Gut-brain axis as a bridge in obesity and depression: Mechanistic exploration and therapeutic prospects

Abstract

A recent study by Wang et al, published in the World Journal of Psychiatry, provided preventative and therapeutic strategies for the comorbidity of obesity and depression. The gut-brain axis, which acts as a two-way communication system between the gastrointestinal tract and the central nervous system, plays a pivotal role in the pathogenesis of these conditions. Evidence suggests that metabolic byproducts, such as short-chain fatty acids, lipopolysaccharide and bile acids, which are generated by the gut microbiota, along with neurotransmitters and inflammatory mediators within the gut-brain axis, modulate the host's metabolic processes, neuronal regulation, and immune responses through diverse mechanisms. The interaction between obesity and depression via the gut-brain axis involves disruptions in the gut microbiota balance, inflammatory immune responses, and alterations in the neuroendocrine system. Modulating the gut-brain axis, for example, through a ketogenic diet, the use of probiotics, and the supplementation of antioxidants, offers new remedial approaches for obesity and depression. Future research that explores the mechanisms of the gut-brain axis is needed to provide more evidence for clinical treatment.

Key Words: Gut-brain axis; Obesity; Depression; Gut microbiota; Mechanism

Core Tip: The gut-brain axis is a crucial pathway that links the intestines to the brain and influences host health through microbial metabolites, neural signals, immune responses, and endocrine pathways. Metabolic byproducts of microbes, such as short-chain fatty acids, lipopolysaccharide and bile acids, modulate appetite, emotional regulation, and immune-inflammatory responses via the gut-brain axis and are closely associated with the onset and progression of obesity and depression. Modulating the gut-brain axis, for example, through the use of prebiotics, specific ketogenic diet, and the supplementation of antioxidants, provides new therapeutic strategies for obesity and depression. Future research needs to delve deeper into the mechanisms of the gut-brain axis to develop more effective interventions.

INTRODUCTION

The global obesity rate has significantly increased over the past few decades, with the rates of childhood and adolescent obesity also increasing and becoming an increasingly serious public health issue[1,2]. Depression is also one of the leading causes of disability worldwide, affecting people of all ages[3]. Depression can occur at any age, with adolescents potentially facing a greater risk[4]. Recently, Wang et al[5] conducted a bibliometric analysis to evaluate the relationship between overweight/obesity and depression in children and adolescents, focusing on the comorbid mechanisms and potential pathways underlying this condition, which has gained increasing research attention in recent years. Both obesity and depression can lead to a range of complications, which can increase the complexity and cost of treatment, reduce an individual’s quality of life, and require more resources for disease prevention, health education, early detection, treatment, and disease management. Therefore, exploring the underlying mechanisms leading to obesity and depression and providing new treatment approaches is particularly important for reducing the social burden.

The gut-brain axis, which serves as an interactive communication network, facilitates close connections between the brain and the gastrointestinal system. It harnesses microbial metabolites, neural signalling, immune responses, and endocrine pathways to tightly link the brain regions responsible for cognition and emotion with the functions of the gut. This axis is crucial in the advancement and progression of numerous diseases., such as neurodegenerative diseases, inflammatory bowel disease, and neuropsychiatric disorders[6-8].

In recent years, research on the gut-brain axis has made significant progress, especially in understanding the interactions among gut health, energy metabolism, and brain function. Therefore, in this editorial, discussing the interaction mechanisms between the gut-brain axis and the comorbidity of obesity and depression has become a popular topic, aiming to offer new perspectives for their prevention and treatment.

