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

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.