Interaction between the brain and multiple organ systems in schizophrenia

Abstract

Schizophrenia is characterized by psychotic symptoms, negative symptoms, and cognitive deficits, profoundly affecting individuals and their families. The etiology is multifactorial, involving genetic, endocrine, and immunological risk factors. It is thought that schizophrenia is exclusively linked to alterations in brain structure and function, while the relationship between the brain and many organs may lack sufficient attention. Increasing evidence indicates abnormalities of the interactions between the brain and many organs in patients with schizophrenia. Inter-organ crosstalk affects the onset, course, and management of schizophrenia. Besides, the complex relationship between autonomic nervous system, endocrine system, and immune system further facilitates the development of schizophrenia. The present review summarizes the relationships between the brain and multiple organ systems in schizophrenia, providing new perspectives on the underlying pathophysiological mechanisms of schizophrenia.

Key Words: Schizophrenia; Brain-body interactions; Pathophysiological mechanisms; Multiple organic systems; Systemic integration

Core Tip: While existing reviews of schizophrenia focus primarily on central nervous system pathophysiology, this minireview uniquely highlights the growing evidence of interactions between the brain and peripheral organ systems, including the cardiovascular, pulmonary, hepatic, immune, and renal systems. It underscores the critical role of brain-organ interaction via the autonomic nervous system, endocrine system, and immune system in the pathophysiology of schizophrenia, providing new insights into its underlying mechanisms and potential therapeutic targets.

INTRODUCTION

Schizophrenia, as a noteworthy public health concern, has a world lifetime prevalence of around 1%[1]. Epidemiological studies show that patients with schizophrenia have a mortality rate that is two to three times greater than the general population, associated with the alterations in non-central nervous systems[2]. Despite schizophrenia is characterized by a multitude of brain abnormalities, several structural and functional imbalances in schizophrenia are related to the organic causes[3,4]. Recent researches have demonstrated that schizophrenia is often accompanied by a range of dysfunctions in the specific organ systems, including cardiovascular, hepatic and metabolic, immune, pulmonary, and renal systems[5-9]. These body systems are interconnected in varying degrees in the pathology of schizophrenia, indicating schizophrenia engage multiple systems[10]. For instance, patients with schizophrenia typically manifests in early adulthood, whereas heart failure and coronary artery disease emerge later in life[5]. Previous meta-analyses have further indicated that a significantly higher risk of schizophrenia in those with other diseases of organ systems, such as the digestive system and immune system[11,12]. These organic systems are not only affected by schizophrenia, but also through the biological pathways on brain function, thereby influencing the onset and progression of the schizophrenia[13,14].

Given the intricate connections between the brain and the organ systems, the integration of evidence on brain-organ crosstalk in schizophrenia is required. In this narrative review, we summarize the evidence of the interactions between the brain and the heart, liver, spleen, lungs, and kidneys in schizophrenia. Besides, we will review the association between the brain and multiple organic systems via the autonomic nervous system, endocrine system, and immune system. The purpose of this review is to provide new perspectives on the pathophysiology of schizophrenia.

INTERACTION BETWEEN THE BRAIN AND THE CARDIOVASCULAR SYSTEM

The interaction between the brain and the cardiovascular system is primarily mediated by the autonomic nervous system[15]. By modulating both sympathetic and parasympathetic nervous systems, the autonomic nervous system controls heart rate, rhythm, as well as the contraction and relaxation of blood vessels, ensuring the proper functioning of the cardiovascular system. Heart rate variability (HRV), as a key physiological indicator, not only reflects the dynamic regulation of the heart by the sympathetic and parasympathetic nervous systems, but is also closely related to a variety of psychological and physiological states[16]. Numerous studies have found that individuals with schizophrenia exhibit significantly lower HRV compared to healthy controls, suggesting dysfunction of the autonomic nervous system[17,18]. And a significantly association between brain activity and cardiac parasympathetic activity has been found in healthy subjects using functional magnetic resonance imaging and autonomic nervous system measurement[19]. Specifically, the prefrontal cortex plays an important role in the regulation of HRV, a view supported by the neurovisceral integration model[20]. Additionally, a recent meta-analysis has further confirmed that reduced HRV may serve as a potential endophenotype for schizophrenia, highlighting not only the importance of HRV in the early identification and intervention of schizophrenia[21]. Besides, the more severe the symptoms of schizophrenia are more pronounced the reduction in HRV[22,23]. Notably, the reduction in HRV in medication-free schizophrenia patients is related to core symptoms of schizophrenia without association of antipsychotic treatments[24]. HRV-targeted interventions, such as HRV biofeedback, may affect mechanisms underlying psychotic symptoms, providing a promising avenue for adjunctive therapy[25]. These findings further underscore the potential of HRV as a biomarker for schizophrenia and provide important insights into the role of brain-organs crosstalk in the development and progression of schizophrenia.

