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Introduction:

Depression, a common illness, technically called Major Depressive Disorder (MDD) has been affecting approximately 280 million people across the globe.  Depression left untreated may escalate into a serious health condition, further leading to even suicide.  Symptoms of depression include depressed moods (lost hope, sadness, and feeling of emptiness), low energy levels, lost enthusiasm or interest in activities, irregular sleep, changes in body weight and appetite. Depression can be mild, moderate, or severe depending on symptoms and individual’s personal experiences and functioning. [1] The available treatments of depression include therapies such as behavioral, interpersonal psychotherapy or visiting a professional or supervised face-to-face psychological treatment and drugs such as antidepressants. Serotonin reuptake inhibitors (SSRIs) and Tricyclic antidepressants (TCAs) are the commonly used antidepressants. In the case of most antidepressants, efficiency is not the same among all patients with mild to moderate symptoms and are often associated with several side effects.[2]

An alternative treatment for depression is emerging in the form of probiotics named Psychobiotics. Psychobiotics, when ingested, confer mental health benefit through interaction with commensal intestinal bacteria. Psychobiotics also include prebiotics that promote the growth of gut microbes. Research on Psychobiotics showed significant improvement of anxiety, depression, neurodegenerative and neurodevelopmental disorders, including Autism Spectrum Disorder (ASD), Parkinson’s Disease (PD) and Alzheimer’s Disease (AD). Recent study showed the role of probiotics in reversing aging of the brain.[3] Gut-brain signaling mechanism enables the psychobiotic effects. Lactobacillus brevis and Bifidobacterium dentium strains, the efficient GABA producers, are considered a promising therapeutic approach for depression.[4]

Background mechanism:

Gut microbiota ‚Äď gut ‚Äď brain – axis

There is lot of growing evidence substantiating the microbiota impact on CNS. Earlier studies on Germ-free (GF) mice or mice treated with broad-spectrum antibiotics have shown neurophysiological and behavioral diversions when compared to conventional mice, thus suggesting the critical role of gut microbiota in gut-brain axis. GF mice that received fecal microbiota transplantation (FMT) showed ¬†similar phenotypes as those of the ‚Äúdonors;‚ÄĚ for example, FMT of GF mice with microbiota from patients with major depressive disorders was found to result in increased¬†depression-like behaviors.¬†Colonization with microbiota from patients with schizophrenia induces schizophrenia-related behaviors in mice. All these studies support the links from microbiota to brain.[5]

The known bidirectional pathways of interaction between the gut microbiota and brain. The pathways of gut microbiota interact with brain include HPA axis and ANS through which the brain regulates gut microbiota. Through vagus nerve and systemic circulation microbiota-derived products, metabolites, neuroactive substances, gut hormones, and inflammatory factors modulate the function of CNS. HPA: Hypothalamic-pituitary-adrenal axis; ANS: Autonomic nervous system; CNS: Central nervous system. [5]

Interactions between gut microbiota and EEC cells. The gut microbiota affects EEC cells through microbiota-derived products (eg, LPS), microbiota-derived metabolites, including SCFA, indole and secondary bile acids. In addition, some microbiota is involved in hormone metabolism. EEC cells can also release gut hormones, and part of hormones released into gastrointestinal lumen can influence gut microbiota. EEC: Enteroendocrine cells; GPBAR1: G protein-coupled bile acid receptors 1; FFAR2: Free fatty acid receptor 2; FFAR3: Free fatty acid receptor 3; PYY: Peptide YY; GLP-1: Glucagon-like peptide 1; GLP-2: Glucagon-like peptide 2; GIP: Glucose-dependent insulinotropic polypeptide; TLR4: Toll-like receptor 4; 5-HT: Serotonin; LPS: Lipopolysaccharide; SCFA: Short chain fatty acid; GIP: Glucose-dependent insulinotropic polypeptide.[5]

The two-way communication network system involves various routes such as endocrine, humoral, immune, and metabolic. The hypothalamic-pituitary-adrenal (HPA) axis and nerves of gastrointestinal tract allow the brain to influence intestinal activities, and the gut to influence mood and mental health. [6]. Study evidence shows that the gut microbial composition further regulates hypothalamic-pituitary-adrenal (HPA) stress response. The study demonstrated HPA response to stress by comparing germ free (GF) and specific pathogen free (SPF). In GF mice, the response to stress (i.e., plasma ACTH and corticosterone levels) was higher compared to SPF mice, and then prolonged intake of Bifidobacterium infantis (microbe) has reversed the stress response.[7]

The underlying mechanisms of gut-brain axis include the 4 major pathways of neurologic, endocrine, humoral, and immune system.

