Gastroparesis in POTS and Long COVID: A Unified Hydraulic–Neuroimmune Model

Dr Graham Exelby November 2025

Abstract

Gastroparesis—delayed gastric emptying without mechanical obstruction—is increasingly observed in Postural Orthostatic Tachycardia Syndrome (POTS) and Long COVID, yet its mechanisms remain fragmented across vascular, metabolic, and neurogenic domains. We propose a unified hydraulic–neuroimmune model integrating preload failure, lymphatic obstruction, microvascular hypoxia, and persistent viral neuroinflammation.

Orthostatic preload failure and venous–lymphatic congestion induce brainstem hypoperfusion within the LC–NTS–PVN axis, destabilizing vagal nitrergic output and impairing gastric accommodation. Concurrent HIF-1α-driven RAGE–NF-κB–STAT3 signalling amplifies glial–endothelial inflammation, while PDH and malate-aspartate shuttle inhibition collapse mitochondrial ATP generation and nitric-oxide-dependent relaxation. Structural amplifiers—coeliac-axis compression (MALS), Nutcracker syndrome, and pelvic congestion—further propagate hydraulic resistance and vagal irritability.

Emerging post-COVID pathology demonstrates SARS-CoV-2 persistence within enteric neurons and glia, sustaining ENS–vagal dysregulation and fibrotic remodelling. This viral–neuropathic substrate intersects with hydraulic stress to form a feed-forward loop of hypoxia, RAGE activation, and metabolic exhaustion. Therapeutic reversal requires multi-axis intervention—mechanical/lymphatic decompression, immune stabilization (H₁/H₂ ± LDN or the currently experimental telmisartan), and metabolic restoration (NR, ALA, vitamin K₂)—with emerging potential for tirzepatide in fascial remodelling.

This framework of a unified hydraulic-neuroimmune model redefines gastroparesis in POTS and Long COVID as a reversible systems disorder of neurovascular and metabolic integration, rather than an isolated neuropathy, offering a basis for precision diagnostics and targeted clinical trials.

Keywords: preload failure, lymphatic obstruction, vagus nerve, RAGE–STAT3 pathway, mitochondrial dysfunction.

Abbreviations (with Full Terms)

Abbreviation	Full Term / Definition
ACE2	Angiotensin-Converting Enzyme 2
ALA	Alpha-Lipoic Acid
AQP4	Aquaporin-4 (astrocytic water channel regulating glymphatic flow)
ATP	Adenosine Triphosphate
BH₄	Tetrahydrobiopterin (NOS cofactor)
CCL2	Chemokine (C-C motif) Ligand 2 (MCP-1)
CNS	Central Nervous System
COVID-19	Coronavirus Disease 2019 (caused by SARS-CoV-2)
CSF	Cerebrospinal Fluid
DAMPs	Damage-Associated Molecular Patterns
ENS	Enteric Nervous System
GABA	Gamma-Aminobutyric Acid
HIF-1α	Hypoxia-Inducible Factor 1-Alpha
H₁/H₂	Histamine Type 1 / Type 2 Receptors
ICH	Intracranial Hypertension
IJV	Internal Jugular Vein
LDN	Low-Dose Naltrexone
LC	Locus Coeruleus
LDV	Left Ventricular Diastolic Volume (context-specific)
MAS	Malate–Aspartate Shuttle
MALS	Median Arcuate Ligament Syndrome
MCAS	Mast Cell Activation Syndrome
ME/CFS	Myalgic Encephalomyelitis / Chronic Fatigue Syndrome
MRI	Magnetic Resonance Imaging
NAD⁺ / NADH	Nicotinamide Adenine Dinucleotide (oxidized/reduced forms)
NADPH	Nicotinamide Adenine Dinucleotide Phosphate (H-reduced form)
NF-κB	Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells
nNOS	Neuronal Nitric Oxide Synthase
NO	Nitric Oxide
NLRP3	NOD-Like Receptor Pyrin Domain-Containing Protein 3 (Inflammasome)
NMR	Nuclear Magnetic Resonance (contextual mention for spectroscopy)
NTS	Nucleus Tractus Solitarius
OVT	Ovarian Vein Thrombosis
PCS	Pelvic Congestion Syndrome
PDH	Pyruvate Dehydrogenase
PDK	Pyruvate Dehydrogenase Kinase
PEM	Post-Exertional Malaise
PEMT	Phosphatidylethanolamine N-Methyltransferase
POTS	Postural Orthostatic Tachycardia Syndrome
PPAR-γ	Peroxisome Proliferator-Activated Receptor Gamma
PRP	Platelet-Rich Plasma
PVN	Paraventricular Nucleus (of the hypothalamus)
RAGE	Receptor for Advanced Glycation End Products
ROS	Reactive Oxygen Species
SAA	Serum Amyloid A
SARS-CoV-2	Severe Acute Respiratory Syndrome Coronavirus 2
SIRT4	Sirtuin 4 (mitochondrial NAD⁺-dependent deacetylase)
SMA	Superior Mesenteric Artery (in SMA syndrome)
SPECT	Single-Photon Emission Computed Tomography
STAT3	Signal Transducer and Activator of Transcription 3
TGF-β	Transforming Growth Factor Beta
TLR4	Toll-Like Receptor 4
TNF	Tumour Necrosis Factor
VEGF	Vascular Endothelial Growth Factor

