Understanding the Role of the Gut Microbiome in Brain Development and Its Association With Neurodevelopmental Psychiatric Disorders

1The gut microbiota with trillions of microbial cells and thousands of species profoundly influences human physiology, including various diseases and disorders. The human gut microbiota starts colonizing during the pregnancy period. Collectively the genome of all these microorganisms represents the microbiome. The process of development and colonization of gut microbes co-occurs with brain development during pregnancy in a coordinated way until the first few years after birth. An imbalance in the gut microbiome during the critical developmental phase can influence the overall developmental process, primarily neuronal plus glial development and maturation. The microbiota composition exhibits the highest intra- and inter-individual variability during the first 12 months of post-natal development until it reaches a stable adult-like organization at the age of ∼ 3 years and can influence the process associated with brain development and in shaping the immune profile of the individual.. Early-life colonization of the host’s mucosal surfaces is crucial for the development and maturation of the host’s immune system in a healthy individual.

2However, exposure to factors such as maternal immune activation (MIA), poor diet, disease/infections and antibiotic overdose can lead to early life gut dysbiosis. The altered gut microbiome can cause dysregulated immune activation, igniting systemic inflammation resulting in atypical brain development leading to symptoms associated with neurodevelopmental psychiatric disorders (NPD) (Figure 1) (;; J.;; ). Hence, the presence of a balanced microbiome is needed for the proper functioning of the immune system, which in turn regulates the neurodevelopmental trajectories.

3NPDs are a spectrum of disorders arising from atypical brain development resulting in cognitive, emotional, and motor deficits. These include attention deficit hyperactivity disorders (ADHD), autism spectrum disorders (ASD), and schizophrenia (SCZ) which affect children in their daily lives through the early adolescence and later periods of life. These NPDs are also associated with psychotic symptoms and behavioral abnormalities characterized by positive symptoms such as psychotic hallucinations, the eccentric overflow of thoughts, and negative symptoms like insensibility, emotional and interactive withdrawal, lethargy, etc.. These behavioral abnormalities often change or maturate and become more severe as a child grows older; some disabilities and behavioral abnormalities remain permanent.

4An increasing number of preclinical and clinical studies have been focusing on how the interaction between the complex gut-microbial ecosystem and central nervous system can regulate brain development and its association with NPDs (Figure 2). However, most of these studies have explored the relationship on core pathology associated with one clinical subtype of NPDs. It is evident that there is a need for a greater understanding of the complex coordinated underlying pathways that’s span major NPDs. In this timely review, we discuss the recent evidence establishing the direct role of commensal gut microbes and associated metabolites on human brain development and how alterations in gut microbiome brain axis mediated communications play a role in the pathology of ASD, ADHD, and SCZ, which stems from aberrant brain development. Secondly, we propose a hypothetical framework illustrating an association between gut microbiota and inflammation affecting brain development and preventive measures in association with diet and probiotic therapy at crucial time points to mitigate the initiation and proper management of existing neurodevelopmental psychiatric disorders.

5Following birth, the colonization of microbes initiates and is very much influenced by the mode of delivery (normal delivery or C-section). Some studies have shown that microbial colonization begins in-utero with the discrete microbial community present in the umbilical cord blood, placenta, and amniotic fluid and may carry out their role in the foetal developmental process. Although some studies have defined the microbial composition of the fetal meconium has been defined in several studies, others have linked premature birth with the decreased microbial diversity within the meconium microbiome. Interestingly some recent studies suggest a similarity within the microbial profile in between placenta, fetal meconium, and amniotic fluid. Younge et al. have confirmed maternal-fetalin utero-translocation of the gut microbiota using a mouse model. The preterm neonate meconium has been shown to have abundant microbes belonging to Lactobacillus, Staphylococcus, and Enterobacteriales. With low diversity and high inter-individual variability, the meconium microbiome is more abundant with genera Bacillus, Escherichia/Shigella, and Enterococcus, whereas Bacteroides and Bifidobacterium are less abundant concerning the fecal microbiome of infants. The placenta is most abundantly colonized by phyla Proteobacteria and Bacteroidetes and various other phyla like Firmicutes, Fusobacteria, Tenericutes, and genera Mycoplasma and Ureaplasma. At the time of birth, the babies born through standard delivery through the vagina are colonized mainly by the maternal vaginal microbial population, predominantly Lactobacillus and Prevotella. In contrast, cesarean section delivered babies are more exposed and colonized by Staphylococcus and Corynebacterium closer to the skin microbiome. The typical microbiome composition of a newborn is mainly dominated by Proteobacteria and Actinobacteria, where the former dominates immediately after birth and later towards the 4 months of age. During the 1st year of life, the gut of the new-born infant is predominantly inhabited by Bifidobacterium, Enterococcus, Escherichia/Shigella, Streptococcus, Bacteroides, and Rothia gut-microbial population closer to maternal microbiota in addition to Clostridium, Ruminococcus, Veilonella, Roseburia, Akkermansia, Alistipes, Eubacterium, Faecalibacterium, and Prevotella, species. Moreover, variation in the maternal microbiota has also been suggested as modulating factor of microbiome composition in offspring. The 1st 3 years of the lifetime are more crucial for establishing a healthy and stable structured microbiome. It has been reported that the process of the microbiome and neuronal development coincides in an intense and coordinated way within this critical time frame and is most vulnerable to disruption. A gut dysbiosis at such period has been reported to bring about many NDD/NPD like ADHD, ASD, SCZ, intellectual as well as learning disability, and behavioral problems. Moreover, after this period, microbiota reconstitution does not normalize the behavioral phenotype or neurochemical disturbances during the critical developmental period (;; Click or tap here to enter text; ). Hence, maintaining a healthy and well-structured microbiota is essential during prenatal and postnatal periods up to a particular developmental phase.

6Emerging studies provide evidence about the active role of microbiota during central nervous system development. It is now clear that gut microbes play an active role in the neurodevelopmental processes (Figure 2), including the establishment of the blood-brain barrier (BBB), neurogenesis, maturation of microglia, and myelination. These processes are critical in shaping animal behavior and cognition. Various dietary components released from the gut are needed for the developing brain for neuronal cell maturity and proper functions. Also, recent evidence describes that gut microbes can directly facilitate the development processes in the brain, which have long-lasting consequences in health (J. ).

7The BBB establishes early in-utero, which constitutes capillary endothelial cells sealed by tight junction proteins, pericytes, and astrocytes, forming the restrictive barrier between the brain and systemic circulation. It also facilitates the exchange of molecules and nutrients for proper maintenance and functioning of the brain. The presence of balanced gut microbiota and microbial-derived metabolites such as SCFAs are essential in regulating the formation and maintenance of intact BBB. The permeability of BBB in developing sterile fetuses decreases towards adulthood. In germ-free (GF) mice, the permeability of BBB increases for macro-molecules due to reduced expression of basic junctional proteins occludin and claudin-5 in the brain endothelial layer. Microbial colonization of the gut or administration of butyrate, a short-chain fatty acid (SCFA) produced by gut-microbial fermentation, has been shown to reduce the blood-brain permeability in GF mice.

8Neurogenesis refers to the development of new functional neurons through differentiation of the neural stem/progenitors’ cells. The functionality of neurogenesis and neuronal plasticity is critical for learning, memory, cognition, and stress response, especially in the hippocampus, as the cognitive center. A balanced gut-microbiota is involved directly or indirectly in maintaining the microenvironment to support the process of neuronal development. A recent comparative study between GF and SPF mice outlines a range of gut microbial metabolites that can cross through the placenta into the foetal compartment, with the ability to induce and regulate the prenatal developmental process. In addition, PG, a bacterial cell wall component, gets crossed through the placenta to reach the foetal brain, there it activates Toll-like receptor 2 (TLR2), triggering an increase in FOXG1 expression, a crucial transcription factor in regulating the development and neurogenesis, thereby inducing neuronal proliferation in the forebrain area. A recent study provides direct evidence linking modulation of microbial function and associated cytokine by microbiota to influence the process of neurogenesis.

9Further, the gut-microbes may indirectly affect neuronal-plasticity by regulating neuronal migration and maturation in CNS may be via regulation of ephrin B and reelin pathway, where ephrin B plays a pivotal role in the maintenance of the gut epithelial barrier integrity and reelin, a membrane glycoprotein responsible for neuronal migration.

