Gut-brain connection in schizophrenia: A narrative review

Abstract

Schizophrenia is a complex neuropsychiatric disorder characterized by cognitive, emotional, and behavioral impairments. The microbiota-gut-brain axis is crucial in its pathophysiology, mediating communication between the gut and brain through neural, immune, endocrine, and metabolic pathways. Dysbiosis, or an imbalance in gut microbiota, is linked to neuroinflammation, systemic inflammation, and neurotransmitter disruptions, all of which contribute to the symptoms of schizophrenia. Gut microbiota-derived metabolites, such as short-chain fatty acids, influence brain function, including immune responses and neurotransmitter synthesis. These findings suggest that microbial imbalances exacerbate schizophrenia, providing a novel perspective on the disorder’s underlying mechanisms. Emerging microbiota-targeted therapies—such as probiotics, prebiotics, dietary interventions, and fecal microbiota transplantation—show promise as adjunctive treatments, aiming to restore microbial balance and improve clinical outcomes. While further research is needed, targeting the microbiota-gut-brain axis offers an innovative approach to schizophrenia management, with the potential to enhance patient outcomes and quality of life.

Key Words: Schizophrenia; Gut-brain axis; Microbiota; Neuroinflammation; Probiotics

Core Tip: Emerging research highlights the critical role of the gut-brain axis in schizophrenia. Dysbiosis, or imbalances in gut microbiota, may contribute to neuroinflammation, neurotransmitter dysregulation, and blood-brain barrier disruption, all of which are central to the pathophysiology of the disorder. Targeting gut health through probiotics, prebiotics, dietary changes, and fecal microbiota transplantation holds promise as adjunctive therapies to traditional antipsychotics, offering new, integrative strategies for improving cognitive, emotional, and behavioral outcomes in schizophrenia. Further research is needed to validate and refine these approaches.

INTRODUCTION

Schizophrenia is a complex mental disorder that profoundly affects cognition, perception, and behavior. First described by German psychiatrist Emil Kraepelin in the 1890s as “dementia praecox” (early dementia), the disorder was initially viewed as a neurological condition characterized by cognitive and motor impairments[1,2]. It affects how a person interprets reality, often leading to hallucinations, delusions, disorganized speech, and cognitive dysfunction. Schizophrenia typically emerges in late adolescence or early adulthood and requires long-term management, including medication and psychosocial interventions[2]. Mental disorders disrupt daily life, limiting social and physical abilities, and their global prevalence is rising. Recent studies suggest a link between schizophrenia and the gut-brain axis, a bidirectional communication system between the gut microbiota and the central nervous system (CNS)[3,4]. The gut microbiota, a complex microbial community in the gastrointestinal (GI) tract, is essential for human health, for supporting immune development, vitamin synthesis, and protection from harmful bacteria[5]. Disruptions in gut microbial balance, influenced by factors such as diet, medication, and stress, may contribute to schizophrenia by affecting neuroinflammation, neurotransmitter production, and immune responses[6,7].

The relationship between schizophrenia and the gut-brain axis has garnered significant interest, particularly how gut microbiota-produced metabolites, such as short-chain fatty acids (SCFAs), affect brain function[8]. Emerging evidence suggests that gut microbiota-produced metabolites, including SCFAs, influence CNS function by modulating microglial activity and cytokine production[9]. Additionally, gut bacteria contribute to the synthesis of key neurotransmitters such as glutamate, gamma-aminobutyric acid (GABA), dopamine, and serotonin, which are critical for mood regulation and cognition. Imbalances in these neurotransmitters are commonly associated with schizophrenia, suggesting that disruptions to gut microbial populations might influence neurotransmitter dysregulation and contribute to symptoms characteristic of the disorder. This growing understanding of the gut-brain axis opens pathways for exploring targeted microbiome-based interventions that could support CNS health and mitigate schizophrenia symptoms[7]. This review explores the intricate relationship between schizophrenia and the gut-brain axis, highlighting key mechanisms, pathophysiology, and emerging therapeutic strategies. By examining the role of gut microbiota in schizophrenia, we aim to shed light on novel approaches that could enhance disease management and improve patient outcomes.

