The gut–brain axis connects the central nervous system, gastrointestinal tract, and peripheral metabolic organs through autonomic nerves, enteroendocrine hormones, microbial metabolites, bile acids, and immune signals. Natural products can act on neural receptors, the gut microbiota, the intestinal barrier, and the circadian clock to regulate appetite, nutrient absorption, glycemic control, lipid distribution, and energy expenditure.

Keywords: natural products; gut–brain axis; vagus nerve; enteroendocrine system; gut microbiota; bile acids; metabolic homeostasis; GABRA1

1 The Gut–Brain Axis as a Bidirectional Communication Network for Metabolic Regulation

1.1 Central Nervous System Integration of Metabolic Information

The hypothalamic arcuate nucleus, brainstem nucleus tractus solitarius, and dorsal motor nucleus of the vagus are major centers for gut–brain metabolic regulation. POMC/CART neurons in the arcuate nucleus primarily transmit satiety and energy-expenditure signals, whereas NPY/AgRP neurons promote food intake and reduce energy expenditure. The nucleus tractus solitarius receives vagal afferent signals from the gastrointestinal tract, while the dorsal motor nucleus of the vagus sends parasympathetic regulatory commands to the gastrointestinal tract.

1.2 Vagal Communication Between the Gut and Brain

Vagal afferent fibers can sense luminal nutrients, gastrointestinal distension, enteroendocrine hormones, and inflammatory mediators and transmit this information to the brainstem. Vagal efferent fibers regulate gastric emptying, intestinal motility, digestive secretion, epithelial structure, and nutrient absorption. This pathway participates in the control of feeding behavior and can also directly alter the intestinal processing of nutrients such as lipids.

1.3 Enteroendocrine Transmission of Nutritional Status

(1) GLP-1 and PYY

Glucose, fatty acids, amino acids, bile acids, and microbial metabolites in the intestinal lumen can activate enteroendocrine cells and induce the release of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). GLP-1 promotes glucose-dependent insulin secretion, delays gastric emptying, and suppresses food intake, whereas PYY primarily enhances satiety signals through the Y-receptor system.

(2) CCK and ghrelin

Cholecystokinin (CCK) promotes gallbladder contraction and pancreatic enzyme secretion and transmits information concerning fat and protein intake to the brainstem through vagal afferent nerves. Ghrelin is mainly produced by gastrointestinal endocrine cells and can activate hypothalamic NPY/AgRP neurons to promote food intake. Its levels are regulated by nutritional status, gastric emptying, and circadian rhythms.

1.4 Long-Distance Signaling by Microbial Metabolites

(1) Short-chain fatty acids

Fermentation of dietary fiber by the gut microbiota produces short-chain fatty acids such as acetate, propionate, and butyrate. Short-chain fatty acids regulate GLP-1 and PYY release through FFAR2, FFAR3, and histone deacetylase-associated processes and influence hepatic gluconeogenesis, adipose tissue metabolism, intestinal barrier function, and immune cell activity.

(2) Bile acids

Primary bile acids undergo deconjugation and structural modification by the gut microbiota to form secondary bile acids, which exert signaling effects through the farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (GPBAR1/TGR5). The intestinal FXR–FGF19 axis participates in bile acid synthesis and hepatic glucose and lipid metabolism, whereas TGR5–cAMP signaling is associated with GLP-1 release, insulin secretion, and energy expenditure.

(3) Tryptophan metabolites

The gut microbiota can convert tryptophan into metabolites such as indole, indole-3-acetic acid, and indole-3-propionic acid. These molecules can regulate the aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and mucosal immune signaling and participate in maintaining intestinal epithelial integrity and local immune homeostasis.

1.5 Restriction of Metabolic Inflammation by the Intestinal Barrier

The mucus layer, intestinal epithelial cells, and tight-junction proteins collectively form the intestinal barrier. Nutrient excess, abnormal bile acid composition, and microbial dysbiosis can reduce the stability of tight-junction proteins such as ZO-1, occludin, and claudins, allowing microbial components such as lipopolysaccharide to enter the circulation and activate TLR4, NF-κB, and the NLRP3 inflammasome. Persistent low-grade inflammation can also interfere with hypothalamic leptin and insulin signaling.

1.6 Coordination of Gut–Brain Metabolic Rhythms by the Circadian Clock

The central circadian clock synchronizes food intake, hormone secretion, and energy expenditure according to the light–dark cycle, whereas peripheral clocks in the intestine and liver are regulated by feeding time, bile acids, and microbial metabolites. Circadian disruption can alter gut microbial oscillations, intestinal barrier permeability, hepatic glucose output, and lipid synthesis, increasing the risk of obesity and insulin resistance.