10Accumulating evidence suggests that gut microbes can impact the neural stem cells’ fate by coordinating with intricate pathways of differentiation and survival through neurotrophins and neurotransmitters in different areas of the brain. The process of synapse development and maturation is associated with neuronal maturation and plasticity. Experimental administration of neonatal prebiotic (BGOs) in comparison to other prebiotic in 22 days old rats has been reported to elevate hippocampal expression of synaptophysin and brain-derived neurotrophic factor (BDNF). Synaptophysin, a synaptic vesicle protein, which controls the synaptic vesicle endocytosis kinetics, and BDNF, a nerve growth factor secreted by neurons, which also act as a signaling molecule for neuronal survival, growth, maturation maintenance of various brain cell populations, as well as the establishment of neuronal circuitry through the formation of the synapse (S. ).

11Serotonin, a neurotransmitter and signaling molecule, can also be synthesized and released by gut microbes into the gut lumen, known to promote adult neurogenesis. In addition, gut microbes have been reported to have an essential involvement in serotonergic signaling pathways in the gut and multiple regions of the brain. Several studies have also reported the role of gut microbiota in regulating adult neurogenesis. By labeling proliferating cells with bromo-deoxyuridine GF mice brain, an increase in the adult dorsal hippocampal neurogenesis was reported compared to conventionally grown mice, and even upon microbial colonization, the phenotypical condition couldn’t be reversed. This indicates that the absence of microbes induces a dysregulated increase in adult dorsal hippocampal neurogenesis, and the microbial signals during crucial early life developmental window act as a controlling force in regulating neurogenesis in the hippocampus.

12Furthermore, the usage of antibiotics, which has a negative impact on gut microbiota, was associated with decreased neurogenesis. The molecular mechanism that regulates the process of adult neurogenesis via microbiota and its associated metabolites is not very clear. It is suggested that neuroinflammatory mechanisms mediate this process along with humoral and metabolic pathways. A number of recent studies provide evidence to support the role of neuroinflammatory mechanisms. Intestinal bacteria maintain the enteric nervous system in adult mice through Toll-like receptor 2-induced neurogenesis.

13Additionally, a decrease in BDNF mRNA level in the whole hippocampus was reported, particularly with a significant decline in neuronal proliferation and survivability in vagotomized mice. Furthermore, microbiome also indirectly influences hippocampal neurogenesis via regulating the neuronal immune system. Induction of acute colonic inflammation via administrating dextran sodium sulfate in mice reported a dysbiotic gut microbial composition, the increased hippocampal expression level of pattern recognition receptor and T-helper 17 cell-associated cytokines and ionized calcium-binding adapter molecule 1, a microglial activation marker, concomitant to depreciated adult hippocampal neurogenesis with consequent behavioral deficits.

14Early life stress, like a lack of social interaction, can also alter the stability of the gut microbiome, along with reduced neurogenesis and IL-6 and IL-10 level in the hippocampus of socially isolated mice as compared to grouped controls. A reduction in hippocampal neurogenesis is strongly associated with impaired learning, anxiety, depressive-like behaviors, neuroinflammation, which again have an explicit association with structural alterations gut microbiome.

15A healthy/intact gut microbiome has been reported to modulate myelination. Humans are born primarily with unmyelinated axons in the central nervous system (CNS) at the time of birth. Rapid myelination of maturing axons occurs within just a few years after childbirth by oligodendrocytes through the process of engagement and ensheathment, with a variable rate of myelination and myelin content over time, until early adulthood.. Any aberration in this process may lead to long-lasting defects. Myelination has the most crucial role in cognitive function, and the scale of myelination has been linked with neuronal plasticity and function. The gut microbiota regulates the critical process of myelination by regulating myelination-related gene expression in oligodendrocytes. Myelin deformities can have a detrimental impact on brain function and behavior. Most notably, the prefrontal cortex (PFC) area of the brain exhibits myelination at a later period, during the initial phase of an infantile life, which makes it more vulnerable to external influencing factors, like intestinal dysbiosis. As in the case of GF mice, irregulated myelin formation in the PFC region has a harmful effect on social behavior. Furthermore, bacterial metabolites such as SCFAs have been demonstrated to have a beneficial impact over stress-induced behavioral difficulties, intestinal barrier dysfunctionalities, and in the regulation of the myelination process. SCFA butyrate, when orally administered, caused recovery of myelination impairments, intestinal physiology, and behavioral deficit in antibiotic-treated mice, indicating a pivotal role of gut microbiota in developing the microbiome-gut-brain (MGB) axis through regulation of myelination process in the PFC region. Thus, the microbiota is crucial for myelination and maintenance of the plasticity of the myelin sheath.

16The endocrine-neurocrine interaction between the hypothalamus, pituitary gland, and adrenal gland in response to stress is known as the hypothalamus-pituitary-adrenal axis, where the corticotropin-releasing factor (CRF) plays the central role in the stress response via initiating a course of events that leads to the release of glucocorticoids from the adrenal cortex by regulating the HPA-axis (S. M. ). In developing the HPA-axis, commensal microbiota also plays a significant role. In GF mice, dopamine deficiency, particularly in the frontal cortex hippocampus and striatum, is one of the major causes of improper stress regulation and anxiety-like behavior. The administration of probiotic formulation consisting of probiotic strains Lactobacillus helveticus and Bifidobacterium longum, the level of anxiety decreased substantially. Also, the comparison between GF and specific-pathogen-free (SPF) mice revealed increased CRF mRNA level in the hypothalamus of the GF mice, indicating an enhanced stress response related to HPA-axis.

17Microglia are resident immune cells (macrophages) that belong to the glial system. They account for 10–15% of the whole total glial cell count in the CNS, thoroughly distributed across the brain and the spinal cord. Unlike the neuronal cells, microglial cells that constitute the innate immune system of CNS are derived from a subset of primitive macrophages that originates from the progenitor cell of the yolk sac. The functionalities of microglia include immune defense and maintenance of the CNS. The microglial cells consistently survey their local microenvironment to detect pathogenic invasion or tissue damage throughout the CNS, guarded by the BBB. Microglia also regulate neuronal proliferation, differentiation, and formation of synaptic connections, that helps in the refurbishing of post-natal neural circuits via controlling synaptic truncation during postnatal development of the mice. Microglia contributes to both innate and adaptive immune system defense in the CNS. Abnormal activation of microglia aberrantly induces inflammation, which has been observed in most brain-related pathologies. Emerging evidence also suggests microglia directly affect neuronal pathology and contributes to disease progression. Recent research data have demonstrated that microbiota has a vital role in the development and maturation of microglia. However, upon damage or depletion of microglial macrophages and the yolk progenitor cells the bone marrow-derived macrophages can replenish them by developing and differentiation with the help of microbial signals at an early point (; J.; ). Moreover, in GF mice, the microglial cells show a significantly altered developmental state, with morphological characteristics and gene expression profile of a developmental and maturation arrest condition. These GF mice-derived microglia usually displayed a limited response towards viral infections and microbe-associated molecular patterns (MAMP), which interestingly rescued by SCFA administration.

18In response to eliminating invading microorganisms such as bacteria, viruses, and other pathogens, the innate immune system triggers an intracellular signaling pathway via activation of toll-like receptors (TLRs) for gene expression of interferons, cytokines, and other immunological mediators. The molecules during pathogenic elimination can also contribute to the development of inflammation response and so-called inflammatory mediators. Inflammation can also be triggered in response to endogenous factors such as predisposition to genetic abnormalities, behavioral anomalies of immune cells (autoimmunity/allergy), as well as external factors such as trauma, heat and cold stress, environmental toxicants, pathogens, diseases, etc.. Among pro-inflammatory mediator IL-1α, IL-1β, IL-2, IL-6, IL-8, IL-12, TNF-α, INF-γ and among anti-inflammatory mediator IL-4, IL-5, IL-10, TGF-β, C-reactive protein (CRP), and serum amyloid-A are considered as inflammation biomarkers.

