Intestinal-related substances in obesity regulation: A comprehensive review

Abstract

With the rising global obesity rates, particularly in industrialized nations, obesity has become an increasingly significant public health concern. This review analyzes 132 relevant studies published between 2020 and 2025, with a focus on the role of gut-derived substances in regulating obesity. These include gut hormones [such as glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), peptide YY, cholecystokinin, and ghrelin], microbial metabolites [such as short-chain fatty acids (SCFA) and indole-3-propionic acid (IPA)], and neurotransmitters (such as serotonin and dopamine).The findings suggest that gut hormones play a crucial role in regulating appetite, glucose metabolism, and energy expenditure, and their dysregulation is closely linked to the development of obesity. Moreover, microbial metabolites like SCFA and IPA are strongly associated with metabolic health and significantly influence obesity-related mechanisms. This review also explores emerging therapeutic strategies, including GLP-1 receptor agonists, dual GLP-1/GIP receptor agonists, modulation of the gut microbiota, and fecal microbiota transplantation, all of which demonstrate promising potential in obesity management. However, challenges remain in optimizing these interventions, mitigating adverse effects, and establishing regulatory standards for microbiota-based therapies. Future research should aim to develop personalized, multi-targeted approaches to more effectively combat obesity and its associated metabolic disorders.

Key Words: Obesity; Gut hormones; Microbial metabolites; Indole-3-propionic acid; Gut-brain axis

Core Tip: Gut hormones, microbial metabolites, and neurotransmitters such as 5-hydroxytryptamine (serotonin), short-chain fatty acids, and indolepropionic acid play crucial roles in regulating metabolism and obesity. Emerging therapies like glucagon-like peptide-1 receptor agonists and gut microbiota modulation show promise in addressing these factors. Future research should focus on personalized, multi-target approaches for effective obesity management, optimizing treatments, and understanding the diverse impacts of gut-derived substances on metabolic health.

INTRODUCTION

Over the past few decades, global obesity rates have significantly increased. In some industrialized countries there has been an alarming rise in the prevalence of obesity from 2019 to 2020, with rates doubling or nearly tripling among the general population[1]. Obesity not only impacts individual health but also incurs substantial socioeconomic costs, including medical expenses and productivity losses. It is closely linked to type 2 diabetes, cardiovascular diseases, certain cancers, and respiratory conditions[2] thereby increasing healthcare burdens. High-calorie diets and sedentary lifestyles are primary drivers of obesity, with genetic susceptibility and environmental factors such as urbanization and changes in food supply also playing significant roles[3]. Gut hormones play a crucial role in metabolic regulation. They mediate their effects directly via acting on areas in the brain lacking blood–brain barrier or indirectly via stimulating the vagal afferent neurons[4]. Some gut hormones are involved in blood sugar regulation, affecting the secretion of insulin and glucagon[5]. By modulating these hormones, we aim to develop new obesity treatment strategies that improve patients' quality of life and reduce socioeconomic burdens. The intestinal metabolism is tightly regulated by hormonal homeostasis, with gut microbiota dysbiosis serving as a critical pathophysiological nexus. Mechanistically, microbial imbalance disrupts intestinal barrier function, precipitating metabolic endotoxemia that subsequently dysregulates enteroendocrine signaling pathways, thereby establishing a self-perpetuating "microbiota-hormone-metabolism" vicious cycle. Conversely, commensal microbial metabolism generates essential bioactive metabolites that facilitate host nutrient assimilation and digestive efficiency.

The obesity pandemic arises from a multidimensional cascade of behavioral, genetic, and microbiome-driven hormonal disruptions. Targeting the gut-hormone-microbiota axis-via dietary interventions, pre/probiotics, or hormone-based pharmacotherapies-holds promise for breaking this vicious cycle. Such strategies could simultaneously alleviate clinical morbidity and socioeconomic strain, offering a paradigm shift in obesity management.

OVERVIEW OF GUT-DERIVED HORMONES AND SUBSTANCES RELATED TO WEIGHT REGULATION

The metabolic regulation of an organism is a highly intricate process, especially the hormonal and neurochemical processes in the intestine, including peptides like glucagon-like peptide-1 (GLP-1), neurotransmitters such as 5-hydroxytryptamine (5-HT), and microbial metabolites. In terms of energy transformation, organismal metabolism can be categorized into two complementary pathways: Anabolism and catabolism. The primary etiological factor underlying obesity is a systemic predominance of anabolic effects over catabolic effects[6].

The intestinal tract, serving as the principal site for nutrient absorption, exerts multifaceted influences on metabolic regulation. Characterized by an extensive neural network, the enteric nervous system possesses autonomous functionality, enabling direct regulation of digestive processes, nutrient assimilation, and secretory activities[7]. Furthermore, the existence of the gut-brain axis facilitates bidirectional communication with the central nervous system via the vagus nerve, thereby indirectly modulating the brain's overarching control of systemic metabolism.

The intestinal lumen harbors a vast and diverse microbial ecosystem, constituting a unique microenvironment. Through microbial metabolism of certain nutrients, bioactive metabolites with hormone-like properties, particularly those containing nitrogenous moieties, are generated. Notably, indole-3-propionic acid (IPA) and short-chain fatty acids (SCFAs) have been identified as critical metabolic regulators[8]. These microbial-derived metabolites function as cellular signaling molecules, capable of activating downstream pathways that suppress catabolic processes while potentiating anabolic activities, thereby promoting adipogenesis and the development of obesity.

Microbial metabolites

Gut commensals synthesize essential metabolites that sustain microbial colonization and host physiological homeostasis[9]. While SCFA derived from fiber fermentation serve as key energy substrates (detailed in subsequent sections), commensal bacteria generate additional critical compounds[10]. Vitamin biosynthesis represents a core function: Bacteroides and Bifidobacterium spp. produce B-group vitamins (B2, B7, B9) essential for microbial cofactor biosynthesis, while Lactobacillus synthesizes vitamin K2, supporting both bacterial growth and host coagulation pathways. Furthermore, aromatic amino acid metabolism yields indole derivatives (e.g., indole-3-aldehyde) that activate epithelial aryl hydrocarbon receptors, reinforcing mucosal barrier integrity and suppressing pathogen colonization. These compounds establish a bidirectional support system: Microbial-derived vitamins act as public goods within the community, whereas indole metabolites concurrently maintain host epithelial defense, exemplifying the symbiotic relationship forged through metabolic cross-feeding[10,11].