Introduction

Gastroparesis occurs in up to 50–90 % of POTS cases and 20–40 % of Long COVID presentations but is still frequently managed as an isolated neuropathy. Increasing evidence suggests a complex, systems-level disorder integrating cardiovascular filling dynamics, brainstem autonomic regulation, enteric neuro-glial networks, and tissue hydraulics.

Gastroparesis—delayed gastric emptying without mechanical obstruction—often stems from impaired vagal efferent signalling to the stomach, leading to reduced motility, nausea, bloating, and early satiety. In POTS and Long COVID, it's not isolated but embedded in a "gastro-cranial hydraulic continuum" where preload failure, hypoxia, and neuroimmune loops converge. 

We synthesize a hydraulic–neuroimmune model in which orthostatic preload failure and venous–lymphatic congestion precipitate and magnify brainstem hypoperfusion within the Locus Coeruleus-Nucleus Tractus Solitarius-Paraventricular Nucleus (LC–NTS–PVN) complex, shifting the locus coeruleus toward tonic hyperarousal and degrading vagal control of gastric accommodation and motility. 

This state undermines the cholinergic anti-inflammatory reflex and impairs vagal nitrergic outflow to gastric smooth muscle, disrupting accommodation and peristaltic coordination, producing characteristic symptoms of early satiety, nausea, and bloating.

In parallel, hypoxia-activated HIF-1α drives RAGE/NF-κB–NLRP3 signalling in glia and endothelium, amplifying cytokines that further bias LC tone and depress vagal control. Within the gut wall, enteric gliosis, ICC dysrhythmia, and mitochondrial redox failure propagate motility impairment.

Mechanical amplifiers—coeliac axis compression and pelvic venous congestion, with hypoxic/fibrotic -driven structural changes  —further restrict splanchnic arterial/lymphatic flow and irritate autonomic plexuses, explaining positional variability and overlap with dysautonomia.  Clinically, SPECT hypoperfusion of brainstem nuclei co-occurs with upright LVEDV/VTI reductions and symptoms of early satiety, bloating, and nausea.

The recurrent finding that lymphatic therapy and targeted cervical and metabolic interventions improve symptoms in many cases posit a reversible gastro-cranial continuum, with lymphatic restoration serving as a physiological “off-ramp” that re-oxygenates the axis and normalizes motility. This paper integrates these threads into a hydraulic–neuroimmune model and outlines a staged therapeutic approach with measurable endpoints. It emphasizes how lymphatic management could resolve it by addressing upstream congestion.

Beyond haemodynamic failure, direct viral persistence has emerged as an equally critical factor. SARS-CoV-2 demonstrates tropism for enteric neurons and glia via ACE2 and RAGE, with mucosal antigen retention documented months after infection. This establishes a chronic neuroinflammatory reservoir that interferes with ENS signalling, distorts the renin–angiotensin balance, compounding preload failure, and induces fibrosis or neuromodulatory dysfunction. Persistent viral antigens and DAMPs prolong RAGE–NF-κB signalling and exacerbate susceptibility to hypoxia and hydraulic congestion.