19The gut microbes also have an essential role in the induction of inflammation. More specifically, the pathogenic/opportunistic pathogenic strains such as E. coli and B. fragilis from the Enterobacteriace family contribute to pathogenesis when outnumbered and eventually to inflammation. Lipopolysaccharides (LPS), a specific cell membrane component present mostly in Gram-negative bacteria like E. coli and B fragilis is endotoxic and, upon interaction with macrophages, cause the release of pro-inflammatory cytokine TNF-α, IL-6, IL-1, which lead to endocytic septic shock and often have fatal outcomes. The LPS from Bacteroides is also a potential stimulator of the innate immune system. In systemic inflammation, there is a reported elevation in the expression of pro-inflammatory cytokines IL-6 and IL-8, which have been correlated with microbial taxa belonging to phylum Proteobacteria within total fecal microbiota.

20Moreover, the combination of different taxa of microbes can enhance the pathogenic effects that lead to inflammation. For example, co-infection of E. coli and B. fragilis can induce an increase in expression of TNF-α, keratinocytes-derived chemokine mRNA (KC mRNA), and proteins in peritoneal tissue and cause early peritonitis, abscess development, and death in the experimental mice model, which is not observed when infected singularly (J. M. ). Colonization of Chloristidium difficle has been reported to have an association with frequent occurrence of eczema, sensitization to allergy, and ectopic dermatitis.

21In contrast to inflammation, inducing microbes, a fraction of gut microbiota can counteract the inflammation. These microbes can act either by directly inhibiting inflammation-inducing microbes, strengthening the gut epithelial/mucosal barrier or directly interacting with inflammation-inducing components of the immune system or all three ways simultaneously. Faecalibacterium prausnitzii from the family Ruminococcaceae has been reported to secrete anti-inflammatory metabolites that block the activation and secretion of NF-κB and IL-8 in Caco-2 cells. Also, F. prausnitzii can induce an increase in the anti-inflammatory ratio of IL-10 and IL-12. An endoscopic recurrence of Chron’s disease has been reported when there is a lower proportion of F. prausnitzii within the composition of the patient’s group.

22Moreover, oral administration of F. prausnitzii can reduce the disease severity induced by 2, 4, 6-trinitrobenzene sulfonic acid in the colitis mouse model (Y. ). Lactobacillus and Bifidobacterium are well-known probiotics and are the most studied taxa having anti-inflammatory properties and are the most crucial part of the gut microbiota. Microbes belonging to taxa Lactobacillus and Bifidobacterium have been reported to suppress an undesired activation of the immune response as in case of autoimmunity and allergy, while capable of inducing an increase in nonspecific IgA antibody secretion in the intestine. Gut dysbiosis can be the consequence of an increase in inflammation-inducing microbes in the gut. Both dysbiosis and inflammation have a negative effect on brain development and can result in NDDs (Figures 3, 4).

23Any alterations in the above neurodevelopmental process lead to a class of disorders affecting brain development and function that are collectively referred to as neurodevelopmental disorders, affecting 15% of the worldwide estimated population. The gut microbiota has a significant role in neuronal development through a complex bidirectional communication, also known as the gut-brain axis. Alteration in the colonization of gut microbiota has a major impact on mammalian brain development that can influence the aberration in adult behavior by altering the expression pattern of several genetic events during the process. Also, the neurocrine disturbances and consequent behavioral phenotypes resulting upon disruption of the gut microbiota colonization during the developmental period cannot be reversed via reconstitution of microbiota at a later period. Inflammation-induced by dysregulation of the maternal immune system via maternal infection, maternal gut dysbiosis, or metabolic disorders during pregnancy has also been considered as modulating risk factors for abnormal brain development prenatally as well as neonatally, subsequently leading to a range of neurodevelopmental and neuropsychiatric disorders in the later period. Fetal exposure to maternal gut microbial products (propionic acid, LPS, or peptidoglycan), immune complexes, antibodies, and inflammation mediators can alter the normal neurodevelopmental process. Some of these specific factors are known to cross the placenta and the immature prenatal BBB and modulate several processes of brain development directly or by inducing neuroinflammation. Dysregulation of immune homeostasis and systemic inflammation share a direct connection with management complications of the gastrointestinal (GI) system, which eventually resulted in increased intestinal permeability (leaky gut) accompanied by various GI problems, and interestingly has a reciprocal correlation with gut microbial dysbiosis. Such GI complications have a reported association with various NDDs. After immediate birth among the first microbial colonizers, Bifidobacteria are the most important and dominant bacterial genera in the infant as well as adults’ gut commensals. Also, Bifidobacteria are considered among most potential probiotics and known to have anti-inflammatory, antimicrobial properties can utilize indigestible polysaccharides and can produce various B-group vitamins. In addition, Bifidobacteria can reduce stress levels and help with depression by improving HPA axis stress response, elevating the serotonergic precursor-tryptophan, and having an anxiolytic effect. Deficiency of intestinal Bifidobacteria has been linked with indigestion, vitamin B12 deficiency, dysregulated immune system, gut inflammation, depression, and anxiety-like behavior in individuals suffering from NDDs (; Y.; ). Moreover, in NDD patients, there is a significant decrease or complete absence of Bifidobacteria, while no such case was observed in any of the control subjects. An association between the total SCFAs level and abundance level of Faecalibacterium, Ruminococcus, and Bifidobacterium was found, whereby R. champanellensis and F. prausnitzii are present in lower abundance in the patients, with several other strains from the genus Bifidobacterium. Desulfotomaculum guttoideum, Romboutsia ilealis, and Intestinibacter bartlettii are the microbial sp closely related to Clostridium clusters were commonly found in the NDD patients. Moreover, microbes classified under genera Bifidobacterium and Ruminococcus cannot self-produce SCFA butyrate but can induce the production of SCFAs because of their ability to digest undigestible carbohydrates. They can induce butyrate production by providing substrates for butyrate-producing microbes in the colon area. SCFAs are important molecular intermediaries of the gut-brain axis, suggesting their involvement in developing autism-like symptoms. Lower numbers of SCFA-producing bacteria, particularly the butyrate-producing bacteria in the affected individual’s gut, have been reported to exert a substantial impact on the etiopathology of NDDs. One of the microbial species, namely Dialister invisus, is isolated from the oral cavity usually present in the gut microbiota of healthy humans, and a decrease in its abundance has been noticed in the NDD patient group. This depicts that the variance in general commensal microbes in the NDD patients is significantly lower, with an abundance of potentially harmful bacteria than the healthy control group. Besides, people suffering from NDD commonly suffer from gut microbiota dysbiosis. However, there is a difference between the type of microbial richness and diversity within the gut microbiota and its association with different NDDs. Tables 1–3 provide a detailed summary of gut microbial abundance and altered cytokine levels in the case of NDDs.

24Evidence suggests that dysregulated inflammation may be at the root of deficits that occur in numerous neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. Correlation between inflammation and NPDs in children has been gaining interest increasingly due to the harmful effects of inflammation on neuronal plasticity, neurogenesis, and overall neuronal development (; Nona M.; ). Inflammatory molecules affect brain development via interacting with MHC class-I molecule, glial cells, monoamine metabolism pathway, and HPA axis (Nona M. ). In addition, immune cells, including B-cell, T cells, and macrophages, play a crucial role in the processes of brain development and are responsible for the onset of NPD. Besides B-1a cell, one of the B-cell subtypes prevalently localizes to the neonatal brain in response to choroid plexus, reportedly involved in oligodendrocyte maturation in the developing brain. However, in normal physiological conditions, B-1a cells preferentially localize in the intra-peritoneal cavity and participate in the neuro-immune defense system against any pathogenicity through the innate immune capability to secrete IgM antibodies, along with suppressing neuroinflammation, hence maintaining the neuroimmune homeostasis of the developing brain. Likewise, T-cells producing interferon-γ (IFN-γ) and IL-4 have been reported to regulate neuronal connectivity, development of cognitive, social behavior, and learning-related memory, respectively. The complete absence of T-cells in nude mice shows significant impaired neurogenesis and brain dysfunctionality. Additionally, M2 macrophages subtypes are known to secrete neurotrophic factors such as IL-4, IGF-1, and upon induction BDNF, which promotes hippocampal neurogenesis, neuronal survival, and enhancement of spatial memory. IGF-1 and IL-4 are also produced by microglia and T cells, respectively. Also, perivascular macrophages support BBB development by providing pericytes progenitor cells.

