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Journal of Clinical Medicine Research

Review

Volume 13, Number 9, September 2021, pages 439-459

Microbial Therapeutics in Neurocognitive and Psychiatric Disorders

The human gut microbiome is the collective genome and microbial cellular or structural elements and metabolites of the microorganisms inhabiting the gastrointestinal (GI) tract and now considered as a virtual organ [1]. Within the GI tract of humans, resides the largest population of microorganisms, known as the gut microbiota (GM) [2]. Metabolites that are produced by the GM help with the physiological and metabolic processes as well as immunity against pathogens. In the elderly, different factors like polypharmacy, decreased gut mobility, and malnutrition can cause changes in the GM [3]. When there is a disruption of the microbial balance, this is known as gut dysbiosis. It can have wide range of consequences and associated with different diseases [4]. Physiologically significant products derived from GM through their interaction with diet and the host can enter into the circulation from the GI tract and can affect distant organs [5]. In 2018, Bambury et al proposed a pathway for discovery of microbial therapeutics in mental health, known as psychobiotics [6]. A possible link exists between the GM and brain processes and behavior through the microbiota-gut-brain axis [7]. The microbiome is also affected by diet and exercise, which may have an affect on the mood and cognition [8, 9]. Thus, the GM may serve as a target for treatment through the use of microbial therapeutics or microbiota-based treatments including gut biotics and fecal transplantation [10].

The authors of this paper are coining a new term called gut biotics. Gut biotics are either food constituents that can affect the gut microbes or live microbial administration or its products for therapeutic purposes. A schematic outlining about the various gut biotics can be found in Figure 1. Gut biotics serve as a type of microbial therapy to help balance the human intestinal microorganisms in numerous medical conditions including mental health and cognitive disorders. Genetically engineered gut biotics are available and may have similar therapeutic benefits. In mental health, gut biotics can affect the synthesis of neuroactive compounds or neurotransmitters.

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Figure 1. Schematic model of the various gut biotics. Prebiotics are dietary fibre that help with the growth of probiotics which are microorganisms that can provide a health benefit. The combination of prebiotics and probiotics (a) is referred as synbiotics as it is felt there is a synergistic effect due to this combination. Postbiotics, paraprobiotics, and proteobiotics are considered non-viable bacterial products or metabolic by products from probiotic microbes. The natural metabolites through the process of fermentation (b) are isolated from the culture media of probiotics which are identified as proteobiotics. When probiotics are treated through sonication, chemical, or enzymatic processes (c), they are broken down to functional bioactive compounds, referred to as postbiotics. Using radiation, heating, pasteurization and other inactivation methods (d), probiotics are converted to non-viable microbial cells known as paraprobiotics.

The paper written by Dinan et al (2013) defined psychobiotics as probiotics and prebiotics that have a mental health benefit [11], whereas Sarkar et al (2016) mentioned psychotrophics and antibiotics contributing to mental health symptoms and disorders should also be considered as psychobiotics [12]. Based on these two above mentioned definitions, there is a no consensus about the use of the term psychobiotics.

Whereas the authors of this paper think that gut biotics is a better terminology for food products and microbial therapeutics which have broader clinical benefits, including in mental health, by repopulating the GM. It is a microbe or microbiome based therapeutic intervention which may help in the treatment or prevention of mental health disorders.

In this scoping review, the different types of gut biotics are discussed in detail with an overview of pharmacological actions, safety concerns, and regulatory issues, as well as their role in neurocognitive and mental health disorders. As well, the effect of life style factors on the GM and possibly on microbial therapeutics has also been included. This manuscript discusses about the available evidence for a possible novel therapy in different mental health disorders.

A literature search was performed using the electronic databases MEDLINE (1966 - July 2021), EMBASE and SCOPUS (1965 - July 2021), PscyhInfo (1966 - July 2021) and DARE (1966 - July 2021). The main search items were mental health, anxiety, depression, bipolar disorder (BP), schizophrenia, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), dementia, Alzheimer’s, probiotics, prebiotics, synbiotics, paraprobiotics, postbiotics, proteobiotics, fecal transplantation, and life style factors. Non-English articles were excluded.

Probiotics are non-pathogenic microorganisms, including bacteria and yeast, seen in certain types of foods or supplements and can positively influence human health (Supplementary Material 1, www.jocmr.org). The World Health Organization defines probiotics as live microorganisms which when administered in adequate amount confer a health benefit on the host [13].

The main types of probiotic bacteria typically belong to the Lactobacillus genus, including the species: acidophilus, sporogenes, plantarum, rhamnosum, delbrueck, reuteri, fermentum, lactus, cellobiosus, brevis; the Bifidobacterium genus, which include: bifidum, infantis, longum, thermophilum, animalis; the Streptococcus genus, primarily the species: lactis, cremoris, alivarius, intermedius as well as other genus consisting of Leuconostoc, Pediococcus, Propionibacterium Bacillus and Enterococcus (specifically E. faecium). The other probiotic microorganisms are yeast and molds which include Saccharomyces cerevisiae, S. boulardii, Aspergillus niger, A. oryzue, and Candida pintolopesii [14]. These supplements may carry the microorganism to the large intestine for better effects, either in the form of pills, capsules, or liquids. Different fermented food products like yogurt, pickles, kefir or tea like kombucha are the source for probiotics and optimize microbial flora in humans. Non-dairy probiotics can be used in lactose intolerant subjects [15], and engineered probiotics are also available [16].

Probiotics can act throughout the GI tract as well as outside the GI system. Within the GI tract, it can interact with the intestinal microbes directly or by enzymatic activity, or on the intestinal mucosa or epithelium, and can alter the intestinal barrier function as well as the mucosal immune system. Outside the GI tract, probiotics can act on the brain, liver, and other organs [17].

No major side effects are seen with probiotic foods and supplements. In the first few days after starting therapy, some subjects may have mild stomach upset, diarrhea, or flatulence (passing gas) and bloating. Rarely, they may trigger allergic reactions. Foods like sauerkraut and kimchi (fermented cabbage) can cause headache due to their richness in amines. In some it can cause lactose intolerance, so non-dairy probiotic food can be an option to overcome this side effect [15].