Regulatory mechanisms of host tissue and gut microbiota

While the impact of microbial metabolites on host physiology is extensively studied, the host actively regulates the gut microbiota through hormonal secretion, nutrient availability, and alterations in the intestinal environment. Enteroendocrine cells (EECs) secrete GLP-1 and peptide YY (PYY) in response to nutrient intake, promoting the abundance of Akkermansia muciniphila while suppressing Enterobacteriaceae proliferation[12]. Glucocorticoids modulate tight junction protein expression via intestinal epithelial receptors, thereby reducing bacterial translocation. Nutrient availability represents another critical pathway: High-fat diets induce bile acid accumulation, fostering the growth of sulfate-reducing bacteria such as Bilophila wadsworthia, whereas SCFA derived from dietary fiber fermentation inhibit pathogenic bacteria. Changes in the intestinal environment similarly exert regulatory effects: Thinning of the mucus layer triggers excessive Akkermansia proliferation, compromising barrier integrity; inflammation elevates oxygen tension, facilitating the expansion of facultative anaerobes[13]; and intestinal motility rate directly influences microbial colonization efficiency[12]. These host-driven regulatory mechanisms are fundamental to maintaining intestinal homeostasis and modulating disease pathogenesis.

IPA in metabolic homeostasis: Systemic anti-aging

IPA was identified as a metabolic product within the aromatic amino acid biosynthetic pathway of the gut commensal bacterium Clostridium sporogenes, where tryptophan serves as the primary substrate for its generation[14]. This bacterial tryptophan metabolite exhibits glucose-lowering effects and enhances insulin sensitivity[15]. IPA exhibits significant therapeutic efficacy in mitigating metabolic syndrome, with its circulating levels serving as a robust predictive biomarker for the onset and progression of metabolic disorders[16]. IPA's insulinotropic activity suggests therapeutic potential for improving lipid metabolism. Although low-dose IPA administration fails to demonstrate significant systemic lipid-modulating effects, it ameliorates hepatic steatosis[17]. Mechanistically, following its secretion from the gut into systemic circulation, IPA targets STAT3 in hypothalamic appetite-regulating centers, promoting its phosphorylation and nuclear translocation, thereby enhancing leptin and modulating the balance between appetite control and energy metabolism[18]. While current data reveal no substantial adverse effects, excessive IPA accumulation may induce leptin tolerance in neural circuits. In addition, experimental murine models demonstrated multiple beneficial effects of IPA[19]: (1) It significantly attenuated body weight gain in diet-induced obese mice; (2) Enhanced expression of genes related to lipolysis and lipid metabolism (e.g., ATGL, HSL, and CPT1-α); (3) Reduced hepatic lipid accumulation as evidenced by histological and biochemical analyses; and (4) Suppressed production of pro-inflammatory cytokines including tumor necrosis factor-alpha and interleukin-6. As the central organ for human lipid metabolism, the liver is significantly influenced by IPA. Emerging evidence indicates that IPA exerts hepatoprotective effects by suppressing fibrotic progression, thereby maintaining hepatic regulatory functions in lipid homeostasis[20]. IPA demonstrates synergistic anti-obesity effects with other gut microbiota-derived metabolites, particularly sodium butyrate (SB) and valerate (VA), through complementary metabolic pathways[21]. The biological effects of IPA underscore the critical influence of the gut microenvironment on systemic metabolism. Notably, obese individuals exhibit a marked decline in circulating IPA levels, which not only reflects dysbiosis-driven alterations in intestinal homeostasis but also provides novel therapeutic insights for clinical interventions targeting obesity through gut microbiota modulation. As indicated in Table 1[22-24], gut-originated IPA plays a significant role in promoting weight loss.

Table 1 The Role of gut origined indole-3-propionic acid in the weight loss.

Affiliation	Method	Result	Conclusion	Ref.
Stanford University, United States	Gene editing using pMTL007C-E2 plasmid with Ll.LtrB group II intron	Identified tryptophan-derived metabolite IPA	Enhances intestinal function: (1) Restores gut barrier integrity; and (2) Attenuates inflammatory responses	[6]
Zhejiang University, China	In vitro pull-down with site mutation to find STAT3 binding site	Trp623 in SH2 domain is key site for IPA binding; IPA enhances leptin sensitivity to combat obesity	Metabolic modulation: (1) Suppresses appetite; and (2) Enhances glucose metabolism	[8]
Shanghai Jiao Tong University, China	Obesity model by high-fat diet; 16S sequencing and LC-MS/MS used for serum IPA quantification	IPA ameliorates hepatic steatosis	Hepatic protection: (1) Suppresses hepatic lipid accumulation; and (2) Promotes intrahepatic lipolysis	[7]
All India Institute of Medical Sciences	Liver histology + LC-MS quantification	Circulating IPA level negatively correlated with liver fibrosis severity	Hepatoprotective effects of IPA. Inhibits liver injury to maintain normal lipid metabolism	[13]
China Agricultural University	High-fat diet mouse model; FMT and microbiome sequencing	IPA + SB + VA combination modulates gut-liver-brain axis and shows anti-obesity potential	Anti-obesity mechanisms: (1) Preserves gut microbiota homeostasis; and (2) Activates hepatic leptin signaling	[14]
King’s College London, United Kingdom	16S rRNA gene sequencing (V3–V4 region)	Gut microbiota composition (esp. butyrate-producers) significantly affects circulating IPA levels	Metabolic function prediction: (1) IPA levels correlate with clinical parameters of metabolic syndrome; and (2) Predicts type 2 diabetes onset	[23]
Southern Medical University, China	IPA administered externally in HFD-induced model	IPA activates tuft cell–IL-25 axis, restores colonic barrier, and prevents obesity/metabolic disorders	Multifunctional effects of IPA: (1) Ameliorates glucose/Lipid metabolic disorders; (2) Attenuates adipose and intestinal inflammation; and (3) Suppresses adipocyte hypertrophy	[24]

16S: 16S ribosomal RNA; 16S-seq: 16S rRNA gene sequencing; FMT: Fecal microbiota transplantation; HFD: High-fat diet; IL-25: Interleukin-25; IPA: Indole-3-propionic acid; LC-MS/MS: Liquid chromatography–tandem mass spectrometry; LC-MS: Liquid chromatography–mass spectrometry; SB: Sodium butyrate; SH2: Src homology 2 domain; VA: Valeric acid.

