Navigating gut-liver metabolic homeostasis: the role of the autonomic nervous system

Abstract

The frequent clinical co-occurrence of intestinal and hepatic disorders points to underlying bidirectional communication along the gut-liver axis. Existing research has primarily focused on metabolic and humoral interactions, including bile acid circulation and portal venous signaling, whereas the autonomic nervous system (ANS) has received comparatively limited attention as an integrative regulatory pathway. This review reframes the axis through a neural perspective, arguing that the ANS functions as a master coordinator of metabolic homeostasis, linking immune regulation, metabolic function, and gut microbiota activity into a unified neuro-immune-endocrine network. The sympathetic and parasympathetic branches, along with the enteric nervous system, modulate barrier integrity, immune cell trafficking, hepatic glucose and lipid metabolism, and microbial composition via neurotransmitter-mediated and receptor-dependent signaling pathways. Dysregulation of this autonomic circuitry disrupts metabolic balance and is implicated in the shared pathophysiology of conditions such as inflammatory bowel disease (IBD) and metabolic dysfunction-associated steatotic liver disease (MASLD). Conversely, neuromodulation strategies, particularly noninvasive vagus nerve stimulation, have demonstrated therapeutic potential in reducing inflammation and restoring metabolic balance. By positioning the ANS as one of the central regulators of gut-liver metabolic cross-talk, this review advances current mechanistic understanding of gut-liver comorbidities and highlights bioelectronic medicine as a promising therapeutic strategy for metabolic disorders. This perspective bridges neuroscience, gastroenterology, and hepatology, offering novel insights for the management of complex, multi-organ metabolic diseases.

Keywords

Autonomic nervous system / vagus nerve / gut-liver axis / metabolic homeostasis / gut microbes

References

[1] Devarbhavi H,Asrani SK,Arab JP,Nartey YA,Pose E,Kamath PS. Global burden of liver disease: 2023 update J Hepatol. 2023 79 516 37

[2] Griffin C,Agbim U,Ramani A,Shankar N,Kanwal F,Asrani SK. Underestimation of cirrhosis-related mortality in the medicare eligible population, 1999-2018 Clin Gastroenterol Hepatol. 2023 21 223 225.e3

[3] Li Q,Kou Y,Zhang M.et al. Sex-specific and socioeconomic disparities in the global burden of inflammatory bowel disease in 204 countries, 1990-2021: projections to 2050 Front. Immunol. 2026 16 1673212 PMC12827582

[4] Ali B,Samuel R,Kramer JR.et al. Evolving burden of metabolic dysfunction-associated steatotic liver disease and its complications in a US nationwide healthcare system Hepatol Commun. 2026 10 PMC12772495

[5] Gu Y,Wu C. The gut-liver axis modulates intestinal immune homeostasis Mucosal Immunol. 2026 19 1470 80

[6] Devkota S,Wang Y,Musch MW.et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice Nature. 2012 487 104 8 PMC3393783

[7] Yan J,Zeng Y,Guan Z.et al. Inherent preference for polyunsaturated fatty acids instigates ferroptosis of Treg cells that aggravates high-fat-diet-related colitis Cell Reports. 2024 43 114636

[8] Rodriguez-duque JC,Calleja JL,Iruzubieta P.et al. Increased risk of MAFLD and liver fibrosis in inflammatory bowel disease independent of classic metabolic risk factors Clin Gastroenterol Hepatol. 2023 21 406 414.e7

[9] Sourianarayanane A,Garg G,Smith TH,Butt MI,Mccullough AJ,Shen B. Risk factors of non-alcoholic fatty liver disease in patients with inflammatory bowel disease J Crohns Colitis. 2013 7 e279 85

[10] Wu S,Liu J,Huang S,Guo Y,Bi Y. Chronic stress induces hepatic steatosis via brain-hepatic sympathetic axis mediated catecholamine resistance Int. J. Biol. Sci. 2026 22 1407 24 PMC12837740

[11] Goldstein DS. Stress and the “extended” autonomic system Auton Neurosci. 2021 236 102889 PMC10699409

[12] Thayer JF,Lane RD. The role of vagal function in the risk for cardiovascular disease and mortality Biol Psychol. 2007 74 224 42

[13] Wang T,Tufenkjian A,Ajijola OA,Oka Y. Molecular and functional diversity of the autonomic nervous system Nat Rev Neurosci. 2025 26 607 22