Neurologic pathway:

The Vagus Nerve (VN), part of parasympathetic nervous system, plays a crucial role in the microbiota-gut-brain axis, by connecting the gut and brain. Vagal afferent fibers indirectly sense signals from gut microbiota through the diffusion of bacterial compounds or metabolites, and via interactions with gut endocrine cells (Enteroendocrine cells). These cells release neurotransmitters and hormones that affect gastrointestinal functions and relay signals to the brain. The VN can also sense microbiota signals directly, like short-chain fatty acids (SCFAs) produced by the gut microbes. Additionally, toll-like receptors (TLR4) on vagal afferent fibers can detect bacterial products. The VN’s activation by microorganisms can influence behavior and brain functions.[8]

The VN also plays a role in maintaining the integrity of the intestinal barrier and preventing the translocation of bacteria and harmful agents. Vagal stimulation can protect the intestinal barrier, improve tight junction protein expression, and decrease intestinal permeability. [9]

Neurotransmitters such as serotonin (5-hydroxytryptamine, 5-HT), dopamine (DA) and ő≥-aminobutyric acid (GABA), melatonin, histamine, acetylcholine, catecholamines are active in regulating gut-brain axis. [10]. The butyrate also shows stimulatory effect on the vagus nerve. [11].

Gut microbes such as Lactobacillus johnsonii La1 [12], Lactobacillus rhamnosus [13] induce in activation of vagus nerve.

 Endocrine Pathway:

Gut-brain axis is influenced by the gut microbes which promote the release of biologically actives such as galanin and ghrelin from endocrine cells. Galanin stimulates the activity of HPA axis and thereby indirectly regulate the release of Adrenocorticotropic hormone (ACTH) and corticotropin-releasing factor (CRF) and also enhances glucocorticoid secretion from adrenal cortex.[14]  Ghrelin contributes to the regulation of glucose homeostasis and metabolic stress.[15]

Immunology pathway:

In cases of intestinal dysbiosis, intestinal microbes trigger immune responses by releasing cytokines like IL-10, IL-4, and interferon-gamma. This dysregulation is evident in conditions like irritable bowel syndrome (IBS), where reduced microbe populations disrupt mucosal immunity, leading to increased gut permeability, sensory pathway activation, and enteric nervous system dysfunction. Such disturbances in the gut-brain axis impact intestinal functions and immune system abnormalities.[17]

Additionally, studies on major depression reveal immune activation and heightened inflammatory cytokine levels, including IL-6, IL-1ő≤, and TNF-őĪ, altering systemic immunity. [18, 19, 20]

Humoral pathway: 

Bacterial metabolites, specifically short-chain fatty acids (SCFAs) and lipopolysaccharides (LPS) infiltrate the sympathetic nervous system and circulatory system. SCFAs, which can traverse the blood-brain barrier, play a pivotal role in regulating diverse activities, including microglia homeostasis, brain development, tissue equilibrium, and behavior. SCFA depletion is associated with the progression of neurodevelopmental disorders like autism due to disrupted microglial populations.[21]

In contrast, LPS from leaky gut syndrome triggers antibody production and is found at elevated levels in depression patients compared to controls.[22]

Clinically proven Psychobiotics:

Lactobacillus
In many of studies investigating the potential therapeutic role of various probiotic strains in addressing depressive symptoms and related factors, compelling evidence emerged. Notably, Lactobacillus plantarum PS128 exhibited promising outcomes in two distinct contexts: improving the mental health of patients with Major Depressive Disorder and enhancing sleep quality in individuals reporting insomnia symptoms. These interventions were marked by significant reductions in depression scores, fatigue levels, and awakenings during deep sleep.[23, 24] Additionally, the combination of S-Adenosylmethionine (SAMe) and L. plantarum HEAL9 showed rapid and clinically relevant improvements in depression symptoms, offering a unique and effective approach, especially for individuals with subthreshold or mild-to-moderate symptoms.[28] Furthermore, fermented milk containing Lacticaseibacillus Paracasei strain shirota demonstrated potential in alleviating constipation and depressive symptoms, accompanied by a decrease in IL-6 levels and positive regulation of the gut microbiota associated with mental health.[27]

Bifidobacterium
Similarly, Bifidobacterium longum NCC3001 and Bifidobacterium breve CCFM1025 showcased their antidepressant-like effects, with the latter displaying a pronounced reduction in serum serotonin turnover.[25, 26]

Clostridium
Clostridium butyricum MIYAIRI 588, when used in conjunction with various antidepressants, led to significant improvements in depression, with a high response rate and no severe adverse events noted.[29]

Collectively, these studies underscore the emerging potential of probiotics as a novel and promising avenue for addressing various facets of depression, from symptom alleviation to inflammation regulation and gut microbiota modulation. These findings challenge the conventional treatment landscape, particularly for subthreshold and mild-to-moderate cases, offering new hope for individuals seeking more effective and well-tolerated therapeutic options in the realm of mental health.

Patent Literature:

US11298384B2 titled Composition for use in the treatment of major depressive disorder assigned to Probiotical SpA pertains to a method for treating or enhancing the condition of individuals with major depressive disorder. This method involves using an oral formulation containing a blend of bacterial strains, which includes Lactobacillus fermentum strain LF16 DSM 26956, Lactobacillus plantarum strain LP01 LMG P-21021 and/or strain LP02 LMG P-21020, Lactobacillus rhamnosus strain LR06 DSM 21981, and Bifidobacterium longum strain BL04 DSM 23233.

US11135181B2titled titled Treatment for depression and depressive disorders and assigned to MedLab IP Pty Ltd. pertains to a method for treating, preventing, or alleviating various depressive disorders, including major depressive disorder, dysthymic disorder, seasonal affective disorder, mood disorder, mixed anxiety-depressive disorder, bipolar disorder, mild, moderate, severe, or postpartum depression, as well as depression, anxiety, or related disorders. This method involves using probiotic microorganisms such as selected species from Lactobacillus (L. bulgaricus, L. paracasei, L. gasseri, L. rhamnosus), Lactococcus (L. lactis), Bifidobacterium (B. animalis subsp. lactis, B. bifidum, B. infantis), and Streptococcus (S. thermophilus). It also includes Saccharomyces boulardii and Saccharomyces cerevisiae.

US10967013B2 titled Lactic acid bacterium for prophylaxis or treatment of a stress-induced disorder and a composition containing the same assigned to Bened Biomedical Co Ltd patent pertains to Lactic acid bacteria, specifically Lactobacillus plantarum subsp. plantarum PS128, are employed in the treatment or prevention of stress-induced disorders, such as depression

US10780103B2 titled Synthetic composition and method for modulating emotion and mood disorders assigned to Glycom AS pertains to a method for treating emotion and/or mood disorders such as depression with effective amount of bifidobacteria of the species B. adolescentis.

JP2019172661A titled Stress alleviating composition, and pharmaceutical composition and food and drink composition using the stress alleviating composition assigned to Morinaga Milk Industry Co Ltd.  pertains to a composition for improving or preventing stress relief containing Bifidobacterium breve MCC1274 (FERM BP-11175) as an active ingredient and the composition is in varied form as pharmaceutical composition, food, or drink composition.

