Keywords

10.1 Introduction

The gastrointestinal (GI) tract’s surface epithelium covers 32 m2 and stretches over 5 m in length (Helander and Fändriks 2014), anatomically GI organs are mesentery sectioned with each organ being composed of the mucosa, submucosa, muscular layer, and serosa. A pathogenic microorganism is an infectious, disease-causing agent which in the case of neurological disorders, negatively impacts the functioning of brain inducing both neurological and mental defects. Infectious diseases like HIV (caused by human immuno-deficiency virus) and Lyme disease (caused by Borrelia burgdorferi) can cause serious psychiatric and neurodegenerative effects on the host. Also in late stages of the parasitic infection, brain toxoplasmosis (triggered by Toxoplasma gondii) has indicated a possible link leading to a suicidal nature (Coccaro et al. 2016). These expressions of neurological infectious diseases are caused by the direct hindrance of neurotransmitter signaling by pathogens. Characterization of the gut microbiome has revolutionized our perception of gastrointestinal and metabolic processes. All bacteria are not pathogenic invaders, instead may have a potential function in maintaining immunity and homeostasis, this notion has impacted a major shift in neuroscience and neuropsychiatric research. The gastrointestinal (GI) microbiome is a distinctive assortment of commensal microorganisms inhabiting in diverse niches in the GI tract which substantially help both in the advancement and improvement of psychiatric and neurological disorders.

Probiotic microorganisms belong to diverse groups and play multiple roles for example short-chain fatty acid (SCFA) production, ferment undigested carbohydrates, synthesize vitamins and metabolites (Quigley 2013). Gestational age, delivery mode, diet, and antibiotic exposure regulate the influence the composition in gastrointestinal colonization by microorganisms (Fouhy et al. 2012). The important potential phyla present in human gut are Bacteroides and firmicutes (Bäckhed 2011). The other beneficial and opportunistic bacterial gut flora including Lactobacillus sp., Bifidobacterium sp., Propionobacteria, Enterococci, Peptostreptococci, etc. are a beneficial group but those such as Actinobacteria, Bacteroides sp., Clostridia, Peptococci, Enterobacteria, Streptococci, Staphylococci, and yeasts are of the opportunistic group (Joshi et al. 2018). The MGB axis is referred to as a bidirectional system of communication by the gut microbiome with the central nervous system (CNS) sending signals to the brain and vice versa (Fung et al. 2017). Behavioral factors like stress accelerate the corticotrophin-releasing hormone production in the hypothalamus, further activating the hypothalamic–pituitary–adrenal (HPA) axis (Belmaker and Agam 2008). The synthesis of neuroactive metabolic molecules by gut microbiota modulates the pathogenesis of several neurological diseases such as amyotrophic lateral sclerosis, Parkinson’s disease, multiple sclerosis, etc. (Girolamo et al. 2017). This chapter focuses on the cross-talk-mediated signaling of gut microbiota to the brain that impacts its functional development, summarizes the involvement of the gut-intestinal microbiota in the progression of neuropsychiatric disorders while making remarks on the potential therapeutic benefits of probiotics particularly in their actions against neurological disorders.

10.2 Microbiome-Gut-Brain Axis: A Bi-directional Communication System

10.2.1 Role and Developmental Role and Mechanism of Action of Gut-Brain Axis

The early life microbial colonization in an individual right after birth proceeds through a rapid development of unique site-specific microbial niches, and change in the microbiota composition from primitive in earlier life to mature form (Dominguez-Bello et al. 2016). “Barker Hypothesis” (1993) stated that the development of a fetus and its sensitivity to neurological and metabolic diseases is substantially affected by its intrauterine habitat in life. The GI tract instantaneously develops and facilitates for the colonization of microbiota. The pathogen Campylobacter jejuni stimulates behavioral abnormalities in early life, decreased motor function and increased anxiety (Forsythe et al. 2010). DNA methylation due to prenatal stress affects functional advancement of the HPA axis leading to hypersensitivity and glucocorticoids hypersecretion also decreased the binding capacity of the hippocampal glucocorticoid receptor (Murgatroyd et al. 2009). The cholinergic signaling synchronized with the HPA axis blocking nicotinic and muscarinic receptors causes the defect in barrier function which prevents an increase in macromolecular permeability (Gareau et al. 2007). Development in the womb is initially established and continued after the birth period but the emotions and storage of memories are controlled by the limbic system.

The process of new neuron formation known as neurogenesis takes place in specific regions of the brain throughout life (Fig. 10.1). Neurogenesis and memory endurance level have a complementary relationship between plasticity and the ability to encompass new information without deteriorating stored knowledge (Zhao et al. 2008). Microbiota communicates with CNS through neuronal pathways of the vagus nerve belonging to the parasympathetic division of ANS which regulates various functions such as gut motility, heart rate, and constriction of bronchi (Forsythe et al. 2010). Probiotic Lactobacillus rhamnosus sp. induces alteration in expression of GABA receptors in the brain resulting in reduced corticosterone and in an anxiolytic effect through signaling from the vagus nerve (Bravo et al. 2011). Probiotic mixture comprising B. animalis subsp. and Propionibacterium jensenii restored the imbalance in gut microbiota and attenuated activation of neonatal stress pathways in HPA axis. Presence of fatty acid composition also influences neurophysiologic conditions (Forsythe et al. 2010) which was observed in the immune conditions of stressed animals while experiencing neonatal maternal separation (Wall et al. 2012).