[14] Mawdsley JE,Rampton DS. Psychological stress in IBD: new insights into pathogenic and therapeutic implications Gut. 2025 54 1481 91 PMC1774724

[15] Luo Q,Liu P,Dong Y,Qin T. The role of the hepatic autonomic nervous system Clin Mol Hepatol. 2023 29 1052 5 PMC10577342

[16] Albillos A,De Gottardi A,Rescigno M. The gut-liver axis in liver disease: Pathophysiological basis for therapy J Hepatol. 2020 72 558 77

[17] Dinan TG,Cryan JF. Regulation of the stress response by the gut microbiota: Implications for psychoneuroendocrinology Psychoneuroendocrinology. 2012 37 1369 78

[18] Sgambato D,Miranda A,Ranaldo R,Federico A,Romano M. The role of stress in inflammatory bowel diseases Curr Pharm Des. 2017 23

[19] Zhai S,Zhu Y,Wang X.et al. Development of a predictive model for radiation pneumonitis based on plasma exosomal miR-200b-5p Front. Oncol. 2025 15 1516348 PMC12405333

[20] Basics of autonomic nervous system function. Clinical Neurophysiology: basis and technical aspects. Elsevier; 2019. pp. 407-18

[21] Linden DR,Sharkey KA. The enteric nervous system Curr Biol. 2025 35 R979 85

[22] Sanders KM,Mutafova-Yambolieva VN. Neurotransmitters responsible for purinergic motor neurotransmission and regulation of GI motility Auton Neurosci. 2021 234 102829 PMC8575072

[23] Furness J. Types of neurons in the enteric nervous system J Auton Nerv Syst. 2000 81 87 96

[24] Janig W,Mclachlan EM. Organization of lumbar spinal outflow to distal colon and pelvic organs Physiol Rev. 1987 67 1332 404

[25] Simmons M. The complexity and diversity of synaptic transmission in the prevertebral sympathetic ganglia Prog Neurobiol. 1985 24 43 93

[26] Altschuler SM,Escardo J,Lynn RB,Miselis RR. The central organization of the vagus nerve innervating the colon of the rat Gastroenterology. 1993 104 502 9

[27] De Groat WC,Nadelhaft I,Milne RJ,Booth AM,Morgan C,Thor K. Organization of the sacral parasympathetic reflex pathways to the urinary bladder and large intestine J Auton Nerv Syst. 1981 3 135 60

[28] Vizzard MA,Brisson M,De Groat WC. Transneuronal labeling of neurons in the adult rat central nervous system following inoculation of pseudorabies virus into the colon Cell Tissue Res. 2000 299 9 26

[29] Shields RW. Functional anatomy of the autonomic nervous system J Clin Neurophysiol. 1993 10 2 13

[30] Zhu YF,Wang X,Lowie B.et al. Enteric sensory neurons communicate with interstitial cells of Cajal to affect pacemaker activity in the small intestine Pflugers Arch - Eur J Physiol. 2013 466 1467 75

[31] Ellis M,Chambers JD,Gwynne RM,Bornstein JC. Serotonin and cholecystokinin mediate nutrient-induced segmentation in guinea pig small intestine Am J Physiol Gastrointest Liver Physiol. 2013 304 G749 61

[32] Travagli RA,Hermann GE,Browning KN,Rogers RC. Brainstem circuits regulating gastric function Annu Rev Physiol. 2006 68 279 305 PMC3062484

[33] Spencer NJ,Dinning PG,Brookes SJ,Costa M. Insights into the mechanisms underlying colonic motor patterns J Physiol. 2016 594 4099 116 PMC4967752

[34] Furness JB,Callaghan BP,Rivera LR,Cho H. the enteric nervous system and gastrointestinal innervation: integrated local and central control. In: Lyte M, Cryan JF, Editors. Microbial Endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease. New York, NY: Springer New York; 2014. pp. 39-71

[35] Parker DR,Wiklendt L,Humenick A.et al. Sympathetic pathways target cholinergic neurons in the human colonic myenteric plexus Front Neurosci. 2022 16 863662 PMC8970288

[36] Guyenet PG. The sympathetic control of blood pressure Nat Rev Neurosci. 2006 7 335 46

[37] Horiuchi J,Mcdowall L,Dampney R. Differential control of cardiac and sympathetic vasomotor activity from the dorsomedial hypothalamus Clin Exp Pharmacol Physiol. 2006 33 1265 8