INTERACTION BETWEEN THE BRAIN AND THE PULMONARY SYSTEM

The interaction between the brain and the pulmonary system is primarily mediated by oxygen homeostasis, with hypoxia influencing neurodevelopment, gene expression, and structural integrity, thereby contributing to the pathophysiology of schizophrenia[26]. The main functions of the pulmonary system are to maintain oxygen supply and facilitate the expulsion of carbon dioxide through gas exchange, and adequate oxygenation is crucial for normal brain function[27]. Recent studies have found that patients with schizophrenia exhibit histogenous hypoxia and acid retention, with reduced venous oxygen pressure emerging as a characteristic variable of schizophrenia[28]. Hypoxia not only alters gene expression but may also disrupt critical neurodevelopmental signaling pathways[29]. Prior studies have indicated that hypoxia not only impacts gene expression but may also interfere with the expression of many candidate genes related to schizophrenia, thereby disrupting key neurodevelopmental signaling pathways[30]. These changes may impair neuronal differentiation, migration, and synapse formation, ultimately leading to abnormalities in brain structure and function, and thus contributing to the onset of schizophrenia[31]. Autopsy-based studies have further demonstrated that the expression of hypoxia-inducible factors in the prefrontal cortex of patients with schizophrenia is increased[32]. In addition, hypoxia may exacerbate the pathological process of schizophrenia by affecting the structural integrity of the brain[33]. Patients with schizophrenia often exhibit the compromised white matter integrity, and hypoxia may further impair myelination, promoting pathological white matter changes[34].

INTERACTION BETWEEN THE BRAIN AND THE IMMUNE SYSTEM

Immune system dysregulation is increasingly recognized as a key component in the pathophysiology of schizophrenia[35]. The spleen, as a vital immune organ, plays a central role in host defense against bacteria, viruses, and other pathogens[36,37]. Recent studies have unveiled direct neuroimmune connections between the brain and the spleen[38]. Specifically, corticotropin-releasing hormone neurons located in the central amygdala and paraventricular nucleus can directly interact with splenic nerves, thereby modulating immune responses such as antibody production[39]. Numerous studies have reported abnormal expression of inflammatory markers in patients with schizophrenia, suggesting a potential link between brain-spleen interactions and the disease’s pathogenesis[40]. Postmortem analyses have further revealed reduced expression of colony-stimulating factor 1 receptor (CSF1R) in the spleens of schizophrenia patients, leading to immune system dysfunction[41]. Significantly, CSF1R is critical for the proliferation, differentiation, and survival of microglial cells in the brain, and its dysfunction is closely related to the pathogenesis of schizophrenia[42,43]. Therefore, the reduction in CSF1R expression in the spleen may influence the brain’s immune microenvironment by affecting microglial cell function, contributing to the pathological mechanisms of schizophrenia[43].

INTERACTION BETWEEN THE BRAIN AND THE HEPATIC AND METABOLIC SYSTEM

The liver plays a pivotal role in lipid metabolism, maintaining systemic lipid homeostasis[44]. Increasing evidence indicates that lipid metabolism abnormalities in patients with schizophrenia, which are closely associated with clinical symptoms[45,46]. These lipid metabolism disorders not only alter the overall physiological state but may also impact brain function via the brain-liver axis. Specifically, reduced lipid content in the dorsolateral prefrontal cortex of schizophrenia patients is closely related to cognitive dysfunction[47]. Furthermore, postmortem studies have demonstrated a synchronized increase in the expression levels of soluble epoxide hydrolase in both the liver and the brain in schizophrenia[48]. Moreover, a prior study has identified a negative correlation between brain-derived neurotrophic factor (BDNF) levels in the parietal cortex and those in the liver of patients with schizophrenia[49]. BDNF plays a crucial role in neuroprotection and neuroplasticity, and its dysregulation in both organs may impact the pathophysiology of schizophrenia via the brain-liver axis[50]. These cross-organ metabolic and neuroregulatory abnormalities further highlight the importance of brain-liver interactions in schizophrenia. Thus, lipid metabolism abnormalities in the liver and brain, as well as BDNF expression dysregulation, may jointly influence the pathophysiological processes of schizophrenia through the interaction of the brain-liver axis.

INTERACTION BETWEEN THE BRAIN AND THE RENAL SYSTEM

The interaction between the brain and the renal system is primarily mediated by the renin-angiotensin system (RAS). RAS plays a pivotal role in blood pressure regulation and is also implicated in various biological processes, including neuroinflammation, oxidative stress, and neurodevelopment[51]. In schizophrenia, aberrant activation of the RAS has been linked to neurotransmitter imbalances, heightened inflammatory responses, and neuronal damage[52]. Increasing evidence suggests that the increased RAS activity may exacerbate neuroinflammation, thereby influencing the clinical presentation of schizophrenia, particularly in terms of affective disturbances and cognitive impairments[53,54]. Furthermore, RAS activation is strongly associated with dysregulation of dopamine signaling, a hallmark of schizophrenia[55,56]. Increasing evidence have revealed that vagus nerve stimulation can regulate both peripheral and central inflammation through the α-7 nicotinic acetylcholine receptor, which may offer therapeutic benefits for schizophrenia[57]. Notably, the kidney significantly impacts on the brain function through the secretion of erythropoietin (EPO)[58]. Beyond its well-established roles in erythropoiesis, EPO exhibits antioxidant, anti-apoptotic, and anti-inflammatory properties, promoting neuroplasticity and neuroprotection[59]. Research indicates that EPO can mitigate gray matter loss in schizophrenia patients, highlighting its potential role in preserving brain integrity[60,61]. Therefore, the kidney interacts with the brain through multiple pathways, shaping the pathogenesis and clinical manifestations of schizophrenia.