Fig. 10.1
figure 1

The development of brain and gut microbiome. During the prenatal stage brain and gut microbiota begins, in first 3 years is critical developmental stage. Disturbance in development can impact communication between these systems and it can also facilitate pathogenesis of neural development disorders for instance autism, IBS, attention-deficit hyperactivity disorders (ADHD), anxiety, and obesity (Ogbonnaya et al. 2015).

Full size image
Table 10.1 Summary of microbiome observed in human studies of different neurological disorders
Full size table

Antibiotics fundamentally show detrimental effects on neurodegenerative and neurodevelopment diseases disrupting gut microbiota involved in neuro-modulatory signaling. SCFAs derived from microbiota have an essential role in the functioning and promotion of microglial maturation (Barouei et al. 2012). When the levels of neurogenesis are low after birth, memories become more resistant to remodeling and a rise in the stability of memories dependent on the hippocampus (Erny et al. 2015). Decrease in neurogenesis due to cortex proliferative subventricular zone and microglia phagocytose neural precursor cells (NPC) arising a change in neural development (Akers et al. 2014) impacting memory formation and cognitive function.

These microglial cells are involved in CNS development at an early stage, and also in phagocytosis, antigen presentation, and regulation of inflammation during their lifetime. The amalgamation of bromodeoxyuridine (BrdU) in the hippocampus accentuated neurogenesis in adult germ-free mice (Cunningham et al. 2013).

The increased volume and modified morphology of dendrites indicated that, for amygdala and hippocampus, normal morphology and ultrastructure requirement of microbiota is significant (Borre et al. 2014). Probiotic Bifidobacterium longum and Lactobacillus helveticus combination can prevent a decrease in neurogenesis in the hippocampus region when influenced by stress (Luczynski et al. 2016). Astrocytes are various operational groups of glial cells, having functions such as neurotransmitter clearance, ion homeostasis, glycogen storage, maintenance of blood–brain barrier, and neuronal signaling additionally to their distinguished neuroinflammatory function (Ait-Belgnaoui et al. 2014). Toll-like receptor (TLR) signaling controls hippocampal neurogenesis in mice signifying the potential regulatory role of microbial components in neurogenesis. TLR4 KO mice demonstrated the formation of spatial reference memory and fear of learning and enhanced neurogenesis (Okun et al. 2012), whereas TLR2 inadequacy diminished both hippocampal volume and neurogenesis (Rolls et al. 2007).

Prenatal oral administration of probiotics to pregnant maternal indicated that lactation normalized high glucocorticoid (cortisol) secretion and restored corticotrophin-releasing hormone (CRH); for example, oral intake of genetically modified Enterococcus faecium to pregnant mice indicated offspring possessing the specific bacterial species in meconium and amniotic fluid (Jiménez et al. 2008) confirming that maternal microbial transmission in mammals is possible and maternal tryptophan along with serotonin (5-HT) neurotransmitter hormone is essential for neurodevelopment conversion led by the placenta that influences fetal brain development. Serotonin [5-hydroxytryptamine (5-HT)] is a biogenic amine neurotransmitter in the CNS and in gut where synthesis depends on the availability of its precursor, and tryptophan synthesis maintains cognitive activity and also regulates gastrointestinal secretion (Costedio et al. 2007). Tryptophan metabolism and availability depend on enteric microbiota and consequently impact the central serotonin concentrations as well as kynurenine, whereas the activity of tryptophan and indoleamine-2,3-dioxygenase enzymes induced altered enzyme activity in irritable bowel syndrome (IBS) (Schwarcz et al. 2012) and downstream neuroactive metabolites in the brain. The probiotic Bifidobacterium infantis sp. affects tryptophan metabolism along this pathway (Desbonnet et al. 2010). The gut communicates through hormonal signaling pathways to the brain resulting in the release of peptides in gut from entero-endocrine cells (such as orexin, ghrelin, and leptin), circadian pattern, sexual behavior, and anxiety (Cameron and Doucet 2007). Saresella M and colleagues (2017) (Saresella et al. 2017) reported that on MS patients where data supported the chance that diet would probably be utilized as a tool to regulate the immune system in anti-inflammatory way as a significance of changes in the gut microbiota.

Present results of this trial study show that a skewing of the constitution of the microbiota characterized by the plenty of Lachnospiraceae family, a diminish of IL-17-producing T CD4+ lymphocytes and PD-1 expressing T CD4+ lymphocytes, and an enhance of PD-L1 stating monocytes was considered in those individuals following a HV/LP diet. In these same patients, positive correlations between Lachnospiraceae and anti-inflammatory IL-10- and TGFβ-producing CD14+ monocytes, as well as between Lachnospiraceae and CD4+/CD25+/FoxP3+ T-reg lymphocytes were also observed. The concurrent development during initial postnatal life of the microbiota, gastrointestinal tract maturation, and neurogenesis of the hippocampus simultaneously forms the MGB axis. Identification of pathways and mechanisms of this complex interconnectedness has substantial therapeutic effects for several diseases.

