogenesis of several brain disorders (Dinan and Cryan, 2017, El Aidy et al., 2015).

Generally, the diverse commensal taxa, namely Archaea, Bacteria, and Eukarya, commonly colonize the human gut environment (Milani et al., 2017). Most of the bacteria belong to the following phyla: Firmicutes, Bacteroidetes, Actinobacteria, Verrucomicrobia, and Proteobacteria, and among them the following genera: Bifidobacterium, Lactobacillus, Bacteroides, Clostridium, Escherichia, Streptococcus, and Ruminococcus dominate the human gut (Eckburg et al., 2005, Human Microbiome Project, 2012). Clinical studies have provided promising evidence indicating an essential role of the gut microbiota in the pathogenesis of brain disorders such as depression, Alzheimer’s, Schizophrenia, Parkinson’s, Autism and Multiple Sclerosis and their notable changes in their profile in the host under those circumstances. Among a group of depressed individuals, the fecal microbiota showed an overrepresentation of Bacteroidales and an underrepresentation of Lachnospiraceae, Oscillibacter and Alistipes to be associated with depression (Naseribafrouei et al., 2014). In other cases, an increase with Bacteroidetes, Proteobacteria, Lactobacillus, Actinobacteria and a significant decrease with Firmicutes were observed in fecal samples of depressed patients (Jiang et al., 2015, Valles-Colomer et al., 2019). In another study with major depressive disorder (MDD) patients, the Bacteroidetes, Bifidobacterium and/or Lactobacillus were reported to be decreased (Aizawa et al., 2016, Chen et al., 2018). Also, Coprococcus and Dialister associated with quality of life (QOL) were depleted in a treatment-free depressed sample (Valles-Colomer et al., 2019). In a recent study, sex-dependent associations were observed in mood disorder subjects, females had an inverse relationship between anxiety scale scores and Bifidobacterium, whereas, males had an inverse relationship between depression scale scores and Lactobacillus (Taylor et al., 2019). Whereas, Zheng et al. (2016) reported a relative abundance of Actinobacteria and a decreased abundance with Bacteroidetes in MDD subjects.

Among Alzheimer’s diseases (AD) patients, Zhuang et al. (2018) documented that at the phylum level, the abundance of Bacteroidetes was decreased, whereas Actinobacteria were increased; at the class level, Actinobacteria and Bacilli increased, while Negativicutes and Bacteroidia decreased; at the family level, Ruminococcaceae, Enterococcaceae, and Lactobacillaceae increased, while Lanchnospiraceae, Bacteroidaceae, and Veillonellaceae decreased. Whereas, in schizophrenia patients, an increase with Candida albicans was observed (Severance et al., 2016). While with Parkinson’s disease (PD) patients, bacteria from the genus Blautia, Coprococcus, Faecalibacterium and Roseburia were significantly less abundant in feces (Keshavarzian et al., 2015). Another study suggested that the abundance of Prevotellaceae in feces of PD patients was reduced (Scheperjans et al., 2015).

Moreover, with CNS disorders, Bacteroidetes, Desulfovibrio spp and Bacteroides vulgatus were found at high levels in severely autistic children (Finegold et al., 2010). Several studies documented changes with fecal microbiota among autistic children: lower levels of Bifidobacter species and higher levels of species of Lactobacillus (Adams et al., 2011); significantly lower abundances of the genera Prevotella, Coprococcus, and unclassified Veillonellaceae (Kang et al., 2013); abundance of Sutterella spp. (Wang et al., 2013, Williams et al., 2011, Williams et al., 2012); abundance of Lactobacillus, Desulfovibrio, Clostridium, cluster I and II with a decrease in Bacteroides/Firmicutes ratio (Parracho et al., 2005, Tomova et al., 2015). Similarly, with Multiple sclerosis (MS) patients, an increase with Methanobrevibacter and Akkermansia and a decrease in Butyricimonas was observed (Jangi et al., 2016). Significant enrichment of the Desulfovibrionaceae and reduction in Lachnospiraceae and Ruminococcaceae was found with young MS patients (Tremlett et al., 2016). In another study, an increased abundance of Pseudomonas, Mycoplana, Haemophilus, Blautia, and Dorea genera and a decreased abundance of Parabacteroides, Adlercreutzia and Prevotella genera were observed in MS subjects (Chen et al., 2016b). Likewise, increased abundancy with Bifidobacterium and Streptococcus genera and a lesser abundancy of Bacteroides, Faecalibacterium, Prevotella, and Anaerostipes genera were documented with MS subjects (Miyake et al., 2015). Summary of studies examining gut microbiota alterations with various psychiatric and neurological disorders are given in Table 1.

The plethora of clinical studies rather convincingly demonstrated an imbalance with gut microbiota in brain-based disorders. All these findings prompt the notion of modulation of microbiota with similar brain disorders but do not remain the same and discrepancy with no uniformity is clearly documented (see Table 1). This disparity may be due to the heterogeneity of the investigated subjects and variable methods of analysis. It appears that stability and uniformed change in microbiota profile thus cannot be generalized, which complicates identification of opportunities for the development of novel therapeutic interventions targeting neurological and psychiatric disorders. However, there is also ample evidence that strain-specific perturbations and selective increase in harmful microbiota with such brain conditions are linked to “leaky gut” mediated inflammation. The further release of pro-inflammatory cytokines as a result of microbiota driven gut-brain axis interaction remains a classical signature found in most of the brain disorders. Research examining brain disorders and gut microbiome have already demonstrated strong evidence for an immune system link between the gut and the CNS. Besides, evidence now exists supporting low-grade inflammation usually exhibited with several diseases are controlled and influenced by the microbiota-derived signals having a multidirectional interaction with nutritional status (Belkaid and Hand, 2014). Indeed, the notable impact on metabolomics and production of crucial molecules by these altered gut microbiota and their precise underlying mechanisms contribute to the disease inception and key interacting factors such as the diet and nutrition need serious consideration, too.

