Autonomic nervous system as a key modulator in stress-related inflammatory bowel disease: Mechanisms and therapeutic implications

Table 1 Autonomic nervous system-targeted interventions for inflammatory bowel disease

Intervention	Molecular mechanism/signaling pathway	Therapeutic effects	Model/population	Limitation	Ref.
Clonidine	Activate α2-AR	↓ muscle sympathetic nerve activity; ↓ plasma epinephrine; restores sympathovagal balance (↓ low-frequency/high-frequency); improves DAI, clinical symptoms, endoscopy	Patients with active UC (n = 9, clonidine group; n = 7, placebo group)	Small sample size; unclear whether sympathetic overactivity is UC-specific or a generic feature of inflammatory states	[127]
Dexmedetomidine	Activate α2-AR	↓ weight loss, ↓ mortality; ↓ histologic damage score; ↓ IL-23, ↑ IL-10/IL-4	TNBS-induced colitis in BALB/c mice (in vivo + in vitro)	Ip. route not clinical iv.; mechanism (Tr1 cells) not fully validated; short observation (6 days)	[128]
Dexmedetomidine	Activate α2-AR; TLR4/MyD88/NF-κB	↓ DAI score, ↓ weight loss, ↑ colon length; ↓ intestinal permeability (↓ FITC-D); ↑ ZO-1, occludin, claudin-1; ↓ serum and colonic IL-1β/IL-6/TNF-α; ↓ intestinal epithelial cell apoptosis (↑ Bcl-2, ↓ Bax and cleaved caspase-3)	DSS-induced colitis in female C57BL/6J mice	Prophylactic administration only	[129]
RX821002	Inhibit α2-AR	↓ body weight loss; ↓ histological damage and inflammatory cell infiltration in lamina propria; ↓ TNF-α, ↓ IL-1β	Restraint stress + TNBS-induced colitis in BALB/c mice	No direct catecholamine level measurement (dopamine β-hydroxylase used as surrogate marker); specific immune cell subtypes not identified	[130]
Clonidine; BRL 44408	Activate α2a-AR and inhibit α2a-AR	Clonidine: ↑ DAI elevation, ↑ weight loss; BRL 44408: ↓ weight loss, ↓ colonic MPO levels; ↓ CCL3, CXCL2, CXCL13, G-CSF, ↑ TIMP-1	DSS-induced colitis in wild-type, α2A/α2B/α2C-AR KO C57BL/6 mice	Specific downstream signaling mechanism of α2A-AR in colitis remains unclear	[126]
Propranolol	Inhibit β1/β2-AR; STAT3 signaling	↓ stress-aggravated body weight loss, ↑ colon length; ↓ histological damage; ↓ peripheral blood neutrophils (CD11b+Ly6C+Ly6G+) and colonic neutrophil infiltration; ↓ IL-6, IL-1β, CXCL1, CXCL2 mRNA levels; ↓ phosphorylation of STAT3	DSS-induced colitis in male C57BL/6 mice under chronic unpredictable stress or chronic restraint stress	Propranolol did not attenuate DSS-induced colitis without stress; other stress-related signaling pathways may also be involved	[131]
Phentolamine + propranolol	Inhibit α1/α2-AR and β1/β2-AR; nerve growth factor/Trka signaling	↓ visceromotor response to graded CRD (visceral hypersensitivity); ↓ nerve growth factor expression in muscularis externa and mucosa/submucosa	Heterotypic chronic stress-induced visceral hypersensitivity in male Wistar rats	Does not distinguish α- vs β-AR contribution individually	[132]
Carvedilol and/or Mirabegron	Inhibit β1/β2-AR; activate β3-AR; GSK-3β/NF-κB, Notch, PS1/BACE-1/Aβ signaling	↓ colon edema index; ↑ body weight; ↓ histological damage score (inflammatory infiltration, edema, hemorrhage, fibrosis); ↓ PS1, BACE-1, Aβ; ↓ Notch1, NICD, HES1; ↑ goblet cells; ↑ PPAR-γ, p(S9)-GSK3-β; ↓ TNF-α, malondialdehyde, NF-κB; ↓ Transforming growth factor-β1, α-smooth muscle actin; ↑ SMAD-7; ↓ collagen deposition (MTC); ↓ p(Y654)-β-catenin; ↑ E-cadherin (mirabegron-specific effect)	Iodoacetamide-induced UC in male Wistar rats	Only validated in single iodoacetamide model; carvedilol also possesses α1-AR blocking activity that may contribute partially; mirabegron off-target effects not fully excluded	[133]