Role of SCFA in metabolism and obesity

SCFAs, as a class of organic fatty acids produced by gut microbial fermentation of dietary fiber, primarily include acetate, propionate, and butyrate. SCFAs exhibit a significant correlation with obesity. SCFAs modulate metabolic homeostasis by activating G protein-coupled receptors (GPCRs), including GPR41, GPR43, and GPR109A[22]. In the context of energy metabolism, SCFAs are predominantly absorbed by intestinal epithelial cells in the human gut. Notably, butyrate serves as a key regulator of intestinal barrier function, thereby indirectly enhancing nutrient absorption efficiency[23]. Acetate enhances hepatic lipid metabolism by promoting mitochondrial function, shifting hepatic lipogenesis toward β-oxidation[24]. This metabolic reprogramming increases thermogenic efficiency and reduces adiposity. SCFAs modulate intestinal endocrine function through multiple signaling pathways. The intestinal epithelium harbors a substantial population of EECs. SCFAs activate these specialized cells via GPCRs, particularly GPR41 and GPR43, stimulating the secretion of metabolically critical gut hormones such as GLP-1 and PYY[25,26]. In addition, SCFAs can directly or indirectly promote insulin secretion through neuroendocrine modulation, particularly via the parasympathetic nervous system[27]. SCFAs enhance insulin sensitivity, thereby contributing to glycemic control and promoting anabolic metabolism[28]. Aberrant SCFA profiles can induce the aforementioned metabolic disturbances and insulin resistance, thereby exacerbating obesity. Specifically, impaired absorption or production of key SCFAs (particularly butyrate and propionate) shows strong correlation with diminished insulin responsiveness and elevated risk of type 2 diabetes mellitus (T2DM)[29]. Obese individuals exhibit reduced circulating SCFAs levels, and this deficiency plays a pivotal role in the development of insulin resistance. As shown in Table 2, the role of SCFAs in the gut is clearly demonstrated.

Table 2 The role of short-chain fatty acid in the gut.

Affiliation	Method	Result	Conclusion	Ref.
Institute of Microecology, Germany	Controlled human study comparing SCFA levels across BMI groups	SCFA levels were significantly higher in obese and overweight groups vs healthy individuals	The acetate/propionate/butyrate ratio modulates obesity development	[24]
Imperial College London, United Kingdom	Nanoparticle-based acetate intervention in HFD-induced obese mice	Acetate improved liver mitochondrial function and reduced lipid accumulation	Anti-obesity effects of acetate: (1) Reduces hepatic lipid accumulation; and (2) Enhances systemic thermogenesis	[17]

SCFA: Short-chain fatty acid; BMI: Body mass index; HFD: High-fat diet.

SCFA-IPA Synergistic effects: A tripartite regulatory mechanism governing metabolism, immunity, and barrier function

SCFAs and IPA demonstrate remarkable synergistic effects in anti-inflammatory immunomodulation, metabolic homeostasis maintenance, and intestinal barrier repair. SCFAs, particularly butyrate, exert their anti-inflammatory effects through dual mechanisms: Activation of G protein-coupled receptors (FFAR2/3) to promote regulatory T cell differentiation, and inhibition of histone deacetylase (HDAC) activity to regulate inflammatory cytokine expression. Simultaneously, IPA binds to methionine adenosyltransferase 2A to promote S-adenosylmethionine synthesis, thereby inhibiting TLR4 ubiquitination and blocking the NF-κB signaling pathway, forming a multi-layered anti-inflammatory network with SCFAs. In metabolic regulation, SCFAs maintain energy balance through direct energy provision (butyrate nourishing intestinal epithelium) and indirect modulation (propionate participating in hepatic gluconeogenesis), while IPA exerts synergistic effects by improving insulin sensitivity, establishing a complementary "substrate supply-signal regulation" mechanism. Notably, these two metabolites also synergistically enhance intestinal barrier function: SCFAs inhibit pathogen colonization by maintaining an acidic microenvironment and promoting mucus secretion, while IPA supports mucosal repair by modulating microbial balance. Furthermore, both compounds collectively protect against inflammatory damage to tight junction proteins and promote epithelial regeneration through activation of pathways such as PPARγ (by SCFAs) and Nrf2 (by IPA), providing dual protection for the intestinal barrier. This trinity of "metabolism-immunity-barrier" synergistic mechanisms offers new perspectives for understanding host-microbiota interactions and establishes a theoretical foundation for developing intervention strategies against metabolic diseases.

In summary, obese individuals exhibit reduced circulating levels of both IPA and SCFAs[30,31]. This suggests a significant inverse correlation with obesity. IPA and SCFAs, as bacterial metabolites, exhibit synergistic effects in the regulation of host metabolism. Both demonstrate anti-inflammatory properties by suppressing pro-inflammatory cytokines, whose elevated levels are mechanistically linked to the development of insulin resistance and obesity. These observations support the consideration of IPA and SCFAs level modulation as a potential therapeutic avenue for obesity.

Metabolite dysbiosis-driven microbial translocation to adipose tissue

Gut microbial metabolites critically regulate intestinal barrier integrity and systemic metabolic homeostasis. Locally, SCFAs (particularly butyrate) enhance gut barrier function by upregulating tight junction proteins (occludin, claudin-1) and stimulating mucus production via GPR109A activation[32]. Concurrently, IPA contributes to epithelial repair mechanisms[33]. Conversely, dysbiosis-induced metabolite depletion disrupts this equilibrium: Diminished SCFA production compromises intestinal barrier integrity, facilitating translocation of microbial components.

Systemically, metabolite imbalances promote microbial translocation to adipose tissue through two interconnected pathways: Barrier dysfunction: SCFA deficiency reduces tight junction protein expression, enabling bacterial DNA and lipopolysaccharides translocation into circulation; Adipose tissue colonization: Compromised barrier integrity permits viable bacterial translocation to visceral adipose tissue (VAT), as evidenced by increased bacterial CFU counts in VAT and decreased occludin expression in high-fat diet models.

This establishes a pathogenic cycle: Microbial components in VAT trigger adipose inflammation, which further exacerbates gut permeability through systemic inflammatory mediators, perpetuating dysbiosis and metabolic dysfunction[32,34].

Strategies for modulating IPA and SCFAs levels

The pleiotropic regulatory effects of IPA and SCFAs on systemic metabolism offer promising therapeutic targets for clinical intervention. Exogenous modulation of IPA and SCFAs levels induces dynamic alterations in cellular signaling molecules, consequently reprogramming downstream pathway activities. Clinically, strategic manipulation of the intestinal microenvironment-including microbial composition, dietary interventions, and pH modulation-can effectively regulate enteric neuroendocrine functions to optimize nutrient absorption and metabolic utilization.