10.2.2 Effects of Human Microbiome and Probiotics on ENS, ANS, and CNS

10.2.2.1 Effect of Human Microbiome and Probiotics on ENS

The enteric nervous system (ENS) or the “second brain” is a part of the peripheral and autonomic nervous system which tends to control GI tract functioning (Turner 2009). It is located within the GI tract wall, hence it remains protected from the intestinal luminal contents, and is composed of ganglia and millions of neurons. It serves several diverse functions such as the secretions from the gut and pancreas, reflexes, blood flow, gastrointestinal motility and physiology, GI-endocrine modulation, and protective reactions (Yan and Polk 2011). The gut microbiome helps in the overall development and maintenance of the intestinal barrier, prevents pathogenic production of emetic toxins, and also protects the intestinal sensory nerves from pathogenic invasion (Borthakur et al. 2008; Kamm et al. 2004). The excitatory irregularity of the ENS often caused as a result of gut dysbiosis has also been considerably reduced with the aid of probiotics (Bercik et al. 2011).

10.2.2.2 Effects of Human Microbiome and Probiotics on ANS

The autonomic nervous system (ANS) comprises the sympathetic and parasympathetic systems and is also composed of both motor and sensory neurons that transverse between the various internal organs and the central nervous system (CNS) (Azpiroz 2005). The sympathetic and parasympathetic systems together constitute the autonomic nervous system (ANS) which is also composed of both motor and sensory neurons that transverse between the various internal organs and the central nervous system (CNS) (Azpiroz 2005). The sympathetic nervous system prepares and aids the body in triggering the fight or flight response and subsequent reflexes, whereas the parasympathetic system on the other hand aids in returning the body functions adjusted by the former, from the excited/activated state to its normal stature (O’Mahony et al. 2011). Both prebiotics and probiotics regulate the generation of pro-inflammatory cytokines, thereby sustaining the intestinal barrier, promoting the ideal functioning of the brain-gut axis (although the supporting evidence is still under scrutiny), and exerting anti-inflammatory effects when administered in combination with certain fatty acid supplements (Desbonnet et al. 2010; Clarke et al. 2010; Wall et al. 2010).

10.2.2.3 Effects of Human Microbiome and Probiotics on Central Nervous System

The central nervous system (CNS) is majorly composed of the brain and spinal cord. It has a network of millions of neurons that transverse the comprehensive length of the body (Neufeld et al. 2011). One of the best examples for a CNS output includes human behavior and few studies have indicated the possible correlation between an individual’s neurochemical characteristics with that of his/her behavioral constitution (Heijtz et al. 2011). The crucial role of the gut microbiome on an individual’s CNS and corresponding mental status is already quite evident from several studies based on animal and human models (Galland 2014). The administration of probiotics has not only been found to positively impact the functioning of the human brain but has also shown to modify its neurochemistry both directly and indirectly. It has also markedly helped to decrease anxiety and depression with prolonged treatment (Bravo et al. 2011).

The mechanisms involved in the effect of probiotics on CNS include (Sharma and Kaur 2020):

  1. (a)

    Restoration of the functioning of the hypothalamic-pituitary-adrenal (HPA) axis that plays an essential role in our response to stress (Varghese and Brown 2001). Indirectly, it can act as a mediator in a number of neurological diseases such as anxiety, depression, IBS, etc. (Smith and Vale 2006). Increased activity of the HPA may be induced in conditions of prolonged stress and anxiety as reported in patients suffering from bipolar or depression associated disorders (Guilliams and Edwards 2010). Probiotic interventions that focus on the normalization of the HPA axis in patients experiencing psychotic disorders via regulating the levels of cortisol (CORT) or adrenocorticotropic hormone (ACTH) have given encouraging results (Savignac et al. 2015).

  2. (b)

    Regulation and production of brain-derived neurotrophic factor (BDNF) and SCFAs; neuronal factors such as BDNF are mostly proteins that aid in controlling the functioning of neurons including their differentiation, integrity, and survival (Edelmann et al. 2014). Neurodegenerative diseases are frequently accompanied by an impaired or abnormal expression of neurotrophic factors (Rao et al. 2007). A study by Ranuh et al. (2019)) demonstrated the direct linkage between the increased BDNF levels in the brain after probiotic administration and their corresponding stimulation of the gut-brain axis. When it comes to SCFAs, their increased production by the gut microbiome was shown to alleviate the oxidative stress induced during neurological disorders (Hamer et al. 2008).

  3. (c)

    Proto-oncogene activation and expression are likely to be enhanced in patients suffering from psychiatric disorders in particular Alzheimer’s disease and dementia (Lu et al. 1998). According to Smith et al. (2014)), probiotic administration can directly reinstate the expression of proto-oncogenes.

  4. (d)

    Stimulation of the vagus nerve, a major constituent of the parasympathetic nervous system by probiotic intervention, can help in the treatment of several neurological disorders like depression, anxiety, schizophrenia, IBS, etc. (Johnson and Wilson 2018). Enhanced activity of the vagus nerve helps to decrease the liberate pro-inflammatory cytokines such as TNF-α in stress-related disorders (Herman et al. 2016) (Fig. 10.2).