[38] Hao S,Dulake M,Espero E,Sternini C,Raybould HE,Rinaman L. Central Fos expression and conditioned flavor avoidance in rats following intragastric administration of bitter taste receptor ligands Am J Physiol Regul Integr Comp Physiol. 2009 296 R528 36 PMC2665842

[39] Sartor DM,Verberne AJM. Cholecystokinin selectively affects presympathetic vasomotor neurons and sympathetic vasomotor outflow Am J Physiol Regul Integr Comp Physiol. 2002 282 R1174 84

[40] Holmes GM,Tong M,Travagli RA. Effects of brain stem cholecystokinin-8s on gastric tone and esophageal-gastric reflex Am J Physiol Gastrointest Liver Physiol. 2009 296 G621 31 PMC2660178

[41] Effects of gut bacteria and their metabolites on gut health of animals. Elsevier; 2024. pp. 223-52

[42] Agibalova T,Hempel A,Maurer HC.et al. Vasoactive intestinal peptide promotes secretory differentiation and mitigates radiation-induced intestinal injury Stem Cell Res Ther. 2024 15 348 PMC11462795

[43] Sun M,Wan Y,Shi M,Meng Z,Zeng W. Neural innervation in adipose tissue, gut, pancreas, and liver Life Metabolism. 2023 2 load022 PMC11749697

[44] Miller BM,Oderberg IM,Goessling W. Hepatic nervous system in development, regeneration, and disease Hepatology. 2021 74 3513 22 PMC8639644

[45] Zou J,Li J,Wang X,Tang D,Chen R. Neuroimmune modulation in liver pathophysiology J Neuroinflammation. 2024 21 188 PMC11295927

[46] Luo Q,Liu P,Dong Y,Qin T. The role of the hepatic autonomic nervous system Clin Mol Hepatol. 2023 29 1052 5 PMC10577342

[47] Alison MR. Regulation of hepatic growth Physiol Rev. 1986 66 499 541

[48] Carty JRE,Devarakonda K,O’connor RM.et al. Amygdala-liver signalling orchestrates glycaemic responses to stress Nature. 2025 646 697 706 PMC12527908

[49] Shimazu T. Innervation of the liver and glucoregulation: Roles of the hypothalamus and autonomic nerves Nutrition. 1996 12 65 6

[50] Abot A,Lucas A,Bautzova T.et al. Galanin enhances systemic glucose metabolism through enteric Nitric Oxide Synthase-expressed neurons Mol Metab. 2018 10 100 8 PMC5985240

[51] Mundinger TO,Taborsky GJ. Differential action of hepatic sympathetic neuropeptides: metabolic action of galanin, vascular action of NPY Am J Physiol-Endoc M. 2000 278 E390 7

[52] Ren W,Hua M,Cao F,Zeng W. The Sympathetic-immune milieu in metabolic health and diseases: insights from pancreas, liver, intestine, and adipose tissues Adv Sci. 2023 11 2306128 PMC10885671

[53] Liu J,Bisschop PH,Eggels L.et al. Intrahypothalamic Estradiol regulates glucose metabolism via the sympathetic nervous system in female rats Diabetes. 2013 62 435 43 PMC3554366

[54] Liu L,Huang Z,Zhang J.et al. Hypothalamus-sympathetic-liver axis mediates the early phase of stress-induced hyperglycemia in the male mice Nat Commun. 2024 15 8632 PMC11452707

[55] Latour MG,Lautt W. The hepatic vagus nerve in the control of insulin sensitivity in the rat Auton Neurosci. 2002 95 125 30

[56] Xue C,Aspelund G,Sritharan KC,Wang JP,Slezak LA,Andersen DK. Isolated hepatic cholinergic denervation impairs glucose and glycogen metabolism J Surg Res. 2000 90 19 25

[57] Lee KC,Miller RE. The hepatic vagus nerve and the neural regulation of insulin secretion* Endocrinology. 1985 117 307 14

[58] Moore MC,Coate KC,Winnick JJ,An Z,Cherrington AD. Regulation of hepatic glucose uptake and storage in vivo Adv Nutr. 2012 3 286 94 PMC3649460

[59] Perseghin G,Regalia E,Battezzati A.et al. Regulation of glucose homeostasis in humans with denervated livers J Clin Investig. 1997 100 931 41 PMC508266

[60] Mahley RW,Innerarity TL,Rall SC,Weisgraber KH. Plasma lipoproteins: apolipoprotein structure and function J Lipid Res. 1984 25 1277 94