25Throughout the pregnancy, the maternal immune system and a fetal-placental immune response protect both mother and fetus in coordination with each other via systematic expression of various immune receptors that recognize diverse extra/intracellular pathogen and related products. And with pathogenic encounters, effectively produce a moderated inflammatory response, downstream signaling pathways related to pathogen clearance along with the secretion of antimicrobial peptides, and Indoleamine 2,3-dioxygenase (IDO) that are directly involved with pathogen clearance at the uterine-placental interface. Thus, the immune system is likely to be present in an activated state rather than in the modulated state. And any case of immune alteration during this period can result in an increased susceptibility towards microbial and parasitic infections. This may trigger the fetal inflammatory response syndrome (FIRS) and results in an increased cytokine level of IL-1, IL-6, IL-8, and TNF-α, which has reported an increased risk of fetal developmental abnormalities. Moreover, human studies have also demonstrated a significant correlation between MIA, FIRs and the development of neurodevelopmental psychiatric disorders such as ASD, schizophrenia, neurosensorial deficits, ADHD, and psychosis in early as well as in the later period of adulthood.

26Further, research in the experimental mouse model has characterized high pro-inflammatory cytokine levels in the blood and amniotic fluid upon immune stimulation during pregnancy. It may likely contribute to the immunopathology of NDDs in their offspring. Certain inflammatory and immune-related conditions specific to particular NDD conditions, associated with inflammation induced by MIA, FIRS induction, nvolved in the development of NDD in offspring. Tables 1–3 provides a detailed summary of elevation and downfall in cytokine level during the inflammatory conditions in NDDs. The association of well-known neurodevelopmental-psychiatric disorders with inflammation and gut microbiome are discussed below.

27Children with ASDs show a range of communication problems like lack of interest in social involvement, trouble expressing their feelings, and mostly avoiding physical contact, with trouble in speaking tendency. In addition, abnormality restrictive and repetitive behaviors, like aligning toys, flapping hands, swinging their body, or revolving in circles, have been the hallmarks of ASD (S. H. ). Around 80% of the children with ASD suffer from GI symptoms that include dyspepsia, abdominal pain, and constipation. The main reason for these severe GI problems could be the disruption of the gut microflora. In a recent study, restrictive food preference-based diet has also been linked with dysbiosis and decreased gut microbial diversity in children with ASD. Whilst the gut microbiome can regulate dietary preference, food choices as well as eating-related behavior, and a healthy gut microbiome is associated with healthy food choices. Moreover, during pregnancy, dysbiosis of the maternal gut effectively alters gut-microbial diversity and immunity in the offspring, bringing an early onset of NDD. Additionally, altered immunity and inflammation also cause dysbiosis.

28Increasing evidence supports an association between gut microbiota dysbiosis and ASD. Through culture methods, aggressive forms of Candida species have been identified in the stool samples of 57% of children suffering from ASD compared to healthy controls. Investigation of correlation between microbiome and ASD revealed that Clostridium histolyticum, a pathogenic anaerobic bacterium (Clostridium clusters I and II), was highly abundant in the fecal microbiota of ASD individuals. Several research groups have also detected an overgrowth of Clostridium sp. in the microbiota of children with autism. Erysipelatoclostridium ramosum was isolated from the fecal specimens of autistic children. Clostridium tetani produce a neurotoxin p-cresol and other toxic metabolites (phenols and indole derivatives) that cause anxiety-like behavior. Clostridium bartlettii is known to synthesize trans-3-indole acrylic acid (IAA), and by glycine conjugation, it can get converted into Indolyl-3-acryloyl glycine (IAG), which is a speculative ASD urinary diagnostic marker. Overgrowth of these kinds of microbes has been associated with ASD pathology. Abnormality in sulfur metabolisms, such as the decline of serum sulfur in blood with a higher urinary excretion, decreased trans-sulfuration, and reduction in methylation capacity, in addition to chronic oxidative stress, have been detected in children with autism. This may be due to an increase in another sulfate-reducing organism, D. guttoideum, similar to Desulfovibrio. In addition to Chloristidium cluster bacteria, Sutterella, associated with gut-immune homeostasis, and GI symptoms, has been found closely related with the intestinal epithelial layer among autistic children while absent in controls (B. L. ). Moreover, a particular relation between microbes Actinomycetaceae, Allisonella, Barnesiella, Coprobacter, Fusobacterium, Olsenella in ASD individuals and constipation have been observed. In contrast, there was an increase in Holdemanella in the case of ASD without associated constipation. The microbiome of ASD individuals represents a phylum level ratiometric increase in Firmicutes/Bacteroidetes due to a significant increase in Firmicutes and a reduction in the abundance of Bacteroidetes. A lower abundance of Eubacteriaceae, Erysipelotrichaceae, Faecalibacterium, Peptostreptococcaceae, Ruminococcaceae, and Streptococcaeceae, has been reported at a taxa level. At the family level, a considerably higher abundance of Bifidobacteriaceae, Lactobacillaceae, Enterobacteriaceae, and Veillonellaceae have been observed. At the genus level, there was a significant increase in Bifidobacterium, Bacteroides, Bacillus, Biophila, Faecalibacterium, Lactobacillus, Lachnospira, Lactococcus, Lachnobacterium, Megamonas, Megasphera, Mitsuokella Oscillospira, Parabacteroides, Sutterella, Collinsella, Corynebacterium, and Dorea. A lower abundance of genera Streptococcus, Veillonella, Escherichia, Alistipes, Dialister, Parabacteroides were observed in autistic children. Additionally, Yap et al. reported a specific decline in Romboutsia timonensis abundance, especially in the gut microbiota of ASD children. Furthermore, SCFAs are crucial for maintaining BBB integrity and essential during the process of brain development, with proper maintenance of the functional intestinal epithelial barrier. SCFAs like butyrate, propionate and acetate solely or in combination with others can stimulate the tight junctions (TJ) formation. Especially butyrate regulates the formation of BBB. Further, butyrate and propionate exert a strong epigenetic effect over-regulation of the gene expression profile of neurotransmitter systems, neuronal cell adhesion molecules, inflammation, mitochondrial function, oxidative stress, and lipid metabolism. All these have been reportedly associated with the development of ASD. Lower SCFAs levels may disrupt epithelial barrier function in the intestine, and BBB thus increases the permeability as reported in ASD patients. Decreased SCFAs levels in the gut can be related to the absence of potential SCFA-producing bacteria in ASD patient microbiota. Assisting all these reports, lower Bifidobacterium sp. levels were found in children with autism.

29Cytokines regulate immune response and are interestingly involved in neuronal development synaptic functions, differentiation, migration, proliferation, and behavioral impairments. Neuropoietic cytokines such as IL-6, IL-1β, and TNF-α have been reported to exert direct influence on the cortical neuron, dendrite development, neural activity, long-term potentiation, neurite outgrowth, regulation of synaptic plasticity in the hippocampus, overall neurodevelopment as well as behavior. Dysregulation in the cytokine levels creates disturbances in immune homeostasis, which potentially contribute to communication and behavioral impairment at the neuronal level in early childhood and, upon becoming severe, can give rise to NDDs like ASD (; H. K.; ). In children with ASD increased number of monocytes and plasma concentrations of IL-8, TNF-α, IL1β are observed, which indicate an abnormal inflammation condition. Increased plasma concentration of IL-8 has been reported as a result of increased IL-17 released by activated Th17 cells in response to epithelial and endothelial infections. Immune dysfunction in ASD patients like abnormal T helper cell profile, increased concentration of complement factors, pro-inflammatory interleukins (IL-1β, IL-6, IL-12p40), TNF-α, and a decreased level of Transforming growth factor β (TGF-β) have been reported to cause acute inflammation analogous to ASD condition. Abnormal cytokine levels have been associated with poor health and communication, impaired social interaction, poor cognition/memory, and behavioral and neuronal dysfunction in ASD. Further, more studies conducted in children with ASD have revealed an elevated plasma level of IL-1β, IL-6, IL-17, IL-12p40, and IL-12p70, including both Th1 and Th2 cytokines, with down-regulation of IL-2. There also has been a report suggesting a sex-specific correlation of cytokine expression profile. According to which the mRNA expression level of TNF-α has been linked with expression of TGF-β, INF-γ, IL-17, and IL-6 in the case of males, whereas it's not the case with the females. Besides, reports also show a difference in cytokine expression profile as per the disease severity in children with ASD. At a mildly severe condition, there is an elevation in plasma level of IL-12p40. In contrast, patients with moderate disease severity have higher plasma levels of TNF-α, which explains the correlation of disease severity with increased plasma concentration of TNF-α.