Fig. 10.2
figure 2figure 2

(a) Effect of neurogastroenterology due to the gut microbial impact in gastrointestinal tract. (b) Representative image of the effect of probiotics on CNS, ENS, and ANS

Full size image

10.3 Neurological Diseases Influenced by Imbalance of Gut-Brain Axis

10.3.1 Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a sequential neurodegenerative disorder. The symptoms include cramping, muscle spasm, weakness, muscle twitching, and stiffness, problems with coordination, speaking, breathing, and swallowing difficulties, weight loss, gastroparesis, and an increase in metabolic rate, relating to the death of motor neurons, spinal cord, and eventually the brain. Neuroinflammation is recognized as a disease driver for the development of ALS disorder (Skaper et al. 2018). Immune pathway de-regulation is a principal feature in the brain and spinal cord tissue affected with ALS (D’Erchia et al. 2017). ALS is of two types: (i) Sporadic ALS, signifying the most general form although causation is unknown, (ii) Familial ALS, occurring due to genetic changes (Steyn et al. 2018; Toepfer et al. 2000).

Modifications in monocytes, neutrophils, CD4+, CD8+, and natural killer T cells have been observed in patients with ALS causing progression in the disease rate (Perner et al. 2018; Zhou et al. 2017). Association of the gut microbiome and ALS in a transgenic mouse model with G93A genetic mutation of the superoxide dismutase gene (SOD1/SOD1 G93A) disclose disrupted BBB and increased permeability of the gut, reduced amount of butyrate-producing bacteria Peptostreptococcus and Butyrivibrio fibrisolvens resulting in an elevated level of serum and IL-17 (intestinal pro-inflammatory cytokine) as well as damaged intestinal wall due to decreased expression of E-cadherin and zonula occludens (ZO-1) (Wu et al. 2015). Furthermore, the mutant mice SOD1G93A treated with 2% butyrate in drinking water, improved intestinal barrier function by bacteria B. fibrisolvens as well as delayed symptoms like weight loss and even death, in comparison to control mice (Zhang et al. 2017). Butyrate-producing bacteria like Lachnospira, Anaerostipes, and Oscillibacter were in reduced levels in feces of ALS patients and indicated increased levels of Dorea spp. which synthesizes harmful end product ethanol in glucose metabolism (Fang et al. 2016). The therapeutic potential of probiotics for the improvement of the ALS condition is yet to be fully explored.

10.3.2 Epilepsy

It is a neurological globally prevalent disease. Symptoms like epileptic seizures are often experienced by the affected individuals and lack of proper medical care during severe seizures can even prove to be fatal (Gómez-Eguílaz et al. 2018). Although multiple therapeutic alternatives are in practice, their benefits remain limited or short-termed. The use of probiotics for the treating of pharmaco-resistant or refractory epilepsy (that often involve highly convulsive seizures) is already undergoing trials (Iannone et al. 2020). Such studies have revealed promising results by reducing the symptomatic seizures by over 50%, thus eventually contributing to a better quality of life among the patients (Krauss and Sperling 2011).

10.3.3 Autistic Spectrum Disorder

Autism or autistic spectrum disorder (ASD) comprises an extensive range of neuropsychiatric disorder exhibited mainly during infancy wherein affected children tend to experience numerous neurodevelopmental disabilities along with stereotypical or repetitive actions, communicational, and social interaction difficulties and intestinal problems (Lord et al. 2000; Horvath et al. 1999). Real-time PCR meta-analysis studies indicated autistic children have a lower copiousness of bacterial phyla comprising Proteobacteria, Bacteroidetes, Firmicutes, Bifidobacteria spp. and especially A. muciniphila mucolytic bacterium in their feces with comparison to controls (Cao et al. 2013; Wang et al. 2011). A probiotic consortium of Lactobacillus, Streptococcus, and Bifidobacterium showed considerable changes in fecal cytokine levels of ASD patients (Tomova et al. 2015).

Gut microbiota produces metabolites such as acetate, valerate, and propionate in lower levels in autistic patients. Also, ASD animal model MIA mouse resembles characteristics of ASD in mouse offspring which are caused due to gut-intestinal barrier defects and exhibited changes in significant microbial metabolite 4-ethyl-phenyl-sulfate (4EPS) associated with anxiety behaviors (Adams et al. 2011) and Bacteroides fragilis reverses gut-intestinal barrier non-regulation in the MIA mouse. Alternative ASD mouse model strain BTBR T+ Itpr3tf/J is directed by multiple genetic modifications inducing autism-like behavior leading to change in gut microbiota with a reduction in SCFAs, tryptophan, and bile acid metabolism (Meyza and Blanchard 2017). Simultaneously, these presymptomatic and symptomatic data substantiate the conception of a MGB axis dysfunction in ASD.