[61] Hurr C,Simonyan H,Morgan DA,Rahmouni K,Young CN. Liver sympathetic denervation reverses obesity‐induced hepatic steatosis J Physiol. 2019 597 4565 80 PMC6716997

[62] Bruinstroop E,Eliveld J,Foppen E.et al. Hepatic denervation and dyslipidemia in obese Zucker (fa/fa) rats Int J Obes. 2015 39 1655 8

[63] Carnagarin R,Tan K,Adams L.et al. Metabolic dysfunction-associated fatty liver disease (MAFLD) - a condition associated with heightened sympathetic activation Int J Mol Sci. 2021 22 4241 PMC8073135

[64] Raulin A,Martens YA,Bu G. Lipoproteins in the central nervous system: from biology to pathobiology Annu Rev Biochem. 2022 91 731 59 PMC9634960

[65] Zhu Y,Yao L,Gallo-ferraz AL.et al. Sympathetic neuropeptide Y protects from obesity by sustaining thermogenic fat Nature. 2024 634 243 50 PMC11446830

[66] Hackl MT,Fürnsinn C,Schuh CM.et al. Brain leptin reduces liver lipids by increasing hepatic triglyceride secretion and lowering lipogenesis Nat Commun. 2019 10 2717 PMC6586634

[67] Metz M,Beghini M,Wolf P.et al. Leptin increases hepatic triglyceride export via a vagal mechanism in humans Cell Metab. 2022 34 1719 1731.e5

[68] Hwang J,Lee S,Okada J.et al. Liver-innervating vagal sensory neurons are indispensable for the development of hepatic steatosis and anxiety-like behavior in diet-induced obese mice Nat Commun. 2025 16 991 PMC11759694

[69] Elsing C,Hubner C,Fitscher BA,Kassner A,Stremmel W. Muscarinic acetylcholine receptor stimulation of biliary epithelial cells and its effect on bile secretion in the isolated perfused liver Hepatology. 1997 25 804 13

[70] Friman S,Radberg G,Svanvik J. Adrenergic influence on bile secretion - an experimental study in the cat Acta Physiol Scand. 2008 140 287 93

[71] Wang F,Lu Z,Wang X,Zhang Y. Impaired vagus function in rats suppresses bile acid synthesis in the liver by disrupting tight junctions and activating Fxr-Fgf15 signaling in the intestine Biochem Biophys Res Commun. 2018 495 1490 6

[72] Chen C,Peng S,Chou Y.et al. Human liver afferent and efferent nerves revealed by 3-D/Airyscan super-resolution imaging Am J Physiol-Endoc M. 2024 326 E107 23

[73] Rossen ND,Touhara KK,Castro J.et al. Population imaging of enterochromaffin cell activity reveals regulation by somatostatin Proc. Natl. Acad. Sci. U.S.A. 2025 122 e2501525122 PMC12088456

[74] Ohtani N,Kamiya T,Kawada N. Recent updates on the role of the gut-liver axis in the pathogenesis of NAFLD/NASH, HCC, and beyond Hepatol Commun. 2023 7 PMC10462074

[75] Kang JW,Vemuganti V,Kuehn JF,Ulland TK,Rey FE,Bendlin BB. Gut microbial metabolism in Alzheimer’s disease and related dementias Neurotherapeutics. 2024 21 e00470 PMC11585892

[76] Van Munster KN,Bergquist A,Ponsioen CY. Inflammatory bowel disease and primary sclerosing cholangitis: one disease or two? J Hepatol. 2024;80:155-68

[77] Kalaitzakis E. Gastrointestinal dysfunction in liver cirrhosis World J Gastroenterol. 2014 20 14686 PMC4209534

[78] Wang S,Farokhian A,Shen B. Clinical association between inflammatory bowel disease and primary sclerosing cholangitis: what changes after colectomy and liver transplantation? egastro. 2025 3 e100199 PMC12336565

[79] Günzel D,Fromm M. Claudins and other tight junction proteins. in: prakash ys, editors. comprehensive physiology. Wiley; 2012. pp. 1819-52

[80] Bonaz B,Sinniger V,Pellissier S. Anti‐inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation The Journal of Physiology. 2016 594 5781 90 PMC5063949

[81] Nijhuis LE,Olivier BJ,De Jonge WJ. Neurogenic regulation of dendritic cells in the intestine Biochem Pharmacol. 2010 80 2002 8