30In addition to all these inflammatory factors that contribute to ASD pathology, dysregulation in the maternal immune system during pregnancy has also been implicated in the development of ASD. Fetal brain reactive antibody, autoimmunity, or IgG antibody from mother can cross the placental barrier, thus entering into the fetal compartment where they can interfere with the developmental process by recognizing self-proteins. Also, in the fetus brain, the BBB is not fully formed or functional. Therefore, the probability of immune-complexes and inflammatory mediators in action can reach the brain stem by crossing the BBB, contributing to microglial activation and neuronal inflammation eventually. Neuroinflammation within the CNS is also associated with severe disease conditions in ASD. Animal and human studies have suggested an elevated IL-6 expression in the autistic brain, causing anatomical aberration. Such overproduction of IL-6 can alter synapse formation and neurotransmission along with distorted patterns and distribution of dendritic spines. Moreover, the ASD animal model studies showed systemic inflammation with up-regulated IL-β, IL-6, IL-18, IL-33, IL-17, and TNF-α along with microglia activation and neuroinflammation principally contributing to the pathological mechanisms of ASD.

31Attention-deficit/hyperactivity disorder is commonly characterized by persistent inattention and hyperactivity-impulsivity onset during childhood. Genetic factors, streptococcal infection, and environmental factors have a close association with ADHD. However, dopamine (DA) deficiency and an altered level of norepinephrine (NE), serotonin, GABA has also been proposed for ADHD, including a decline in cortisol level, indicating disruption of the HPA-axis as well. The microbiota has an important role in the development of the HPA-axis, and individuals with ADHD experience an imbalance in their microbiota and a reduced microbial diversity and composition, which resulted in lower levels of cortisol to cause improper management of the HPA-axis stress response. Children with ADHD unusually have a higher load of the family Bacteroidaceae, Neisseriaceae differing from a higher level of Prevotellaceae, Catabacteriaceae, and Porphiromonadaceae in the control group. An increased microbial load of family Neisseriaceae and Bacteroidaceae has been reported causing a significant decline in the gut microbial diversity in ADHD. At a family level, the ADHD-specific fecal microbiome represents a substantial rise in the richness of Moraxellaceae, Peptostreptococcaceae, Peptococcaceae, Xanthomonadaceae, and a firm decline in Alcaligenaceae. While, at a genus level, Dialister, Faecalibacterium, Lachnoclostridium, and Sutterella were the major representatives that brought the differences among children with and without ADHD, respectively. Besides, a certain group of gut microbiota can synthesize neuroactive monoamine molecules (dopamine, noradrenaline, serotonin, GABA) and its precursors (phenylalanine, tyrosine, tryptophan) that are involved in ADHD pathomechanism. These microbes also induce intestinal epithelial cells to synthesize neuroactive compounds and indirectly control the neurotransmission system to have a crucial impact on brain functioning and behavior (; Y.;; ). In a study including 28 participants, functional magnetic resonance imaging (fMRI) revealed a nominal increase in the genus Bifidobacterium in ADHD. This increase has a significant association with enhanced bacterial gene functionality that encodes the enzyme cyclohexadienyl dehydratase, an enzyme involved in the phenylalanine (a dopamine precursor) synthesis pathway. Phenylalanine can cross the BBB and regulate dopamine synthesis positively or negatively by inhibiting tyrosine hydroxylase during dopamine synthesis. Dopamine deficiency can cause decreased neural responses to reward anticipation, which is one of the hallmarks of ADHD. On the other hand, diminished Bifidobacterium population during early childhood has been correlated with a greater risk of developing ADHD. Bacillus macerans can synthesize dopamine, as it possesses an enzyme called cyclomaltodextrin glucosyltransferase or CTGase, a key enzyme to produce dopamine. Deficiency and decrease in abundance of such microbes in gut microbiota may contribute to stress, depression, and anxiety-like behavior that has been witnessed in ADHD. In individuals with ADHD, altered serotonin levels have been linked with abnormal cognitive function and various other processes during neuronal development. Studies have demonstrated that gut microbes regulate the serotonin (5-HT) levels in the colon and blood, while the GI tract contains the majority of total serotonin present in the body either as 5-hydroxytryptamine or 5-HT. Microbes in the colon produce certain metabolites that stimulate the chromaffin cells to increase Tph levels and 5-HT biosynthesis. The serotonergic system resolves brains involvement in stress, anxiety, and depression. Specific gut bacteria can produce important inhibitory neurotransmitters gamma-aminobutyric acid (GABA). Moreover, Bifidobacterium and Lactobacillus can produce GABA, while Streptococcus sp. and Enterococcus sp. which produce serotonin, are less abundant in the fecal microbiota of ASD and ADHD patients. Another study showed an increase in Alistipes and Oscillibacter and a significant decrease in Bacteroidales in depressed individuals. Bacteroidetes has been associated with obesity previously, which is again associated with depression and mild inflammatory conditions. In addition, the genus Oscillibacter produces a metabolic end-product valeric acid, which is structurally similar to gamma-Amino Butyric acid (GABA). As a structural homolog of GABA, it can also bind to GABA receptors, facilitating increased inhibitory neurotransmission. This signifies the correlation of intra-microbiome coordination with depression and anxiety-like behavior in NDDs such as ADHD.

32ADHD is reported to be immune-associated with an acute inflammatory response that emerges during childhood. Immune-associated genetic factors and heritability have been the most common cause of ADHD, estimated at around 70–78%. Most potentially genetic polymorphism of cytokine genes IL-6 and tumor necrosis factor-alpha (TNF-α) has been found in ADHD patients. Moreover, cytokines play a significant role in tryptophan metabolism and dopaminergic pathways in the brain. Therefore, in the case of ADHD, an alteration in proportional expression of pro-inflammatory and anti-inflammatory cytokine can alter the required level of monoamine neurotransmitter. Administration of IL-6, IL-2, IL-1β caused altered neurotransmission in the rodent model due to increased norepinephrine and decreased dopamine level, resembling the ADHD condition. Also, in ADHD patients, there is an increased expression of innate pro-inflammatory cytokines like tumor necrosis factor-α (TNF-α) and a reduction in expression of anti-inflammatory cytokines like IL-4, IL-2, and INF-γ. These pro and anti-inflammatory cytokine alterations can induce microglial activation and neuroinflammation. The activated microglia release more pro-inflammatory cytokines and other associated factors, contributing to chronic neuroinflammation. During the prenatal period, the peripheral and neuroinflammation alone or in combination may interfere with the maturation of the prefrontal cortex and neurotransmitter system, such as the dopaminergic system, which increases the risk of developing ADHD in offspring. Dopamine deficiency in CNS is one of the well-reported pathogenesis hallmarks of ADHD. Moreover, allergic diseases that are considered high inflammatory disorders are also reported to be associated with ADHD.

33SCZ is a chronic, heterogeneous neurodevelopmental psychiatric disorder with multifactorial involvement of genetic and epigenetic disturbances, gut microbiome alteration, immune system dyshomeostasis, and environmental influence correlated with hallucinations, delusional thoughts, perturbing mental awareness, and social interaction. The disorder commonly involves continuous or intermittent occurrences of paranoia, with positive, negative, and cognitive psychotic symptoms. The positive symptoms include hallucinations, unsystematic speech patterns, and cataleptic behavior based on the excessiveness of normal function. In contrast, the negative symptoms involve a reduction in normal physiological processes, such as lack of emotions or interest, poor speech, aimlessness, and cognitive impairments, which comprise poor retention of verbal information and confusion. SCZ is thought to begin in utero and is associated with prenatal famine, poor pregnancy, fetal growth conditions, emergency C-section delivery, and low birth weight. The functionalities of bidirectional gut-brain communication are related to emotional and cognitive centers such as the central nervous system, peripheral nervous system, enteric nervous system, and enteroendocrine system. Dysregulation might hold implications over the occurrence and etiology of SCZ.

34As in ASD, Schizophrenic individuals suffer high rates of GI problems like gastroenteritis, colitis, irritable bowel syndrome (IBS) and are mostly at high risk for emergence of hyperglycemia/diabetes, obesity, hypertension, and cardiovascular disease. Such metabolic disorders are strongly associated with microbiota dysbiosis, including neuropsychiatric disorders such as SCZ. Furthermore, the comorbidities of metabolic disorders in SCZ and enrichment of the specific gut microbes may disrupt brain white matter, causing the manifestation of negative symptoms and cognitive functional anomalies. Alteration in the gut microbiota is associated with a decreased species diversity within the microbiota in SCZ.