Table 1 Major Metabolic Signals of the Gut–Brain Axis

2 Direct Regulation of Gut–Brain Neural Circuits by Natural Products

2.1 Puerarin and the GABRA1–Vagus Nerve Pathway

(1) GABRA1 as a direct target of puerarin

Puerarin can bind to an allosteric site on the GABA_A receptor composed of α1, β3, and γ2L subunits, with the α1 subunit encoded by GABRA1. This interaction enhances inhibitory GABA signaling in neurons associated with the dorsal motor nucleus of the vagus, providing receptor- and structure-level evidence that natural products can directly regulate gut–brain neural circuits.

(2) Regulation of jejunal lipid absorption by the dorsal motor nucleus of the vagus

Neurons in the dorsal motor nucleus of the vagus that project to the jejunum can regulate the structure of intestinal epithelial microvilli. Inhibition of this neural circuit shortens jejunal microvilli, decreases intestinal lipid absorption, and increases fecal lipid excretion, whereas activation of the circuit enhances intestinal lipid absorption.

(3) Primary effect of puerarin on lipid absorption

Puerarin can reproduce the metabolic phenotype caused by inhibition of the dorsal motor nucleus–vagus nerve pathway, and its body-weight-regulatory effect is closely associated with reduced intestinal lipid absorption. Conditional deletion of Gabra1 markedly attenuates the puerarin-induced increase in fecal lipids, indicating that this mechanism differs from weight-loss patterns driven solely by reduced food intake.

2.2 Honokiol and GABAergic Neural Signaling

Honokiol can regulate certain GABA_A receptor subtypes and influence central inhibitory neurotransmission. GABAergic neural networks participate in stress, sleep, food intake, and autonomic output. Honokiol can be used to investigate the relationships among emotional state, feeding behavior, and gastrointestinal function, although its receptor-subtype selectivity, effective brain exposure, and sedative effects must be evaluated separately.

2.3 Nuciferine and Coordinated Central–Peripheral Regulation

Nuciferine can act on 5-HT₂- and dopamine receptor-associated neural signaling while also affecting HBXIP, TFEB, and autophagy–lysosomal metabolism. Its effects on body weight and lipid metabolism may involve feeding behavior, lipid-droplet degradation, and peripheral energy utilization. Central neural effects must be distinguished from direct actions in the liver and adipose tissue.

2.4 Celastrol and Hypothalamic Leptin Sensitivity

Celastrol can improve leptin responsiveness under obese conditions and regulate endoplasmic reticulum stress, inflammation, and mitochondrial homeostasis. Restoration of leptin signaling can suppress food intake and increase energy expenditure. However, celastrol also acts on targets such as CAP1, Nur77, and GRP78, and its metabolic phenotype may result from the combined involvement of multiple central and peripheral mechanisms.

3 Regulation of Enteroendocrine and Bile Acid Signaling by Natural Products

3.1 Berberine Remodels the Microbiota–Bile Acid Network

(1) Local actions within the intestinal lumen

Orally administered berberine has low systemic bioavailability but relatively high exposure within the intestinal lumen, allowing it to directly influence intestinal bacteria, bile acid composition, and intestinal epithelial metabolism. Berberine can also alter bile acid synthesis and excretion, making the intestine an important initial site for its regulation of systemic glucose and lipid metabolism.

(2) Functional remodeling of the microbiota

Berberine-induced changes do not necessarily manifest as a marked increase or decrease in microbial diversity. They may instead involve functional remodeling of bacterial carbohydrate metabolism, amino acid metabolism, cell-wall homeostasis, and ion transport. These effects should be analyzed together with the bile acid profile, microbial transcriptional functions, GLP-1, and peripheral metabolic indicators.

3.2 Oleanolic Acid and TGR5 Signaling

Oleanolic acid can activate the membrane bile acid receptor TGR5 and initiate Gαs–cAMP–Ca²⁺ signaling. In enteroendocrine cells, TGR5 activation is associated with GLP-1 release; in pancreatic β cells, this pathway can promote glucose-dependent insulin secretion. Oleanolic acid can be used to investigate the relationship among bile acid sensing, incretin signaling, and glycemic regulation.

3.3 Polyphenolic Natural Products and Incretins

(1) Enteroendocrine responses

Natural products such as epigallocatechin gallate, resveratrol, quercetin, naringin, and baicalin can affect intestinal nutrient sensing, bile acid composition, and microbial metabolism while regulating GLP-1, PYY, and insulin responses.