The hydraulic–neuroimmune model therefore unites these mechanisms. Hydraulic stress—mediated by coeliac axis compression, pelvic congestion, and lymphatic stasis—interacts with viral–neuropathic persistence and vagal dysregulation, to maintain a self-reinforcing cycle of hypoxia, immune activation, and metabolic exhaustion. The reproducible improvement seen with lymphatic decompression and NAD⁺ restoration combined with immune stabilization supports this integrated perspective. Emerging experimental evidence supports telmisartan and tirzepatide’s usefulness in therapeutic intervention and plasmapheresis in patients with persistent spike antibody levels. This paper outlines the evidence, mechanisms, and therapeutic implications of this unified framework.

This hypothesis integrates research from preload failure modelling in POTS and Long COVID, the Locus Coeruleus (LC)-Vagus-Vestibular axis, pericyte-astrocyte dysfunction, and inflammation/hypoxia pathways, weaving in document insights and search findings, then proposes a unified model.  The hypotheses align well with emerging understandings of gastroparesis as a multifactorial sequela of autonomic dysregulation, mechanical compression, and hydraulic/inflammatory stressors in these conditions.

While gastroenterologists often attribute gastroparesis in POTS to faecal loading or local neuropathy, treating with aperients and coeliac plexus blockade, emerging evidence suggests these are downstream effects of systemic autonomic dysregulation. This model complements conventional approaches by addressing upstream drivers, potentially enhancing long-term outcomes.

1. Brainstem Hypoxia Dysregulating the ANS via LC and PVN

This presents as a core upstream driver, directly linking to vagal dysfunction and gastric hypomotility. (Elbeltagi et al. World Clin Cases.2023)(Camici et al. Front Cell Infect Microbiol. 2024)

Brainstem hypoperfusion (e.g., from orthostatic preload drops: 20-40% LVEDD reduction, as shown in supine/standing echocardiography studies) affects key hubs like the NTS (vagal afferent terminus), LC (noradrenergic modulator), and PVN (hypothalamic regulator of vasopressin and autonomic outflow). (Baker et al.JACC Basic TransL Sci.2024)

Hypoxia stabilizes HIF-1α (from the inflammation/hypoxia document), activating RAGE-NF-κB-STAT3 loops that inflame pericytes/astrocytes, impairing glymphatic clearance and sustaining neurovascular constriction. This biases LC toward tonic firing (hypervigilance/stress mode), inhibiting phasic adaptive responses and removing its β-adrenergic "brake" on glial inflammation.(D'Ignazio et al.FEBS J.2016)(Dinarello et al. Cell Death Discov.2023)(Carlsson et al. PLoS One.2018)(Cui et al. Cell Mol Neurobiol.2024)(Grimm et al. Nat Neurosci.2024)

For the vagus: NTS integration falters, disrupting efferent signals to the dorsal motor nucleus (DMN), which controls gastric smooth muscle relaxation via nitrergic pathways (e.g., nNOS/NO release).(Travagli et al. Nat Rev Gastroenterol Hepatol.2016)(Gillis et al.Cell Mol Neurobiol.2022) This results in defective gastric accommodation and motility, mimicking diabetic or post-viral gastroparesis.(Nguyen et al. Neurogastroenterol Motil.2020)(Park et al. Clin Auton Res.2013)(Wu et al. Front Neurol.2024)(Loavenbruck et al. Neurogastroenterol Motil.2015)

Relevance to POTS/Long COVID:

Post-COVID gastroparesis may arise from viral nerve damage (e.g., SARS-CoV-2 affecting oesophageal/stomach nerves via ACE2/RAGE) and autonomic dysregulation. (Elbeltagi et al. World Clin Cases.2023)( Camici et al. Front Cell Infect Microbiol. 2024)  In POTS, this overlaps with orthostatic intolerance, where hypoxia exacerbates symptoms like PEM. PVN hypoperfusion (seen in brain SPECT scanning) could dysregulate vasopressin, worsening splanchnic pooling and GI stasis. Studies confirm parasympathetic dysfunction is associated with delayed gastric emptying in gastroparesis, with autonomic impairment common in POTS patients. (Baker et al.JACC Basic TransL Sci.2024)

Hypoxia-associated autonomic dysregulation aligns with vagal low tone in gastroparesis patients, where stimulation improves motility.(Gottfried-Blackmore et al. Neurogastroenterol Motil. 2020)(Kornum et al. Diabetologia 2024)