Under conditions of gut microbiota dysbiosis, the produced SCFA can activate carbohydrate-responsive element-binding protein and sterol regulatory element-binding transcription factor 1, thereby inducing lipogenesis and increasing triglyceride storage through related molecular pathways. Concurrently, SCFAs suppress the expression of fasting-induced adipose factor, which subsequently inhibits lipoprotein lipase activity, leading to triglyceride accumulation in adipocytes and ultimately contributing to obesity development[35].

Furthermore, indole derivatives, particularly indole-3-carboxaldehyde and indole-2-carboxaldehyde, can activate AMP-activated protein kinase and protein kinase A, downregulating the expression of PPARγ and CCAAT/enhancer-binding protein alpha, thereby inhibiting the differentiation of 3T3-L1 preadipocytes. When indole metabolism is dysregulated (e.g., insufficient production of indole derivatives or abnormal metabolic pathways), this regulatory mechanism becomes impaired, leading to the release of preadipocyte differentiation inhibition. Consequently, enhanced adipogenesis may promote the initiation and progression of obesity[36].

Microbial exosomes in metabolic regulation

Microbial exosomes, including bacterial outer membrane vesicles (OMVs) and extracellular vesicles (EVs), play a pivotal role in host metabolic regulation. Gut microbiota-derived exosomes modulate key metabolic pathways, such as SCFA and bile acid metabolism, thereby influencing systemic energy homeostasis. These vesicles not only regulate local intestinal microenvironments but also exert distal effects on peripheral organs (e.g., liver, adipose tissue, and brain) via systemic circulation, orchestrating an intricate balance between anabolic and catabolic processes. Emerging evidence highlights that exosomes from specific bacterial taxa-including Bacteroides, Akkermansia, and Lactobacillus-mediate obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD) through multifaceted mechanisms, offering novel therapeutic avenues for metabolic disorders.

Bacteroides-derived OMVs: Hormonal and receptor-mediated metabolic control

OMVs secreted by Bacteroides species (e.g., B. thetaiotaomicron and B. fragilis) modulate host energy intake and expenditure by regulating metabolic hormones and receptors. Studies demonstrate that OMVs significantly upregulate PYY, GLP-1/2, prohormone convertase 1 (PC1/PCSK1), and G protein-coupled receptors (GPR119, GPR120), as well as bile acid receptor TGR5, enhancing satiety and reducing caloric intake to mitigate weight gain[37]. Furthermore, OMV-associated phosphatidylcholine suppresses inflammation (e.g., via the cGAS-STING pathway) while potentiating crosstalk between GLP-1 receptor and insulin signaling cascades, upregulating insulin receptor substrates (IRS1/IRS2) to improve insulin sensitivity. Notably, Sundaram et al[35] revealed that OMVs from Akkermansia muciniphila, pre-conditioned with garlic exosome-like nanoparticles (GaELNs), reversed high-fat diet-induced T2DM in mice. GaELN treatment elevated OMV levels of Amuc-1100, P9, and phosphatidylcholine, augmenting GLP-1 secretion, attenuating inflammation, and activating insulin signaling[38]. These findings underscore OMVs as promising metabolic modulators.

Lactobacillus-derived EVs: Immunometabolic crosstalk and adipose remodeling

EVs from Lactobacillus and Bifidobacterium species reshape host immunometabolic networks and lipid metabolism. Adipocyte-derived EVs function as novel adipokines, promoting white adipose tissue (WAT) browning and energy expenditure. Specifically, EVs from brown adipose tissue or adipose-derived stem cells transfer mitochondrial proteins (e.g., UCP1) and regulatory miRNAs (e.g., miR-27a) to enhance thermogenesis and metabolic flexibility[39]. Beyond obesity, EVs are implicated in insulin resistance, diabetes, and NAFLD. For instance, hepatocyte-derived EVs deliver fibroblast growth factor 21 to ameliorate glucose/Lipid metabolism, while gut microbiota EVs modulate bile acid homeostasis to reduce hepatic steatosis. These insights advocate for EV-based therapies targeting metabolic dysregulation.

The broad metabolic influence of microbial exosomes spans hormonal regulation, anti-inflammatory actions, insulin signaling potentiation, and adipose tissue remodeling. Current strategies-including engineered exosomes and targeted delivery systems-have demonstrated efficacy in murine models, with some advancing to clinical trials. Future research must delineate species-specific exosomal mechanisms, refine isolation and delivery technologies, and evaluate translational safety and efficacy. Converging advances in synthetic biology and nanomedicine position microbial exosomes as a transformative paradigm for precision medicine in metabolic diseases.

Gut peptide hormones: Altering intestinal mucosal permeability affects nutrient absorption efficiency and weight loss

In recent years, intestinal-derived peptide hormones including GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and ghrelin have been identified as critical modulators of energy homeostasis and appetite regulation. These hormones coordinate peripheral metabolism with central nervous system signaling through distinct yet synergistic mechanisms. Under physiological conditions, GLP-1 and GIP serve as primary anabolic regulators: GLP-1, secreted by intestinal L cells, enhances glucose-dependent insulin secretion while suppressing glucagon release, and delays gastric emptying via vagal activation-the "ileal brake" effect-that prolongs intestinal transit time and reduces colonic motility[40]. Simultaneously, GIP secreted by K cells promotes insulin biosynthesis predominantly in the fed state[41]. This hormonal system ensures energy balance by integrating nutrient sensing, appetite modulation, and metabolic adaptation.

In conditions such as obesity and T2DM, the roles of these hormones become more complex. GLP-1 receptor agonists, such as Semaglutide and Tirzepatide, have been developed to mimic the action of GLP-1. They activate downstream signaling pathways, exerting hypoglycemic and weight loss effects. These agonists regulate appetite and energy metabolism through both central and peripheral pathways. Specific mechanisms include reducing leptin resistance to enhance leptin signaling, thereby increasing the effectiveness of leptin in suppressing appetite and regulating the appetite center of the brain, improving blood glucose control, and delaying gastric emptying[42]. The Wong et al[39] analysis evaluated the effects of GLP-1 receptor agonists on weight, BMI, and waist circumference in obese or overweight patients, showing significant weight loss. GIP agonism has also gained attention due to its potential therapeutic benefits, especially when combined with GLP-1. Co-activation of GLP-1 and GIP receptors can enhance weight loss, insulin release, and hypoglycemic effects compared to single GLP-1 receptor agonists[43]. Ghrelin, secreted by the stomach and small intestine, is known as the "hunger hormone" and primarily stimulates appetite and increases fat storage[44]. In pathological states, Ghrelin's role shifts towards mediating blood glucose through multiple downstream effectors, including reducing insulin sensitivity, inhibiting insulin secretion, and regulating GLP-1 secretion[45].