MECHANISMS OF GUT-BRAIN COMMUNICATION

The gut-brain axis is a complex bidirectional communication system between the CNS and the GI tract[10]. This communication involves multiple pathways, including neural, endocrine, immune, and metabolic signaling mechanisms[11]. The gut and brain interact through the vagus nerve, the enteric nervous system (ENS), neuroendocrine pathways, and immune mediators, which allow the brain to influence gut function and vice versa. Disruptions in these communication pathways are implicated in various neurological, psychiatric, and metabolic disorders[12].

NEURAL PATHWAYS

One of the most prominent neural communication routes within the gut-brain axis is mediated by the vagus nerve and the ENS, both of which play vital roles in transmitting information between the brain and the gut[13,14]. The vagus nerve, a key component of the parasympathetic nervous system, serves as the primary route for transmitting information from the gut to the brain[12]. Moreover, it has been shown to modulate mood and emotional states, largely owing to its connections to regions in the brain associated with emotion and memory, such as the amygdala and hippocampus[15,16]. The vagus nerve plays a key role in schizophrenia by regulating autonomic balance, inflammation, and neurotransmission. Dysfunction leads to low heart rate variability, immune alterations, and increased inflammation, worsening symptoms. Low vagal activity is linked to reduced social engagement and cognitive deficits. Vagus nerve stimulation has shown the potential to reverse hippocampal hyperactivity, mesolimbic dysfunction, and cognitive deficits, though clinical results are mixed. The α7 nicotinic acetylcholine receptor (α7nAChR), modulated by the vagus nerve, is reduced in schizophrenia, contributing to impaired neurotransmission and cognitive dysfunction. α7nAChR agonists may improve symptoms, but many patients self-medicate with smoking, which has harmful effects. Stress further impairs α7nAChR function, increasing schizophrenia risk. While vagus nerve stimulation and α7nAChR agonists offer potential treatments, more research is needed[17].

Often referred to as the “second brain”, the ENS is an intricate network of neurons embedded in the lining of the GI tract[18]. It communicates extensively with the brain, influencing overall physiology and behavior[19], responsible for the bidirectional signaling between the gut and the brain. This interaction involves afferent fibers (from gut to brain) and efferent fibers (from brain to gut), allowing the CNS to adjust gut function in response to stress, anxiety, or other stimuli. The ENS plays a significant role in interacting with the mucosal immune system gut microbiota and the intestinal epithelium[20]. This interaction is essential for maintaining gut homeostasis and regulating the gut-brain axis. Disruptions in this signaling can lead to alterations in gut motility, permeability, and immune responses, which may manifest as functional GI disorders or exacerbate neurological conditions (Figure 1)[21,22].

Figure 1 Gut-brain axis and roles of the vagus nerve and the enteric nervous system in brain function and their relevance to schizophrenia. The vagus nerve regulates feeding and autonomic nervous system activity and transmits gut-derived signals to the brain, influencing mood and cognition. The enteric nervous system controls local gut function, modulates immune interactions, and communicates with the brain while mediating microbiota interactions. Disruptions in these pathways, including altered gut-brain signaling, immune activation, and microbiota imbalances, have been linked to neuropsychiatric disorders such as schizophrenia and autism spectrum disorder. GI: Gastrointestinal; ASD: Autism spectrum disorder.