The United States Food and Drug Administration consider probiotics as live biotherapeutic products and associate four possible safety concerns with probiotics which are listed as: 1) systemic infections; 2) deleterious metabolic activities; 3) excessive immune stimulation in susceptible individuals; and 4) gene transfer [18].

The trials so far showed mixed results regarding systemic infections in immunocompromised individuals, subjects with cardiac valvular disorders, central venous catheters, and also with short bowel syndrome; thus, caution is needed in these groups. There is a case report of a 58-year-old diabetic with multiple co-morbidities developing a fungemia and sepsis by S. boulardii used as a supportive therapy for diarrhea [19]. There are other reports of this rare complication occurring, typically in immunocompromised individuals [20]. Another example includes a 23-year-old Turkish man with a history of diabetes insipidus and a bicuspid aortic valve developing Lactobacillus endocarditis; the strain was isolated from yogurt where he was consuming 1.5 L of yogurt and sour milk a day [21]. A 64-year-old male with previous history of mitral valve prolapse with regurgitation developed endocarditis from taking freeze-dried probiotic capsules containing L. rhamnosus after dental surgery [22]. Another report discussed the case of a 74-year-old man with lymphocytic leukemia who developed septicemia after ingestion of Bacillus subtilis spores, commonly found in probiotics in Italy [22]. A clinical trial studying probiotic in severe pancreatitis (the PROPATRIA trial) found an unexpected increase in mortality with probiotic treated patients. However, in this trial, there are concerns regarding the design and analysis of this study [23]. Based on these reports, some caution may be warranted when probiotics are used in immunocompromised subjects and in patients with heart valvular conditions.

Van den Nieuwboer in their systematic review reported no increased risk of adverse events with probiotic or synbiotic treatment in immunocompromised adults. Of a total of 57 clinical studies that enrolled 2,563 participants, 22% of studies did not report safety concerns, which is a limitation of this systematic review [24]. In this study, patients were classified as immunocompromised if critically ill, underwent a recent surgery, and had an organ or autoimmune disease, or human immunodeficiency virus (HIV) positive. From this systematic review, no major safety concerns or adverse events were related to the use of probiotics or synbiotics. In fact, adverse events occurred less in the treatment group compared to the immunocompromised controls [24]. The study results are similar to the evidence by Didari et al (2014) which indicates that probiotics are safe but suggested to do risk-benefit analysis for specific cases [25]. Despite studies showing safety with probiotics, caution is needed in certain population groups as discussed above [26, 27].

In contrary to the above mentioned information, a meta-analysis study of 30 clinical trials and 2,972 patients, probiotics and synbiotic mixtures showed significant reduction in infections (relative risk (RR): 0.80, 95% confidence interval (CI): 0.68 - 0.95, P = 0.009), ventilator associated pneumonia (RR: 0.74, 95% CI: 0.61 - 0.90) and found no effect on mortality [28]. A recent systematic review and meta-analysis of randomized clinical trials (RCTs) showed that probiotic use was associated with a significant lower incidence of ventilator associated pneumonia (RR: 0.70, 95% CI: 0.56 - 0.88, P = 0.002, and in-hospital mortality (odds ratio (OR): 0.73, 95% CI: 0.54 - 0.98, P = 0.04) [29]. Another recent meta-analysis by Fan et al (2019) showed synbiotics have the potential to reduce in-hospital and intensive care unit (ICU) mortality [30]. Evidence from these studies points out that probiotics are reasonably safe in immunocompetent subjects.

Prebiotics have been described as non-digestible dietary components that can reach the colon intact and can promote the growth and activity of positive bacteria of the GI tract [31]. The original definition has recently been adapted to include any substrate that the host microorganisms can use resulting in health benefit [32]. This updated terminology allows the inclusion of other substances such as polyphenols and polyunsaturated fatty acids along with the typical carbohydrates, as long as there is evidence of action on the host microorganisms [33]. In 2008, the International Scientific Association of Probiotics and Prebiotics (ISAPP) defined “dietary prebiotics as a selectively fermented ingredient that results in specific changes in the composition and/or activity of the gastrointestinal microbiota, thus conferring benefit(s) upon host health” [32, 34].

Prebiotics can be obtained through a variety of different foods, such as fruits and vegetables as well as dietary supplements [35] (Supplementary Material 1, www.jocmr.org). They can help with probiotic growth and with the production of short-chain fatty acids (SCFA) [36]. Most prebiotics are oligosaccharides [37] and are indigestible by humans; however, the gut bacteria can utilize them and this substance can restore the composition of the GM and enhance the action of probiotics [38].

Flatulence and abdominal discomfort can be observed. This often occurs when large quantities are consumed and can be avoided with reduced amounts.

Overall prebiotics are deemed safe. However, there are very rare instances of anaphylactic reactions including a case report in a 39-year-old male after intake of salsify and artichoke vegetables that contained oligofructose and inulin [39]. A study by Soh et al in 2015 describes anaphylaxis to galacto-oliogosaccharides (GOS) in atopic patients from South-East Asia. When testing commercial formulations, Vivinal™ (vGOS) and Oligomate™, 30 subjects out of 487 had positive skin prick tests and when given oral challenge, six patients have positive reactions to vGOS and none to Oligomate™ [40]. The authors suggest that the prevalence of the vGOS allergy may be up to 3.5% (95% CI: 2.2-5.5%) among atopic patients from Singapore [40]. Future studies need to monitor for these types of reactions.

As the name suggests, synbiotics are the combination of prebiotics and probiotics to obtain a synergistic effect (Supplementary Material 1, www.jocmr.org). This combination is known as synbiotic therapy and it is designed to help make the probiotic more effective [41]. Synbiotics can help with restoring gut dysbiosis in many health conditions. This can be achieved through improvement of immune function, reduction of incidence of nosocomial infections and other effects on human health [35, 42]. It was also shown that presence of prebiotics can help protect probiotics from bile acid stress; however, this may vary with different combination of probiotics and prebiotics [43].

Reporting of safety data for synbiotics in RCTs is lacking, but trials with individual gut biotics, probiotics and prebiotics showed some side effects and safety concerns as discussed above [44].