35There is an increase in the abundance of oropharyngeal microbial species like Bifidobacterium dentium, Lactobacillus oris, Veillonella atypica, Dialister invisus, Veillonella dispar, and Streptococcus salivarius in schizophrenic individuals than in healthy controls (Zhu et al., 2020; ). Whereby the increased abundance of genera Streptococcus and Veillonella have positive cross-correlation, which also indicates a close association between the intestinal and the buccal microbiota in SCZ (Zhu et al., 2020). The increased translocation of oral microbe can be linked with disrupted the mucosal barrier, giving rise to leaky gut, pathological intestinal conditions, and decreased immune surveillance towards foreign microbes in SCZ patients (Zhu et al., 2020). Schizophrenic patients harbor a unique combination of facultative anaerobes, including Lactobacillus fermentum, Alkaliphilus oremlandii, Enterococcus faecium, and Cronobacter sakazakii/turicensis, that are usually not present in a healthy gut (Zhu et al., 2020).

36An elevated phylum level of Proteobacteria characterizes the schizophrenic microbiome. Particularly, with a substantial rise in genera Methanobrevibacter, Clostridium, Collinsella, Succinivibrio, Klebsiella, Megasphaera, with a decrease in Coprococcus, Blautia, and Roseburia, which also has been associated with disturbed metabolic pathways like fatty acid, vitamin B6 metabolism in SCZ. Contrarily a decline in phylum Proteobacteria, family Rumimococcaceae, genus Haemophilus, Sutterella, and Clostridium have been reportedly associated with disease progression. In contrast, increased Anaerococcus and Bacteroids has also been reported in such schizophrenic conditions. The relative decrease in Rumimococcaceae is directly related to negative symptoms, and increased Bacteroids have been reported in association with the increase in the symptoms of depression in SCZ patients. Moreover, in the early stages of the disease, an increase in Lactobacillaceae, and at a later stage, bacterial taxa Lachnospiraceae and Veillonellaceae have been linked with the disease severity in SCZ. Higher Clostridiales, Lactobacillales, Bacteroidales suggest an overlap between altered microbiome with those identified in SCZ and ASD.

37Moreover, the increase in diversity of the microbes in the blood can be related to the indefinite overall increase of microbial load in SCZ. The blood microbiota is thought to emerge from the gut and the buccal cavity. Schizophrenic patients suffering from GI inflammation and IBS have been reported to have elevated levels of anti-Saccharomyces cerevisiae antibodies (ASCA), used for diagnosis of Crohn’s disease. Zhu and co-workers reported 11 bacterial species (Table. 3) that were significantly enriched and have been particularly associated with symptom severity and poor cognitive performance in SCZ (Zhu et al., 2020). Again, the frequency of Clostridium difficile infection has been highly related to the schizophrenic patient population. Zheng et al. reported an increased abundance of Acidaminococcus, Akkermansia, Alistipes, Citrobacter, Dialister, Veillonella in SCZ. In addition, a metagenomic study in SCZ patients revealed a strong association of 12 increased taxonomic abundant groups including Deltaproteobacteria, Actinobacteria, Sphingomonadales, Actinomycetales, Sphingomonadaceae, Megasphaera, Eggerthella and, Megasphaera elsdeniis, Clostridium perfringens, Akkermansia, muciniphila, Lactobacillus gasseri, and Bifidobacterium adolescentis, along with 7 decreased taxonomic groups including Rhodocyclales, Enterococcaceae, Rikenellaceae, Alcaligenaceae, Rhodocyclaceae, Leuconostocaceae, and Enterococcus in comparison to age and sex-matched healthy controls.

38A decrease in diversity of family Erysipelotrichaceae and genus Allobaculum, along with a dysbiosis, has been reported in the metabotropic glutamate receptor 5 (mGlu5) knockout mice model of SCZ. Further, a significantly low level of Bifidobacterium, Lactobacillus, E. coli, and a higher level of Clostridium coccoides were reported in fecal samples of SCZ individuals compared to healthy subjects. However, treatment with either olanzapine or risperidone was reported to alter the level of Akkermansia, Sutterella, and Lachnospiraceae with a considerable increase in Bifidobacterium, E. coli and a decrease in fecal Clostridium coccoides and Lactobacillus compared to untreated. Studies have shown that prenatal and inherent microbial infections in neonates can increase the risk of developing SCZ. Infection by Helicobacter pylori is associated with nutrient malabsorption during childhood and induces disruption in biochemical homeostasis, which may play an essential role in the pathogenesis of SCZ. Toxoplasma gondii infection during pregnancy is positively associated with SCZ in offspring. Moreover, Streptococcus vestibularis has been considered a microbial biomarker of SCZ that can induce deficits in social behaviors, alteration in neurotransmitter levels (Zhu et al., 2020), hyperactivity, cognitive impairments associated with SCZ.

39SCZ is associated with the aberration of various physiological pathways involving dopamine, glutamate, and γ-aminobutyric acid (GABA) signaling, synthesis of SCFAs like butyrate, acetate, propionate, and isovaleric acid, tryptophan metabolism, and synthesis of several neurotransmitters (glutamate, GABA, and nitric oxide). Alteration of which are associated with symptoms, such as depression, anxiety, and pathophysiology of SCZ, which again can be related to the alteration of gut microbial diversity in SCZ. Experimental, fecal transfer from SCZ patients into the GF mice gut induces SCZ-related behaviors resembling glutamatergic hypo-functionality related SCZ mice model behavior in receiver mice with observably distorted glutamate, glutamine, and GABA ratio in the hippocampus region of the brain.

40Aberration in glutamatergic signaling system-related genes is closely associated development of SCZ. Meanwhile, Glutamate synthase (GOGAT), validated as SCZ gut marker, an increase in expression and activity in SCZ patients is co-related with a characteristic decrease in gut microbial diversity and an altered IgA related mucosal immunity as compared to healthy controls.

41Tryptophan metabolism is one of the essential pathways for the maintenance and homeostasis of gut microbiota and disturbances have been reported to contribute to the pathophysiology of SCZ. Tryptophan is metabolized chiefly through the kynurenine pathway, and schizophrenic individuals are reported to have high serum kynurenine metabolites and low serum tryptophan levels (Zhu et al., 2020; ). A study involving fecal microbiota transplantation from drug-free SCZ patients into SPF mice reported an alteration of the kynurenine metabolic pathway and schizophrenic behavior in receiver mice. This alteration in tryptophan and kynurenine pathway metabolite level is directly associated with the gut-microbiota alteration and enrichment of schizophrenic specific microbes (Zhu et al., 2020). The translocation of microbes along with microbial components like LPS into the bloodstream due to gut dysbiosis as well as increased gut epithelial barrier integrity may be inducing systemic inflammation, that consequently leads to neuroinflammation, neurological impairment, and apoptosis, leading to immune-mediated development of SCZ. In addition, SCFAs have a direct role in anxiety and behavioral changes such as antisocial, repetitive, ritualistic behaviors associated with neuropsychiatric disorders like obsessive-compulsive disorder hyperactivity in SCZ. Furthermore, the reported elevation in microbial translocation marker sCD14 has been correlated with a reduction in butyrate-producing species Roseburia and Coprococcus with increased inflammation and CNS infections. SCFAs also indirectly regulate DNA repair mechanisms by reducing the excessive activity of histone deacetylases (HDACs) in schizophrenic conditions, and reduced levels can negatively affect the diseased condition, suggesting an additional indirect role of SCFA in SCZ.

42SCZ affects approximately 1% of the worldwide population. The complex interaction between genetic and environmental risk factors manipulates the immune system to cause inflammation, disruption of neuroimmune homeostasis, chronic neuroinflammation, and neurodevelopmental disturbances in SCZ. The risk factors include genetic anomaly, MIA, maternal infection, gut dysbiosis, early-life stress, and exposure to pollution, resulting in the dysfunctional BBB and microglial function that leads to neuroinflammation that gives rise to the onset and progression of SCZ. The characteristic brain damage in SCZ starts in the early periods of life manifests later in the lifetime. The disease symptoms usually appear in late adolescence and early adulthood.