ENDOCRINE PATHWAYS

The gut communicates with the brain through direct neural connections and hormones and other signaling molecules[23]. The enteroendocrine cells of the GI tract release a variety of hormones in response to food intake, gut microbial metabolites, and other environmental factors. These hormones play a crucial role in regulating appetite, energy homeostasis, and mood[24]. Gut hormones such as ghrelin, leptin, peptide YY (PYY), and glucagon-like peptide 1 (GLP-1) are essential for appetite regulation and energy balance[25]. These hormones act on receptors in the brain, particularly in the hypothalamus, to signal hunger, satiety, and energy expenditure[26,27]. Ghrelin, also known as the hunger hormone, is produced in the stomach and stimulates appetite by activating neurons in the hypothalamus. Its levels increase before meals and decrease later, playing a crucial role in meal initiation[28]. Research indicates that ghrelin activates the mesolimbic dopamine system, enhancing reward-related behaviors through mechanisms involving nitric oxide in the ventral tegmental area[29]. This activation can lead to increased sensitivity to rewards and decreased sensitivity to negative feedback, potentially contributing to impulsivity and risk-taking behaviors often observed in schizophrenia[30]. Leptin, produced by adipose tissue, is a key hormone in regulating energy balance[31]. It inhibits hunger by signaling the brain that the body has sufficient energy stores[32]. Dysregulation of leptin signaling is implicated in obesity and metabolic disorders[33]. PYY and GLP-1 promote satiety and reduce food intake[34]. PYY is secreted by the small intestine postprandially (after eating) and acts on the hypothalamus to reduce appetite[35]. Similarly, GLP-1, produced in the intestines, promotes satiety and also enhances insulin secretion, contributing to glucose homeostasis[36]. Studies indicate that GLP-1 receptor agonists exert neuroprotective effects by reducing neuroinflammation, promoting synaptic function, and enhancing memory formation, all of which are vital in counteracting the pathophysiological mechanisms underlying Schizophrenia and Alzheimer’s disease[37]. Additionally, GLP-1 has been linked to improved amyloid-β clearance, a key factor in slowing the progression of Alzheimer’s disease. Modulating GLP-1 signaling, especially in relation to N-methyl-D-aspartate receptor pathways, offers a promising therapeutic approach for addressing cognitive deficits in neurodegenerative disorders[38].

Several neuropeptides and neurotransmitters that regulate mood, cognition, and emotional well-being are influenced by gut-derived signals. Approximately 90% of the body’s serotonin is produced in the gut, where it regulates motility, secretion, and vascular tone[39,40]. Serotonin also plays a major role in mood regulation, cognition, and emotional states. Alterations in serotonin signaling in the gut have been linked to depression, anxiety, and irritable bowel syndrome[39,41]. Neuropeptide Y, a potent orexigenic (appetite-stimulating) neuropeptide, is secreted in response to stress and fasting. It acts on receptors in the brain to increase food intake and reduce anxiety-like behavior[42]. Imbalances in neuropeptide Y levels are associated with eating disorders and stress-related behaviors (Table 1)[24,43].

Table 1 Overview of the roles and implications of various gut hormones and neuropeptides in appetite regulation, energy balance, and mood.

Hormone/ neuropeptide	Source	Function	Mechanism of action	Clinical implications
Ghrelin	Stomach	Stimulates appetite	Activates neurons in the hypothalamus; levels increase before meals and decrease afterward	Implicated in meal initiation; dysregulation linked to impulsivity and risk-taking behaviors in schizophrenia
Leptin	Adipose tissue	Inhibits hunger	Signals the brain regarding energy stores; reduces appetite	Dysregulation associated with obesity and metabolic disorders
Peptide YY	Small intestine	Promotes satiety and reduces food intake	Secreted postprandially; acts on the hypothalamus	Linked to appetite regulation; imbalances can affect weight management
Glucagon-like peptide 1	Intestines	Promotes satiety; enhances insulin secretion	Acts on receptors in the brain; improves glucose homeostasis	Neuroprotective effects; may counteract Alzheimer’s disease progression by enhancing memory and reducing neuroinflammation
Serotonin	Gut (90% produced)	Regulates motility, secretion, vascular tone, mood, cognition	Alters motility and secretion; regulates mood and emotional states	Alterations linked to depression, anxiety, and irritable bowel syndrome
Neuropeptide Y	Brain	Increases food intake; reduces anxiety-like behavior	Stimulated by stress and fasting; acts on receptors in the brain	Imbalances associated with eating disorders and stress-related behaviors

IMMUNE AND INFLAMMATORY PATHWAYS

The immune system also plays a crucial role in the gut-brain axis. The gut is home to the gut-associated lymphoid tissue, which is the largest immune organ in the body[44]. Gut microbiota and their metabolites significantly influence immune responses, and dysregulation of this interaction can lead to systemic inflammation, affecting brain function[45]. The gut microbiota modulates the activity of various immune cells, such as T cells and macrophages, which can migrate to different parts of the body, including the CNS[46]. The migration of immune cells can lead to neuroinflammation, contributing to neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease[47,48]. Cytokines, which are small proteins released by immune cells, serve as key mediators in the communication between the gut and the brain[49]. Elevated levels of pro-inflammatory cytokines, such as tumor necrosis factor α and interleukin-6, have been associated with mood disorders such as depression and schizophrenia[50,51]. Chronic low-grade inflammation, often driven by gut dysbiosis, has been implicated in exacerbating these psychiatric conditions. Conditions such as traumatic brain injury can significantly disrupt the gut-brain axis[52]. Traumatic brain injury often leads to increased gut permeability (leaky gut) and systemic inflammation. The resulting immune response, including the release of inflammatory mediators, affects brain function and cognitive recovery after injury[53].