MECHANISMS OF THE GUT-BRAIN AXIS

The gut-brain axis forms a crucial bridge between the intestine and the brain, regulating the host's physiological state and psychological conditions through the interplay of microbial metabolites, neurotransmitters, vagus nerve and the immune system. In children, the structure of the gut microbiota community is relatively simplistic. The main short-chain fatty acid (SCFA)-producing bacteria commence colonization during infancy. Once children gradually initiate the consumption of complementary foods, the quantity of other bacteria, such as Bacteroides, increases. These bacteria are capable of decomposing dietary fibre to generate more varieties of SCFAs, such as propionic acid and butyric acid. The growth and metabolic activities of these microorganisms are markedly influenced by alterations in children's diet. Additionally, the pH of the intestines of children is relatively unstable, which also affects the production of SCFAs. In contrast, the gut microbiota community structure in adults is complex and relatively stable, which is why we focused on adults in this study[9,10]. Metabolites produced by microbes, such as SCFAs, lipopolysaccharide (LPS) and bile acids, along with neurotransmitters such as 5-hydroxy tryptamine (5-HT) and gamma-aminobutyric acid (GABA), collectively influence intestinal barrier function, appetite regulation, mood modulation, and immune responses (Figure 1). These findings highlight the significant role of the gut-brain axis in the pathophysiology of obesity and depression and underscore its therapeutic potential.

Figure 1 The gut-brain axis's role in obesity and depression. This figure delineates the intricate mechanisms through which the gut-brain axis modulates obesity and depression, highlighting potential preventative and therapeutic strategies. Gut microbiota-derived metabolites and neuroendocrine signaling pathways are shown to exert significant influence on these conditions via the gut-brain axis. Adopting a healthy diet rich in protein and fiber and low in fat, supplementing probiotics and prebiotics, supplementing antioxidants, and restoring the balance of the hypothalamic-pituitary-adrenal axis are regarded as means to reduce the risk and symptoms of obesity and depression through the gut-brain axis. LPS: Lipopolysaccharide; 5-HT: 5-hydroxy tryptamine; SCFAs: Short-chain fatty acids; GABA: Gamma-aminobutyric acid; ARC: Arcuate nucleus; PYY: Peptide YY; GLP-1: Glucagon-like peptide-1.

Microbial metabolites play a pivotal role in the gut-brain axis. SCFAs can alleviate inflammation caused by increased intestinal barrier permeability[11], and they can also act on enteroendocrine cells to regulate the release of appetite-regulating hormones and thus affect the function of the nervous system[12]. Additionally, secondary bile acids and LPS by gut microbes affect both the intestinal metabolism and central nervous system functions[13] (Figure 1).

The connections between the nervous, immune, and endocrine systems and the gut-brain axis are equally close. Neurotransmitters such as the 5-HT and GABA act in specific areas of the cerebral cortex, regulating physiological and psychological states such as appetite, anxiety, and depression[14]. Vagal-mediated signalling from the gut to the central nervous system enables the modulation of appetite and the suppression of proinflammatory cytokine production, thereby conferring neuroprotective effects[15,16]. Immune cells produced in an inflammatory environment, such as Th17 cells, can migrate to the central nervous system and affect neuroinflammatory responses[17]. Inflammatory cytokines, such as interleukin-1β and tumour necrosis factor-α, in conjunction with the gut microbiota and their metabolic byproducts, are capable of modulating the permeability of the blood-brain barrier and influencing the development, maturation, and functionality of immune cells[18,19]. Moreover, gut hormones such as glucagon-like peptide-1 (GLP-1) not only regulate insulin secretion, but also participate in regulating the activity of microglia, affecting the occurrence and progression of diseases[20,21] (Figure 1). These findings reveal the importance of the gut-brain axis in maintaining host health and expanding its potential applications in treatment.