Products:

Optibac

Optibac, launched by Optibac Probiotics, a UK-based company, contains multi-strain probiotic and prebiotic FOS for digestive health and wellbeing. Optibac capsule contains various probiotic strains, Lactobacillus rhamnosus Rosell-11, Lactobacillus acidophilus/helveticus Rosell-52, Bifidobacterium longum Rosell-175, Lactococcus lactis Rosell-1058, Bifidobacterium breve Rosell-70, Bifidobacterium bifidum Rosell-71[30]

Target gb-X

Target gb-X, launched by Klaire Labs (currently Soho Flordis Intl., USA), was developed in partnership with Winclove Probiotics (Amsterdam, NL), a company that researches, develops and manufactures evidence-based probiotics. Target gb-X is 5B CFU (colony forming unit) probiotic with 9-strains for the gut-brain axis, supporting gut barrier function, modulating cytokines and inflammatory response, metabolite production, and HPA axis.[31]

Cerebiome¬ģ

Cerebiome, a product of Lallemand Health Solution Inc. contains Lactobacillus helveticus Rosell¬ģ-52 and Bifidobacterium longum Rosell¬ģ-175. The formulation elevates mood, maintains healthy cortisol levels, enhances brain health and synthesis of neurotransmitters such as serotonin, tryptophan and their precursors. ¬†Cerebiome¬ģ is found as an ingredient in OTC probiotics products. [32]

Startups:

BIOHM: Ohio’s BIOHM, a microbiome startup, recently secured $7.5 million in equity financing for its groundbreaking product, BIOHM FX. This probiotic supplement targets the digestive biofilm in the gut. BIOHM has also developed an advanced microbiome innovation platform and established a promising B2B pipeline. They leverage AI for valuable insights and collaborate with major global ingredient companies, underscoring the significance of their dataset.[33]

Holobiome: Holobiome, a US-based company established in 2015, is dedicated to uncovering the connection between the gut microbiome and mental health. Founded by Philip Standwitz, Mike La Fleur, and Kim Lewis, Holobiome has raised $1.3 million in funding since its inception. Notably, Philip Standwitz, with a background in bacterial cultivation and gut-brain axis research at Northeastern University, is one of the driving forces behind the company’s mission. Their research efforts received a significant boost when Corundum System Biology, a Japanese venture capital firm, contributed $1 million to support Holobiome’s two-year research program. Furthermore, Holobiome recently formed a partnership with Johnson & Johnson to collaborate on the development of prebiotics aimed at enhancing infant and maternal immune health.[34]

Seed Health: Seed Health is a leading microbiome science company focused on developing probiotics and living medicines to enhance human and planetary health[35]. California-based Seed Health, founded in 2016 by Ara Katz and Raja Dhir, produces probiotic and prebiotic supplements, formulated for gut, digestive and immune benefits. In collaboration with Axial Therapeutics, Seed Health announced a program targeting the microbiome-gut-brain axis to improve mental health, including anxiety, depression, and stress response. The initiative builds on the pioneering work of Dr. Sarkis Mazmanian, a co-founder of Axial and a board member of Seed Health, who first identified the crucial role of intestinal microbes and their metabolites in neuropsychiatric conditions.

Taylored Biotherapeutics: Taylored Biotherapeutics, established in 2020 by Valerie Taylor, a Psychiatry Professor at the University of Calgary, focuses on pioneering treatments for various mental health conditions. Their work explores the connection between the brain’s well-being and the gut microbiome, enabling personalized treatments for different illnesses. [36] Their partnership with Nurosene Health Inc., a healthtech company specializing in advanced AI technology solutions for mental well-being and performance, is aimed at elevating the level of AI expertise needed to assess the outcomes of clinical trials.[37]

Conclusion:

In the ever-changing world of healthcare, the combination of microbiome science and mental health holds the potential for groundbreaking Psychobiotics as treatments that could significantly help people dealing with depression. Combining artificial intelligence and advanced research methods may contribute to shaping the future of Psychobiotics. This emerging field offers great hope for changing the way of treating depression, providing customized and highly effective solutions for those seeking alternatives to traditional therapies. As the field of mental health treatment progresses through exploration, innovation, and collaboration, it stands on the brink of a new era. In this emerging landscape, Psychobiotics have the potential to play a pivotal role in enhancing the lives of millions across the globe.

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