2. Coeliac Axis Compression and Splanchnic Ischaemia

Median Arcuate Ligament Syndrome (MALS) as a Mechanical and Inflammatory AmplifierCompression of the coeliac axis by a thickened or low-lying median arcuate ligament (MAL) restricts arterial inflow and lymphatic outflow to the stomach, pancreas, and liver. In POTS and Long COVID cohorts, this phenomenon has emerged as a significant mechanical amplifier of splanchnic hypoperfusion and neurogenic irritation. (Saleem et al. StatPearls 2023)(Gaillard et al. Radiopedia 2025)(Brandeis et al. Am Surg 2025)

Coeliac plexus irritation contributes to tachygastria, postprandial pain, early satiety, and delayed gastric emptying. Ischaemia of the coeliac plexus irritates vagal and sympathetic fibres, producing tachygastria, postprandial pain, and delayed gastric emptying.  These effects compound preload failure and propagate vagal dysregulation.(Bayati et al.Gastrointest Disord.2021)

This compression is often aggravated by splanchnic pooling due to low central venous pressure (CVP) and hypermobility-related ligamentous laxity.

Post-COVID Onset and Case LiteratureCase studies have also identified de novo or worsened MALS following SARS-CoV-2 infection.  Post-viral inflammatory remodelling of the median arcuate ligament, possibly via TGF-β–driven pericyte-to-myofibroblast transition, may thicken the ligament and constrict the coeliac axis, which offers a mechanistic rationale for newly emergent MALS after SARS-CoV-2 infection.

Clinic investigations have confirmed this occurrence. 

• Brandeis et al. (Am Surg 2025) described seven patients developing symptomatic MALS approximately one month after COVID-19 infection. Cross-sectional imaging demonstrated new or aggravated coeliac axis compression, often in combination with other vascular syndromes such as Nutcracker and May–Thurner. Coeliac plexus block and surgical release improved post-prandial pain and dysautonomia.

• Okuno et al. (Acute Med Surg 2024) reported six patients with retroperitoneal haemorrhage due to rupture of pancreaticoduodenal arcade aneurysms precipitated by MALS during acute COVID-19. These cases highlight haemodynamic stress within the collateral network secondary to coeliac obstruction.

Together these studies confirm that post-viral inflammatory remodelling of the MAL can precipitate or unmask clinically significant coeliac axis compression.

Mechanistic Integration: Hypoxia, Pericytes, and Fibrotic Thickening

The proposed pathophysiology aligns with hypoxia-driven pericyte dysregulation observed in other post-COVID vascular beds. (Brandeis et al. Am Surg 2025) SARS-CoV-2 infects endothelial and perivascular cells through ACE2 and RAGE, provoking oxidative stress, endothelial swelling, and pericyte detachment.

Activated pericytes undergo phenotypic transition to myofibroblasts under TGF-β/Smad2/3 and Akt/mTOR signalling (Zhao et al. Exp Mol Med.2022), producing extracellular-matrix deposition and ligamentous stiffening. In the MAL, this transformation thickens the fibrotic arch overlying the coeliac axis, narrowing the lumen and increasing shear stress on the coeliac plexus.

Functional Consequences in POTS and Long COVID

• Ischaemia–hypoxia loop: Reduced splanchnic perfusion and lymphatic drainage increase local hypoxia, stabilizing HIF-1α and perpetuating RAGE/NF-κB activation. (Brandeis et al. Am Surg 2025)

• Autonomic irritation: Mechanical and inflammatory traction on the coeliac ganglion distorts vagal–sympathetic balance, aggravating post-prandial tachycardia and nausea. (Saleem et al.StatPearls 2023)

• Hydraulic coupling: Intravascular resistance at the coeliac origin augments upstream venous pressure, linking MALS with Nutcracker and pelvic congestion syndromes through shared valveless venous channels.(Abu-Hilal et al. J Invest Med Impact Case Rep. 2023)

  
  

Clinical Correlates and Therapeutic Implications

Duplex ultrasound with respiratory variation, CTA/MRA, and gastric emptying studies should be considered in post-COVID or dysautonomic patients presenting with post-prandial pain and early satiety.(Maddox et al. Am Surg 2025)   Where compression is confirmed, staged management mirrors other hydraulic amplifiers: mechanical decompression (surgical or fascial), immune modulation (H1/H2 blockade ± LDN), and metabolic restoration (NR, ALA, vitamin K₂).(Chen et al. Ann Vasc Surg.2023)

