The ANS functions as a major neural interface between the central nervous system (CNS) and the gut. The gut nervous system comprises the enteric nervous system (ENS), sympathetic nervous system (SNS), and parasympathetic nervous system (PNS)^[20,21]. The ENS, an intrinsic neural network within the gastrointestinal tract, comprises a meshwork of enteric neurons and glial cells embedded within the myenteric and submucosal plexuses. It senses intestinal alterations and maintains normal gastrointestinal function^[22]. The SNS and PNS belong to the exogenous nervous system. Preganglionic sympathetic neurons innervating the upper gastrointestinal tract arise from the T6-T9 thoracic spinal segments, while those destined for the colon originate within the L2-L5 lumbar spinal segments [Figure 1]^[23]. Most postganglionic sympathetic neurons innervating the gastrointestinal tract are located within the prevertebral ganglia, with some originating from paravertebral ganglia^[24,25]. The intestinal parasympathetic nerves consist of the vagus nerve and sacral plexus nerves^[26]. The vagus nerve, which provides widespread innervation to the stomach, small intestine, and proximal colon, arises from a discrete topographic network within the brainstem, encompassing the dorsal motor nucleus of the vagus, the nucleus tractus solitarius, and the nucleus ambiguus. Sacral plexus nerves in the distal colon originate primarily from preganglionic neurons within the S1-S4 spinal cord^[27,28]. Unlike the SNS, the PNS lacks a continuous ganglion chain. Instead, it comprises discrete ganglia juxtaposed to their terminal target organs, featuring elongated preganglionic fibers coupled with shortened postganglionic counterparts^[29].

ANS is involved in coordinating and regulating key functions of the gastrointestinal tract via neurotransmitter release and neural circuits [Table 1], including movement, secretion, vasomotor regulation and local reflexes, all of which fundamentally sustain efficient nutrient absorption and metabolic processing. Both the small and large intestines possess considerable autonomous control and can function independently without exogenous neural input^[30]. This intrinsic activity is primarily mediated by the ENS through the pacemaker function of interstitial cells of Cajal. The ENS modulates gastrointestinal function through neuropeptides such as vasoactive intestinal peptide and cholecystokinin, contributing to digestive function^[31]. The coordinated action of the PNS and SNS, which encompasses motility, vasoconstriction/vasodilation, and glandular secretion, provides finer control over gastrointestinal function than either system alone, and all these processes are critical for optimal nutrient metabolism and energy balance. Overall, maintenance of autonomic homeostasis is essential for normal intestinal physiology and systemic metabolic balance.

Sympathetic nerves to the liver originate from the thoracolumbar spinal cord (T7-T12). Preganglionic fibers travel by means of greater splanchnic nerves to the celiac and superior mesenteric ganglia, where synapses form^[43]. Postganglionic fibers, primarily releasing norepinephrine (NE), then innervate the liver^[43,44]. Parasympathetic innervation primarily originates fromthe craniosacral region, predominantly cholinergic (acetylcholine, ACh), and mainly via the hepatic branches of the vagus nerve, exerting a stimulatory effect on liver function^[43,45,46]. Both sympathetic and parasympathetic fibers enter the liver under the mediation of hepatic portal, forming plexuses around three major vascular structures: the hepatic artery, portal vein, and bile duct^[47]. The anterior hepatic plexus primarily distributes along the hepatic artery, while the posterior hepatic plexus distributes along the extrahepatic bile duct and portal vein^[44-47] [Figure 2].

The ANS is a pivotal contributor to regulating liver metabolism, such as hepatic glucose, lipid, and bile acid metabolism, making the liver a central hub for systemic metabolic control.

Rapid regulation of glucose homeostasis is mediated by hepatic autonomic efferent pathways. Sympathetic nerve terminals release NE, thereby engaging hepatocyte β2-adrenergic receptors (β2-ARs) to augment hepatic glucose output^[48,49]. Neuropeptides like galanin released from SNS terminals can also enhance hepatic glucose metabolism^[50-52]. Interestingly, Liu et al. delineated a rapid glucoregulatory circuit: paraventricular nucleus (PVN) corticotropin-releasing hormone (CRH) neurons → ventromedial nucleus of the hypothalamus (VMH) → raphe pallidus → sympathetic nerves → liver (the hypothalamic-sympathetic-liver axis), distinct from the classic HPA axis that raises blood sugar comparatively slowly^[53]. In adrenalectomized mice, physical stressors induced rapid hyperglycemia and increased activity of key gluconeogenic enzymes in the liver, indicating that HSL axis activation promotes glucose release via hepatic gluconeogenesis^[54]. On the other hand, the PNS generally promotes anabolic processes, enhancing glucose storage and insulin sensitivity^[55,56]. Acute hepatic vagotomy or central vagal stimulation in rats significantly increased arterial and portal venous insulin levels or inhibited insulin secretion, respectively, suggesting a role for hepatic vagal nerves in insulin secretion regulation^[57]. Complete hepatic denervation may abolish net hepatic glucose uptake^[58], as observed in liver transplant recipients during hypoglycemia^[59].