Paraprobiotics (or ghost probiotics) are inactivated and non-viable probiotic cells, when taken in adequate amounts, can confer health benefits through antioxidant, anti-inflammatory and through several metabolic and immune pathways [45] (Supplementary Material 1, www.jocmr.org). Current research is exploring the potential benefit of adding paraprobiotics to probiotic containing yogurt. Paraprobiotic yogurt will contain dead Lactobacillus and Bifidobacterium and the advantage of this will be increased stability of the yogurt for a wide range of temperatures and a prolonged shelf life [46], but the functional effect will be similar to probiotic yogurt [47].

Postbiotics can be considered the metabolic by-products of gut microbes, in particular the crude extracts from probiotics that elicit a biological response, such as protecting the intestinal mucosal barrier [48, 49]. Thermal, irradiation, sonication, and even enzymatic process can lead to cell rupture of the bacteria and fungi when extracted from various fermented foods [50] (Supplementary Material 1, www.jocmr.org). In essence, postbiotics are the by-products of probiotics after feeding on prebiotics and often isolated through gas chromatography [48] (Supplementary Material 2, www.jocmr.org).

Both postbiotics and paraprobiotics have the potential to be used as pharmacological agents in the prevention and treatment of various psychiatric and neurocognitive disorders. Currently there are no interventional studies in humans examining the role of postbiotics in mental health and neurocognitive disorders. Since some studies have suggested caution around the use of probiotics in immunocompromised patients, postbiotics may serve as a safer alternative.

The metabolites of probiotics that possess antimicrobial activity through interruption of cell-to-cell communication and interrupting the virulence strategies are known as proteobiotics [51] (Supplementary Material 1, www.jocmr.org). This prevents bacterial colonization by not killing the bacteria that can help to prevent the development of antibiotic resistance [51]. A study has shown effects of proteobiotics from Lactobacillus acidophilus on enterohemorrhagic Escherichia coli (EHEC) O157:H7 infection, in preventing the virulence of this organism [52].

Absorption, distribution, metabolism, and excretion are the main components of pharmacokinetics with traditional medications. With gut biotics, these principles will be difficult to delineate and is complex. Microbial therapeutics is complex and has a unique pharmacology. Some gut microbes are killed by the acidity in the stomach as well as by the bile flow in the small intestine and permanent colonization and potential translocation is rare. The GM has been found to affect the pharmacokinetics of various drugs either positively or negatively [53].

The method of delivery plays a vital role in the efficacy of gut biotics. The typical mode of oral delivery in the form of tablet, capsule, and powders, may cause decreased bacterial survival due to the tablet processing technique requiring bacteria to tolerate temperature up to 60 °C [54]. With commercial food products, such as cheese, milk, and yogurt, the bacteria are less protected from the hostile acidity of the stomach [55]. A study by Bolla et al (2011) found that freeze dried formulations may be a preferred method of delivery [56]. The beneficial effect of probiotics depends on the survival of probiotic microbiota in the intestines [57]. The survival varies with different gut microbial strains, and with their ability to attach with the gastrointestinal tract mucosa. Most of the microbes are eliminated via feces after a few days [58].

GM can produce different metabolites which act at distant sites of the body like brain receptors [59-61]. A review by Lyte (2011) expressed the notion that probiotics are capable of synthesizing neuroactive compounds that can affect the GI and psychological health of the host [62]. The author hypothesized a microbial endocrinology-based mechanism where probiotics produce neurochemicals which binds to the receptors on immune and neuronal cells and affect the functions of the GI tract and central nervous system (CNS) [62].

Microbial biotransformation by xenobiotic metabolism is important and helps in the up and downregulation of the action of medications [5]. This GM and medication interactions depend on many factors like micro-genomics as well as the metabolic potential of the gut microbiome which are now defined as Pharmacomicrobiomics [63]. The main component of the hepatic drug metabolism is oxidation and conjugation reactions, whereas in GM-mediated metabolism, reduction and hydrolysis reactions are commonly seen [64, 65]. Drug-microbe interactions are bi-directional and the effect is seen with microbes and metabolites on the host drug metabolism and is responsible for the drug response or toxicity. With any new drug development, interaction between the medication and GM should be considered, which may alter the current understanding of pharmacokinetics and pharmacodynamics.

Mechanisms of action of probiotics, prebiotics and synbiotics can be direct or indirect through modifications of the endogenous flora, enhancement of the epithelial barrier, concomitant inhibition of pathogenic microorganisms and through modulation of the immune system [66, 67]. Peyer’s patches in the gut help with the immune response due to probiotics [68]. An animal study using mice confirmed that probiotic lactic acid bacteria were identified in the dome area of Peyer’s patches 6 - 12 h after their ingestion [69]. Research evidence pointed out that probiotics, prebiotics and synbiotics have an effect on inflammatory and bio-oxidative factors and have a clinical impact on GI chronic diseases [70]. Studies have also shown that probiotics, prebiotics, and diet modification can have a positive effect on brain function and neurochemistry and help to reduce neuroinflammation and amyloidogenesis and thereby prevent Alzheimer’s disease (AD) pathogenesis [71, 72] (Fig. 2).

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Figure 2. The role of the gut microbiome in neurocognitive and metal health conditions. In a state of eubiosis, the gut bacteria are controlled by the host immune system to prevent systemic spread. Since many of the gut bacteria have a polysaccharide coating the immune system can recognize potential pathogens from the commensal organism. This can prevent systemic spread and inflammation that has been shown to play a role in various mental health conditions. Different species of bacteria in the gut microbiome can produce different neurotransmitters, such as serotonin through tryptophan metabolism. Short-chain fatty acids (SCFAs) are also produced by different gut bacteria and have been found to play a role in microglial maturation which can help remove amyloid β peptide (the major component in Alzheimer’s disease (AD)). Various factors, such as lifestyle and diet, can lead to microbial dysbiosis. A weakened intestinal barrier can result in bacterial translocation causing increased lipopolysaccharide (LPS) serum levels. The result is systemic and neuroinflammation that can contribute to amyloid β deposition leading to AD. The systemic inflammation can become chronic and lead to an alteration of the hypothalamic pituitary adrenal axis (HPA) and has been linked to various mental health conditions. The disrupted microbiome can affect neurotransmitter production and tryptophan metabolism, again impacting the host’s mental health.