Surgical release of the MAL restores gastric perfusion and motility in 70–90% of identified cases, but integrating lymphatic rehabilitation and neuro-vagal retraining may enhance durability of outcomes in POTS/Long COVID phenotypes.(Skelly et al. Semin Pediatric Surg. 2021)(Sun et al. Intractable Rare Dis Res.2019)

Potential Role of Tirzepatide Although untested in MALS, the theoretical rationale for tirzepatide arises from its observed effects on extracellular-matrix integrity, endothelial shear responsiveness, and fascial tone in metabolic tissues. GLP-1/GIP agonists enhance microvascular perfusion, reduce oxidative stress, and modulate TGF-β/VEGF signalling—all relevant to ligamentous and perivascular fibrosis.(Batiha et al. Inflammopharmacology. 2023)

Clinically, improvements in cervical and cranial fascial compliance have been reported in Long COVID cohorts receiving tirzepatide, suggesting potential benefit in reducing tension within the head-neck-thoracic fascia continuum that contributes to coeliac axis strain, and remains a significant therapeutic option for these patients. This remains a hypothesis pending formal study but aligns with the broader concept of pharmacologically restoring fascial elasticity and microvascular oxygenation within the hydraulic continuum.

3. Pelvic Congestion and the Vagal Paradox

Concept and Anatomy

Pelvic congestion syndrome (PCS) arises from valvular failure and reflux in the ovarian/internal iliac veins, producing varices and venous hypertension. In dysautonomic phenotypes, PCS acts as a downstream amplifier that elevates vertebral venous pressures via the valveless spinal plexus and perturbs autonomic plexuses (inferior hypogastric, coeliac), with cranio-caudal hydraulic coupling to the brainstem and cervical fascia.

Clinical features include post-prandial abdominal discomfort, pelvic heaviness, urinary urgency, dyspareunia, and end-of-day worsening, with duplex/CTV markers include ovarian vein ≥6–8 mm, dilated uterine plexus, and cross-pelvic reflux. (Bell et al. Radiopedia 2025)

Post-COVID Signals (Indirect but Convergent)

• Hypercoagulability after COVID-19 elevates venous thrombosis risk, plausibly increasing gonadal/iliac microthrombotic load → venous hypertension/valvular failure → PCS physiology. (Whiteley & Wood.Lancet Infect Dis. 2022)

• Ovarian (gonadal) vein thrombosis cases during/after COVID-19 can mimic or precipitate PCS via impaired outflow and collateralization. (Glazner et al.Journal Surgical Case Reports 2021)(Fatimazahra et al.Thromb Thrombolysis 2021)(Veyseh et al.BMJ Case Rep.2020)(DeBoer et al.Cureus.2021)

• Renal vein thrombosis after COVID-19 highlights susceptibility of the renal–gonadal axis, relevant to PCS/NCS overlap. (Janbazi et al.Clin Case Rep. 2020)(Petrou et al Life.2023)

• Weight-loss–mediated angle narrowing (SMA syndrome) reported in COVID contexts can co-generate Nutcracker physiology; the narrowed aorto-mesenteric angle compresses the LRV, increasing gonadal vein reflux and pelvic varices. (Yazdani et al. Eat Weight Disord.2022)(Raj et al.AME Case Rep.2024)

Nutcracker Syndrome (NCS) IntersectionWhile direct, peer-reviewed post-COVID de novo NCS evidence is very limited,( Sarikaya et al. Ann Vasc Surg.2025) strong background NCS literature, and clinic studies demonstrating Nutcracker Syndrome after COVID provide solid evidence.

The Vagal Paradox—MechanismPelvic venous hypertension irritates the inferior hypogastric plexus and, via viscero-visceral reflexes and coeliac–vagal integration, may trigger paradoxical vagal overactivity (nausea, presyncope, brady-episodes) while degrading coordinated gastric efferents.

Elevated pelvic/vertebral venous pressures propagate cranially through the valveless plexus, congesting the dorsal vagal complex and reducing oxygen delivery, thereby biasing LC–NTS signalling toward dysautonomic instability. This reconciles defaecation-related syncope, post-prandial nausea, and orthostatic exacerbations.