THE INTERACTION BETWEEN OBESITY AND THE GUT-BRAIN AXIS

Research has shown that the incidence of self-reported depression among obese adolescents has increased. During the coronavirus disease 2019 (COVID-19) pandemic, depressive symptoms and eating disorders in adolescents have intensified. This trend underscores the urgent need to delve into the interaction mechanisms between depression and obesity[22]. The metabolic byproducts of the gut microbiota significantly influence the development of obesity, with SCFAs and LPS being particularly pivotal. These SCFAs are synthesized predominantly by the gut microbiota from dietary components and function as signalling molecules, regulating insulin signalling and inhibiting inflammatory responses. Among these effects, butyrate plays an especially critical role in preserving the integrity of the intestinal epithelial barrier[11,23]. Furthermore, SCFAs also regulate appetite and influence energy intake, thereby assisting in weight reduction through the stimulation of the secretion of satiety hormones such as peptide YY (PYY), GLP-1, and leptin[22,24,25]. The detailed mechanism is shown in Table 1. Unlike SCFAs, LPS, an endotoxin originating from the majority of gram-negative bacteria, incites an immune reaction via the activation of TLR4, leading to the propagation of inflammatory responses[26]. Weight reduction or bariatric surgery can decrease LPS levels and ameliorate obesity-related metabolic complications[27]. Furthermore, changes in the balance of the gut microbiota can regulate the biosynthesis of bile acids and thus exert an anti-obesity effect[28] (Table 1).

Table 1 The gut-brain axis mainly plays a key role in the pathogenesis of obesity and depression through the interaction between the gastrointestinal system and the central nervous system.

Mechanism	Obesity	Depression
Gastrointestinal system
SCFAs	As a signal molecule, SCFAs interacts with receptors such as G protein-coupled receptors GPR41 and GPR43, regulates and inhibits insulin signals in adipocytes, inhibits fat accumulation, inhibits the TLR4/NF-κB signaling pathway, and inhibits obesity. The L cells of the intestine secrete peripheral GLP-1, which mainly acts on the vagus nerve and transmits signals to the brainstem and hypothalamus	Acting on FFAR 2 and 3, SCFAs affects the secretion of intestinal hormones such as GLP-1 and has a neuroprotective effect and reduces inflammatory reactions. It regulates the inflammatory state of microglia and inhibits pro-inflammatory signaling pathways through NF-κB inhibition and Erk1/2 activation, reducing the risk of depression
LPS	In obese individuals, the elevated level of LPS is related to the increase in intestinal permeability, which may lead to metabolic endotoxemia. It triggers an immune response by activating the TLR4 receptor, causing low-grade inflammation and insulin resistance, and then promoting the development of obesity	LPS activates IDO, leading to changes in the tryptophan catabolic pathway. This may then, through the production of neuroactive metabolites such as 3-hydroxykynurenine and quinolinic acid, which are excitotoxic and may play a key role in the development of depression
Secondary bile acids	Changes in the gut microbiota increase the circulating level of secondary bile acids, inhibit the expression of intestinal Car1, and reduce the intestinal absorption level of ingested energy, thereby exerting an anti-obesity effect	The neural circuit from the LHA to the dCA3 and then to the DLS mediated by the secondary bile acid receptor TGR5, which is acted on by secondary bile acids, can regulate depressive-like behaviors in male mice. The downregulation of TGR5 or the enhancement of GABAergic excitability promotes stress-induced depressive-like behaviors
Central nervous system
Brain	The central GLP-1 is predominantly produced by glucagon precursor neurons in the brainstem and exerts its anorexigenic effects by acting on the hypothalamus and mesolimbic areas like the VTA and NAc. The intestinal vagal afferent signals generated by gastrointestinal nutrient contact are capable of reducing dietary intake and terminate in the caudal nucleus tractus solitarius of the brainstem in a medical academic context	The cerebellum directly promotes the mechanism by which depressive-like behaviors develop due to stress by activating a specific circuit composed of DCN neurons that project to the VTA. Deep brain stimulation of the NAc-DBS can regulate the level of GABA in the VTA, relieve the inhibition of dopaminergic neurons in the VTA, and improve depressive-like behaviors
HPA axis	In the situation of continuous psychological stress, chronically elevated glucocorticoids are capable of leading to high concentrations of ghrelin, thus promoting alterations in higher calorie intake and energy expenditure, and chronically stimulating eating behavior and excessive weight gain. Glucocorticoids can act directly on the hypothalamus and mesolimbic regions, such as the VTA	When the gut microbiota is absent, it affects the HPA response, including an increase in CORT and ACTH levels. Surgical ablation of gut-originating vagal afferent/sensory signaling through subdiaphragmatic vagal deafferentation, which results in the loss of vagal afferent fibers, can promote depressive-like behaviors
5-HT	By activating the 5-HT2C receptor on neurons, it enhances the signal transduction of α-MSH. This enhanced signal helps to reduce food intake and increase energy consumption, thereby inhibiting the development of obesity	5-HT regulates the expression of brain-derived neurotrophic factor by modulating the GTP-Cdc42/ERK pathway and enhances the release of 5-HT to improve depressive behaviors; In TGR5 knockout mice, the level of 5-HT in serum and hippocampus is significantly reduced, and at the same time, the expression of 5-HT1A receptor in hippocampus is decreased, thereby increasing the risk of depression