Fermented foods contain probiotic bacteria, yeast and microbial metabolic products [73]. Representative examples of GM targeted fermented foods such as yogurt, kefir, kombucha, sauerkraut, kimchi, tempeh, natto, miso, sour dough bread favor gut diversity which would be considered beneficial for our gut microbes and indirectly for neurocognitive and mental health conditions [74]. In the American Gut Project, subjects who consumed fermented foods one or two times had gut microbe diversity when compared with non-consumers [75]. In the study by Ton et al (2020), probiotic-based kefir intervention for 3 months in AD patients showed satisfactory improvement in memory function in these subjects [76]. In another study, by Mohammadi et al (2016), a benefit with probiotic yogurt but not with conventional yogurt, on mental health disorders was seen [77]. Whereas, a study showed when healthy medical students partook in daily conventional yogurt consumption, they exhibited an increase in alpha diversity of their GM along with reduced stress indicators [78]. However, the benefit of fermented food for treating or preventing depression and anxiety is not well studied [79].

Promising human clinical researches with single and multiple probiotic strain specific therapies are seen in neurocognitive and mental health conditions. By targeting the beneficial species of the GM could be a novel approach for management.

Single strain intervention with Bifidobacterium breve A1 and Lactobacillus plantarum in RCTs with mild cognitive impairment (MCI) subjects showed some benefit [80-82]. Multi-strain probiotic intervention with L. acidophilus, L. casei, Lactobacillus fermentum,and Bifidobacterium fermentum in RCT showed beneficial effect on cognitive function in AD subjects [83]. It was also found that probiotic and selenium co-supplementation resulted in a significant improvement in cognition over a 12-week period in AD patients [84]. A meta- analysis of probiotic studies in MCI and AD by Den et al (2020) showed improved cognitive performance [85]. When examining studies of human subjects, another meta-analysis found that probiotic supplements improved cognitive function in cognitively impaired individuals but not on healthy subjects [86].

In a study looking at single bacterial strain probiotic interventions, Lacticaseibacillus paracasei strain Shirota showed reduction in symptoms with major depressive and BP [87]. Other studies have examined probiotics with multiple strains, such as Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum [88] or with Bifidobacterium longum and Lactobacillus helveticus [89] which helped improve mood outcomes.

When individuals were treated with a multi-strain probiotic intervention involving B. longom, B. bifidum, Bifidobacterium lactis, and L. acidophilus a reduction in anxiety symptoms was witnessed. It was also found to be useful as an adjunctive therapy along with sertraline [90].

Oats and barley have been used in foods like bread, biscuits and cereals [91]. There is some evidence that this may help to improve mood and cognition [92, 93]. Fruits and vegetables have high fiber and a meta-analysis study showed reduced risk of cognitive impairment (OR: 0.79; 95% CI: 0.67 - 0.93; P = 0.006) [94] and the Hordaland health study found there was an improvement to different cognitive domains like attention, memory, executive functions, speed of processing, and global cognition [95]. Overall fruits and vegetables play a role in improving cognitive health [96]. Observational studies showed a decreased association of depression with intake of vegetables, fruit, or seaweed, but this is not seen with cereals [97, 98]. A meta-analysis study of observational studies showed reduced risk of incident depression (vegetables: OR: 0.91; 95% CI: 0.87 - 0.96; P < 0.001; fruit: OR: 0.85; 95% CI: 0.81 - 0.90; P < 0.001) [99].

Studies on dietary fiber to improve cognition and mood have used prebiotic supplements [33, 100]. The prebiotic supplements are galactooligosaccharides (GOS), fructooligosaccharides (FOS), oligofructose, chicory fiber and inulin. A study by Smith et al (2015) showed an oligofructose-enriched inulin improved memory and mood in healthy volunteers [101].

The limitations of the above-mentioned supplements studies in general are the lack of replications studies investigating the same strain of probiotic or type of prebiotics. Information on the right dose and duration of supplement treatment is not clear. Future research should try to address these issues. Future studies should also use nutrient biomarkers to assess the effect of probiotics and prebiotics [102].

Psychotropic medications in general can affect the GM and cause dysbiosis, which induce inflammation and neurodegeneration [103]. Co-administration with conventional medications, probiotics have the potential to improve cognition both in normal and AD subjects [83, 104]. An animal study with transgenic mice showed reduced amyloid plaques and improved cognitive performance when administered with pre- and probiotics [105]. GM helps with the expression of hippocampal N-methyl-D-aspartate (NMDA) receptors similar to memantine, whereas this expression is less in germ-free mice [106], and in rats treated with antibiotics [107]. GM, by their anti-inflammatory, metabolic, and pleiotropic effects, reduce the neurodegeneration seen in dementia. Diet rich in probiotics and prebiotics will help to lower the risk of AD and retard the development of neurocognitive decline [108]. Ruminococcus flavefaciens affects gene networks in the brain, suggesting a mechanism for microbial regulation of antidepressant treatment efficiency [109]. Prebiotics have been shown in animal studies to attenuate some of the side effects of antipsychotics, like weight gain [110]. Few animal studies pointed out that probiotic, prebiotic and synbiotic treatment can have some synergistic effect with conventional drug treatments for Alzheimer’s and depression, but more future research is needed in this area especially with human subjects.

The human gut microbiome is a dynamic virtual organ that is influenced by diet and lifestyle. Lifestyle medicine is a term referring to altering health behaviors to influence factors such as physical activity, diet, tobacco smoking, alcoholism and sleep [111, 112].

Intestinal dysbiosis can occur with smoking [113]. The effects of cigarette smoking have been examined and it has shown that it can induce changes in intestinal microbiome along with increasing the permeability of the mucosa and even impair the mucosal immune response [114]. The mechanism of action is not fully understood; however, some of the effect is thought to be due to the harmful compounds found in cigarettes. It was found that nicotine can lead to microbial dysbiosis with an increase in Firmicutes and Proteobacteria while causing a decrease in Bacteroidetes [115]. Smoking cessation helps to improve intestinal dysbiosis to a certain extent [116, 117].

With alcoholism, drinking amount and unhealthy diet may predict gut dysbiosis. With abstinence over 4 weeks, a study showed reduction with gut dysbiosis. With microbial therapeutics, the study showed an improvement in the speed of recovery of the microbiome [118].

Stressful life events contribute to mental illness. Psychological stress could lead to altered gut microbial composition [119]. A recent pilot study done in information technology professionals experiencing high stress showed significantly improved stress (self-perceived and job stress), mood and sleep disturbances as well as quality of life after an 8-week intervention of a probiotic Lactobacillus plantarum PS128TM [120].