Therapeutic interventions targeting these hormones have shown promise. GLP-1 receptor agonists, such as Semaglutide and Tirzepatide, are widely used for their hypoglycemic and weight loss effects[46]. Additionally, novel dual-receptor agonists like LY3298176, which target both GLP-1 and GIP receptors, provide clinically meaningful improvements in glycemic control and weight loss. Acupuncture has also been explored as a potential therapy to modulate these hormones. Studies have shown that acupuncture can influence the secretion of GLP-1 and Ghrelin, thereby affecting appetite and energy metabolism[47]. Future developments in multi-target agonists will likely offer new strategies for the treatment of obesity and diabetes (Table 3).

Table 3 The role of peptides in the gut.

Affiliation	Method	Result	Conclusion	Ref.
Eli Lilly and Company, United States	Administer once weekly. Phase 1 included SAD, MAD, and POC with dulaglutide as control.	LY3298176 activated GIP/GLP-1 receptors, improving glucose tolerance and reducing weight/food intake in mice	This drug achieves the goal of weight loss by reducing food intake and lowering blood sugar	[31]
National University Health System, Singapore	Evaluate GLP-1 RAs on weight, BMI, and waist circumference in overweight/obese adults. 47 RCTs included	GLP-1 RAs reduced weight, BMI, and waist	GLP-1 RAs demonstrated significant weight, BMI, and waist circumference reduction benefits	[29]
McGill University Health Centre, Canada	Narrative review using keywords on GLP-1-based therapies, obesity, and energy regulation	GLP-1 RAs act centrally and peripherally to reduce appetite, improve glucose control, and enhance metabolic health	GLP-1 RAs regulate obesity via central/peripheral mechanisms, suppressing appetite and improving metabolism	[28]
King Saud University, Saudi Arabia	Review of gut hormones' role in obesity, SCFAs, and protein-based interventions. Covered GLP-1, PYY, ghrelin, individual/combined therapies, and SCFAs' influence on hormone secretion	GLP-1 RAs and PYY reduce intake/weight, while SCFAs stimulate GLP-1/PYY for satiety/weight control	PYY and GLP-1 receptor mechanisms drive weight loss by regulating appetite and energy balance through gut hormone modulation	[4]
University of Texas Southwestern Medical Center, United States	Explored ghrelin’s effect on insulin, glucagon, and CNS, and glucose’s feedback on ghrelin secretion	Ghrelin increases blood glucose, reduces insulin effects, and worsens glucose tolerance. May contribute to hyperglycemia in obesity/diabetes	Ghrelin elevates blood glucose via insulin resistance and appetite stimulation, promoting obesity; blocking its action aids weight loss	[45]

GLP-1 RA: Glucagon-like peptide-1 receptor agonist; GIP: Glucose-dependent insulinotropic polypeptide; PYY: Peptide YY; CCK: Cholecystokinin; HFD: High-fat diet; RCT: Randomized controlled trial; SAD: Single ascending dose; MAD: Multiple ascending dose; POC: Proof-of-concept.

Neurotransmitters and their defining role in metabolic regulation and obesity

Serotonin (5-HT) signaling: Dual roles in intestinal physiology and systemic energy homeostasis. Serotonin (5-HT), an important metabolite of tryptophan, not only governs the development and neurogenesis of the enteric nervous system but also regulates intestinal motility, secretory functions, inflammatory responses, sensory transduction, and epithelial cell development[48,49]. Beyond its intestinal functions, 5-HT critically regulates systemic energy balance. In healthy states, central serotonin (5-HT) regulates energy intake by suppressing appetite, whereas peripheral 5-HT supports whole-body energy homeostasis through promoting adipogenesis, modulating insulin secretion, and maintaining glucose metabolic balance. However, excessive activation of the peripheral 5-HT system not only disrupts this energy homeostasis but also triggers visceral fat accumulation, insulin resistance, and dysregulation of lipid metabolism[50]. As a key systemic signaling molecule, 5-HT is involved in regulating various physiological functions within the gastrointestinal system, including intestinal peristaltic rhythm and secretory activities[51]. Furthermore, abnormal changes in 5-HT signal transduction may be associated with the regulation of the severity of intestinal inflammation[52].

Gut-originated dopamine in weight regulation: Therapeutic potential and obesity risk via dopamine D1 and D2 receptor desensitization. Dopamine and gut hormones exhibit complex interactions in the regulation of body weight. As a core central neurotransmitter, dopamine not only governs reward, motivation, and motor function regulation but also forms an intricate signaling network with gut hormones in the regulation of metabolic homeostasis[53]. Under healthy physiological conditions, dopamine acts on DRD2 and DRD1 receptors to modulate metabolic processes (including the maintenance of glycemic homeostasis and regulation of energy expenditure) and endocrine functions (such as inhibiting prolactin secretion). A deficiency in the Trappc9 gene, leading to impaired Rab11 protein function, can result in reduced formation of dopaminergic synapses, accompanied by downregulation of DRD2 receptor expression and upregulation of DRD1 receptor expression. This, in turn, induces metabolic disorder phenotypes including hyperglycemia, obesity, and NAFLD[54]. Research indicates that activation of dopamine neurons in the ventral tegmental area can antagonize GLP-1R signaling, thereby diminishing its mediated satiety effect, which in turn promotes hedonic feeding behavior and can induce obesity[55]. Conversely, dietary glucose can stimulate local intestinal dopamine release, synergistically enhancing the efficacy of GLP-1 in regulating lipid metabolism within WAT. This reveals a potential mechanism by which dietary components and neurotransmitters collaboratively maintain energy balance[56]. Recent research on Orexin-A indicates that this factor can activate dopamine neurons in the mesolimbic pathway, promoting an increased release of endocannabinoids (e.g., 2-AG). This, in turn, inhibits synaptic input to GABAergic neurons, ultimately leading to elevated dopamine concentrations in the nucleus accumbens region. In obese mouse models, this mechanism can trigger the desensitization of dopamine D2 receptors, subsequently leading to compulsive intake of high-calorie foods[57].