In lipid metabolism, the SNS and PNS collectively maintain hepatic lipid homeostasis^[60]. The SNS primarily promotes hepatic lipid accumulation. Elevated hepatic sympathetic tonus drives steatosis by simultaneously accelerating free fatty acid uptake and intrahepatic de novo lipogenesis^[61]. Consistent with this, sympathetic denervation has been shown to reverse established hepatic steatosis in obese mice^[61] and to reduce VLDL-TG secretion in dyslipidemic rats^[62]. Together, these findings indicate that chronic sympathetic overactivity is a central pathogenic factor in the development of MASLD^[63-65]. In contrast, the PNS mediates anti-steatotic signals from the brain. Adipose tissue-derived leptin translocates across the blood-brain barrier to exert central actions on the dorsal vagal complex, subsequently enhancing triglyceride export and suppress hepatic de novo lipogenesis through vagal efferent signaling^[66]. These centrally mediated leptin effects depend on intact hepatic vagal innervation and are absent in liver-transplanted recipients lacking neural input to the graft^[67]. Vagal sensory neurons innervating the liver are required for the development of diet-induced hepatic steatosis^[68].

The ANS precisely regulates bile acid synthesis and secretion through bidirectional actions of sympathetic and parasympathetic nerves, serving as a crucial component in maintaining bile acid pool stability. The PNS enhances cholecystokinin-induced Cl^-/HCO₃^- exchange in cholangiocytes by releasing acetylcholine, synergizing with secretin to promote bile secretion^[69]. The SNS primarily acts on cholangiocyte α₁-adrenergic receptors by virtue of norepinephrine, reducing bile secretion^[70]. This dual innervation ensures bile secretion adapts to varying physiological demands. Animal studies in Wistar rats demonstrate that vagus nerve transection significantly elevates levels of bile acids such as TMDCA, GHDCA, ω-MCA, α-MCA, CA, isoCDCA, CDCA, DCA, 7-oxo-HDCA, and 12-oxo-CA. This mechanism involves the vagus nerve activating the intestinal FXR-Fgf15 signaling pathway while simultaneously suppressing hepatic expression of the bile acid synthase Cyp7a1^[71]. Recent studies further confirm that parasympathetic nerve terminals in the human hepatic biliary system release vesicular acetylcholine transporter (VAChT, a parasympathetic marker)^[72], providing direct evidence for cholinergic nerves directly regulating bile secretion.

Although the ENS is anatomically localized within the gastrointestinal tract, it exerts indirect regulatory effects on liver function via a complex, multi-component gut-liver axis. Central to this regulation are EECs, which act as specialized chemosensory epithelial cells capable of detecting luminal chemical and microbial stimuli. Upon activation, EECs secrete neuroactive hormones, including serotonin, glucagon-like peptide-1 (GLP-1), and CCK, that signal to the central nervous system primarily by means of vagal afferent fibers^[68]. Subsequent central integration modulates autonomic outflow to the liver and affects hepatic metabolic, synthetic, and detoxification functions^[73]. Concurrently, the gut microbiota contributes to this regulatory network by producing bioactive metabolites that modulate EEC activity, maintain intestinal barrier integrity, and shape both local and systemic immune responses, collectively impacting hepatic physiology and pathophysiology^[74,75]. Collectively, current evidence indicates that ENS-mediated regulation of liver function involves bidirectional crosstalk among neural, endocrine, microbial, and immune components. However, the precise molecular and neural circuit mechanisms underlying this inter-organ communication remain incompletely understood.

Sympathetic and parasympathetic nerves jointly constitute a refined neuro-immune dialogue network within the gut-liver axis by regulating barrier function, immune cell migration, and intercellular communication, all of which have secondary effects on tissue metabolic function.