43Genome-wide association studies have revealed genetic polymorphism of immune-related genes in SCZ etiopathophysiology. For example, genetic polymorphisms of C4 complement factor, major histocompatibility complex (MHC) locus on chromosome 6, interleukin-1β, IL-6, the soluble IL-6 receptor (sIL6R), and IL-10 are associated with increased risk of SCZ. In contrast, polymorphism of IL-2, IL-4, tumor necrosis factor-α (TNF-α), or transforming growth factor- β1 (TGF-β1), are not associated with increased risk of SCZ. In addition, CD19 and CD20 genes associated with B-cell the onset of SCZ. Genetic aberration in oligodendrocyte and myelination-associated genes also have been detected in schizophrenic patients. Moreover, a significant rise of CD5+ B-cell is reported blood of schizophrenic individuals. This suggests a crucial contribution of B-cell functionalities in immunity, oligodendrogenesis, and myelination during brain development. A B-cell dysfunctionality was reported in pathophysiology and increased vulnerability in SCZ.

44However, a higher blood level of acute-phase reactant CRP is negatively correlated with a decreased risk of SCZ, and higher soluble IL-2 receptors (sIL-2R) levels indicate an increased risk of schizophrenic events. Increased expression of complement protein C4A involved in microglia-mediated synaptic pruning has been reported to reduce connectivity/sociability, which contributes directly to pathophysiology in SCZ. In addition, variation in structural alleles of C4 poses an increased risk for autoimmunity and sex-specific vulnerability in SCZ in males. A blood spot study on 892 newborns revealed increased C4A complement protein levels; those later developed SCZ. CUB and sushi multiple domains 1 (CSMD1), expressed at the time of early perinatal development, which regulates C4 protein expression and a genetic disruption or pathway dysregulation may lead to deficits in average cognitive aptitude and management ability in SCZ.

45Any deviation in expression of cytokines involving elevation in interferon regulatory factor 3 (IRF3) (crucial transcription factor during viral infection) (X. ), IFN-γ (regulates viral multiplication), pro-inflammatory IL-1α, IL-1β, IL-6 and anti-inflammatory IL-10, along with elevated mRNA levels of CRP, IL-6, IL-1β, TNF-β, and TGF-β, have been reported in SCZ individuals. Immune receptors like MHC receptors that are involved in immune surveillance and Toll-like receptors (TLRs) that engaged in cognition of microbe-derived molecular signals by innate immune cells and microglia, early brain development (; C. Y.; ), synaptic plasticity and neurogenesis have been found altered in either the blood or post-mortem brain tissue of SCZ individuals. A disruption in gene disrupted-in-schizophrenia- 1 (DISC1) was discovered in a Scottish family affected with SCZ and later worldwide. Such genotypes disrupt the immune system network, thereby inducing inflammation, suggesting a dysfunctional immune-related gene and inflammation co-ordinately contributes to the pathophysiology of SCZ. MIA during pregnancy has reportedly caused an increase in mesencephalic dopaminergic neurons in the foetal brain, which is associated with excessive dopaminergic signaling in the midbrain area in SCZ. Besides, in utero MIA precondition offspring exhibit, a triggered HPA-axis stress response when exposed to cannabinoids in adolescence and exhibit SCZ associated behavior in a sex-specific manner with a remarkable decline in Bifidobacterium longum gut abundance. Exposure to viral or bacterial pathogens in-utero also has been reported to enhance the risk of developing SCZ. Maternal infection with Toxoplasma gondii, influenza, rubella, and Borna disease virus intensely increased the risk factor for SCZ. Moreover, autoimmune disorders, prenatal infections, and childhood exposure to different viruses, Toxoplasma gondii infection respiratory infections, genital or reproductive tract infections,, and other infections, have been reported to induce, behavioral and cognitive dysfunction and overall increased risk of development of SCZ in the offspring.

46Unmedicated SCZ patients have a specific cytokine expression pattern with an abrupted type 1 IFN-γ, IL-2, sIL-2R, and a complimentary increase in type 2 cytokine pattern IL-6 and IL-10, indicating an imbalanced type 1 and type 2 immune responses in SCZ. An increased IL-8 level during the prenatal period is also associated with decreased brain cortex volume and increased ventricular volume in the schizophrenic progeny. In addition, genetic risk for elevated expression of the immune marker IL-1β has been linked to brain volume loss. A recent study in SCZ patients has revealed increased serum cytokine levels of IL-6, IL-8, and IL-10, substantially associated with the cortical volume in the orbital frontal cortex, cingulate cortex, and frontotemporal gyrus. Increased level of IL-6 is associated with resurfacing SCZ associated factors preconditioned before birth (D. ). Also, IL-6 has a strong influence on the decreased survivability of serotonergic neurons in the fetal brain, and IL-1β has been reported to induce the differentiation of mesencephalic progenitor cells into dopaminergic neurons in the animal model. This is relatable to the potential impact of cytokines on the establishment of neurotransmitter systems in schizophrenic conditions. Further, higher blood levels of IL-6 in early life have been associated with an increased risk of experiencing psychotic episodes with manifestations of fulminant psychotic disorder at age 18. IL-6 and IL-17 may bring on the poly (I: C), an immune stimulant in the MIA model, which affects the fetal brain (; S. E. P.; ). Studies show associations of higher CRP levels with elevated serum IL-6 with a significantly altered cognition in chronic and first-episode SCZ, along with poor verbal and learning memory, poor management skills, and disrupted psychomotor speed. Also, CRP levels have a significant positive correlation with BMI. In contrast, a negative correlation with HDL levels in psychosis periods and higher CRP levels are associated with increased waist circumference in males compared to sex as well as age-matched patients. In addition, higher IL-6 and hs-CRP levels were notably positively correlated with BMI only in females (C. W. ). Psychotic patients with an increased CRP level are most likely to have metabolic syndrome. A meta-analysis revealed that increased inflammatory marker CRP, IL-8, and IL-10 in maternal blood during pregnancy, associated with higher risks, along with an early sign and symptoms in SCZ, suggesting prenatal inflammation alter the brain development process in the fetus, with increased susceptibility to SCZ. CRP has essentially been correlated with negative symptoms and psychopathology, whereas IL-18 has been positively associated with total and general psychopathology in SCZ (B. ). In clinically high-risk patients, there has been a reported increase in CRP, IL-6, IL-4, IL-12, and a decrease in IL-1β, IL-10 (anti-inflammatory cytokine). A higher concentration of IL-12/IL-23p40 was detected in particulars who started to experience psychosis.

47In Patients with the first episode of psychosis (FEP), considerably higher levels of IFN-γ and IL-12 were inversely correlated with whole-brain grey matter. Also, IL-12 is the only inflammation marker associated with the transition into psychosis in clinically high risk (CHR) individuals. However, unlike CHR individuals, IL-1β and IL-10 are elevated in individuals with FEP than controls. An increased concentration of IL-6 and decline of IL-17 in serum has been revealed in individuals at ultra-high risk (UHR) for psychosis, which explains the association that increased IL-17 levels can improve disease condition. And the expression of TNF-α has also been found to worsen the negative symptoms. Collectively individuals with FEP and chronic psychosis has been found elevated cytokine levels, including IFN-γ, IL-1 receptor antagonist (IL-1RA), IL-1β, IL-6, IL-8, IL-10, IL-12, sIL-2R, TGF-β, and TNF-α. However, among all IL-6 and TNF-α, levels were considerably higher in FEP individuals relative to healthy controls. Unlike FEP individuals, the IFN-γ level was lower in chronic outpatients. Moreover, a meta-analysis study revealed an elevation in IL-1b, sIL-2R, IL-6, and TNF-α in FEP is independent of antipsychotic treatment. Further inflammation has also been correlated with suicide. As in psychotic patients with mood disorders, increased serum levels of IL-1β and IL-6 have been detected in blood and autopsy brain samples from suicidality compared with both SCZ non-suicidal patients and healthy controls. SCZ patients who committed suicide had an extreme rise in microglial density inside the dorsolateral prefrontal cortex, anterior cingulate cortex, mediodorsal thalamus, along with a course of hippocampal microgliosis, which explains an extreme and hazardous level of neuroinflammation can induce suicidality in SCZ.