10.3.4 Dementia

It is a term collectively used to describe the various signs and symptoms of both cognitive and psychological impairment, often characterized by difficulties associated with communication, coordination, visual perception, memory loss, etc. Many conditions can contribute to dementia such as Alzheimer’s disease, Parkinson’s disease, brain injury, and traumas (Bachstetter et al. 2015). The administration of probiotics and prebiotics helps in stimulation of the functioning of the gut microbiome, in turn affecting the MGB axis (Cryan and Dinan 2012). With the advancement in age, the composition of gut microbiome changes denoted by the loss of a few beneficial microbes reduced heterogeneity and a possible increase of pathogenic microbes. Aging is probably one of the major risk factors that lead to the development of dementia and hence the microbiome-gut-brain axis is also likely to be a crucial factor in the development of dementia (as per the ongoing study references from Medical University of Graz, probiotics in dementia-undergoing clinical trials).

10.3.5 Multiple Sclerosis (MS)

Multiple sclerosis (MS) is a chronic autoimmune neurological disorder of the central nervous system. The neuropathological characteristics of MS include axonal damage, demyelination, progressive neurological disability, neurodegeneration, and abnormal T-cell-facilitated immune responses triggered against myelin antigens (Ota et al. 1990). The clinical disclosures include dizziness, vision loss, vertigo, motor dysfunction, pain, numbness, impaired coordination, fatigue, and depression. MS is mainly divided into four: (i) Progressive-relapsing MS (PRMS), (ii) Primary Progressive MS (PPMS), (iii) Secondary Progressive MS (SPMS), (iv) Relapsing-Remitting MS (RRMS) (Noseworthy et al. 2000).

Neuropathogenesis of MS is dependent upon important environmental factors like gut dysbiosis (Mowry and Glenn 2018). RRMS is distinguished by a reduction in bacteria responsible for generating T regulatory cells (Tregs) which are immune cells accountable to anti-inflammatory reactions, CD4+ T cells that generate tolerogenic dendritic cells, regulatory B cells, IL-10, and macrophage suppression. CD4+ T cells, dendritic cells, monocytes, or B cells produce pro-inflammatory reactions due to the increase in specific bacteria (Shahi et al. 2017). Germ-free mice having autoimmune encephalomyelitis (EAE) develop a substantially weakened pathology while the commensal microbiota in experimental mice stimulates CD4+ T cells which are myelin-specific and also obtained autoantibodies produced to myelin oligodendrocyte glycoprotein by B cells (Berer et al. 2011).

MS patient’s fecal gut microbiota has a different bacterial composition in comparison with controls (Shahi et al. 2017). Presence in increased concentration of Proteobacteria species like Acinetobacter calcoaceticus (Cekanaviciute et al. 2017), Pseudomonas, Mycoplasma, (Chen et al. 2016), Bilophila (Miyake et al. 2015) in white matter lesions; Akkermansia, Acinetobacter, Prevotella, Clostridium, Bacteroidetes, and Lactobacillus bacterial genera in MS patients gut microbiota induces production of SCFAs (Berer et al. 2011; Branton et al. 2016) and helps in the maintenance of immune cell for producing an anti-inflammatory reaction. The importance of bacteria Faecalibacterium in MS patients is its production of butyrate which increases the production of Tregs (Arpaia et al. 2013). Colonization of Clostridium perfringens type B in the human GI tract increases epsilon toxin level which deteriorates the blood–brain barrier (BBB), dominating oligodendrocyte and neuronal damage and also activating autoimmune demyelinating action (Rumah et al. 2013).

Oral administration of various combinations of probiotics like Lactobacillus species increased regulatory T cells and increase in IL-10 production and decreased IL-17 and (Takata et al. 2011), Streptococcus thermophiles, Bifidobacterium bifidum in both rat and mouse models improved clinical score of EAE and showed a decrease in Th1 and Th17 cells together with Tregs development (Kwon et al. 2013). Clinically, it was indicated that laboratory mice colonizing with MS patients gut microbiota increased the severity of experimental autoimmune encephalomyelitis (EAE) in MS animal models which can be reduced by the oral administration of Bifidobacterium animalis (Ezendam et al. 2008). An anti-inflammatory bacterium Prevotella histicola from human celiac disease patients has immunomodulatory potential which suppresses disease in EAE models through the initiation of tolerogenic dendritic cells, and FoxP3+ regulatory T cells and a decrease in pro-inflammatory Th1 and Th17 responses (Mangalam et al. 2017). Lactobacillus sp., Bifidobacterium bifidum, and Streptococcus thermophiles enhanced regulatory T cells, producing increased IL-10 and decreased TNF-α, IFN-c, IL-17, and reduced Th1 and Th17 cells along with the development of Tregs (Ezendam et al. 2008). These results produce evidence that the microbiome present in the human GI tract has a substantial impact on CNS-specific autoimmunity.