[82] Nakai A,Suzuki K. Adrenergic control of lymphocyte trafficking and adaptive immune responses Neurochem Int. 2019 130 104320

[83] Henriksen EKK,Jørgensen KK,Kaveh F.et al. Gut and liver T-cells of common clonal origin in primary sclerosing cholangitis-inflammatory bowel disease J Hepatol. 2017 66 116 22

[84] Liang H,Xu L,Zhou C,Zhang Y,Xu M,Zhang C. Vagal activities are involved in antigen‐specific immune inflammation in the intestine J Gastroenterol Hepatol. 2011 26 1065 71

[85] Langness S,Kojima M,Coimbra R,Eliceiri BP,Costantini TW. Enteric glia cells are critical to limiting the intestinal inflammatory response after injury Am J Physiol - Gastrointest Liver Physiol. 2017 312 G274 82

[86] Teratani T,Mikami Y,Nakamoto N.et al. The liver-brain-gut neural arc maintains the Treg cell niche in the gut Nature. 2020 585 591 6

[87] He X,Hu M,Xu Y.et al. The gut-brain axis underlying hepatic encephalopathy in liver cirrhosis Nat Med. 2025 31 627 38

[88] Sun J,Debosch BJ. Reciprocal oscillation and host-microbial communication in liver metabolic control Gut Microbes. 2025 17 2545413 PMC12931712

[89] Zhang J,Chen K,Chen F. Exploring the impact of the liver-intestine-brain axis on brain function in non-alcoholic fatty liver disease J Pharm Anal. 2025 15 101077 PMC12104701

[90] Zhang T,Wang W,Li J.et al. Free fatty acid receptor 4 modulates dietary sugar preference via the gut microbiota Nat Microbiol. 2025 10 348 61

[91] Li H,Yuan W,Tian Y.et al. Eugenol alleviated nonalcoholic fatty liver disease in rat via a gut-brain-liver axis involving glucagon-like Peptide-1 Arch Biochem Biophys. 2022 725 109269

[92] Wan M. Role of gut-brain axis dysregulation in the pathogenesis of non-alcoholic fatty liver disease: mechanisms and therapeutic implications Am J Transl Res. 2025 17 3276 92 PMC12170361

[93] Kwiecien S,Sliwowski Z,Pajdo R,Ptak-Belowska A,Brzozowski T. Role of brain-gut axis in mechanism of gastrointestinal defense. J Physiol Pharmacol. 2025;76:487-99

[94] Raybould HE. Nutrient sensing in the gastrointestinal tract: possible role for nutrient transporters J Physiol Biochem. 2008 64 349 56

[95] Secher A,Jelsing J,Baquero AF.et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss J Clin Investig. 2014 124 4473 88 PMC4215190

[96] Dai F,Yin J,Chen JDZ. Effects and mechanisms of vagal nerve stimulation on body weight in diet-induced obese rats Obes Surg. 2020 30 948 56

[97] Krieger J,Arnold M,Pettersen KG,Lossel P,Langhans W,Lee SJ. Knockdown of GLP-1 receptors in vagal afferents affects normal food intake and glycemia Diabetes. 2016 65 34 43

[98] Hoffman S,Alvares D,Adeli K. GLP-1 attenuates intestinal fat absorption and chylomicron production via vagal afferent nerves originating in the portal vein Molecular Metabolism. 2022 65 101590 PMC9486018

[99] Visschers RG,Luyer MD,Schaap FG,Olde Damink SW,Soeters PB. The gut-liver axis Curr Opin Clin Nutr Metab Care. 2013 16 576 81

[100] Muller PA,Matheis F,Schneeberger M,Kerner Z,Jové V,Mucida D. Microbiota-modulated CART⁺ enteric neurons autonomously regulate blood glucose Science. 2020 370 314 21 PMC7886298

[101] Macpherson AJ,Pachnis V,Prinz M. Boundaries and integration between microbiota, the nervous system, and immunity Immunity. 2023 56 1712 26

[102] Pan L,Xie L,Yang W.et al. The role of brain-liver-gut axis in neurological disorders Burns & Trauma. 2025 13 tkaf011 PMC12048006

[103] Chen W,Deng F,Tsai Y. Lactiplantibacillus plantarum as a psychobiotic strategy targeting parkinson’s disease: a review and mechanistic insights Nutrients. 2025 17 3047 PMC12525601

[104] Ren W,Chen J,Wang W.et al. Sympathetic nerve-enteroendocrine L cell communication modulates GLP-1 release, brain glucose utilization, and cognitive function Neuron. 2024 112 972 990.e8