Proper nutrition and diet are directly correlated with better health and, more importantly, govern brain health, immune function and healthy gut microbiota composition (Barratt et al., 2017, Cryan et al., 2019, Sandhu et al., 2017). Diet or nutrition is a key contributor in shaping the composition of gut microbiota and remains a potential risk factor for the development of neuropsychiatric disorders (Sandhu et al., 2017). Evidence shows that the low content of plant-derived nutrients, like fibre and phytochemicals and increased fat or protein, influences the levels of Bifidobacteria and butyrate-producing bacteria (Russell et al., 2011). Whereas diets containing more plant-based products and low amounts of fat and animal protein have been shown to increase beneficial Bacteroides, Clostridium and Prevotella phyla and decrease Proteobacteria and Bacillaceae phyla, with abundance in short-chain fatty acids (SCFAs) contributing to their anti-inflammatory effects (Del Chierico et al., 2012, Del Chierico et al., 2014). Similarly, when compared with omnivores, the fecal microbiota of strict vegetarian or vegan diet individuals had lower microbial counts of Bifidobacterium, Bacteroides, Escherichia coli and Enterobacteriaceae species and lower stool pH (Zimmer et al., 2012). Outcomes from these studies show the role of diet–host–gut microbiome axis to be a potential and effective target in treating brain disorders via enhancing gut health. Therefore, when confronting unmet clinical results, a potential new paradigm of manipulating and shaping the gut microbiota composition via altered diet, and nutritional supplementation to improve brain and psychiatric wellbeing needs thorough investigation.

The newest approach of dietary or nutritional supplements or nutraceuticals administered as therapeutic agents or consumed in hope of an healthier life-style has become a multi-billion global market. Although the term “Nutraceutical” is not yet clearly defined, it can still be elucidated as “a food or part of a food, such as a dietary supplement, that has a medical or health benefit, including the prevention and treatment of disease” (DeFelice, 1995). Similarly, over the years, there has been an increase in the consumption of “alternative” or “natural” over-the-counter probiotics to prevent, alleviate or treat specific diseases (Doron and Snydman, 2015, Suez et al., 2019). Thus in this article, we will review the clinical outcomes of two different nutraceutical supplements and probiotics in managing neurological and psychiatric disorders with possible potential relevance to the gut (gut bacteria)-brain-immune axis. The first, vitamins, the essential and multifunctional micronutrient established for their potential link with several psychiatric disorders (Degner, 2016, Lang et al., 2015), are generally ingested via diet or synthesized by the gut microbiota maintaining a healthy gut flora and a better health status (Biesalski, 2016). The second is popular fish oil which contains two types of omega-3 polyunsaturated fatty acids (n–PUFAs). Namely Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been rigorously studied and are known for their efficacy, tolerability, and utility in prevention and treatment of several neuropsychiatric disorders (Guu et al., 2019). The third most beneficial agents are probiotics which are gaining popularity more than the other two nutraceutical supplements for their prospective application in manipulating the gut microbiota composition and potentiating a significant role with psychological disorders (Quigley, 2019, Reijnders et al., 2016). Interesting enough, each of these nutraceuticals and probiotics is widely used, having different properties and interactive mechanisms with the gut microbiota and host physiology. To our understanding, the prevalence of usage and recommendations of these nutraceuticals and probiotics are increasing dramatically worldwide, especially in Asia Pacific countries. Thus it is of interest to provide an overview of the potential role and mechanism of these nutraceuticals and probiotics in influencing the microbiota-gut-immune-brain axis and to exploit further their therapeutic potential in managing brain disorders.

Section snippets

Vitamins

Within the past two decades, studies have extended to decipher the genuine relationship between vitamins and gut microbiota. Also, the relationship of vitamins with general health and the CNS is undeniable; likewise, several reports have established their significant involvement with the pathophysiology of several neuropsychiatric disorders (Fenech, 2017, Patrick and Ames, 2015). A summary of trials evaluating vitamins and their correlation with psychiatric and neurological disorders is

Probiotics

As per the Food and Agriculture Organization of the United Nations and the World Health Organisation (FAO/WHO), probiotics are defined as “live microorganisms which when administered in adequate amounts confer a health benefit on the host” (Hill et al., 2014, Organization 0000). Generally, beneficial microbes belonging to genera Bifidobacterium (adolescentis, animalis, bifidum, breve and longum) and Lactobacillus (acidophilus, casei, fermentum, gasseri, johnsonii, paracasei, plantarum, rhamnosus

Conclusions and perspectives

Research on natural products and live biotherapeutics is at a fascinating crossroad with the growing understanding from the explosion of discoveries associated with disease states. The current rationale for the use of nutraceuticals and probiotics is largely based on scientific and clinical research promoting or restoring human health. Further, the renewed interest in the relationship between brain-based disorders, the gut microbiota, and the immune system COULD advance our understanding and

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