SR58611A	Activate β3-AR	↓ colonic MPO activity; ↓ tissue TNF-α, IL-1β, IL-6 levels; restored c-kit-positive ICC network in myenteric plexus	DNBS-induced colitis in male Sprague-Dawley rats	Preventive administration only; no β3-AR antagonist or KO validation	[134]
(R)-salbutamol	Activate β2-AR; nuclear factor erythroid 2-related factor 2/heme oxygenase-1; NF-κB	↓ body weight loss, ↓ DAI score, ↑ colon length, ↓ splenomegaly; ↓ histological damage score (inflammatory infiltration, crypt destruction); ↓ serum and colonic TNF-α, IL-1β, IL-6, IFN-γ; ↓ colonic CD4+ leukocyte infiltration; ↓ p-NF-κB p65; ↑ Nrf-2, heme oxygenase-1; ↑ ZO-1, occludin; ↓ transforming growth factor-β1, α-smooth muscle actin expression; ↓ collagen deposition (picrosirius red staining); restores intestinal microbiome structure	Repeated DSS-induced chronic colitis in male C57BL/6 mice	β2-AR-specific downstream signaling mechanism not fully elucidated; mechanism of microbiome regulation by β2-AR unclear	[135]
Superior mesenteric nerve electrical stimulation		↓ DAI; no significant change in body weight, endoscopy score, histology score; no significant change in colonic IL-1β, IL-6, TNF-α, CXCL3, CCL3, CXCL2, CXCL1	DSS-induced acute colitis in male SD rats	SMN does not completely innervate the colon; stimulation parameters not optimized (optimal frequency/amplitude)	[136]
Splenic nerve stimulation	β2-AR; hypoxia-inducible factor-1α signaling	↓ colon weight/length ratio; ↓ DAI; ↓ colonic TNF-α, S100A8, S100A9 mRNA; trends toward ↓ colonic MCP-1, IL-6, TNF-α, IFN-γ protein; spleen weight; no significant change in body weight, endoscopy score, histology score	DSS-induced acute colitis in female C57BL/6N mice	Mechanism of spleen-to-colon communication unclear; stimulation parameters not optimized for colitis (adopted from arthritis model)	[137]
Optogenetic activation of local colonic sympathetic innervations; intra-rectal optic fiber insertion; blue LED (460 nm)	β-AR-CREB	↓ weight loss, ↓ colon shortening, ↓ histology score; ↓ CD45+ immune cell abundance in lamina propria and intraepithelial lymphocyte; ↓ colonic IL-6, TNF-α, IL-12, IL-21, IL-1β, IL-17 mRNA; ↓ endothelial MAdCAM-1 and ICAM-1 (mRNA and protein)	DSS-induced acute colitis in male/female chr2/TH transgenic mice (C57BL/6 background)	Optogenetic manipulation not limited to blood vessel-surrounding fibers; translatability of optogenetic approach to human IBD	[138]
Galantamine	Activate α7nAChR; JAK2/STAT3, NF-κB, and p-Akt/Bcl-2 pathways	↓ ulcerative area; ↓ colon mass index; ↓ colonic malondialdehyde; neutrophil infiltration: ↓ ICAM-1; ↓ MPO activity; ↓ NF-κB; ↓ TNF-α; ↓ HMGB1; ↓ RAGE; ↑ p-JAK2; ↓ SOCS3; ↑ p-Akt; ↑ Bcl-2; ↑ IL-10	TNBS-induced colitis in male Wistar rats	No assessment of central vs peripheral contribution	[139]
GST-21	Activate α7nAChR	↓ serum IL-6, IL-2; ↑ serum IL-10; ↓ colonic IL-6; ↓ colonic permeability; ↑ claudin-1 mRNA; restored GI motility; ↓ bacterial translocation to blood and mesenteric lymph nodes	CLP-induced polymicrobial abdominal sepsis in OF-1 mice; Chrna7-/- mice	Polymicrobial sepsis model, not IBD	[140]
Nicotine; Huperzine A	Activate α7nAChR; inhibit ACh esterase; NF-κB signaling	Nicotine: ↓ macroscopic lesion score; ↓ colonic MPO activity; ↓ NF-κB expression; ↓ serum IL-1β; restored serum visfatin levels. Huperzine A: ↓ macroscopic and microscopic lesion scores; ↓ colonic MPO activity; ↓ NF-κB expression; ↓ serum IL-1β and TNF-α; ↓ colonic malondialdehyde	Acetic acid-induced colitis in Sprague-Dawley rats	Muscarinic receptor involvement not excluded	[141]