Sleep deprivation can cause gut dysbiosis [121]. Ingesting probiotics/paraprobiotics may help to improve subjective and objective sleep metrics [122].

Individuals with more sedentary lifestyles were shown to have less microbial diversity with more disease-causing species, such as E. coli. However, individuals with more active lifestyles, such as elite athletes, have a greater bacterial diversity, particularly bacteria responsible for producing SCFA [123].

Fast foods, commercial baked foods and sugar-sweetened beverages have been shown to increase the risk of depression [124, 125]. A study by Zhu et al (2020) found that an individual’s GM can undergo a shift in composition based on their diet, in as short as 4 days. When exposed to a Mediterranean diet that is rich in vegetables and whole grains subjects showed an increase in more fiber-fermenting bacteria, than, when consuming a more fast-food diet (high in fats and carbohydrates), as well as more bile tolerant microbial genera were present [126].

Even though gut biotics have been around for many years, only in the last decade a lot of research is going on this area. Gut biotics are usually found in foods or dietary supplements. Some studies point out that gut biotics may supplement regular treatments, but do not often replace them. Since there are many kinds of gut biotics with different strains and combinations, it is important for patients to talk to their healthcare professional before starting one.

Microbial therapeutics are available as over the counter medications as a non-regulated nutritional supplement or as dietary products. At this point, microbial therapeutics would not replace the current evidence-based pharmacological or psychological treatments. But health care providers treating mental health disorders should consider gut-related principles of therapy with some optimism and caution in their holistic approach [127, 128].

The gut biotics be developed as food products (functional foods or diet supplements) or drug products (biological or microbiome products). Regulatory framework for the development of these products has to be optimized and considered by food and drug regulatory agencies in different countries. The efficacy and safety have to be determined by these agencies with specific guidelines and requirements. According to the US FDA regulations, depending on the intended use of this microbiome, products may be considered as a functional food or dietary supplement which does not require FDA approval before marketing, whereas if it is a drug, it needs FDA approval.

A form of microbial therapeutics comes as fecal microbiota transplantation (FMT), which is the transfer of fecal bacteria from a healthy donor to a recipient with the goal of repopulating the GI tract with beneficial bacteria, sharing a similar role as probiotics. FMT has been in use for the treatment of Clostridium difficile infections. Outside of this, research is being done to explore its role in the treatment of metabolic and neurological disorders such as multiple sclerosis, Parkinson’s disease, as well as neurocognitive and psychiatric conditions [129].

To explore the effects of FMT on cognition, a study by D’Amato et al (2020) examined the effects of transplanting the fecal microbiota from aged donor mice to young adult mice. They found that there was a significant impairment in spatial learning and memory, while anxiety, explorative behavior, and locomotor activity remained unchanged in the young adult mice recipients [130]. Changes were also seen with the composition of the gut microbiome, in particular a reduction in SCFA producing bacteria (Lachnospiraceae, Faecalibaculum, and Ruminococcaceae). The authors suggest that age-related shifts in the microbiota may play a role in cognitive decline, and developing techniques to restore “young-like microbiota” may improve cognitive functions in the elderly [130]. It has also been shown that the use of FMT reduced amyloid-β deposition and improved cognitive deficits in mice brains, thus alleviating Alzheimer’s pathology [131]. A case report highlights the improvement seen in an 82-year-old male who received FMT for a C. difficile infection. This individual also showed improved memory and mood up to 6 months post FMT with higher scores on the mini-mental status exam [132].

With psychiatric conditions FMT has been studied with mood disorders, such as anxiety and depression. A study by Zhang et al (2019) found that an FMT from an NLRP3 KO mouse to a chronic unpredictable stress (CUS) mouse helped to reduce depressive-like symptoms [133]. Studies have also shown that when taking FMT from human into mice, these mice can display noticeable behavioral changes. When germ-free rats were given an FMT from depressed human patients, they started to exhibit more depression-like behavior in the form of increased immobility time in the forced swimming test [134]. When mice received FMT from anxious patients with irritable bowel syndrome (IBS), the animals showed an increase in anxious behavior [135]. These animal studies showed both depressive and anxious behavior can be transferred from afflicted individuals to mice.

Current research is being done exploring the role of FMT in treating psychiatric conditions in humans, typically in those with IBS. A study by Huang et al in 2019 found that patients with refractory IBS had improved GI symptoms and reduced anxiety and depression scoring after receiving FMT from healthy donors [136]. A case report of a female patient with major depressive disorder (MDD) showed an improvement in depressive symptoms after an FMT and alteration in the gut microbiome with increased Firmicutes and decreased Bacteroides [137]. More research is needed to explore the role of FMT in other psychiatric conditions.

As an individual ages, there is a shift in the microbiome and decrease in microbial diversity that can result in gut dysbiosis [138]. The microbiota-gut-brain axis along with alterations of the GM and gut dysbiosis has been shown to play a role in MCI and dementia [139]. Prevalence of MCI ranges from 16% to 20% above the age of 60 years [140]. The annual rate of conversion of MCI to dementia is 15% [141]. The prevalence of dementia worldwide in 2015 was 46.8 million and expected to increase to 74.7 million by 2030 [142]. In the brain, neuronal loss with the reduction of trophic factors that affect neurogenesis, along with synaptic plasticity alterations, and in combination with oxidative changes that lead to microglia activation and neuroinflammation which can contribute to cognitive impairment. The microbiota-gut-brain axis involves multiple physiological systems through bidirectional communication [103]. Dysregulation of this axis plays a role in causing AD and its progression. Dysbiosis with reduction in gut bacteria like Lactobacillus and Bifidobacterium can lead to reduced production of neurotransmitter acetylcholine and cause cognitive decline [143]. In AD, abundance in Escherichia and Shigella along with a reduction in Eubacterium rectale microbiota has been studied, resulting in the increase of proinflammatory cytokines leading to changes in neurotransmitters levels [144]. Hence, the modification of the GM may serve as a target to counter this disease process.