INTERACTION BETWEEN THE BRAIN AND THE MULTIPLE ORGANIC SYSTEMS

The multiple organic systems involvement highlights that the pathophysiological mechanisms of schizophrenia extend well beyond the brain itself[62]. Bidirectional communication between the brain and peripheral organs is mediated through several complex pathways, most notably the autonomic nervous system, the endocrine system, and the immune system[63-65]. Autonomic dysfunction has been found to be correlated with multiple aspects of schizophrenia pathogenesis, comprising symptom severity, cognitive dysfunction, and the emergence of cardiometabolic comorbities[64]. An inverse link exists whereby the cardiometabolic alterations may be partially triggered by a shift in sympathovagal balance towards sympathetic hyperactivity, resulting in diminished insulin secretion and elevated concentrations of circulating adrenaline, norepinephrine, glucagon, and cortisol[66]. The endocrine system, particularly the hypothalamic-pituitary-adrenal axis, is involved in the body’s stress response[67]. Chronic cortisol elevation in patients with schizophrenia affects neurotransmitter systems, including glutamate and dopamine, contributing to neurotoxicity and cognitive impairment[68]. Furthermore, immune system dysfunction is increasingly recognized as a key factor in schizophrenia, including altered pro-inflammatory cytokines, and abnormal gut bacterial communities[63]. Similar patterns of changes in inflammatory mediators have been found in the plasma and postmortem brain tissues of patients with schizophrenia, suggesting that the bidirectional communication between the brain and multiple organs may be finely regulated by a range of inflammatory mediators[69]. Significantly, the intricate relationship between autonomic nervous system, endocrine system, and immune system further promote the progression of schizophrenia, particularly impacting on the connections between the brain and the organic systems[62].

CONCLUSION

In summary, the pathogenesis of schizophrenia involves not only the central nervous system but also the dynamic interactions between the brain and other organs (Figure 1). The brain-organs crosstalk is mediated through various biological pathways, affecting the function of peripheral organs and, in turn, regulating brain function via feedback mechanisms in schizophrenia. Although significant progress has been made in elucidating these interactions, current research remains fragmented, and many critical questions remain unanswered. To achieve a more comprehensive understanding of inter-organ dynamics and their contributions to schizophrenia, the application of multi-omics approaches is particularly valuable. Multi-omics technologies enable simultaneous detection of changes across multiple biological levels, thereby uncovering shared molecular mechanisms and dynamic fluctuations of signaling molecules among different organs. For instance, transcriptomic analysis can identify genes that are co-expressed or differentially expressed across multiple organs, revealing potential molecular pathways. Metabolomic profiling can detect alterations in metabolites within blood or tissues, providing insights into metabolic links between peripheral dysfunction and central nervous system pathology. We propose the construction of a “brain-organ network” model as a future research direction. This model would integrate transcriptomic, proteomic, and metabolomic data from multiple organs, and apply network-based computational approaches to identify key nodes and pathways involved in inflammation, oxidative stress, and neurotransmission. Such a systems-level strategy could help uncover novel biomarkers and therapeutic targets for schizophrenia, particularly those that address multi-organ dysregulation. Furthermore, future studies should incorporate animal models and longitudinal interventional designs to validate these interactions and dissect causal mechanisms underlying brain-organ communication. These efforts will be essential for advancing our understanding of schizophrenia as a systemic disorder and for the development of more effective, multi-target treatment strategies.

Figure 1 Dynamic interactions between the brain and other organs in schizophrenia. Cardiovascular system: Connected to the brain via the autonomic nervous system. Reduced heart rate variability indicates dysfunction of the autonomic nervous system in schizophrenia. Pulmonary system: Interacts with the brain through oxygen homeostasis. Hypoxia can affect neurodevelopment and contribute to schizophrenia’s pathophysiology. Metabolic system: In schizophrenia, increased soluble epoxide hydrolase expression and decreased brain-derived neurotrophic factor levels may affect brain function through the brain-liver axis and lipid metabolism. Renal system: In schizophrenia, the renal system interacts with the brain via the renin-angiotensin system and is associated with neuroinflammation and erythropoietin. SEH: Soluble epoxide hydrolase; BDNF: Brain-derived neurotrophic factor; HRV: Heart rate variability; RAS: Renin-angiotensin system.