METABOLIC PATHWAYS AND MICROBIAL METABOLITES

The gut microbiota produces a wide range of metabolites that are crucial in regulating brain function[54]. These metabolites include SCFAs, secondary bile acids, and tryptophan metabolites, which affect various brain processes from neuroinflammation to neuroplasticity[55,56]. SCFAs are gut-derived metabolites that have anti-inflammatory properties and play a neuroprotective role[57]. SCFAs influence the integrity of the blood-brain barrier (BBB) and modulate the immune responses within the CNS, reducing the risk of neuroinflammatory diseases[58]. SCFAs can cross the BBB and modulate neuronal signaling pathways. For example, butyrate has anti-inflammatory properties and can enhance brain-derived neurotrophic factor levels, which are crucial for neuroplasticity and cognitive function, potentially increasing neuroprotection and cognitive function in individuals with schizophrenia[59].

Tryptophan, an essential amino acid obtained from the diet, serves as a precursor for the production of serotonin in the gut[60]. The gut microbiota influences tryptophan metabolism, affecting the balance between serotonin production and the kynurenine pathway[61]. This balance is crucial because while serotonin is a key neurotransmitter associated with mood regulation, the kynurenine pathway can produce neuroactive metabolites that influence brain function and immune responses[62]. The metabolism of tryptophan can follow either of the two major routes: serotonin synthesis and kynurenine production. In a healthy system, tryptophan is primarily converted to serotonin, supporting mood regulation and cognitive processes[63]. However, during inflammation or stress, tryptophan metabolism shifts toward the kynurenine pathway, leading to the production of quinolinic acid, a neurotoxin associated with neuroinflammation and neurodegenerative diseases[64,65]. Conversely, other metabolites in the kynurenine pathway, such as kynurenic acid, have neuroprotective properties[66]. The balance between these pathways significantly affects neurological health, influencing conditions such as depression, anxiety, and schizophrenia (Figure 2)[67]. Secondary bile acids, produced through microbial metabolism of primary bile acids in the gut, are important regulators of host metabolism and immune function[68,69]. Emerging research shows that bile acids can influence the brain through their action on the hypothalamic-pituitary-adrenal (HPA) axis, which regulates stress responses[70]. Altered bile acid signaling has been implicated in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, where dysregulated metabolism and chronic inflammation are key features[71].

Figure 2 Tryptophan metabolism. Tryptophan can be metabolized into serotonin or kynurenine (this process is influenced by gut microbiota and inflammation/stress). Inflammation or stress shifts tryptophan metabolism toward the kynurenine pathway. Serotonin helps in mood regulation, sleep cycle, and cognitive function. Quinolinic acid is a neurotoxin, while kynurenic acid is neuroprotective.

MICROBIOTA, GUT-BRAIN AXIS, AND COGNITIVE HEALTH

The gut microbiota is a critical modulator of the gut-brain axis. Composed of trillions of microorganisms, the microbiota directly affects the neural, endocrine, immune, and metabolic pathways discussed above. The microbiome plays an essential role in shaping the brain and behavior, influencing everything from emotional states to cognitive functions[72]. The gut microbiota influences neurodevelopment from early life stages. During critical periods of brain maturation, it helps shape the development of the CNS, particularly by regulating immune responses, maintaining the integrity of the BBB, and influencing myelination[73,74]. The composition of the microbiota in early life is crucial for brain development. Dysbiosis (an imbalance in the gut microbiota) during this period can result in altered neural circuits and increased susceptibility to neurodevelopmental disorders, such as autism spectrum disorder and attention-deficit/hyperactivity disorder[75].