Among the risk factors for AD, diet is an important one to consider. Nutritional approaches may prevent and halt the progression of AD [145]. GM through defective mucosal barrier affects the entero-endocrine system and causes pathological proteins in the brain [101]. Newer nutritional therapeutic approaches should be explored. Hence, we want to explore the evidence for probiotics in modulating the cognitive decline. Probiotics through changes in inflammatory reaction, oxidative stress and amyloid-β deposition can prevent the progression of cognitive decline in AD.

It was found that mice fed with amyloid-β caused significant changes to the bacterial structure of the GM [146]. When microflora of AD patients was transplanted to gnotobiotic mice, cognitive decline was seen [147]. Microbiome generated amyloid and SCFA through activation of microglia which can help to remove β-amyloid peptide within the brain, which is the main pathological change seen in AD [148]. With neuropsychiatric diseases known as “microgliopathies”, microglial dysfunction is the primary pathogenesis in these conditions [149]. Microglia maturation and function is determined by SCFA and microbiota-derived bacterial fermentation products. Animal studies have found that microglial maturation and function can be restored with the recolonization of gut bacteria [150].

Cognitive impairment can be mitigated through the modification of the GM, with Bifidobacterium breve A1 in Aβ-induced AD mice model [151]. In a study, rats treated with L. plantarum MTCC1325 for 60 days, help to restore the neurotransmitter acetylcholine deficit and also prevents cognitive decline [143]. In an experimental study with the transgenic mouse model of AD, treatment with the probiotic SLAB 51 mixture modified the gut microbiome leading to a change in intestinal metabolite content, including SCFA that helps to improve cognitive function [152]. Studies done in animals with B. longum, B. breve, B. infantis, L. helveticus, L. rhamnosus, L. plantarum, and L. casei were found to be most effective in improving CNS function as well as anxiety, depression, stress and memory [153, 154] (Supplementary Material 3, www.jocmr.org).

One of the targets of probiotic use is to increase the presence of beneficial bacteria which will help to reduce intestinal permeability which in turn decreases lipopolysaccharide (LPS) and reduces inflammatory response [155]. Higher levels of zonulin, a marker of intestinal permeability, have been found to be associated with cognitive decline [156]. As well, insulin resistance, oxidative stress, and inflammatory processes have been shown to contribute to AD, and probiotics can influence these pathways [83]. Supplementation with fermented milk products can activate specific areas of the brain in healthy human females [157]. However, a cross- sectional study showed probiotics can modulate CNS function leading to alleviated cognitive dysfunction [158]. An RCT on patients with memory problems had beneficial effects on cognitive function with supplementation with Bifidobacterium breve A1 [80]. Bifidobacterium breve A1 intake can also suppress the immune reaction and inflammation induced by amyloid in the hippocampus [159]. Two RCTs showed that probiotic supplementation led to a significant improvement in cognitive function in AD with modulation of brain activity [83, 160]. Even in MCI subjects, 12 weeks supplementation of probiotics increased brain-derived neurotrophic factor (BDNF) levels and improved cognitive performance [82].

Meta-analysis data from three RCTs found no benefit of probiotic supplementation on cognitive function when examining 161 AD patients who received Lactobacillus and Bifidobacterium strains (standardized mean difference (SMD): 0.56; 95% CI: -0.06 to 1.18). This result could be due to selection bias of the RCTs used in this study. However, probiotic supplementation improved plasma triglycerides, very-low-density lipoprotein cholesterol, insulin resistance, and plasma malondialdehyde [161]. However, another meta-analysis using all the RCTs from five available studies involving 297 subjects with cognitive decline (either MCI or AD) showed a significant improvement in cognition (SMD: 0.37; 95% CI: 0.14 - 0.61; P = 0.00) [85]. Overall, more evidence from large-scale, longer-term RCT is needed to show the beneficial effect.

Certain strains of probiotics, through the microbiota-gut-brain axis, appear to influence the CNS and behavior. Based on clinical studies, patients suffering from cognitive impairment have been shown to have a decreased abundance of anti-inflammatory bacteria, such as Eubacterium rectale and Bacteroides fragilis, while exhibiting an increased amount of proinflammatory bacteria belonging to the Escherichia and Shigella genus which can contribute to the brain amyloidosis [162, 163]. Supplementation of Lactobacillus and Bifidobacterium has improved both cognitive and mood function [164]. With the current evidence from the research in the field of the gut microbiome and cognitive impairment, probiotics may play a role in the prevention and treatment of AD. The main mechanisms of this beneficial action are likely through the modulation of inflammatory processes, oxidative stress, and other possible mechanisms that help to ameliorate the progression of AD.

Prebiotics have been found to influence neurobiology and impact brain function [165]. A recent clinical review found that FOS and inulin (at doses around 5 - 10 g/day) help to improve learning and memory along with behavior. However, this appears to be short-lived, for 4 - 12 weeks, and seen in young, healthy, middle-aged subjects, but not in the elderly [166].

A study by Chen et al (2017) found that FOS from Morinda officinalis (perennial slender climbing shrub) showed memory improvement in rodent AD models [167]. While a study by Sun et al (2019) found that in a male APP/PS1 transgenic mice AD model, those treated with a 2% FOS solution for 6 weeks showed improvement in cognitive deficits and increased expression of synapsin I, PSD-95 and GLP-1, as well as decreased phosphorylated JNK level [168]. Another study using E4 FAS mice to model late onset AD found that when animals were supplemented with the prebiotic inulin, a reduction in neuroinflammation was seen due to an increase of SCFAs [169]. Dietary inulin alters the gut microbiome, enhances systemic metabolism and reduces neuroinflammation in an APOE4 mouse model. When Sprague-Dawley rats were treated with chitosan (an oligosaccharide), improvement in cognitive function and a decrease in pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β) were found [170].

Various clinical studies have been done examining the role of prebiotics on cognition. A study by Smith et al (2015) took 47 healthy volunteers and those given 5 g of oligofructose-enriched inulin performed better on recognition memory tasks and showed an increased recall performance (immediate and delayed) [101]. In another study by Prasad et al (2007) examining 61 patients with minimal hepatic encephalopathy and when given 30 - 60 mL of lactulose for 3 months, there was an increase in some cognitive functions and indicators of quality of life, such as emotional and social behavior [171]. It has also been found that certain herbal products, such as dietetic polyphenols, can influence the gut microbiome and help restore dysbiosis and be effective in counteracting the onset of AD [151]. Supplementation with prebiotics can alter microbiota composition and function. Prebiotics form SCFAs and stimulate probiotics, and through antioxidant effect and anti-inflammatory activity, as well as stimulation of BDNF the neurotrophic factor can help in reducing the pathogenesis of AD.