Nicotine	Activate α7nAChR	Nicotine patch therapy combined with standard treatment: ↑ complete remission rate; ↑ quality of life scores; ↓ clinical symptom scores; ↓ endoscopic and histologic inflammation scores. Nicotine carbomer enema combined with standard treatment: ↓ St Mark’s score; ↓ stool frequency; ↓ sigmoidoscopic and histologic score; 3/17 achieved complete remission; 10/17 improved; 5/6 partial responders further improved with extended treatment	Active UC in human patients (n = 72, mild-to-moderate); active ulcerative colitis in human patients (n = 22, all non-smokers)	Small sample size; single-center; combined with standard therapy (nicotine efficacy alone not established)	[142,143]
Nicotine; mecamylamine	Activate/inhibit α7nAChR; macrophage polarization; caspase-3-dependent apoptosis	Nicotine: Pro-inflammatory effect (m1 polarization, ↑ iNOS, ↑ IL-6, ↑ TNF-α, ↓ CD206, ↓ IL-10; ↑ intracellular bacterial viability/survival; ↓ caspase-3-dependent apoptosis. Mecamylamine abrogates all nicotine effects	Thp-1-derived macrophages infected with mycobacterium avium subspecies paratuberculosis UCF4 (CD-associated pathogen), MTB, or lipopolysaccharide	Immortalized cell line (THP-1) may not fully recapitulate primary human macrophages; no in vivo validation; no primary cells from CD/UC patients	[145]
High-fat feeding	Activate CCK1 receptors; activate peripheral nicotinic receptors	↓ TNF-α; ↓ IL-6; ↓ intestinal permeability; ↓ plasma endotoxin; ↓ bacterial translocation to distant organs; protective effects abrogated by vagotomy, CCK-A/B receptor antagonists, and peripheral nicotinic receptor antagonist (chlorisondamine)	Hemorrhagic shock model in male Sprague-Dawley rats	No direct measurement of vagal ACh release or α7nAChR activation; not directly tested in IBD models	[146]
Polymeric diet		↑ mucosal healing (endoscopic + histologic); ↑ weight; ↓ endoscopic score (CDEIS); ↓ histologic score; ↓ ileal and colonic ulcer	Children with active, newly diagnosed CD (n = 37)	Open-label; single-center; small sample size; short-term; no long-term relapse data	[148]
Yoga		↑ quality of life (IBDQ); ↓ disease activity; no effect on social function	Adult patients with UC in clinical remission but impaired quality of life (n = 77)	Single-center; open-label; low compliance; no measurement of ANS function; self-reported outcomes may be affected by lack of blinding	[150]
Routine physical exercises targeted to the abdomen		↑ clinical remission rates in CD; ↓ disease activity; stabilization of fecal calprotectin; ↑ quality of life	Patients with mild-to-moderate IBD (15 CD, 11 UC)	Small sample size; short duration (4 weeks); single-center; no endoscopic assessment	[15]
Electroacupuncture at ST36	Vagus-adrenal axis; S100β/RAGE/MyD88/NF-κb signaling	↓ visceral hypersensitivity; ↓ disease activity (DAI scores); ↑ colon length; ↓ histologic score; ↓ TNF-α, IL-6, IL-1β; ↓ mast cell counts and tryptase expression; ↓ enteric glial cells activation; ↑ serum NE levels	Male Sprague-Dawley rats with DSS-induced colitis in remission stage	No receptor blocker validation; potential interference from skin mechanoreceptors	[152]
Electroacupuncture at ST37	Activate α7nAChR	↓ weight loss; ↓ DAI scores; ↑ colon length; ↓ histologic score; ↓ TNF-α, IL-6, CXCL1, IL-1β, IL-5; ↑ activation of chat+ neurons in dorsal motor nucleus of the vagus; ↑ vagal efferent fiber discharge frequency; ↑ α7nAChR content in proximal colon. Effects blocked by α7nAChR antagonist methyllycaconitine citrate	Male C57BL/6J mice with DSS-induced colitis	No exclusion of vagal-adrenal anti-inflammatory pathway; precise identity of α7nAChR+ immune cells unclear	[153]