The gut microbiota produces several metabolites that can influence brain function. As mentioned earlier, SCFAs such as butyrate not only maintain gut barrier integrity but also cross the BBB, where they have been shown to modulate neuroinflammation, support neuronal health, and regulate neurotransmitter release[76,77]. Some gut bacteria can synthesize GABA, a key inhibitory neurotransmitter in the brain. GABA production in the gut can influence central GABAergic signaling, potentially affecting mood and anxiety regulation[78]. Specific gut microbiota, including Bifidobacterium longum, enhance the production of homovanillic acid, a dopamine metabolite, which has been shown to alleviate depressive symptoms by protecting synaptic integrity in the brain[79]. Certain gut bacteria are capable of producing precursors to key neurotransmitters such as serotonin and acetylcholine, which are essential for mood, cognition, and motor control (Table 2)[80-82].

Table 2 Key gut-derived metabolites, their bacterial sources, their function in the brain, and how they impact mental health and cognition[81,82].

Metabolite	Source (gut bacteria)	Role in the brain	Influence on mental health and cognition
Butyrate	Firmicutes (e.g., Clostridium, Faecalibacterium)	Modulates neuroinflammation, supports neuronal health, regulates neurotransmitter release	Enhances neuroprotection, reduces neuroinflammation, and supports cognitive function; potential to alleviate mood disorders
Gamma-aminobutyric acid	Lactobacillus, Bifidobacterium	Inhibitory neurotransmitter, regulates mood, anxiety, and central GABAergic signaling	Reduces anxiety and stress responses; GABA imbalance linked to mood disorders like depression and anxiety
Homovanillic acid	Bifidobacterium longum	Dopamine metabolite, involved in synaptic integrity and reward pathways	Alleviates depressive symptoms, enhances emotional regulation, and protects synaptic health
Serotonin	Enterococcus, Escherichia, Streptococcus	Regulates mood, cognition, and motor control	Deficiency linked to depression and anxiety; essential for mood regulation and emotional well-being
Acetylcholine	Gut bacteria involved in producing precursors (Lactobacillus, Bifidobacterium)	Key neurotransmitter for motor control, learning, and memory	Deficiency associated with cognitive decline, memory disorders, and Alzheimer’s disease

GABA: Gamma-aminobutyric acid.

Mounting evidence suggests that the composition of the gut microbiota is closely linked to mental health. Dysbiosis is associated with a range of neuropsychiatric disorders, including depression, anxiety, schizophrenia, and bipolar disorder[83]. Studies have shown that individuals with major depressive disorder often have altered gut microbiota profiles, with reductions in beneficial bacteria such as Bifidobacterium and Lactobacillus, which are known to produce SCFAs and other neuroactive compounds[84]. Recent studies show that individuals with schizophrenia experience gut dysbiosis, marked by an imbalance in microbial diversity, with elevated levels of Clostridium and Megasphaera, which may contribute to the development and symptoms of the disorder[85]. Prebiotic interventions, such as oligofructose-enriched inulin, have demonstrated potential in increasing butyrate levels, supporting gut health, and potentially easing schizophrenia symptoms[86]. Fecal microbiota transplantation (FMT) has also emerged as a promising therapeutic option, although its use in neuropsychiatric disorders remains largely unexplored[87]. These alterations may contribute to the chronic inflammation observed in depression and the disruption of serotonin metabolism[88]. Gut microbiota can influence the HPA axis, which governs the body’s response to stress. Alterations in gut microbiota composition have been linked to heightened HPA activity, which is associated with increased levels of cortisol and a greater risk of anxiety-related behaviors[89].

GUT-BRAIN AXIS AND SCHIZOPHRENIA

The microbiota-gut-brain axis is involved in various phenomena such as neurological development, modulation of immune response, and disorders that involve both the brain and the body, such as inflammatory bowel disease, depression, and schizophrenia, among others. Nguyen et al[90] hypothesized that there are significant differences in the gut microbiome composition between individuals suffering from schizophrenia and controls. They observed that Proteobacteria, Haemophilus, Sutterella, and Clostridium were present at lower levels, while Anaerococcus spp. was present at increased levels in individuals with schizophrenia compared to controls[90-93].

THERAPEUTIC IMPLICATIONS

It has been well researched that the gut microbiota affects the mental state of the affected individual via the gut-brain axis. This microbiota can be influenced by a variety of factors, of which diet is the most important. This makes the diet of a patient a possible avenue of research in treating psychiatric conditions adjunct to traditional treatment. This was studied by Aucoin et al[94], who reported significant improvement in quality of life, functioning, and cognition and a decrease in the use of medications by patients with schizophrenia after dietary changes[94].