48Furthermore, air pollution has also been reported to induce inflammation associated with SCZ pathogenesis. Interestingly, immune genes, most importantly microglia expressed genes, play a central role in the immune system’s interaction with pollution. Exposure to traffic-related air pollution (TRAP) revealed an elevated pro-inflammatory cytokine, IL-6, IL-1ß, CD14, and TNF-α in children, when compared to children living in more eco-friendly areas. Additionally, polluted air evoked an identical inflammatory cytokine profile in a healthy young population, with a characteristic increase of IL-6 and an increased frequency of inflammatory cells and related microparticles, which may indicate endothelial injury. Moreover, in animal models, TRAP exposure showed an elevated expression of IL-1α, IL-6, and TLR4 in the brain. TRAP specifically influences the microglial TLR4 signaling in a MyD88-dependent pathway. In male children, this interactive inflammatory signaling is subsequently followed by circumstantial and auditory cue fear conditioning and anxiety along with behavioral deficits. With such a condition, prolonged brings harmful consequences like altered synaptic plasticity altered brain development and function, featured on MIA models of SCZ.

49Treatment of NPDs with the drug has been challenging due to the involvement of diverse etiopathology, where drug resistance is posing a threat to the treatment due to improper counseling during treatment, post-zygotic genetic changes, unpredictable immune response, differential hormonal response, sex-specific and the dose-dependent response of the drug. The interference of drug in metabolic pathways also contribute to unforeseen development of metabolic disorders, and lastly, the drug addiction and behavioral issues in response to minimal treatment time and disease severity ensure difficulties towards drug-associated treatment. Current treatment strategies for NDDs include psychotherapy, anti-inflammatory drugs, and antipsychotic drugs with significant side effects.

50Meta-analysis studies revealed that nonsteroidal anti-inflammatory drugs hold considerable impact on schizophrenic total, positive and negative symptoms. However, this effect is only in subjects with short-term disease or first episode manifestation. Moreover, individuals with short-term (0–2 years) disease duration significantly benefited from the same treatment combined with celecoxib. In contrast, patients with longer disease duration and chronic inflammatory diseases did not differ from the placebo control. Anti-inflammatory treatment involving IFN-γ also comes with side effects, including a high risk of unexpected immune responses. Although long-term anti-inflammatory treatment in chronic SCZ has a considerable positive impact this also has been associated with higher inflammation and poorer response to antipsychotics. Exposure to psychological stressors causes alteration and fluctuation in basal cortisol levels, correlated with fluctuating psychological symptoms. Antipsychotic medication directly affects cortisol secretion. Celecoxib (cyclooxygenase-2 (COX-2) inhibitor) treatment along with risperidone has been significantly more efficient than the patients receiving risperidone alone in SCZ and had a positive effect on cognition. However, this therapeutic effect is only restricted until the first years of the schizophrenic disease progression. Risperidone (a second-generation atypical antipsychotic) treatment causes glucose dyshomeostasis and endocrine dysregulation in autistic children and young adults, bringing leptin and insulin resistance in a dose and treatment duration-dependent manner. Moreover, in children and teenagers suffering ASD, termination of medication is associated with aggressive behavior; thus, a long-life medication is suggested. Individuals receiving a high dose of risperidone treatment for the long term are at increased risk of developing type 2 diabetes mellitus.

51Further, administration of olanzapine and aripiprazole for a short duration directly impacts tissue function enhances peripheral insulin resistance, independent of weight gain in healthy people. A second-generation antipsychotic treatment including amisulpride, clozapine, olanzapine, quetiapine, risperidone has been demonstrated to be associated with increased appetite, and gain in weight may be through interacting with dopamine receptors. Besides, antipsychotic drugs administered to children and adolescents come with a risk of dyslipidemia and expression of HDL-C, and triglycerides are the main lipid biomarkers for cardiometabolic syndrome in SCZ. PUFAs such as omega-3 and omega-6 protect the neuronal cells from oxidative damage inflammation, regulate neurogenesis and preserve overall neuronal function (; S. W.; ), therefore involved in many mental health conditions and related diseases such as SCZ. In SCZ, patients have considerably low levels of omega-3 in the cell membranes. Additionally, antipsychotic treatments have been reported to decrease the PUFAs levels (S. W. ). Antipsychotics can also potentially intervene in the metabolic process and biomarker levels, including the metabolites from the kynurenic pathway.

52Twenty-four weeks of treatment with risperidone resulted in a significantly lower abundance of fecal E. coli, Lactobacillus spp. Bifidobacterium spp. when compared with healthy controls, suggesting that risperidone treatment causes a distinctive amendment in fecal microbiota, indicating metabolic changes induced by antipsychotic medication. As discussed previously, microbial species have been substantially associated with disease severity, poor cognitive performance, and diagnosis. And antipsychotic treatment can influence the gut microbiota but cannot completely reconstruct the dysbiotic microbiota related to SCZ (Zhu et al., 2020). Current microbiome therapies have shown promising results in managing NDDs and metabolic disorders. Therefore, manipulating gut microbes with enrichment of beneficial microbes to create a balance and other microbiome therapy may have duplex therapeutic potential for neurodevelopmental and metabolic disorders.

53NDDs can be readily linked with gut microbial dysbiosis and inflammatory state, which affect the development of learning, language, cognitive, motor, and behavioral skills with lifelong consequences. Early identification of infants at risk for NDDs is a prerequisite for taking therapeutic measures hypothesized in (Figure 5). There is an imbalance in Bifidobacteria sp. Lactobacillus sp. and a deficiency of potential SCFA producing microbes in the gut microbiota of individuals suffering from NDD. Treatment with the probiotic strain of Bifidobacteria sp. and Lactobacillus sp. and probiotic bacterial species to normalize the dysbiosis associated with inflammation, neuropsychological distress, GI, and behavioral problems. Moreover, treatment with B. fragilis has been reported to reduce the intestinal permeability, normalize the organization of the gut microbiota, and ease disease symptoms in the ASD mice model. Administration of probiotics, Lactobacillus rhamnosus and Lactobacillus reuteri, have improved barrier integrity and function by regulation of the tight junction proteins expression and thereby reducing the microbial translocation in-vitro or in animal models. Lactobacillus and Bifidobacteria were proven to decrease anxiety symptoms considerably. Supplementation of the probiotic formulation containing Lactobacillus, Bifidobacteria, and Streptococci has been reported to normalize the Bacteroidetes/Firmicutes ratio along with imbalanced abundance Desulfovibrio sp. and Bifidobacterium sp. in the fecal samples of autistic children, as with that of healthy controls. In addition to probiotic therapy, fecal microbiota transplantation (FMT) and microbiota transfer therapy (MTT) have been increasingly considered promising therapies in treating NDDs. FMT has been reported to treat IBD and IBS successfully, resulting in a typical gut microbiota composition in patients, improving constipation symptoms. Microbiota transfer therapy (MTT) is a kind of modified FMT. The patient goes through antibiotic treatment for 14 days and then cleans the bowel before administrating a high initial dose of systematized human gut microbiota (SHGM) for up to 7–8 weeks. MTT in a clinical trial has been reported to improve GI symptoms such as indigestion, abdominal pain, constipation, and diarrhea and symptoms related to ASD and normalized any alteration in the gut microbiota in ASD patients (D. W., ). Thus, there is increasing interest in using FMT and MTT as a therapeutic intervention for treating children with NDDs, following all the concerning safety issues.

54There is a bidirectional communication network between the CNS and the microbiome ecosystem that we possess. To understand this relationship in a more elaborative way still much has to be discovered. Disturbances in the simultaneous coordinated process of neuronal as well as gut-microbiome development due to overdoses of antibiotics in infants can lead to an inflammatory state at this critical phase of brain development. Compositional alterations in the gut microbiome can result in systemic inflammation and neuroinflammation. Moreover, the microbiome also plays an essential role in the process of microglial maturation and can modulate glial activation in CNS, which also has been considered as regulating factor of neuroinflammation in the CNS. All these events during the developmental process put up a foundation for the onset of NDDs like ASD, ADHD, SCZ, etc. Investigating intricate pathways for a brief illustration of the microbiome-gut-brain-immune axis in developing NDDs, disease onset, and progression will be beneficial towards the discovery of clinically relevant targeted biotherapies to combat the continuous rise in worldwide NDDs. The future perspective holds the exciting potential of sophisticated microbiome-based therapeutics to prevent the emergence and treatment of NDDs (Figure 5). Further studies are required to elucidate specific molecular signaling pathways associated with processes neuronal development, related disease, diagnosis, and to develop individualized microbiome therapeutics.