Key Takeaway

Pelvic congestion participates in a bidirectional loop with splanchnic and cranial hydraulics. Post-COVID thrombo-inflammatory vulnerability and weight-loss-mediated anatomic narrowing plausibly can unmask or worsen PCS/NCS, providing a coherent substrate for the “vagal paradox” within the hydraulic–neuroimmune model.

4. Mitochondrial and Redox Dysfunction in Gastric Smooth Muscle

Hypoxia-induced PDH inhibition limits ATP generation, impairing gastric smooth muscle contractility. Elevated lactate and oxidative stress reduce nNOS-dependent relaxation, while GABA depletion and excess glutamate drive excitotoxicity within vagal circuits. Therapeutic restoration using nicotinamide riboside, ALA, and vitamin K2 (Feng et al. Int Immunopharmacol. 2024) indirectly helps rebalance NAD+/NADH ratios and restores nitrergic tone.  Vitamin K2 MK-7 in hypoxic astrocytes reduces ROS, boosts ATP production, and suppresses inflammation (e.g., lowered IL-6, TNF-α) via upregulation of Gas6 (a vitamin K-dependent protein), again focusing on mitochondrial integrity without referencing PDH or glycolysis shifts.(Yang et al. Eur Rev Med Pharmacol Sci. 2020)

Hypoxia-Driven Bioenergetic Failure

Under hypoxic or inflammatory stress, pyruvate dehydrogenase (PDH) is inhibited through phosphorylation by PDH kinase (PDK), diverting pyruvate away from the Krebs cycle toward lactate production. This reduces acetyl-CoA formation and oxidative phosphorylation efficiency. (Luo et al. Sig Transduct Target Ther 2022)

In hypoxia, the malate–aspartate shuttle (MAS)—critical for transferring reducing equivalents from cytosolic NADH into the mitochondria for oxidative phosphorylation—is impaired by mitochondrial redox imbalance (e.g., NADH accumulation due to limited electron transport chain activity) and aspartate depletion (e.g., via HIF-1α-mediated suppression of biosynthesis pathways). This disrupts the shuttle's flux, leading to an elevated cytosolic NADH/NAD⁺ ratio and a collapse of the intercompartmental NAD⁺/NADH gradient. (Bouhamida et al. Biology 2022)(Jespersen et al J Physiol 2017)( Støttrup et al. Cardiovascular Research 2010)

In smooth muscle, hypoxia rapidly reduces contractility by impairing ATP generation, as seen in studies on gastrointestinal and vascular tissues where low oxygen decreases force output.(Taggart et al. J Physiol 1998)(Hu et al. Sci Bull 2023)  Gastric-specific evidence is indirect but consistent, with hypoxia altering glucose metabolism (e.g., via G6PD overactivation) in related smooth muscle cells, contributing to contractile dysfunction.( Chettimada et al. Am J Physiol 2015)

Together, these bottlenecks reduce mitochondrial ATP production, impairing ATP-dependent myosin light-chain kinase activity, myosin light-chain phosphorylation, and consequently gastric smooth-muscle contractility.

Redox and Nitric Oxide Interactions

In the gastric wall, nitrergic relaxation depends on neuronal nitric-oxide synthase (nNOS) activity, which itself requires adequate NADPH and oxygen. Hypoxia, superoxide excess, and peroxynitrite formation inhibit nNOS, reducing NO bioavailability.

This loss of inhibitory tone contributes to tonic constriction, dysrhythmic contractions, and gastroparesis-type motility patterns. Concurrent oxidative stress oxidizes tetrahydrobiopterin (BH₄), leading to NOS uncoupling and further ROS production—a vicious cycle that maintains muscle rigidity and delayed emptying.(Dick et al Br J Pharmacol 2001)(Lundberg & Weitzberg Cell 2022)

Studies show HIF-1α stabilization restores nNOS in gastric neurons, improving emptying, while NO collaborates with CO as cotransmitters in intestinal relaxation. (Teng et al Am J Physiol 1998) Elevated lactate and oxidative stress reducing nNOS-dependent relaxation is plausible, though direct gastric links are stronger for vascular tissues.