The number of studies involving synbiotics is limited. However, one study found that when male Sprague-Dawley rats were given 860 mg/kg of inulin or inulin with E. faecium for 5 weeks, the synbiotic group showed better cognitive performance and a reduction of IL-1β [172].

Similar to preclinical studies, clinical studies with synbiotics on cognition are also limited. It is possible with regular intake of probiotics and prebiotics, along with other nutrients may help to reduce the cognitive decline [108]. A study by Louzada e Ribeiro (2018) found that in 49 elders given 6 g of FOS and a probiotic for 24 weeks, they showed some improvement in depressive symptoms and cognition [173]. To our knowledge, at present no RCTs have been done with synbiotic supplementation in demented subjects.

With other gut biotics like paraprobiotics, postbiotics and proteobiotics, lack of research is seen with cognitive impairment. Future research is needed to identify the usefulness of these gut biotics in this disorder.

Currently the majority of research examining the role of the gut microbiome and cognitive function has been done using animal models. There is a gap between the observational and interventional studies seen both with animal models and clinical studies of dementia [151]. Only small sample size has been examined and the profiling of the GM composition and functioning has been lacking, thus more longitudinal studies in high-risk population for cognitive impairment are needed [160]. An animal study found that memantine acts synergistically with L. plantarum and helps reduce AD pathology in APPS1 mice [174]. It even has an antimicrobial activity against E. coli, thus suggesting its influence on the GM [175]. Understanding the particular role of certain bacteria species on cognition and also about the molecular mechanisms involved may serve as another means to develop direct therapeutic targets [160].

MDD has a prevalence of around 7% affecting an estimated 264 million people, and approximately 284 million people suffer from an anxiety disorder [176]. Depression was the most common disorder in 17.1%, followed by panic/anxiety in 11.3%. There is a growing body of literature linking the role of the microbiota-gut-brain axis in depression and anxiety [73]. Thus, modulation of the gut microbiome is being considered as a therapeutic target through the use of prebiotics and probiotics.

In the study by McVey Neufeld et al (2017), prebiotics such as GOS (using 7 g/kg) and polydextrose (PDX) alone or in combination with L. rhamnosus in male Sprague-Dawley rats, showed decreased anxiety-like behavior in these animals [177]. In the study by Szklany et al (2019), pregnant BALB/cByJ mice where given a 3% mixture of short-chain galactooligosaccharides (scGOS) and long-chain fructooligosaccharides (lcFOS) for 11 weeks showed a decrease in anxiety-related repetitive behavior and an improvement in social behavior along with increased expression of BDNF [178]. Another study found that when male Fischer 344 rats where given a variety of prebiotics including GOS (21.23 g/kg), PDX (6.58 g/kg), lactoferrin (1.86 g/kg) and “whey protein concentrate MFGM-10” (15.9 g/kg) for 4 weeks, there was a reduction in anxiety-like behaviors in addition to increased BDNF levels [179].

The study by Schmidt et al (2015) found that when 45 healthy volunteers were given Bimuno^®-GOS for 3 weeks, there was a decrease in salivary cortisol levels and an increase in “positive versus negative attentional vigilance” [180]. In comparison, another study took 81 randomized patients with MDD and gave them GOS for 8 weeks and found no influence on depressive symptoms; however, those receiving the probiotic B. longum and L. helveticus showed improvement in mood symptoms [89]. When 40 patients with moderate depression were given two capsules of FamiLact^® with 20 mg/day of fluoxetine for 6 weeks, it was found there was a decrease in Hamilton Rating Scale for depression compared to the placebo group [181]. Another study examined 44 patients with IBS; when treated with Bimuno^®-GOS for 3 months, they had lower anxiety scores and self-reported improved quality of life [182]. A study looked at IBS patients found those receiving short-chain FOS for 4 weeks had reduced anxiety scores and increased levels of fecal Bifidobacteria [183]. A study by Talbott et al (2012) looked at 39 healthy women who were given Baker’s yeast β-glucan for 12 weeks and showed an improvement in mood state [184] (Supplementary Material 3, www.jocmr.org).

There have been some human studies as discussed below looking at probiotic consumption and its influence on individuals with increased stress levels. A study by Gruenwald et al investigated the use of probiotics on an individual’s stress tolerance and found they may be effective in helping to reduce stress and exhaustion [185]. Stress can affect GI function and probiotics may help to alleviate GI symptoms brought on by stress [186]. It has also been shown that probiotics can help to reduce anxiety as well as pre-surgery stress in laryngeal cancer patients [187]. Evidence points out that probiotics can improve mood, anxiety, and reduce psychological stress in various psychiatric conditions (Supplementary Material 4, www.jocmr.org).

To model PTSD in animals, mice are subjected to chronic social defeat. When mice were treated with Lactobacillus rhamnosus JB-1 for 28 days prior to stress exposure, there was a decrease in anxiety-like behavior and social interaction deficits [188]. However, if mice underwent the stress of chronic social defeat and were treated with Lactobacillus rhamnosus JB-1 or sertraline, there was an increase in both aggressor avoidance and reduced sociability, suggesting a possible detrimental effect [189]. In human subjects, a study by Gocan et al (2012) looked at individuals who developed a combat-related PTSD and monitored symptoms after consumption of fermented soy products. After 6 months of daily ingestion, there was a reduction of anxiety, derealization/detachment, as well as insomnia [190]. Many of the participants were noted to develop flu-like symptoms, skin infections, and even herpes labialis during the beginning of the trial. Further research is needed to look into the potential role the gut biotics may have in the management of patients with PTSD.