[105] Cook TM,Gavini CK,Jesse J.et al. Vagal neuron expression of the microbiota-derived metabolite receptor, free fatty acid receptor (FFAR3), is necessary for normal feeding behavior Mol Metab. 2021 54 101350 PMC8567301

[106] Sharma D,Malik A,Locher V.et al. A myeloid Tet2-IL-1β axis modulates intestinal inflammation by restricting catecholaminergic stimulation of enterochromaffin cell differentiation Immunity. 2025 58 2785 2798.e4 PMC12619111

[107] Shen B,Gu T,Shen Z.et al. Escherichia coli promotes endothelial to mesenchymal transformation of liver sinusoidal endothelial cells and exacerbates nonalcoholic fatty liver disease via its flagellin Cell Mol Gastroenterol Hepatol. 2023 16 857 79 PMC10598062

[108] Ahmed O,Caravaca AS,Crespo M.et al. Hepatic stellate cell activation markers are regulated by the vagus nerve in systemic inflammation Bioelectron Med. 2023 9 6 PMC10064698

[109] Boicean A,Birlutiu V,Ichim C,Brusnic O,Onișor DM. Fecal microbiota transplantation in liver cirrhosis Biomedicines. 2023 11 2930 PMC10668969

[110] Wu L,Li J,Zou J,Tang D,Chen R. Vagus nerve modulates acute-on-chronic liver failure progression via CXCL9 Chin Med J (Engl). 2024 138 1103 15 PMC12068771

[111] Siripen N,Chonprasertsuk S,Aumpan N,Siramolpiwat S. Efficacy of a 12-week supervised home-based exercise program and nutritional supplementation in cirrhotic patients with sarcopenia: A prospective pilot study Clinical Nutrition ESPEN. 2026 72 102810

[112] Carabotti M,Scirocco A,Maselli M A,Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015;28:203-9 PMC4367209

[113] Gershon MD,Margolis KG. The gut, its microbiome, and the brain: connections and communications J Clin Investig. 2021 131 e143768 PMC8439601

[114] Bonaz B,Sinniger V,Pellissier S. Vagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease J Intern Med. 2017 282 46 63

[115] Xie Z,Zhang X,Zhao M.et al. The gut-to-brain axis for toxin-induced defensive responses Cell. 2022 185 4298 4316.e21

[116] Coulter AA,Rebello CJ,Greenway FL. Centrally acting agents for obesity: past, present, and future Drugs. 2018 78 1113 32 PMC6095132

[117] Ma L,Wang H,Hashimoto K. The vagus nerve: an old but new player in brain-body communication Brain, Behavior, and Immunity. 2025 124 28 39

[118] Patterson TT,Nicholson S,Wallace D,Hawryluk GW,Grandhi R. Complex feed-forward and feedback mechanisms underlie the relationship between traumatic brain injury and the gut-microbiota-brain axis Shock. 2019 52 318 25

[119] Yang Y,Eguchi A,Wan X,Mori C,Hashimoto K. Depression-like phenotypes in mice with hepatic ischemia/reperfusion injury: A role of gut-microbiota-liver-brain axis via vagus nerve J Affect Disord. 2024 345 157 67

[120] Yang X,Qiu K,Jiang Y,Huang Y,Zhang Y,Liao Y. Metabolic crosstalk between liver and brain: from diseases to mechanisms Int J Mol Sci. 2024 25 7621 PMC11277155

[121] Yin J. Transcutaneous vagal nerve stimulation for gastrointestinal disorders J Transl Gastroenterol. 2025 000 000 PMC12377475

[122] Hong GS,Zillekens A,Schneiker B.et al. Non‐invasive transcutaneous auricular vagus nerve stimulation prevents postoperative ileus and endotoxemia in mice Neurogastroenterology Motil. 2018 31 e13501

[123] Jin H,Guo J,Liu J.et al. Anti-inflammatory effects and mechanisms of vagal nerve stimulation combined with electroacupuncture in a rodent model of TNBS-induced colitis Am J Physiol - Gastrointest Liver Physiol. 2017 313 G192 202

[124] Sahn B,Pascuma K,Kohn N,Tracey KJ,Markowitz JF. Transcutaneous auricular vagus nerve stimulation attenuates inflammatory bowel disease in children: a proof-of-concept clinical trial Bioelectron Med. 2023 9 23 PMC10583463