(2) Mechanistic boundaries

Changes in incretin levels induced by natural products may involve direct intestinal epithelial effects, microbial metabolite mediation, bile acid receptor regulation, and altered gastric emptying. An increase in GLP-1 only indicates that the enteroendocrine system has responded and cannot independently demonstrate that a specific receptor is a direct target of the natural product.

3.4 Convergence of Intestinal Signals on Central Satiety Circuits

GLP-1, PYY, and CCK can enter the circulation and activate local vagal afferent nerves. After initial integration in the nucleus tractus solitarius, these signals regulate food intake together with hypothalamic POMC/CART and NPY/AgRP neural networks. Evaluating the effects of natural products on appetite also requires exclusion of nonspecific factors such as markedly delayed gastric emptying, nausea, taste aversion, and reduced activity levels.

4 Remodeling of Microbiota–Metabolite Networks by Natural Products

4.1 Bidirectional Transformation Between Natural Products and the Gut Microbiota

(1) Microbial metabolism of natural products

Many glycosides, polyphenols, and saponins exhibit limited absorption in the small intestine and can enter the colon, where they undergo microbial deglycosylation, demethylation, reduction, and ring-cleavage reactions. The resulting metabolites may have greater absorption or distinct target activities. Interindividual differences in microbial composition can also affect the metabolic exposure and biological activity of natural products.

(2) Representative microbial metabolic processes

Ginsenoside Rb1 can undergo stepwise microbial deglycosylation to form rare ginsenosides and metabolites such as Compound K. Rutin can be converted into quercetin and small phenolic acids, whereas naringin can be converted into naringenin. The parent compounds, microbial metabolites, and host-conjugated metabolites of these natural products should be measured separately.

4.2 Short-Chain Fatty Acids Connect the Microbiota with Neuroendocrine Signaling

(1) Metabolic signaling effects

Natural products can indirectly affect acetate, propionate, and butyrate production by altering microbial substrate utilization and metabolic functions. Short-chain fatty acids can promote GLP-1 and PYY release from enteroendocrine cells and regulate the vagus nerve, hepatic glucose metabolism, adipose tissue function, and immune cell differentiation.

(2) Interpretation of microbial changes

Changes in microbial abundance do not correspond directly to short-chain fatty acid levels. An increase in the abundance of a particular bacterial group cannot independently demonstrate increased short-chain fatty acid production. Metagenomics, targeted metabolomics, and receptor-dependent results are still required to identify the mediators responsible for the effect.

4.3 Bile Acids as Joint Metabolic Products of the Host and Microbiota

(1) Structural modification of bile acids

After entering the intestine, primary bile acids synthesized by the liver can undergo microbial deconjugation, oxidation–reduction, and 7α-dehydroxylation to form different secondary bile acids. By altering bile acid synthesis, enterohepatic circulation, or microbial enzyme activity, natural products can reset the intensity of FXR and TGR5 signaling.

(2) Functional interpretation of bile acids

Bile acids function both in lipid emulsification and as signaling molecules. An increase in total bile acids, enhanced fecal bile acid excretion, and activation of specific bile acid receptors represent distinct mechanisms and must be distinguished through bile acid profiling, receptor activity, and tissue-specific downstream indicators.

4.4 Tryptophan Metabolism Influences the Intestinal Barrier and Central State

(1) Regulation of the intestinal barrier

Microbiota-derived indole metabolites can regulate AhR, PXR, and mucosal immune signaling and participate in maintaining mucus secretion, tight-junction proteins, and intestinal epithelial renewal. Microbial changes induced by polyphenolic natural products may alter tryptophan metabolic flux and the levels of indole metabolites.

(2) Interpretation of central effects

Intestinal tryptophan metabolism may also affect circulating tryptophan availability, kynurenine metabolism, and serotonin-associated processes. Changes in blood tryptophan or serotonin levels do not directly represent neurotransmitter activity in the brain and must be interpreted together with metabolite distribution across different tissues.

5 Maintenance of the Intestinal Barrier and Interruption of Inflammatory Signaling by Natural Products

5.1 Improvement of Tight-Junction and Mucus Barrier Stability

Natural products such as curcumin, quercetin, luteolin, apigenin, kaempferol, and sulforaphane can regulate ZO-1, occludin, claudins, and mucus-associated processes and reduce intestinal epithelial permeability under inflammatory or lipotoxic conditions. Improved barrier function can reduce the entry of lipopolysaccharide into the circulation and decrease the inflammatory burden on the liver, adipose tissue, and central nervous system.