OCD is characterized by the presence of obsessive thoughts that are persistent and intrusive, along with compulsions which are consider repetitive behaviors that are done in response to these obsessions [191]. With regard to treatment, cognitive behavioral therapy (CBT) and pharmacological management with selective serotonins reuptake inhibitors (SSRIs), either alone or in combination, are typically used. When examining the role of gut biotics in the treatment of this condition, a study by Kantak et al (2014) induced OCD-like behavior in mice using RU24960 (a 5HT1A1B receptor agonist) and treated them with either fluoxetine, or a probiotic (Lactobacillus rhamnosus GG), or a neutral substance. The mice treated with the probiotic or fluoxetine showed a reduction in OCD-like behaviors [192]. In another preclinical study, mice were injected with quinpirole hydrochloride (a D2/D3 dopamine agonist) to induce OCD-like behavior [193]. The mice treated with Lactobacillus casei shirota, fluoxetine, or a combination of the two showed improvements in OCD behaviors [193].

One clinical study showed that the administration of Lactobacillus helviticus and Bifidobacterium longum helps to reduce the obsessive-compulsive scores in healthy volunteers [194]. Thus, there is some evidence that probiotics may play a role in the treatment of OCD; however, the research is in its infancy at this time to draw any significant conclusions.

Patients diagnosed with schizophrenia often experience both positive and negative symptoms. The positive symptoms are often characterized by delusions, hallucinations, and disorganized thoughts/speech. In contrast, they may present with negative symptoms including avolition, decreased emotional expression, and a decline in function, both social and occupational. Recent studies have examined the role of the gut microbiome in the disease pathogenesis of schizophrenia [195-197]. A study by Olde et al. (2018) found an increase in microbial diversity in the blood of schizophrenia patients compared to healthy controls [198]. This may suggest influence of gut permeability leading to increased diversity in the blood microbiota in these patients. Thus, treatment of the gut microbiome in schizophrenia patients may be another target in their management, and probiotics may play a role as an adjuvant to conventional antipsychotic therapy.

An animal study using an MIA mouse model of schizophrenia found that the probiotic B. fragilis helped to restore gut permeability, gene expression and interleukin (IL)-6 in the colon, and showed behavioral improvement related to anxiety-like behavior while no change was seen in the sociability of the mice [199].

Patients with schizophrenia tend to have a high prevalence of GI symptoms, which may be related to antipsychotic treatment [200]. Probiotics have been shown to help with constipation [201] that may be seen with some schizophrenia patients due to their treatment. Based on the current evidence, there was no significant change in the positive or negative symptoms of schizophrenia patients treated with probiotic supplementation [202-204]. A case report showed improvement in negative symptoms after 30 days of probiotic treatment [205]. In a study by Okubo et al (2019), patients with schizophrenia receiving a probiotic Bifidobacteriam breve A-1 strain had improved anxiety and depressive symptoms [206]. The use of probiotics can relieve GI discomfort in male schizophrenia patients and also lower Candida albicans antibodies; these antibodies have been found to be elevated in patients with GI afflictions [202]. Immunomodulatory effects have been observed in treatment-resistant patients receiving probiotics in combination with atypical antipsychotics [203]. Further research is needed to examine the role of probiotics in the treatment regimen for patients with schizophrenia.

BP is a chronic mental health condition where patients may experience changes in mood and energy level. Patients with BP have been found to have an altered gut microbiome compared to healthy controls [207, 208]. In particular BP patients have decreased levels of Faecalibacterium, which has been associated with depressive symptoms and often seen in patients with MDD and IBS [209, 210]. Individuals with BP often experience diarrhea and satiety, both of which can be improved with probiotics [211].

Some clinical studies showed that patients with BP, who were treated with probiotic supplementation, had a lower rate of rehospitalization following a recent discharge for mania [212]. It was also observed that individuals with BP treated with probiotics had improved cognitive function [213]. Currently, the research is limited, in this disorder with gut biotics.

Evidence has clearly indicated that gut dysbiosis plays a role in neurocognitive and psychiatric disorders. GM can be administered as gut biotics, dietary interventions and by FMT. Gut biotics are considered as a medicine for many diseases (panpharmacon) like GI and metabolic diseases. Growing evidence points out that it can be helpful with mental health disorders (Supplementary Material 5, www.jocmr.org). It is considered as a bio-therapy, given as food and pharmaceuticals. Food industry uses gut biotics as functional foods and nutraceutical supplements. Changing food behaviors is a desirable direction for gut bacterial management. Our traditional understanding of pharmacokinetics and pharmacodynamics may be altered by GM interactions.

Relationship between gut biotics and improving cognitive and mental health functions is an exciting new area of research. Current data from research studies showed the potential of treating and preventing both neurocognitive and some psychiatric disorders. Gut biotics like probiotics, prebiotics and synbiotics have some benefit in AD and MDD, but more longitudinal studies are needed. To our knowledge, there are no interventional studies using postbiotics, paraprobiotics and proteobiotics on neurocognitive disorders and mental illness. Microbial therapeutics using natural and genetically engineered technology need further research for the management of these conditions. Some studies have pointed out that gut microbe-based therapeutic interventions along with current psychological treatments may have the potential of synergistic effect and have the potential as an adjuvant therapy of mental health disorders. Even though the overall safety seems to be good, caution is needed to watch for any known and unknown side effects as well as the need for risk benefit analysis with certain ill populations. Since some gut biotic products have active substance that is made by a living organism, it should be considered like any other bio-therapeutic intervention, and the risk-benefit ratio should be considered in each patient. Evidence is also pointing out life style factors also influence gut microbes and indirectly microbial therapeutics. A large gap exists with healthcare providers about the understanding and use of gut biotics.

More clinical research is needed with microbial therapeutics to show evidence that can help to improve balance with mental health. Longitudinal and RCT studies with reproducibility of the results are warranted. For the translation of these findings into clinical practice, further research is needed with good regulatory framework.

Suppl 1. Types of Gut Biotics.

Suppl 2. Methods for the Identification of Gut Biotics.

Suppl 3. Selected Animal Studies Exploring the Role of Gut Biotics on Neurocognitive and Mental Health Conditions.

Suppl 4. Selected Human Studies Examining Gut Biotics in Neurocognitive and Mental Health Conditions.

Suppl 5. Summary of Results From Both Animal and Human Models About the Role of Gut Biotics in Mental Health Conditions.

Acknowledgments

None to declare.

Financial Disclosure

None to declare.

Conflict of Interest

The authors declare no potential conflict of interest.

Author Contributions

Both the authors contributed to the conception and drafting of this manuscript as well as revising it. The final draft is approved by both the authors for consideration of publication.

Data Availability

The authors declare that data supporting the findings of this study are available within the article and its supplementary file.

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