[125] Brinkman DJ,Simon T,Ten Hove AS.et al. Electrical stimulation of the splenic nerve bundle ameliorates dextran sulfate sodium-induced colitis in mice J Neuroinflammation. 2022 19 155 PMC9204975

[126] Zhu Y,Xu F,Lu D.et al. Transcutaneous auricular vagal nerve stimulation improves functional dyspepsia by enhancing vagal efferent activity Am J Physiol - Gastrointest Liver Physiol. 2021 320 G700 11 PMC8887908

[127] Shi X,Hu Y,Zhang B,Li W,Chen JD,Liu F. Ameliorating effects and mechanisms of transcutaneous auricular vagal nerve stimulation on abdominal pain and constipation JCI Insight. 2021 6 e150052 PMC8410029

[128] Yuan P,Taché Y. Abdominal surgery induced gastric ileus and activation of M1-like macrophages in the gastric myenteric plexus: prevention by central vagal activation in rats Am J Physiol - Gastrointest Liver Physiol. 2017 313 G320 9 PMC6134391

[129] Jiang Y,Wu L,Zhu X,Bian H,Gao X,Xia M. Advances in management of metabolic dysfunction-associated steatotic liver disease: from mechanisms to therapeutics Lipids Health Dis. 2024 23 95 PMC10985930

[130] Liu A,Huang M,Xi Y,Deng X,Xu K. Orchestration of gut-liver-associated transcription factors in MAFLD: from cross-organ interactions to therapeutic innovation Biomedicines. 2025 13 1422 PMC12191254

[131] John S,Bhowmick K,Park A,Huang H,Yang X,Mishra L. Recent advances in targeting obesity, with a focus on TGF-β signaling and vagus nerve innervation Bioelectron Med. 2025 11 10 PMC12042417

[132] Ueda T,Tategaki A,Hamada K.et al. Effects of Pediococcus acidilactici R037 on serum triglyceride levels in mice and rats after oral administration J Nutr Sci Vitaminol. 2018 64 41 7

[133] Feng R,Yang W,Feng W.et al. Time-restricted feeding ameliorates non-alcoholic fatty liver disease through modulating hepatic nicotinamide metabolism via gut microbiota remodeling Gut Microbes. 2024 16 2390164 PMC11332628

[134] Gupta H,Suk KT,Kim DJ. Gut microbiota at the intersection of alcohol, brain, and the liver JCM. 2021 10 541 PMC7867253

[135] Pan Y,Yang Y,Wu J,Zhou H,Yang C. Efficacy of probiotics, prebiotics, and synbiotics on liver enzymes, lipid profiles, and inflammation in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis of randomized controlled trials BMC Gastroenterol. 2024 24 283 PMC11342484

[136] Kobayashi H,Iida T,Ochiai Y.et al. Neuro-mesenchymal interaction mediated by a β2-adrenergic nerve growth factor feedforward loop promotes colorectal cancer progression Cancer Discovery. 2025 15 202 26 PMC11729495

[137] Wang T,Teng B,Yao DR,Gao W,Oka Y. Organ-specific sympathetic innervation defines visceral functions Nature. 2024 637 895 902

[138] Shi X,Zhao L,Luo H.et al. Transcutaneous auricular vagal nerve stimulation is effective for the treatment of functional dyspepsia: a multicenter, randomized controlled study Am J Gastroenterol. 2024 119 521 31

[139] Kovacic K,Hainsworth K,Sood M.et al. Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial Lancet Gastroenterol Hepatol. 2017 2 727 37

[140] Krasaelap A,Sood MR,Li B.et al. Efficacy of auricular neurostimulation in adolescents with irritable bowel syndrome in a randomized, double-blind Trial Clin Gastroenterol Hepatol. 2020 18 1987 1994.e2

[141] Huang Z,Lin Z,Lin C.et al. Transcutaneous electrical acustimulation improves irritable bowel syndrome with constipation by accelerating colon transit and reducing rectal sensation using autonomic mechanisms Am J Gastroenterol. 2022 117 1491 501

[142] Zhou J,Wang J,Ning B.et al. Sustained ameliorating effects and autonomic mechanisms of transcutaneous electrical acustimulation at ST36 in patients with chronic constipation Front Neurosci. 2022 16 1038922 PMC9720110

[143] Liu Z,Yan S,Wu J.et al. Acupuncture for chronic severe functional constipation: a randomized trial Ann Intern Med. 2016 165 761 9