Gamma-aminobutyric acid: Regulating feeding neurons in metabolic disorders and gut immunity. Gamma-aminobutyric acid (GABA), a key inhibitory neurotransmitter in the mammalian central nervous system, not only governs neural signal regulation but also plays a vital role in intestinal physiology, regulating motility, secretory functions, mucosal homeostasis, and inflammatory responses. Research indicates that GABA modulates the activity of immune cells (such as macrophages and T cells) or intestinal motor function to influence the local microenvironment[58]. Under healthy conditions, AgRP neurons inhibit MC4R neurons in the dorsal part of the bed nucleus of the stria terminalis (dBNST) via GABA, thereby maintaining normal food intake and energy balance. Whereas in pathological states, a high-fat diet desensitizes AgRP neurons, leading to reduced GABA release, which results in the overactivation of dBNST-MC4R neurons, promoting hyperphagia and obesity. Concurrently, the expression of the GABA_A receptor α5 subunit decreases, weakening inhibitory function, and further exacerbating metabolic disorders[59]. In the field of metabolic diseases, GABA's immunomodulatory effects and its ability to induce β-cell regeneration make it a highly promising candidate target for the treatment of type 1 diabetes. Furthermore, the synthesis of GABA in the liver has been identified as a potential therapeutic target, as its action can improve systemic glucose homeostasis independently of other pathways and reduce food intake in obese patients[60].

THE ROLE OF GUT SUBSTANCES IN OBESITY PATHOPHYSIOLOGY

Altered hormone profiles in obese individuals

Hormonal changes observed in obese individuals, particularly those regulating appetite and metabolism, play a critical role in the onset and maintenance of obesity. Studies show that gut hormones such as GLP-1, PYY, and cholecystokinin (CCK) often exhibit reduced postprandial responses, while hormones like insulin and pancreatic polypeptide (PP) show altered baseline levels or responses. Additionally, key central-peripheral signaling hormones like leptin and ghrelin also undergo significant alterations.

Leptin, a hormone secreted by adipose tissue, normally signals satiety to the hypothalamus to suppress appetite. However, in obese individuals, despite elevated plasma leptin levels, leptin resistance occurs, meaning the brain becomes less responsive to its signals[61]. This leads to a breakdown in appetite control, causing increased hunger despite adequate energy reserves. Studies indicate that higher leptin levels correlate with obesity severity, particularly in individuals with greater visceral fat accumulation[62].

Conversely, ghrelin, the only known hunger hormone that significantly stimulates appetite, shows reduced baseline levels and attenuated suppression after meals in obese individuals. This altered ghrelin response may weaken the satiety feedback loop, encouraging excessive energy intake and weight gain[63]. Additionally, the reduced postprandial response of GLP-1 and PYY means that obese individuals may not experience sufficient signals of satiety after eating, contributing to prolonged eating behavior[64]. Weight loss interventions have shown that, while dieting significantly decreases leptin levels (35% reduction with 15% weight loss), ghrelin levels may increase, which partly explains the propensity for weight regain after dieting[65]. In contrast, exercise interventions tend to have a more moderate effect on hormonal regulation but can improve GLP-1 and PYY responses to some extent, offering a beneficial role in weight maintenance.

These hormonal changes affect not only appetite regulation but also energy metabolism, insulin sensitivity, and overall fat distribution. For example, excess visceral fat promotes cortisol production, which exacerbates insulin resistance and increases the risk of metabolic syndrome. In women, obesity is also commonly associated with hyperinsulinemia, particularly in those with polycystic ovary syndrome, where insulin promotes ovarian androgen production, disrupting ovulation and menstrual cycles.

In conclusion, the hormonal changes associated with obesity are bidirectional, acting both as potential causes and consequences of the condition. Regardless of the direction of causality, these changes play a significant role in the onset, persistence, and treatment of obesity, and should be a focal point in future research and clinical interventions (Table 4).

Table 4 Changes in gut hormones under obesity conditions.

Hormone	Alteration in obesity	Response to weight loss	Ref.
GLP-1	Blunted postprandial response, reduced levels	Diet reduces fasting levels, exercise may increase postprandial levels	[55]
Peptide YY	Attenuated postprandial response, lower levels	Diet decreases fasting levels, exercise may increase in some cases	[55]
Pancreatic polypeptide	Conflicting results, often lower fasting levels	Diet increases postprandial levels, sustained for 1 year	[55]
Cholecystokinin	Reduced postprandial levels post-weight loss	Diet reduces levels, exercise has minimal effect	[55]
Leptin	Higher baseline levels in obese individuals	Decreases significantly with diet (35% with 15% weight loss), sustained reduction	[55]
Ghrelin	Lower fasting/postprandial levels, less suppression post-meal	Increases with diet (17% with 4.5% weight loss), exercise enhances post-loss levels	[55]

Further disruption in satiety and appetite signaling: A deeper look into hormonal dysregulation

The dysregulation of the intricate network governing satiety and appetite is a central element in the pathophysiology of obesity. This dysregulation involves complex neuroendocrine signaling pathways, manifesting particularly as an imbalance in gut hormone signals, a decline in central and peripheral sensitivity to satiety cues, and an abnormal influence of food components on hormone release. Normal energy homeostasis relies on the synergistic action of various gut hormones that precisely modulate the generation and suppression of appetite. However, this balance is frequently disrupted in individuals with obesity. For instance, levels of ghrelin, often termed the hunger hormone, may be excessively elevated before meals or insufficiently suppressed postprandially, persistently driving feeding behavior. A research highlight the critical roles of leptin and ghrelin in appetite regulation and their dysregulated state in obesity[66]. Conversely, the secretion patterns or biological activity of hormones involved in generating satiety, such as GLP-1, PYY, and CCK, may also be altered. Another research explored the role of appetite-related peptides like ghrelin, PYY, and GLP-1 in children and adolescents, suggesting that dysregulation of these signals can occur early in life. This imbalance in gut hormone signaling leads to weakened appetite-suppressing signals and amplified appetite-stimulating signals reaching the brain, thereby promoting increased energy intake and weight gain[67]. Beyond alterations in hormone secretion, a common phenomenon in obesity is the decreased sensitivity of the body to satiety signals, notably "leptin resistance". Leptin, primarily secreted by adipose tissue, acts on the hypothalamus to suppress appetite and increase energy expenditure. However, in many individuals with obesity, its appetite-suppressing effect is markedly diminished despite high circulating leptin levels. Structural insights into the leptin receptor activation mechanism offer a molecular basis for understanding the complexity of leptin signal transduction and potential impairments in a resistance state[68]. Further, Mondal et al[70] investigated the interplay between miRNA and leptin signaling in metabolic diseases, suggesting that epigenetic regulation may also contribute to the modulation of leptin sensitivity[69]. Additionally, research found that dysfunction of the adhesion G protein-coupled receptor latrophilin 1 (ADGRL1/LPHN1) increases the risk of obesity, potentially implicating broader signaling pathways in the regulation of appetite, energy balance, and their sensitivity[70]. It is noteworthy that reported no significant differences in the expression of satiety hormones in the human colon of obese vs non-obese individuals, which underscores the importance of receptor sensitivity and downstream signaling pathways beyond hormone levels themselves[71].