10.3.6 Alzheimer’s Disease

Alterations occurring to the gut microbiome have the ability to influence the advancement of neurological diseases such as Alzheimer’s Disease (AD), often recognized with a gradual decrease in cognitive abilities and memory and eventually in most cases, cause dementia (Mangalam et al. 2017). Although age is regarded as a notable risk factor for AD, the causative factors that majorly trigger it are still unclear (Kohler et al. 2016). There are several crucial factors that accompany the degenerative process of AD such as an impaired immune response, markers or signaling processes (Bhattacharjee and Lukiw 2013). Currently, no cure or treatment protocol is available for AD and the ways of disease progression by plaque and tangle formation or its further propagation in the brain still remain unknown (Aisen and Davis 1994). Probiotics possibly modulate and prevent the cognitive impairment in AD by the production of metabolites and neurotransmitters such as SCFAs and GABA. They help maintain a state of eubiosis, promote inflammatory responses and reduce cell damage caused by oxidative stress (Balin and Hudson 2014).

10.3.7 Anxiety and Depression

Anxiety is a psychological state of an individual characterized by apprehension or intense fear, associated with a lack of response of adaptation by the subject in a particular situation often commonly experience psychiatric disorders. Depression is a psychological state characterized by unhappiness or irritability and joint from various psycho-physiological alterations such as appetite distortions, sleep, constipation, and inability to experience work pleasure. Due to the intervention of the ANS, the two disorders generate alteration in the stability and constitution of the gut microbiota causing changes in colon mobility.

These patients exhibit increased inflammatory levels, dysfunction of the HPA axis, and neurotransmitter signaling. MDD patients showed significantly reduced Firmicutes and an increase in Bacteroidetes, Proteobacteria, and Actinobacteria but compared with controls confirmed the constitution of the altered gut microbiome. MDD patients also had increased Enterobacteriaceae, Prevotella, Klebsiella, Streptococcus, Clostridium, and Alistipes, decreased levels of Faecalibacterium, Bifidobacterium, Lactobacillus, Prevotellaceae and increase in Thermoanaerobacteraceae revealed that gut microbiota dysbiosis is significantly linked with metabolic changes of bile acids and tryptophan against the controls (Lin et al. 2017a). Desbonnet et al. 2008 (Desbonnet et al. 2010) observed peripheral HPA levels and concentrations of the serotonin precursor, tryptophan altered due to B. infantis for development of protective mechanisms preceding stress disclosure.

Germ-Free (GF) mice present an excessive liberation of adrenocorticotropic hormone (ACTH) and corticosterone resulting in stress. GF mice exhibit low anxiety suggesting that the intestinal microbiota affects the developmental behavior (Neufeld et al. 2011). Supplementing GF mice with Bifidobacterium infantis enhanced HPA stress response, comprising a reverse in an increase of plasma (ACTH) and corticosterone (Sudo et al. 2004). L. rhamnosus reduced stress-induced corticosterone and changed GABA receptor gene expression levels in the brain also signifying modulatory communication pathway as vagus nerve between the gut microbiome and the brain (Bravo et al. 2011). When fecal microbiota of MDD patients was transplanted to GF mice, induced metabolic disturbances in host and induced depression indicating dysfunctionality of gut microbiota playing a significant role in MDD.

Individuals with depression indicated higher levels of cytokines and immunoglobulins IgA and IgM, resulting in inflammatory processes and gastrointestinal disorders (Lima-Ojeda et al. 2017). Enteropathogens disturb mood through the immune system in humans. Reichenberg et al. (2001) indicated that following intravenous infusion with endotoxins from Salmonella abortus equi to healthy volunteers underwent an increase in anxiety, and depression levels. Alterations in the neuroendocrine pathways and several neurobiological mechanisms involving serotonin neurotransmitter reduction, reduction of dopamine in anxiety and noradrenaline in depression. The low doses of Campylobacter jejuni through oral administration can stimulate anxiogenic effects in mice (Lyte et al. 2006). The intake of probiotics has anti-inflammatory and antioxidant effects on depressed patients and their ability to regulate BDNF growth factor levels (Logan and Katzman 2005).

Lactobacillus rhamnosus JB-1 and combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 improved anxiolytic activity in specific-pathogen-free (SPF) rat and GF mice, reduced extreme HPA, changing GABA receptor level in particular brain regions, restored serotonin and norepinephrine levels in inflammatory stress response, and also promoted potential psychological properties in humans (Liang et al. 2015). The enteric microbiota shows a significant impact on potential therapeutic approach, modifying the host’s gut microbiota affecting neurochemical, behavioral, and immunological parameters appropriate to the brain-gut axis disorders provided health benefits to the host with psychobiotics as emerging treatment (Petschow et al. 2013).

10.3.8 Schizophrenia

Schizophrenia is a mental illness that disturbs the human mind’s functioning with severe occurrences of psychosis and passivity, followed by periods of normal mental activity (Grover et al. 2019). The prevalence of schizophrenia and autism has been correspondingly higher in patients suffering from C. difficile infection, possibly because the organism is known to synthesize a phenylalanine derivative in the gut that in turn regulates the levels of catecholamine in the brain (Argou-Cardozo and Zeidán-Chuliá 2018).

Further evidence from genetic studies focusing on twins and their adoption also suggests a linkage between the gut microbiome and schizophrenia. Patients suffering from schizophrenia often experience both mental and inflammatory stress, poor nutrition, and lactose sensitivity. These symptoms can be relieved with sufficient and proper probiotic administration (Ledochowski et al. 1998).