Right cervical vagus nerve stimulation	VN	Prophylactic: ↑ epithelial proliferation; ↓ apoptosis. Therapeutic: ↓ infiltration of eosinophils, neutrophils, monocytes, immature macrophages, and mature CD169- macrophages; ↓ pro-inflammatory cytokine (TNF-α, CXCL1); ↓ splenic CD11b+	Wild-type female C57BL/6J mice with DSS-induced colitis	Transient body weight loss after prophylactic VNS masks true benefit; exact molecular mechanisms of anti-inflammatory effect remain unclear; DSS model is T cell-independent, limiting assessment of adaptive immunity	[154]
Right cervical vagus nerve stimulation	Sumoylation	Restores vagal tone (↓ low-frequency/high-frequency); improves DAI, body weight, intestinal bleeding, survival; preserves colon length/histological integrity and ↓ intestinal permeability; ↓ colon IL-6 and TNF-α; ↑ IL-10; inhibits sumoylation (↓ SUMO1, ↓ SUMO2/3)	Male C57BL/6 mice with DSS-induced colitis	Use of global SUMO KO models limits cell-specific mechanism delineation	[155]
Left cervical vagus nerve stimulation	VN	↓ CDAI (clinical remission); ↓ CDEIS (endoscopic remission); ↓ CRP and fecal calprotectin; restores vagal tone (HFNU) and sympatho-vagal balance (low-frequency/high-frequency); ↓ perceived digestive pain (VAS); improves anxiety and depression (HAD); ↓ plasma and gut pro-inflammatory cytokines; ↑ anti-inflammatory transforming growth factor-β1	Mild-to-moderately active CD patients (n = 7); moderately active CD patients (n = 9)	Small sample size; open-label pilot study without control group; cannot exclude placebo effect	[156,157]
Left cervical vagus nerve stimulation	VN	↓ CDAI (clinical remission); ↓ fecal calprotectin; ↓ serum TNF and IFN-γ; tendency of ↓ SES-CD; ↓ ileal histopathology (Geboes score); improved quality of life (IBDQ, SHS)	Biologic-refractory patients with moderately to severely active CD (n = 16)	Small sample size; open-label design without control group; cannot exclude placebo effect	[158]
Subdiaphragmatic abdominal vagus nerve stimulation	VN	Improved stool quality; no blood in feces. ↓ histological damage (mucosal architecture, leukocyte infiltration); ↓ plasma CRP; ↓ infiltration of eosinophils, neutrophils (MPO+), and CD3+ T cells in mucosal, submucosal, and muscle layers	TNBS-induced intestinal inflammation in Sprague-Dawley rats	Small sample size; exact anti-inflammatory molecular mechanisms not elucidated	[159]
Sacral nerve stimulation	VN	↓ DAI; ↑ colon length; ↓ histological damage and MPO activity; increases vagal activity (↑ HF, ↑ plasma pancreatic polypeptide) and decreases sympathetic activity (↓ plasma norepinephrine); ↓ serum IL-2, IL-5, IL-12p70, IL-13, EGF; ↓ tissue IL-1α, IL-6, IL-17A, TNF-α; ↑ serum IL-4; ↑ tissue IL-10	TNBS-induced colitis in Sprague-Dawley rats	Exact anti-inflammatory molecular mechanisms not fully elucidated	[160]
Sacral nerve stimulation targeting the S3 and S4 sacral foramina	VN	↑ clinical response rate; ↓ Mayo score; ↓ plasma CRP; ↓ serum TNF-α; restores autonomic activity (HRV: Vagal/sympathetic balance); changes absolute abundance of fecal microbiota (↑ Bacteroidetes-related species, ↓ Firmicutes/Proteobacteria/Actinobacteria)	Patients with mild and moderate UC (n = 26)	Small sample size; short duration (2 weeks); single-center study; clinicians not blinded; baseline imbalance in Mayo score and microbiota abundance	[161]