SCFAs: Short-chain fatty acids; LPS: Lipopolysaccharide; 5-HT: 5-hydroxy tryptamine; ACTH: Adrenocorticotropic hormone; CORT: Corticosterone; HPA: Hypothalamic-pituitary-adrenal; PYY: Peptide YY; GLP-1: Glucagon-like peptide-1; FFAR: Fatty acid receptors; α-MSH: Alpha-melanocyte-stimulating hormone; IDO: Indoleamine 2,3-dioxygenase; LHA: Lateral hypothalamic area; dCA3: Dorsal CA3; DLS: Dorsolateral septum; Car1: Carbonic anhydrase 1; VTA: Ventral tegmental area; NAc: Nucleus accumbens; GABA: Gamma-aminobutyric acid; NAc-DBS: Deep brain stimulation of the nucleus accumbens.

The hypothalamus, brainstem, and limbic cortical regions are pivotal in modulating food intake and energy balance. The hypothalamus is the centre for appetite regulation. The arcuate nucleus (ARC) therein participates in the modulation of appetite hormones and the hypothalamic-pituitary-adrenal (HPA) axis[29]. The brainstem, particularly the dorsal vagal complex, relays these signals to the hypothalamus, promoting communication between the gastrointestinal system and the hypothalamus and thereby regulating food intake. The limbic cortical area, with structures such as the nucleus accumbens (NAc), and ventral tegmental area (VTA), processes reward and memory information of food and influences the modulation of food intake[15,30,31]. Under conditions of continuous psychological stress, glucocorticoids are chronically elevated, leading to changes in energy consumption[32-35]. Neurotransmitters serve as essential regulators in a variety of critical physiological processes, including mood stabilization, sleep cycle sustenance, and appetite regulation. Moreover, they are intricately involved in cognitive functions, pain perception, cardiovascular modulation, and the processes of learning and memory. For example, enhanced 5-HT signalling contributes to reducing food intake[36] (Table 1). Furthermore, research has indicated that the action of 5-HT in the hypothalamic ARC can regulate different types of feeding behaviours[37] (Figure 1).

THE INTERACTION BETWEEN DEPRESSION AND THE GUT-BRAIN AXIS

In recent years, studies have shown that depression and anxiety among young people have increased significantly. The American Children's Health Survey revealed that the incidence rate increased by approximately 30% from 2016-2020. During the COVID-19 pandemic, the number of depressed children increased significantly[38]. There is evidence that SCFAs not only are crucial for the preservation of intestinal well-being but also may affect mood disorders, such as depression, via the gut-brain axis. This provides us with an additional approach to reducing depression and obesity in children and adolescents. Initially, SCFAs can affect the secretion of gut endocrine cells through GPCRs, such as the secretion of GLP-1 and PYY, and reduce inflammatory responses[21,39]. Recent studies have revealed that propionate can protect against brain damage caused by oxidative stress. Concurrently, butyrate has been shown to attenuate the activation of microglia, thereby inhibiting the development of inflammation and alleviating depression. Notably, the dysregulated activation of microglia is implicated in the pathophysiology of depressive behaviours[18,19,40]. Additionally, secondary bile acids can also affect mood regulation[41,42]. The detailed mechanism is illustrated in Table 1. Similarly, LPS has been implicated in the induction of depressive behaviours[35,43] (Table 1).