10.4 Psychobiotics

Probiotic microorganisms that may positively impact the psychological condition of a host upon adequate administration are referred to as psychobiotics (Dinan and Cryan 2013). The correlation of the gut microbiome with an individual’s psychological condition via the gut-brain axis is increasingly gaining importance. Hereby, gut microbiota has found to exert an anti-inflammatory effect along with a modulatory reaction on the functioning of neurotransmitters (Beck et al. 2019). It has often been implied that a healthy mind means a healthy body vice versa possibly indicating their close relationship and also the fact that the gut microbiome can have both a direct and indirect connection with the mental status of a host (Dinan et al. 2013).

The gut microbiome has the ability to shape and alter one’s thinking and mental abilities proving why it has been termed as the second brain. Dinan et al. (2013)) referred psychobiotics to some psychotropic bacteria colonizing the gut which could either positively or negatively influence the mental status of a host. Gut microbiota dysbiosis has also been associated with an unstable mental status of the host often leading to neurological disorders such as depression (Luczynski et al. 2016), autism disorders (Critchfield et al. 2011), schizophrenia (Grover et al. 2019), Parkinson’s disease (Holmqvist et al. 2014), Alzheimer’s disease, dementia (Kohler et al. 2016), etc. Psychobiotics are capable of releasing hormones and modulating the functioning of neurotransmitters which in turn act upon the gut-brain axis in Table 10.2 below (Ho et al. 2015). Studies reveal that the cytokines such as INFα and TNF-α have the ability to cause depression depending on their circulation and production levels, therefore a therapeutic dosage of psychobiotics is likely to alleviate such conditions and even improve mood swings (Petschow et al. 2013). Psychobiotics offer promising results in the treatment of various neurological diseases; targeting the gut microbiome and alteration of the same in a positive manner would greatly benefit the host (Rooks and Garrett 2016).

Table 10.2 Representative table of gut microbiota producing neurochemicals within the human gut
Full size table

10.5 Therapeutic Manipulation, Implications, and Future Prospects

The significant functional and structural alteration of central nervous system can be concomitant with gut dysbiosis directing to the assumption that manipulation of gut microbiota is potentially a sensible method to confine clinical complications in neurological disorders. Certain treatments with antibiotics active against specific species are used to control intestinal flora of children with ASD and their GI tract showed a considerable negative impact on CNS with a reduction of pathogenic bacteria (Critchfield et al. 2011), but this method has only been partially successful and was found to follow a significant development in neurological disorder only during the administration of adequate drug dosage (Sandman et al. 2012). However, soon after treatment with certain phytochemicals reverses the neurological impairment in its initial phase (Tripathi et al. 2022).

A probiotic is defined as living microorganisms that aid in recovering the gut microbiota balance, with improvement in the integrity of the gut mucosal barrier and immunomodulation, ensure health benefits to the host, and IgA mucosal response to the benefit of the host when governed in acceptable amounts (D'Mello et al. 2015). Administration of probiotic bacteria modifies the bacterial composition of the gut, with an increase in protected positive strains and a reduction in negative strains. Furthermore, the concentration of specific bacterial products which causes immune system alterations, anti-anxiety effects (Curran et al. 2016), memory and learning improvements (Adler and Wong-Kee-You 2015), inflammation, modification of the CNS function and structure, and modulation of gene expression is reduced by probiotics when it exceeds the intestinal wall (Murgatroyd et al. 2009). This beneficial effect is different and strain-dependent.

Many presymptomatic and animal research investigations indicated the probiotic potential for treatment and prevention of numerous diseases, comprising of CNS and GI diseases, mainly using genera Lactobacillus and Bifidobacterium bacteria (Sánchez et al. 2017). Across the MGB axis, probiotics initiate brain function, for example anxiety and depression normalization (Wallace and Milev 2017); the brain neurological processing is influenced by the mechanism of probiotic supplements, for depression and anxiety in particular. For instance, chronic therapy with the probiotic Lactobacillus rhamnosus diminishes anxiety, depression, and stress responses merely in the existence of an intact vagus nerve, by reducing mRNA expression of GABAAα2 in the amygdala and prefrontal cortex, however, enhanced GABAAα2 mRNA expression in the hippocampus, therefore, vagus nerve identification plays a significant role in modulatory communication pathway between the gut, which is susceptible to probiotics or bacteria, and the brain (Bravo et al. 2011).