Maintaining intestinal barrier integrity relies on stable expression of epithelial tight junction proteins^[79]. Sympathetic-derived norepinephrine engages β2-ARs on intestinal epithelial and immune cells populations, subsequently driving the downregulation of tight junction proteins, compromising epithelial barrier integrity, and facilitates the translocation of microbial products into the circulation^[80]. At the cellular level, sympathetic-derived NE targets dendritic cell populations via β-AR pathways, a signaling axis that critically patterns subsequent T cell activation and dictates the localized immunometabolic microenvironment^[81]. Sympathetic signaling additionally regulates immune cell migration by altering portal vein blood flow and metabolic substrate delivery. Sympathetic activation induces intestinal vasoconstriction, reduces immune cell infiltration into the gut and suppresses local immune responses^[82]. Clinical studies have identified memory T cells of common origin in intestinal and hepatic samples from PSC-IBD patients, suggesting bidirectional migration of immune cells between the gut and liver that jointly shapes the immune and metabolic microenvironments of both organs^[83].

In contrast to the PNS, the vagus nerve exerts protective effects in the gut-liver axis by the “cholinergic anti-inflammatory pathway.” Within the intestine, the vagus nerve can sense antigens through high-affinity Immunoglobulin E receptors and release glutamate to modulate dendritic cell function, suppressing Th2-skewed inflammation^[84]. Following injury, enteric glial cells are critical for transmitting vagal anti-inflammatory signals, enhancing barrier repair and limiting immune cell recruitment^[85]. Concurrently, gut-derived microbial metabolites and luminal inflammatory signals are monitored by hepatic vagal sensory afferents. Through the liver-brain-gut neural arc, these signals are transmitted to the solitary nucleus in the brainstem. Subsequently, through the vagus nerve’s parasympathetic efferent pathway, the vagus nerve modulates the abundance of gut immune cells, forming an indirect pathway influencing the hepatic immune and metabolic environment^[86].

Traditionally, the liver was regarded as a passive metabolic executor, and the gut was viewed primarily as an absorptive organ. Recent paradigms have illuminated the liver not merely as a passive metabolic sink, but as an active sensory organ participating in neuroendocrine feedback loops, operating in concert with extensive gut-CNS conduits via EECs, the ENS, and the microbiota^[87-90]. This gut-liver-brain triad forms the physiological basis for metabolic homeostasis, whose disruption precipitates various metabolic disorders such as MASLD^[91,92].

A key mediator in this circuit is the gut hormone GLP-1, whose actions illustrate the integrated neural control of metabolism across organs. Upon intraluminal nutrient engagement, mucosal L-cells liberate GLP-1, which subsequently docks with cognate receptors localized on vagal afferent terminals within the intestinal wall and portal vein, initiating a neural signal to the brainstem^[93]. The metabolic actions of GLP-1 receptor agonists, including the inhibition of gastric emptying and stimulation of insulin secretion, are mediated through the vagus nerve^[94]. Evidence shows that knockdown of GLP-1 receptors in vagal afferent neurons blunts these effects, while vagal nerve stimulation can mimic them by enhancing vagal activity and increasing GLP-1 release^[95-97]. The same neural circuit directly controls liver lipid metabolism^[98]. In another key experiment, researchers injected GLP-1 into the portal vein and observed a significant reduction in blood triglycerides and hepatic VLDL secretion in both hamsters and mice. When the vagal afferent pathway was interrupted either surgically or pharmacologically, this lipid-lowering effect disappeared^[98]. Moreover, the anti-lipemic effect of portal GLP-1 requires not only intact vagal signaling but also efferent changes in sympathetic tone^[98]. This indicates that the brain’s processing of vagal GLP-1 input includes adjustments to SNS outflow. Regarding bile acid metabolism, activation of intestinal FXR transmits signals to the liver by virtue of vagus nerve and regulates cholesterol 7α-hydroxylase expression, forming a neural component of the enterohepatic feedback loop^[99]. Recently, single-cell technologies have advanced the field. Newly identified vagal CART⁺ neuron subsets regulate insulin and hepatic gluconeogenesis, a mechanism linked to commensal microbiota dysbiosis or depletion, representing a breakthrough in understanding the microbiota-gut-liver axis^[100].

Taken together, these paradigms establish the ANS as a critical rheostat that fine-tunes gut-liver metabolic homeostasis utilizing an integrated neuroendocrine framework.

As a core component of the gut-liver axis, the gut microbiota function as a critical determinant in the dynamic balance between the intestine and liver^[88,101]. The ANS, in turn, reshapes the microbiota-gut-liver network via direct neural modulation, metabolite intervention, and regulation of microbial translocation, emerging as a novel therapeutic target for metabolic diseases.