[144] Liu B,Wu J,Yan S.et al. Electroacupuncture vs prucalopride for severe chronic constipation: a multicenter, randomized, controlled, noninferiority trial Am J Gastroenterol. 2021 116 1024 35

[145] Iqbal F,Thomas GP,Tan E.et al. Transcutaneous sacral electrical stimulation for chronic functional constipation Diseases of the Colon & Rectum. 2016 59 132 9

[146] Iqbal F,Collins B,Thomas GP.et al. Bilateral transcutaneous tibial nerve stimulation for chronic constipation Colorectal Dis. 2016 18 173 8

[147] Gokce AH,Gokce FS. Effects of bilateral transcutaneous tibial nerve stimulation on constipation severity in geriatric patients: a prospective clinical study Geriatrics Gerontology Int. 2019 20 101 5

[148] Chase J,Robertson VJ,Southwell B,Hutson J,Gibb S. Pilot study using transcutaneous electrical stimulation (interferential current) to treat chronic treatment‐resistant constipation and soiling in children J Gastroenterol Hepatol. 2005 20 1054 61

[149] Clarke MC,Chase JW,Gibb S.et al. Decreased colonic transit time after transcutaneous interferential electrical stimulation in children with slow transit constipation J Pediatr Surg. 2009 44 408 12

[150] Clarke MC,Chase JW,Gibb S,Hutson JM,Southwell BR. Improvement of quality of life in children with slow transit constipation after treatment with transcutaneous electrical stimulation J Pediatr Surg. 2009 44 1268 73

[151] Ismail KA,Chase J,Gibb S.et al. Daily transabdominal electrical stimulation at home increased defecation in children with slow-transit constipation: a pilot study J Pediatr Surg. 2009 44 2388 92

[152] Yik YI,Ismail KA,Hutson JM,Southwell BR. Home transcutaneous electrical stimulation to treat children with slow-transit constipation J Pediatr Surg. 2012 47 1285 90

[153] Queralto M,Vitton V,Bouvier M,Abysique A,Portier G. Interferential therapy: a new treatment for slow transit constipation. A pilot study in adults Colorectal Dis. 2012 15

[154] Clarke MC,Catto-smith AG,King SK.et al. Transabdominal electrical stimulation increases colonic propagating pressure waves in paediatric slow transit constipation J Pediatr Surg. 2012 47 2279 84

[155] Yang Y,Yim J,Choi W,Lee S. Improving slow-transit constipation with transcutaneous electrical stimulation in women: A randomized, comparative study Women & Health. 2016 57 494 507

[156] Moore JS,Gibson PR,Burgell RE. Randomised clinical trial: transabdominal interferential electrical stimulation vs sham stimulation in women with functional constipation Aliment Pharmacol Ther. 2020 51 760 9

[157] Xiao W,Liu Y. Rectal hypersensitivity reduced by acupoint TENS in patients with diarrhea-predominant irritable bowel syndrome: a pilot study Dig Dis Sci. 2004 49 312 9

[158] Xiao Y,Xu F,Lin L,Chen JD. Transcutaneous Electrical Acustimulation Improves Constipation by Enhancing Rectal Sensation in Patients With Functional Constipation and Lack of Rectal Sensation Clin Transl Gastroenterol. 2022 13 e00485 PMC9132522

[159] Çoban Ş, Akbal E, Köklü S, et al. Clinical trial: transcutaneous interferential electrical stimulation in individuals with irritable bowel syndrome - a prospective double-blind randomized study Digestion. 2012 86 86 93

[160] Adams D. The course and prognostic factors of familial amyloid polyneuropathy after liver transplantation Brain. 2000 123 1495 504

[161] Zhao J,Zhao X,Wang Q.et al. Efficacy and safety of electroacupuncture for metabolic dysfunction-associated fatty liver disease: a study protocol for a multicentre, randomised, sham acupuncture-controlled, patient-blinded clinical trial BMJ Open. 2024 14 e084768 PMC11575283

[162] Fu L,Huang L,Gao Y.et al. Investigating the efficacy of acupuncture in treating patients with metabolic-associated fatty liver disease: a protocol for a randomised controlled clinical trial BMJ Open. 2024 14 e081293 PMC11733782

[163] Jakovljevic DG,Hallsworth K,Zalewski P.et al. Resistance exercise improves autonomic regulation at rest and haemodynamic response to exercise in non-alcoholic fatty liver disease Clin Sci. 2013 125 143 9