5.2 Inhibition of TLR4–NF-κB Inflammatory Signaling

(1) Gut-derived inflammatory pathways

After entering the circulation, gut-derived lipopolysaccharide can activate TLR4–MyD88–NF-κB and MAPK signaling and promote the production of inflammatory mediators such as TNF-α, IL-6, and IL-1β. Persistent inflammation can inhibit insulin receptor substrate and AKT signaling and interfere with hypothalamic leptin sensitivity.

(2) Regulatory effects of natural products

Compounds such as curcumin, quercetin, luteolin, and salidroside can regulate TLR4–NF-κB-associated inflammatory responses. Decreases in inflammatory factors should be analyzed together with intestinal barrier permeability, circulating lipopolysaccharide, and tissue metabolic function to exclude effects caused by cytotoxicity or nonspecific free-radical scavenging.

5.3 Regulation of the NLRP3 Inflammasome

(1) Representative natural products

Oridonin can directly regulate NLRP3, licochalcone B can interfere with NEK7–NLRP3-associated interactions, and carnosol can affect HSP90 chaperone function and NLRP3 stability. These natural products can be used to investigate the relationships among intestinal inflammation, steatohepatitis, and insulin resistance.

(2) Assessment of inflammasome activity

NLRP3-associated mechanisms should be evaluated by examining inflammasome assembly, ASC speck formation, caspase-1 cleavage, and the maturation and release of IL-1β and IL-18. Reduced transcription of inflammatory factors primarily reflects attenuation of the priming signal and cannot independently demonstrate direct inhibition of inflammasome assembly by a natural product.

5.4 Activation of Nrf2-Mediated Antioxidant Defense

Sulforaphane, ginsenoside Rb1, curcumin, and carnosol can regulate the Keap1–Nrf2-associated antioxidant network and promote the expression of HO-1, NQO1, and glutathione metabolism-related genes. Reduced oxidative stress can protect intestinal epithelial mitochondria and tight junctions and decrease interference by inflammatory signaling with vagal and hypothalamic metabolic circuits.

6 Coordination of Circadian Rhythms and Peripheral Metabolic Execution by Natural Products

6.1 Nobiletin and the ROR Circadian Oscillator

(1) Regulation of ROR nuclear receptors

Nobiletin can act on ROR nuclear receptors and enhance molecular circadian oscillations. ROR regulates circadian genes such as BMAL1, and its downstream programs encompass hepatic glucose output, fatty acid oxidation, bile acid metabolism, and energy expenditure.

(2) Time dependence

The metabolic effects of nobiletin are time-dependent. Administration time, feeding phase, and sampling time can all influence blood glucose, lipid levels, and circadian gene expression. A single time point cannot fully reflect changes in amplitude, period, and phase.

6.2 Microbial Oscillations and Feeding Rhythms

(1) Circadian variation in microbial metabolism

The composition and metabolic activity of the gut microbiota vary with circadian and feeding cycles. Bile acids, short-chain fatty acids, and tryptophan metabolites also exhibit temporal fluctuations. Natural products that alter feeding time, gastrointestinal motility, or bile acid circulation may simultaneously alter microbial oscillations.

(2) Assessment of rhythm restoration

Determining whether a natural product restores the circadian clock requires comparison of amplitude, period, and phase across multiple time points and distinction between central rhythms and peripheral rhythms in the liver, intestine, and other tissues. Increased expression of a circadian gene at a single time point does not demonstrate rhythm restoration.

6.3 Peripheral Tissues Execute Gut–Brain Metabolic Signals

(1) Lipid oxidation and thermogenesis

Baicalin can regulate CPT1A-associated fatty acid oxidation, whereas hyperforin can promote thermogenesis through a DLAT-dependent AMPK–PGC-1α–UCP1 axis. These processes determine whether neural and endocrine signals are converted into increased fatty acid utilization and overall energy expenditure.

(2) Regulation of lipid synthesis

Betulin can act on SCAP and restrict SREBP maturation, reducing fatty acid and cholesterol synthesis programs. These peripheral effects are not components of gut–brain communication itself but can alter how the liver and adipose tissue respond to metabolic signals from the gut–brain axis.

7 Products Related to Gut–Brain Axis and Metabolic Homeostasis Research

7.1 Products Related to Neural Circuits, Enteroendocrine Signaling, and Circadian Rhythms

7.2 Products Related to the Intestinal Barrier, Metabolites, and Inflammatory Signaling

Natural products can coordinate appetite, nutrient absorption, glucose and lipid metabolism, and energy expenditure through the GABRA1–DMV–vagus nerve–jejunum pathway, incretin signaling, microbial metabolites, FXR/TGR5-mediated bile acid signaling, the intestinal barrier, and the ROR circadian network.

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