PROBIOTICS

The word probiotic was first coined by Ferdinand Vergin in 1954, who used it to refer to gut microbiota beneficial to the host. World Health Organization working groups define probiotics as “live strains of strictly selected microorganisms which, when administered in adequate amounts, confer health benefits on the host”[95]. Throughout history and in various cultures, humans have consumed a variety of fermented foods, thus introducing large amounts of lactic acid fermenting bacteria to the gut. The most commonly used probiotics are Lactobacillus, Bifidobacterium, Streptococcus, Enterococcus, Escherichia, and Enterococcus species, along with spores of Saccharomyces cerevisiae[96]. As these microorganisms belong to different backgrounds but produce similar results, their mechanism of action must also be based on more than one principle. These principles are as follows: the production of antimicrobial substances, competition for nutrition and surface epithelium, effects on the immune system of the host, and inhibition of bacterial toxins[97].

Probiotics alter the gut microbiota and consequently confer many beneficials effects such as decrease in the symptoms of lactose intolerance and irritable bowel syndrome, decrease in the gut transit time, inhibition of gastric pathogens such as Helicobacter pylori and Clostridium difficile, treatment of antibiotic-associated diarrhea, decrease in the incidence of systemic infection, preventions of allergic conditions such as atopic dermatitis, and prevention and treatment of vaginal infections[98]. The gut-brain axis presents new targets for diagnosing and treating psychiatric disorders. Probiotic therapy may also help alleviate GI comorbidities and psychiatric symptoms. A pilot study of 56 outpatients with schizophrenia found that probiotics significantly reduced Candida albicans antibodies in male patients over 14 weeks, with seropositive male patients experiencing greater bowel discomfort on placebo. Trends suggested improved psychiatric symptoms in seronegative male patients receiving probiotics. A larger cohort confirmed the association between Candida albicans seropositivity and worse symptoms. These findings highlight the potential of probiotics in managing Candida albicans-related gut and psychiatric issues, warranting further research[5].

PREBIOTICS

Prebiotics are considered non-digestible food components that stimulate the growth of one or more bacterial species that are beneficial to the host[99]. Prebiotics can be mostly classified into fructans (fructose oligosaccharides and inulin) and galactans (galactose oligosaccharides), which increase the levels of Bifidobacterium and Lactobacillus in the gut[100]. Although ingestion of probiotics such as inulin-type fructans can statistically significantly increase the severity of abdominal symptoms such as flatulence and abdominal cramping, which may limit their use, their potential benefits include reducing carbohydrate availability and slowing gastric emptying, reducing triglyceride concentration in animal and human models, decreasing arterial stiffness in obese men and increasing post-prandial satiety. In animal models, fibers such as inulin-type fructans are also shown to decrease systemic and gut inflammation along with positively affecting mineral absorption and bone mineral density, although this may not be easily extrapolated to humans because of the different mechanisms of absorption[101].

SYMBIOTICS

Manigandan et al[102] define a symbiotic as “a mixture of prebiotic and probiotic that beneficially affects the host by improving the survival and implantation of live microbial dietary supplements in the GI tract by selectively stimulating the growth or activating the metabolism of one or a limited number of health-promoting bacteria and thus improving host welfare”. As the word symbiotic implies synergy, this should ideally be used in the context where the prebiotic half is selectively supportive of the probiotic half. The most commonly used probiotics in symbiotics are Lactobacilli, Bifidobacteria species, Saccharomyces boulardii, and Bacillus coagulans, whereas fructose oligosaccharide, galactan oligosaccharide, inulin, and xylose oligosaccharide form the major prebiotic component[103]. Symbiotics work mainly by two principles. First, they enhance the survival and viability of the probiotic component, and second, they confer specific health benefits[97]. Daily use of symbiotic supplements is associated with decreased inflammation, as observed by decreased levels of pro-inflammatory markers and an increase in anti-inflammatory markers, enhanced immunity through increasing the mucus immunoglobulin A levels, increased production of SCFAs, and an overall decrease in pro-inflammatory bacteria such as Parabacteroides compared to baselines[104]. The supplements are also associated with a decrease in blood glucose and cholesterol levels, treatment of neurological disorders associated with hepatic dysfunction, induction of remission in inflammatory bowel disease, and prevention of traveler’s diarrhea[97,103].