The gut-brain axis is a complex bidirectional network that links brain regions involved in emotion and cognition with peripheral gut function and coordinates metabolic homeostasis^[5,112]. The gut signals up to the brain through spinal and vagal visceral afferents and receives “top-down” signals under the mediation of sympathetic and parasympathetic efferents, forming a circuit for metabolic regulation^[113]. Vagal afferents from the gut smooth muscle transmit information regarding nutrient status to the CNS^[114,115]. Clinically, vagotomy performed for peptic ulcer disease has been associated with an increased incidence of mental health disorders. In animal studies, transection of subdiaphragmatic vagal afferents induces anxiety- and fear-related behaviors^[116,117], suggesting that disruption of gut-derived vagal signaling can trigger psychiatric symptoms. Diverging from the bidirectional modality of the vagus nerve, the SNS operates predominantly as an obligate efferent axis, dictating gastrointestinal motility and glandular output via norepinephrine release during stress states.

Similarly, within the liver-brain axis, hepatic vagal afferents indirectly sense the hepatic microenvironment and relay this information to the NTS, which subsequently modulates hepatic parasympathetic outflow^[5,116,118]. Exogenous vagal reflex activity can connect hepatic vagal afferents, the brainstem, vagal efferents, and enteric neurons^[118]. Hepatic ischemia-reperfusion (HIR) injury often induces systemic inflammation, depression-like behavior, and reduced prefrontal synaptic protein levels in mice^[102]. Notably, subdiaphragmatic vagotomy attenuates these symptoms^[119], implicating the vagal signaling in this pathological process. As in the gut-brain axis, parasympathetic pathways mediate bidirectional communication in the liver-brain axis, while sympathetic signaling predominantly provides efferent output^[120]. Chronic stress further drives CRH⁺ CeM → PVN projections, sustaining hepatic sympathetic outflow. This process compromises intrahepatic sympathetic fibers, elevated circulating norepinephrine levels, β3-adrenergic receptor downregulation, and impaired cAMP signaling in hepatocytes, ultimately contributing to hepatic catecholamine resistance and MASLD progression^[10].

Interactions among the brain, liver, and gut involve highly complex regulatory mechanisms^[102]. Currently, the liver-brain-gut neural reflex arc proposed by Teratani et al. has gained wide recognition^[102]. Specifically, hepatic vagal afferents sense the gut microenvironment and signal to the NTS^[102]. Central integration within the NTS subsequently modulates peripheral vagal and enteric outputs, culminating in the induction and phenotypic preservation of intestinal pTregs^[86]. This reflex arc provides a representative example of how CNS-processed autonomic signaling coordinately regulates immune homeostasis along the gut-liver axis.

Despite the therapeutic promise, neuromodulation strategies for gut-liver diseases face challenges. A core technical bottleneck is a lack of stimulation specificity. Current studies vary considerably in stimulation frequency, target sites, and treatment duration, highlighting the need for large-scale randomized controlled trials to establish universal protocols^[121]. In addition, the metabolic effects of sympathetic activation are highly context dependent. In the tumor microenvironment, SNS-derived NE can promote colorectal cancer progression via a β2-ARs-mediated positive feedback loop that stimulates cancer-associated fibroblasts to secrete nerve growth factor, potentially altering tumor metabolism^[136]. These findings emphasize the importance of precise neural targeting and a clearer understanding of the diverse roles of sympathetic signaling in metabolic regulation. This issue is pronounced in the emerging field of “microbiota-neural combination therapy.” It remains unclear how neural stimulation precisely affects specific gut microbes and how microbial metabolites feedback onto neural pathways. This knowledge gap hinders the rational design of combined therapies.

Future progress requires integrated multi-organ monitoring systems capable of simultaneously assessing neural activity, gut motility, microbiome, and inflammatory status. In parallel, advances in highly selective neuromodulation technologies are needed to precisely target functional neural subpopulations. Recent studies have shown that distinct sympathetic neuron subsets separately regulate gastrointestinal motility and secretion^[137], providing opportunities for more targeted interventions while minimizing off-target effects. Importantly, substantial interspecies differences must also be considered. The distribution of hepatic autonomic innervation differs between rodents and humans, limiting the direct translational applicability of rodent-based findings^[44]. Collectively, improving personalized precision medicine approaches is a promising direction in the future. Greater integration of neuroscience, immunology, microbiology, and clinical medicine is essential for developing safe and effective targeted therapies for gut-liver disorders.