The mechanisms whereby brain regions influence depression involve multiple aspects, such as the NAc modulating neural activities in the VTA and the neural circuit connection between the cerebellum and the VTA, all of which jointly participate in the occurrence and development of depression[44-46] (Table 1). The HPA axis serves as the principal neuroendocrine response system for stress in the body, and its dysregulation is closely linked to a spectrum of mood disorders, including depression[47,48]. Research has demonstrated that trauma in early childhood can lead to permanent dysregulation of the HPA axis, leading to an elevated risk of depression, which offers a new orientation for the treatment of childhood depression[35,49]. Furthermore, the gut microbiota can influence the regulation of the HPA axis by affecting signal transmission through the vagus nerve, thereby directly impacting the brain[16]. Completely blocking the afferent fibres of the vagus nerve also promotes depressive-like behaviours[16]. Additionally, gut microbes can affect brain function by altering neurotransmitter levels. For example, increasing the release of 5-HT can improve depressive-like behaviours[14,50]. In addition, studies have shown that TGR5 knockout mice have an increased risk of depression. This finding is consistent with the induction of depression by the downregulation of TGR5 (Table 1)[41,51]. These findings indicate that the modulation of the gut-brain axis may alleviate the onset of depression.

THE BIDIRECTIONAL MODULATORY ROLE OF THE GUT-BRAIN AXIS

Obesity and depression are prevalent health issues with a complex bidirectional relationship. An increasing number of studies indicate a significant positive correlation between obesity and depression in children and adolescents[52]. Studies have shown that low-grade systemic inflammation during childhood may predispose individuals to depression and obesity. Moreover, metabolic dysfunctions such as insulin resistance are relatively evident from a relatively young age, which may provide a basis for the positive correlation between depression and obesity from childhood and adolescence onwards[53]. Additionally, youth with depressive symptom scores higher than the 90th percentile are twice as likely to be obese[54]. Therefore, exploring the interaction mechanism between obesity and depression in children and adolescents is particularly important. Recent research has revealed potential shared biological mechanisms, categorized into microbial metabolites and neuroendocrine and inflammatory immune activation pathways. Metabolites from the gut microbiota, such as SCFAs, can alleviate HFD-induced intestinal inflammation by inhibiting the TLR4/NF-κB signalling pathway while also affecting the differentiation of microglia, leading to neuroinflammation and neuronal damage. The dysregulation of the gut microbiota leads to a decrease in SCFAs, making the comorbidity of these two conditions possible[18,23,55]. Furthermore, studies indicate that the activation of TGR5 can improve mitochondrial function and increase antioxidant capabilities, modulating depressive behaviours while also ameliorating obesity[56]. Alterations in the gut microbiota composition among obese individuals leading to increased intestinal permeability may result in LPS leakage and endotoxaemia. This low-grade systemic inflammatory state can activate immune cells to produce more inflammatory factors, which can remotely affect the brain, leading to alterations in neurotransmitters and impairments in neural plasticity, thereby impacting mood and behaviour[57] (Table 1).

The mechanism of the comorbidity of obesity and depression caused by brain regions is complex. The central GLP-1 secreted by the glucagon precursor neurons in the brainstem, acts on the hypothalamus and mesolimbic system, including the VTA and NAc, to suppress appetite, while the intestinal vagal afferent signal of the gastrointestinal tract terminates at the caudal nucleus tractus solitarius of the brainstem to reduce dietary intake. Reduced GLP-1 levels or blocked vagal afferents can lead to the occurrence of obesity. The cerebellum promotes depressive-like behaviours by activating DCN neuron circuits projecting to the VTA. Deep brain stimulation of the deep brain stimulation of the NAc regulates GABA levels in the VTA to improve depressive-like behaviours. These changes involve all brain regions, such as the VTA, which is a common information processing site, suggesting a neurobiological connection between obesity and depression. Changes in the hypothalamus's response to metabolic signalling molecules are related to the development of obesity, particularly the progression of leptin resistance. Additionally, the hypothalamus plays a pivotal role in stress responses related to depression, with functional changes associated with elevated levels of cortisol and leptin. Activation of the HPA axis may lead to depressive-like behaviours and hyperphagia[58,59]. In addition, signals transmitted upwards through the vagus nerve reduce appetite. Loss of vagal afferent signals promotes depressive-like behaviours and simultaneously increases appetite. Studies have shown that obesity induced by a HFD can lead to depressive-like behaviours in rats, and such a diet diminishes the activity of the 5-HT-activated Akt/GSK3β signalling pathway in the dentate gyrus of the hippocampus[28,41,51]. Therefore, a reduction in 5-HT promotes the occurrence of obesity. These findings illustrate that neurotransmitters also significantly contribute to the comorbidity of obesity and depression[60] (Table 1).