The type and composition of food, along with dietary patterns, exert a direct and significant influence on the release of gut hormones, and disturbances in this relationship are a crucial aspect of dysregulated satiety and appetite signaling. Specific nutrients, such as fats, carbohydrates, and proteins, differentially stimulate the secretion of various gut hormones. For example, a high-fat diet may alter the release patterns of certain satiety hormones. Research reviewed the role of gut microbiota in diet-driven alterations in food intake, emphasizing how microbiota can influence the release of satiety peptides, thereby affecting energy balance. Furthermore, some research has begun to focus on environmental factors like endocrine-disrupting chemicals (EDCs)[72]. The study investigated the role of EDCs like bisphenols and phthalates in obesity, which may indirectly impact appetite-regulating hormones by disrupting normal hormonal signaling pathways[73]. Consequently, long-term adherence to unhealthy dietary structures or exposure to specific environmental compounds can lead to dysregulated appetite control by altering the response patterns of gut hormones, thereby promoting the onset and progression of obesity. The work which elucidated pathways to obesity from the perspectives of energy balance, body composition, sedentary behavior, and appetite regulation, indirectly supports the long-term impact of lifestyle and diet on appetite signals.

Gut microbiota-derived substances and obesity: Implications for metabolic health and therapeutic potential

Beyond the direct influence of gut hormones, the intricate ecosystem of the gut microbiota plays a pivotal role in obesity pathogenesis through the production of diverse bioactive substances. These microorganisms metabolize dietary components and host-derived products, generating a variety of compounds that can significantly impact host energy metabolism, appetite regulation, and immune responses, ultimately contributing to the development and progression of obesity and its metabolic complications. Key among these are microbial metabolites such as SCFA, bile acids, amino acids, and lipid-like metabolites, as well as other bacterial products.

Research indicates that the profiles of these gut microbiota-derived metabolites are often altered in individuals with overweight and obesity[74]. A systematic review highlighted that altered levels of amino acids, lipids, and bile acids, among others (including metabolites derived from carnitine, choline, polyphenols, and purines), are frequently observed in obese states and are implicated in associated metabolic complications such as insulin resistance, hyperglycemia, and dyslipidemia[75]. While the exact mechanisms by which all these substances exert their effects are complex and still under investigation, SCFAs, primarily acetate, propionate, and butyrate, produced through the fermentation of dietary fibers by gut bacteria, are known to influence host metabolism through various pathways, including serving as energy substrates, signaling molecules, and regulators of gene expression.

The gut microbiota and its products are closely linked to the inflammatory state commonly associated with obesity. Dysbiosis, or an altered microbial ecosystem, can increase gut permeability, allowing bacterial products such as lipopolysaccharides to enter the bloodstream. This process triggers low-grade systemic inflammation, contributing to insulin resistance and metabolic dysfunction, which are hallmarks of obesity. The interaction between gut microbes, host metabolism, and inflammation forms a critical axis in the pathophysiology of obesity-related metabolic diseases. Consequently, managing the gut microbiota is emerging as a promising therapeutic approach for obesity, as it can influence the production and bioavailability of these microbial products. Understanding the mechanisms through which these physiologically active compounds affect host physiology is essential for developing novel interventions aimed at restoring a healthy metabolic balance and mitigating obesity's adverse effects.

CLINICAL AND THERAPEUTIC APPLICATIONS

Rapid efficacy accompanied by gastrointestinal and neuropsychiatric side effects?

The pivotal role of gut hormones in regulating appetite, energy metabolism, and glucose homeostasis has established them as highly promising targets for the development of novel pharmacotherapies for obesity and related metabolic diseases, particularly T2DM[76]. Leveraging the physiological effects of these endogenous peptides offers a strategy to restore or enhance the body's natural satiety signals and metabolic regulation. Current drug development efforts primarily focus on synthesizing analogues of anorexigenic gut peptides that exhibit improved pharmacological properties, such as extended half-life and increased resistance to enzymatic degradation, or on developing compounds that modulate the activity of their receptors[77]. Key targets include GLP-1, PYY, CCK, amylin, and GIP, while strategies also exist for modulating the orexigenic hormone ghrelin[78]. GLP-1 receptor agonists, such as Semaglutide, have already demonstrated significant efficacy in promoting weight loss and improving glycemic control, becoming a cornerstone of obesity and diabetes management. These drugs mimic the action of native GLP-1, enhancing glucose-dependent insulin secretion, suppressing glucagon release, slowing gastric emptying, and promoting satiety, thereby reducing food intake.

Building upon the success of single-target therapies, the field is rapidly progressing towards multi-target approaches, particularly dual and triple agonists that activate receptors for multiple gut hormones simultaneously. For instance, dual agonists targeting both GLP-1 and GIP receptors, such as Tirzepatide, have shown even greater weight loss and metabolic benefits in clinical trials compared to GLP-1 monotherapy[79]. These polyagonists aim to harness the synergistic effects of different gut hormones to achieve more profound and comprehensive metabolic improvements[80]. Research is also exploring combinations or individual modulators of other gut peptides like PYY and CCK, which have shown appetite-reducing effects in studies, though translating these findings into clinically effective pharmaceuticals still requires overcoming obstacles like ensuring sufficient half-life and delivery[81]. Amylin analogues and dual amylin and calcitonin receptor agonists are also progressing through advanced stages of clinical trials, highlighting the ongoing innovation in this space[82].

The remarkable efficacy achieved with some of these gut hormone-based medications has led to discussions about their potential to rival or even replace traditional obesity interventions like bariatric surgery in certain patients[83]. Furthermore, the scope of gut hormone-targeted therapies is expanding beyond obesity and diabetes, with research exploring their potential roles in conditions like osteoporosis, where hormones such as GIP, GLP-1, GLP-2, and PYY have shown effects on bone metabolism[84]. Despite the significant progress, challenges remain, including optimizing drug delivery and formulation for peptide-based therapies, managing potential side effects, and addressing individual variability in response. Nevertheless, the continued exploration of novel gut peptides and pharmacological strategies offers promising prospects for the future of anti-obesity and metabolic disease treatments[85].