Bercik et al. (2011)) demonstrated a chronic administration of Bifidobacterium infantis in rats which was restricted by early age from maternal contact and possessed stress-related mood and gastrointestinal disorders resulting in immune normalization, reversal of behavioral deficiencies, and rehabilitation of basal noradrenaline concentrations in the brainstem. Moreover, Bifidobacterium longum NCC3001 and Bifidobacterium longum 1714 normalize anxiety-like behavior, with beneficial effect on cognition, Bifidobacteria infantis raised serotoninergic precursors and weakened inflammatory immune response, further indicated an antidepressant effect (Quigley et al. 2012) and hippocampal brain-derived neurotrophic factor (BDNF) in mice with infectious colitis (Bercik et al. 2011). In rats, the administration of Lactobacillus helveticus, Lactobacillus farciminis, and Lactobacillus rhamnosus can prevent chronic-stress-induced intestinal abnormalities and decreases psychological distress (Zareie et al. 2006). Lavasani et al. (2010)) observed that instead of administrating monostrain probiotic strains, three Lactobacillus strains such as L. paracasei DSM 13434, L. plantarum DSM 15312, and L. plantarum DSM 15313 in mice showed therapeutic efficiency on development of experimental autoimmune encephalomyelitis (EAE), by inhibiting disease progression (Boksa and El-Khodor 2003), gut microbiota modulation and improved destructive antisocial behavioral pattern, communication and anxiety problems in patients (Cai et al. 2015). Hsiao et al. (2013) described oral administration of Bacteroides fragilis which is a human commensal by a maternal immune activation (MIA) model of ASD in mouse offspring; modified the gut permeability, changed the composition of gut microbiota, and ameliorated the defects in communicative, stereotypic, with improved anxiety-like and sensorimotor communicative behaviors also Bacteroides thetaiotaomicron administration has also substantially improved abnormal behaviors and signifies that modulating therapies utilizing probiotics is a safer and efficient treatment for autism spectrum disorder (Cai et al. 2015).

Fecal microbiota transplantation (FMT) is used for the treatment of gastrointestinal diseases by introducing the enteric bacteria from healthy donor’s feces to affected/diseased individuals with the sole purpose of restoring gut microbiota balance or to effect in eubiosis. This is done through oral administration of capsules comprising of donor microbiota sample in freeze-dried form. So far the results have been promising without any adverse effects and hence maybe considered as a safe alternative strategy for the treatment in organ transplant recipients (Bajaj et al. 2017) and cancer patients (Hefazi et al. 2017). Although this mode of treatment would be most ideal for gut dysbiosis-related diseases for instance inflammatory bowel diseases, metabolic syndromes, etc. (Sayar and Cetin 2016).

Clustered and regularly interspaced short palindrome repeats (CRISPR) technology can be utilized to make genetic changes in probiotic microorganisms via gene editing. This technology in association with the bacterial neuroimmune and metabolic systems can be used to engineer genes through upregulation and downregulation of their expression via therapeutic signaling molecules and blocking exopolysaccharides produced by the bacteria (Petimar et al. 2019). CRISPR-CAS targets the bidirectional gut-brain axis changing the neurological and intestinal effects leading to neurodegeneration (Aliev et al. 2008). Also, CRISPR technology suppresses or silences the expression of bacterial inflammatory signaling molecules and endotoxins. CRISPR-CAS9 is also used to target antibiotic resistance through phage-specific 16 s sequences of Gram-negative bacteria; these CRISPR antimicrobials can be tailored to treat patient-specific dysbiosis without changing bacterial populations, yet help in achieving effective therapeutic potential (Martella et al. 2019; Konermann et al. 2015)

Daily consumption of a fermented milk product containing probiotics such as Bifidobacterium animalis subspp. sss, Lactobacillus bulgaricus, Streptococcus thermophilus, and Lactococcus lactis subspp. showed significant alteration of the activity of CNS and brain regions that control the treatment of sensation and emotion (Tillisch et al. 2013), and HTLV-1-associated myelopathy/tropical spastic paraparesis (TSP/HAM) patients were treated with oral administration of Lactobacillus casei strain Shirota and exhibited development of motor function due to improved activity of NK cell (Finegold et al. 2002). Furthermore, probiotic administration in early age could lower the neuropsychiatric disorder risk development subsequent in infancy and the structured neurological evaluation in children administrating probiotics disclosed a substantially lower prevalence of neurological abnormalities (Pärtty et al. 2015).

10.6 Conclusion

The potential probiotics existing in the gut microbiota of the human intestinal tract are composite and live microorganisms that perform well in microvilli advancement, maintaining homeostasis, immune-potentiation, prevention of pathogen colonization in the GI tract, and gut-brain axis regulation. It could be utilized as a neuroprotective nutraceutical for treating or preventing a wide range of neurological diseases. The probiotic development emphasizes on microbial psychobiotics to potentially treat and prevent psychiatric disorders. Postbiotics which are gut microbial signaling molecules should be exploited to identify targets for therapeutic benefits. Dysbiosis in gut microbiota can cause impairment of gut barrier function and inflammation in the gut-brain axis leading to mental disorders. The gut microbiota dysbiosis and neurological dysfunction have aroused its importance in several fields, including neuroscience, immunology, bioinformatics, and microbiology, which provide potential treatment approaches for a diverse set of neurological disorders. Clinical research on the potential impact of probiotic mechanism and manipulation can positively improve the understanding of neurodevelopmental disorders and also may help evaluate the microbial effect on the gut-brain axis, this should be comprehended more in the future. It remains unclear whether the genetic modification of gut microbiota is capable of resulting in neurological diseases as there still exists only a limited amount of information concerning such protective or beneficial bacteria. The therapeutic role of psychobiotics has been studied in animals but more efficient human clinical trials are required to confirm their roles in microbiome-targeted therapies for treating gut-brain disorders. Probiotics have also shown to play a prominent role in the neuropathogenesis of neural disorders by altered gut-brain axis function.