According to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, there may be a phenomenon of decreased appetite accompanied by depressive symptoms. In subtypes such as persistent depressive disorder, major depressive disorder, and premenstrual dysphoric disorder, one of the diagnostic criteria is a change in appetite, either increased or decreased appetite. The part with atypical features also mentioned that there may be a situation of increased appetite. These findings provide a basis for our research regarding the interaction between depression and obesity through the gut-brain axis[61]. The intricate bidirectional relationship between obesity and depression may be explained through shared mechanisms of the gut-brain axis, including the impact of microbial metabolites, dysfunction of neuroendocrine pathways, and activation of inflammatory immune responses. These mechanisms converge on key brain regions, influencing mood and behaviour, and suggesting that the developing new therapeutic strategies for the comorbidity of obesity and depression could target these common biological pathways (Figure 1).

THERAPEUTIC PROSPECTS AND FUTURE RESEARCH DIRECTIONS

Currently, prevalent strategies for modulating the gut microbiota involve the administration of probiotics and prebiotics. These probiotics exert immunomodulatory effects, mitigate inflammatory responses, and facilitate the biosynthesis of SCFAs, thereby reinforcing the protective function of the intestinal mucosal barrier. The anti-inflammatory and immunomodulatory effects of prebiotics offer pathways for alleviating obesity and depression[62-64]. In addition, dietary adjustments, such as low-fat, high fibre diets and diets rich in antioxidants, are beneficial for neurological diseases and obesity. Research indicates that a ketogenic diet has protective effects on the nervous system[65], and it can also aid in reducing obesity by increasing the level of secondary bile acids through KD consumption[28]. Children who are obese or overweight have lower levels of vitamin D, increased thickness of visceral and subcutaneous fat, and higher levels of C-reactive protein and myeloperoxidase. Supplementing antioxidants to reduce the body's inflammatory response provides another approach for reducing childhood obesity and depression in line with the requirements of medical research[66,67]. Regulating the HPA axis and restoring cortisol levels has also become a path worthy of in-depth study to reduce the incidence of obesity and depression[22].

The gut-brain axis, which plays a pivotal role in many physiological and pathological processes, has intricate mechanisms of interaction that warrant further in-depth investigation. Research on the mechanisms of the gut-brain axis has provided novel therapeutic targets beyond traditional pharmacological and psychological treatments, fostering interdisciplinary integration across neuroscience, microbiology, immunology, and nutrition. Future work should focus on the design of clinical trials to validate gut-brain axis-based treatment regimens. The gut-brain axis is associated with obesity and depression, yet the specific mechanisms remain unclear, with many unresolved questions. A key challenge lies in elucidating the causal chain in the comorbidity of obesity and depression, with numerous aspects still necessitating further exploration.

CONCLUSION

The gut-brain axis plays a pivotal role in the pathogenesis of obesity and depression. Obesity and depression are associated with an imbalance of the gut microbiota, enhanced inflammatory immune responses, and altered functions of the neuroendocrine system. Modulating the gut-brain axis, such as through the use of probiotics, a ketogenic diet, and the supplementation of antioxidants, offers new therapeutic strategies for obesity and depression. Future research should delve deeper into the mechanisms of the gut-brain axis, design clinical trials to validate gut-brain axis-based treatment plans, and promote interdisciplinary integration to provide new perspectives for the prevention and treatment of obesity and depression.