From diet to fecal microbiota transplantation: The expanding scope of gut microbiota modulation in metabolic health

Given the increasing understanding of the gut microbiota's significant role in the pathogenesis of obesity and related metabolic disorders[86], modulating the composition and function of this microbial ecosystem has emerged as a promising therapeutic strategy. The rationale for these interventions stems from observed alterations in the gut microbiota of obese individuals, including reduced diversity and shifts in the relative abundance of dominant phyla, such as an increased Firmicutes to Bacteroidetes ratio, which are associated with altered energy harvest and metabolic inflammation[87]. By targeting these microbial imbalances (dysbiosis), modulation therapies aim to restore a healthier gut environment, potentially improving metabolic health and promoting weight management.

Several approaches are being explored for gut microbiota modulation in the context of obesity. These include dietary interventions, supplementation with probiotics and prebiotics, and fecal microbiota transplantation (FMT)[88].

Dietary interventions are fundamental in shaping the gut microbiota composition and function. Diets rich in fiber, such as the Mediterranean diet, have been shown to favorably alter gut microbial profiles, increasing the abundance of beneficial bacteria that produce SCFA. These SCFAs can influence host metabolism, enhance gut barrier function, and reduce inflammation, potentially contributing to weight loss and improved metabolic markers[89].

Probiotics, which are live microorganisms, and prebiotics, non-digestible food ingredients that selectively stimulate the growth and activity of beneficial gut bacteria, are widely studied modulation strategies[90]. Supplementation with specific probiotic strains or combinations, and the intake of prebiotics, have shown potential in clinical trials to influence gut microbiota composition, improve metabolic parameters, and modestly aid weight management in some individuals. However, the efficacy can vary depending on the specific strains used, dosage, duration of intervention, and individual host factors.

FMT involves transferring fecal material from a healthy donor to the gastrointestinal tract of a recipient, with the aim of restoring a healthy microbial community. While primarily established for the treatment of Clostridioides difficile infection, FMT is being investigated as a more radical approach to modulate gut microbiota in obesity and metabolic syndrome. Early studies have shown some promising results in improving insulin sensitivity and metabolic profiles in obese individuals, suggesting its potential to alter the gut ecosystem in a way that favors metabolic health. However, FMT for obesity is still considered experimental, and more research is needed to establish its long-term safety, efficacy, optimal protocols, and the identification of suitable donors. As can be s seen in Figure 1.

Figure 1 Bidirectional mechanisms of gut microbiota in obesity regulation. The immune pathway involves B cells, T cells, dendritic cells, neutrophils, and macrophages. The neuroactive substance pathway includes metabolites such as gamma-aminobutyric acid, short-chain fatty acids, and tryptophan. The microbial pathway encompasses microbiota-derived signals. The endocrine pathway features gut peptides such as peptide YY and glucagon-like peptide-1 secreted by enteroendocrine cells. The neural pathway is mediated by the vagus nerve. The hypothalamic-pituitary-adrenal axis involves corticotropin-releasing factor, adrenocorticotropic hormone, and cortisol, which interact with gut hormones to regulate physiological processes.

Despite the promising potential, the field of gut microbiota modulation therapies for obesity is still evolving. Challenges include the significant variability in gut microbial composition across individuals, the complex interplay between diet, host genetics, environment, and microbiota, and the need for well-designed, large-scale randomized controlled trials to confirm efficacy and determine optimal therapeutic strategies. While current evidence supports the concept, results vary, and the long-term effects of many interventions require further study. Nevertheless, ongoing research is dedicated to exploring the gut microbiota's role and developing targeted microbial interventions for the management of obesity and related metabolic disorders[91].

While microbial metabolites affect host physiology, evidence reveals bidirectional crosstalk: Host factors reciprocally shape the gut microbiota. SCFAs activate GPR41/43 on enteroendocrine L cells, triggering GLP-1 release to regulate appetite and metabolism. Conversely, host immune states (e.g., chronic inflammation) alter intestinal oxygen tension, promoting pathobiont expansion and dysbiosis[92]. Furthermore, host-microbe co-metabolism of tryptophan generates AhR ligands, modulating host IDO activity and immune responses[93]. This interdependence exacerbates metabolic dysfunction in obesity.

CONCLUSION

The intricate interplay between gut-derived hormones, microbial metabolites, and neurochemical pathways establishes the gastrointestinal system as a central regulator of systemic energy metabolism and obesity pathophysiology. Emerging evidence underscores the significant roles of gut microbiota-derived metabolites, such as IPA, SCFA, and secondary bile acids, in maintaining metabolic homeostasis, modulating insulin sensitivity, and attenuating inflammation-critical processes disrupted in obesity. These microbial metabolites act through host receptors (e.g., GPR41/43 for SCFAs, FXR/TGR5 for bile acids) and epigenetic mechanisms to influence energy metabolism. Concurrently, gut peptide hormones (e.g., GLP-1, GIP, PYY, ghrelin) and neurotransmitters (e.g., serotonin, dopamine, GABA) function through complex gut-brain-liver-adipose axis signaling networks, regulating appetite, energy expenditure, and glucose metabolism.

Therapeutic advances targeting these pathways-including GLP-1/GIP dual/triple agonists, selective ghrelin antagonists, microbiota modulation (prebiotics, probiotics, FMT), and dietary interventions (high-fiber, polyphenol-rich diets)-demonstrate substantial efficacy in weight reduction and glycemic control. However, challenges remain due to inter-individual variability in gut microbiome composition, host genetics, and metabolic responses, as well as concerns regarding long-term safety, microbial resistance, and potential neuropsychiatric side effects (e.g., mood alterations with serotonin-modulating agents).

Future research should prioritize the integration of multi-omics approaches, including gut microbiome sequencing (16S rRNA, metagenomics, metatranscriptomics), plasma and tissue metabolomics to map microbial-host co-metabolites (e.g., IPA, SCFAs), and host genomics/epigenomics to uncover genetic polymorphisms (e.g., FTO, MC4R) and epigenetic modifications influencing gut-brain crosstalk. These data-driven strategies will enable the development of machine learning-based predictive models to stratify patients for tailored interventions, such as microbiome-targeted therapeutics (e.g., engineered probiotics like Akkermansia muciniphila over expressors or phage therapy to selectively modulate obesogenic bacteria) and personalized nutrition strategies optimized for individual microbial carbohydrate utilization capacity.

ACKNOWLEDGEMENTS

We thank the reviewers and editorial team for their insightful comments and the staff of Nanjing University of Chinese Medicine for technical support.