MEDITERRANEAN DIET

Individuals with Schizophrenia suffer from a wide range of co-morbidities such as obesity, diabetes, and metabolic abnormalities. These problems mainly result from a lifestyle associated with less physical activity and poor dietary habits, and the long-term effects of schizophrenia medications, which cause effects such as obesity and affect glucose metabolism[105]. In this setting, adopting a Mediterranean-style diet can significantly improve the patient’s condition. Mediterranean diet trials have shown that they improve overall cardiovascular disease risk by providing a better omega-6/omega-3 ratio and reduce the levels of inflammatory mediators such as C-reactive protein and tumor necrosis factor α. They are also associated with decreased levels of HbA1c in type 2 diabetes and increased levels of beneficial microbes in the gut[106]. This is especially important because patients with schizophrenia often have an imbalanced or poor gut microbiota.

FMT

FMT is a procedure that involves the transplantation of fecal content from the recipient to the donor by means such as peroral ingestion, enema, and endoscopies. It was discovered in fourth and sixteenth-century China by Ge Hong and Li Shi-Zhen, respectively, who used it to treat food poisoning and diarrhea. It was also described by an Italian anatomist, Fabricius Aquapendente, for use in veterinary medicine[107]. Currently, in modern medicine, it is only indicated for the treatment of Clostridium difficile diarrhea, where it acts as a sort of probiotic to restore the normal gut microbiota[108]. As FMT involves the transfer of fecal contents, donor selection and safety are of paramount importance, as lapses can lead to the transfer of multidrug-resistant infections. Ideally, the donor should be young, as the quality of gut microbiota decreases with age[109]. The selection of a donor should be based on a comprehensive interview and a complete physical examination. The interview should solicit information about the dietary habits and chronic use of drugs (antibiotics, chemotherapy, etc.) by the donor. Similarly, a complete physical examination and biochemical testing should be done to rule out any chance of transfer of infection and parasites from the donor to the recipient. Also, the donor should be prepared to donate samples multiple times, and at each instance, new testing should be carried out[110]. The risk-to-reward ratio in the case of FMT is favorable for schizophrenia, as traditional treatment modalities are associated with a range of side effects[111].

DIETARY FIBER

Dietary fiber is composed of polysaccharides that humans are unable to digest but act as an important source of nutrition for the gut microbiota. They may help in restoring the gut barrier function by producing SCFA, which not only acts as a source of nutrition by the colonocytes but also causes increased production of mucus. Studies have shown that diets deficient in dietary fiber have thinner mucus layers and greatly increased markers of systemic and local inflammation[112]. Dietary fiber plays a crucial role in cognitive function, particularly in the elderly, by influencing brain health through the gut-microbiota-brain axis. Fiber intake, especially from vegetables and fruits, has been positively associated with improved cognitive performance, including better learning ability, processing speed, and memory. These findings suggest that dietary fiber may serve as a potential nutritional intervention to support cognitive health and reduce the risk of cognitive decline[113].

CONCLUSION

Schizophrenia, a complex neuropsychiatric disorder, has increasingly been linked to dysfunctions in the microbiota-gut-brain axis. This intricate communication network connects the gut and brain through neural, endocrine, immune, and metabolic pathways, significantly influencing neurodevelopment, neurotransmitter synthesis, and immune modulation. Dysbiosis, or gut microbial imbalance, has been implicated in neuroinflammation, systemic inflammation, and disruptions in the BBB, all of which are central to the pathophysiology of schizophrenia. Emerging research highlights the therapeutic potential of targeting gut health to improve schizophrenia outcomes. Probiotics, prebiotics, symbiotics, and dietary interventions such as the Mediterranean diet can modulate gut microbiota, enhance beneficial metabolites such as SCFAs, and reduce systemic inflammation. Additionally, FMT represents a novel strategy for restoring microbial diversity. These approaches complement traditional treatments, addressing underlying mechanisms rather than merely alleviating symptoms. The microbiota-gut-brain axis offers a promising avenue for developing integrative schizophrenia therapies, with the potential to improve cognitive, emotional, and behavioral symptoms. While further research is essential to validate these interventions and refine their application, focusing on gut health presents an innovative paradigm shift in managing neuropsychiatric disorders, paving the way for enhanced patient outcomes and quality of life.