Transcutaneous vagus nerve stimulation	VN; IL-6/JAK2/STAT3 signaling	↓ DAI and ameliorates histopathological damage (reduced inflammatory infiltration, restored crypt architecture and goblet cells); ↓ IL-6, p-JAK2, p-STAT3; ↑ occludin, ↑ ZO-1; suppresses systemic inflammatory cytokines (↓ IL-2, IL-4, IL-5, IL-6, IL-12p70, IL-17A, macrophage-colony stimulating factor, IFN-γ, TNF-α)	DSS-induced acute UC in male Sprague-Dawley rats	Mechanistic focus limited to IL-6/JAK2/STAT3 without exploring α7nAChR-mediated cholinergic anti-inflammatory pathway or other signaling cascades	[162]
Transcutaneous vagus nerve stimulation	VN	In DSS colitis: ↓ DAI, macroscopic and histological scores; ↓ weight loss, colon bleeding, fecal consistency loss; ↑ colon length; ↓ colonic pro-inflammatory markers (IL-1β, TNF-α, Mip1β, metalloproteinases 9, Nos2); ↓ (Bax, Bak1, Casp8); in DNBS colitis: Only partially mitigates weight loss and DAI; no significant effects on macroscopic/histological scores, colonic pro-inflammatory markers, or apoptotic markers	DSS- and DNBS-induced acute colitis in male C57BL/6 mice	Possible non-vagal innervation of auricular stimulation site; lack of mechanistic validation	[163]
Transcutaneous vagus nerve stimulation	VN	↑ clinical remission; ↓ fecal calprotectin; improves anxiety scores (PROMIS); modulates HRV (recalibration of vagal tone based on baseline HFNU)	Pediatric and young adult patients with mild to moderate CD or UC (n = 22; 10 CD, 12 UC)	Small sample size; single-center; not double-blind; no endoscopic disease assessments; heterogeneity in baseline disease activity; HRV analysis not standardized	[164]

AR: Adrenergic receptor; TLR4: Toll-like receptor 4; NF-κB: Nuclear factor-κB; GSK-3β: Glycogen synthase kinase-3β; CREB: CAMP-response-element-binding protein; JAK: Janus kinase; STAT: Signal transducer and activator of transcription; Akt: Protein kinase B; Bcl-2: B-cell lymphoma-2; α7nAChR: Α7 nicotinic acetylcholine receptor; ACh: Acetylcholine; CCK1: Cholecystokinin-1 receptor; VN: Vagus nerve; IL: Interleukin; FITC-D: Fluorescein isothiocyanate-dextran; ZO-1: Zonula occludens-1; TNF-α: Tumor necrosis factor-α; MPO: Myeloperoxidase; CCL3: C-C motif chemokine ligand 3; CXCL2: C-X-C motif chemokine ligand 2; G-CSF: Granulocyte-colony-stimulating factor; TIMP-1: Tissue inhibitor of metalloproteinase-1; CRD: Colorectal distension; PS1: Presenilin-1; BACE-1: Beta-site amyloid precursor protein-cleaving enzyme-1; Aβ: Amyloid-beta; PPAR-γ: Peroxisome proliferator-activated receptor-γ; SMAD-7: SMAD family member 7; MTC: Masson’s trichrome staining; ICC: Interstitial cells of Cajal; IFN-γ: Interferon-γ; MCP-1: Monocyte chemoattractant protein-1; SOCS3: Suppressor of cytokine signaling 3; GI: Gastrointestinal; iNOS: Inducible nitric oxide synthase; IBDQ: Inflammatory Bowel Disease Questionnaire; CD: Crohn’s disease; NE: Norepinephrine; CDAI: Crohn’s Disease Activity Index; CDEIS: Crohn’s Disease Endoscopic Index of Severity; CRP: C-reactive protein; HFNU: High-frequency normalized units; VAS: Visual analogue scale; HAD: Hospital Anxiety and Depression scale; SES-CD: Simple Endoscopic Score for Crohn’s Disease; SHS: Short Health Scale; HF: High-frequency power; EGF: Epidermal growth factor; HRV: Heart rate variability; Mip1β: Macrophage inflammatory protein-1β; Nos2: Nitric oxide synthase 2; PROMIS: Patient-Reported Outcomes Measurement Information System; UC: Ulcerative colitis; MTB: Mycobacterium tuberculosis; IBD: Inflammatory bowel disease; ANS: Autonomic nervous system; VNS: Vagus nerve stimulation.