Neurotransmitter and Excitotoxic Imbalance

Energy deprivation affects glutamate and GABA metabolism within vagal nuclei and enteric ganglia. Low ATP and NAD⁺ suppress glutamate decarboxylase activity, reducing GABA synthesis. The resulting low GABA / high glutamate ratio increases excitatory drive through NMDA receptors on vagal efferents and enteric neurons, generating excitotoxic stress and further mitochondrial depolarization.  (McMenamin et al Exp Biol Med 2016)(Ben-Ari et al Physiol Rev 2007)(Cui et al. Cell Mol Neurobiol 2024)

Disruptions lead to visceral hypersensitivity and dysrhythmia, manifest clinically as nausea, and post-prandial autonomic storms. Clinical manifestations align with vagal dysregulation, though evidence is more robust for CNS hypoxia than peripheral gastric circuits.

Metabolic Crosstalk with Pericytes and Glia

Mitochondrial failure in pericytes and enteric glia amplifying oxidative stress, inflammation (via RAGE–NF-κB–STAT3), and microvascular constriction worsening microvascular constriction and local hypoxia.    Hypoxia induces mitochondrial dysfunction in endothelial cells and pericytes, leading to BBB compromise and vascular issues, extensible to gastric microvasculature.

In the gut, mitochondrial ROS from ischaemia-reperfusion affects epithelial and glial function, worsening perfusion and hypoxia in the gastric wall. This feedback loop is a cause-and-consequence of impaired perfusion in the gastric wall and brainstem autonomic centres.(Xiao et al Clin Transl Med 2024)(Grossini et al Antioxidants 2025)( Dumitrescu et al. Oxid Med Cell Longev. 2018)

Therapeutic Restoration

Reversal of these metabolic blocks relies on re-establishing NAD⁺ pools and redox balance: 

• Nicotinamide riboside / nicotinamide mononucleotide replenish NAD⁺ and activate sirtuin-mediated deacetylation of PDH, restoring flux through oxidative metabolism.

• Alpha-lipoic acid (ALA) functions as a PDH cofactor and universal antioxidant, regenerating glutathione and improving nNOS coupling.

• Vitamin K₂ supports mitochondrial electron transport through menaquinone shuttling and stabilizes membrane potential, improving smooth-muscle energetics.

• Magnesium and CoQ10 assist ATP synthase function and reduce oxidative load.

• Telmisartan, via PPAR-γ activation, indirectly improves mitochondrial biogenesis and redox resilience.   This potential interventions is as yet largely preclinical and experimental.

  
  

Together these interventions may re-establish nitrergic tone, normalize gastric rhythm, and close the loop between hypoxia, oxidative stress, and impaired motility.

5. Microvascular and Endothelial Hypoxia

Microvascular dysfunction represents a unifying substrate linking central and peripheral manifestations of gastroparesis in POTS and Long COVID, the brainstem in autonomic control and gastric wall in dysmotility.   Both endothelial and pericyte injury generate patchy tissue ischaemia, oedema, and impaired neurovascular transmission within the gastric wall and brainstem autonomic circuits. (Daisley et al Autops Case Rep 2021)These microvascular changes mirror those observed in cortical and brainstem SPECT imaging, suggesting a shared hypoxic–inflammatory axis.(Seeley et al Sci Rep 2025)

Pericyte and Endothelial Injury

SARS-CoV-2 has high tropism for vascular and perivascular cells via ACE2 and RAGE, provoking endothelial swelling, glycocalyx loss, and pericyte detachment. (Maccio et al EBioMedicine 2021) Electron microscopy and immunohistochemistry from autopsy series demonstrate pericyte dropout and capillary rarefaction across multiple organs, including gastrointestinal mucosa. (Jin et al. Sig Transduct Target Ther 2020)  Detached pericytes enter a proinflammatory phenotype, secreting IL‑6, VEGF, and MCP‑1/CCL2, amplifying local cytokine signalling and endothelial activation.(Beltramo et al Int J Mol Sci 2024)(Yang et al. J Neuroinflammation 2022)

Pericyte–Myofibroblast Transition (PMT) and Fibrosis

Under hypoxia and TGF‑β signalling, pericytes transdifferentiate into contractile myofibroblasts via Smad2/3 and Akt/mTOR pathways (Zhao et al., Exp Mol Med 2022). This transformation increases extracellular‑matrix deposition, basement‑membrane thickening, and microvascular rigidity. (Chen et al. J Translat Med 2023)  In gastric tissue, PMT leads to impaired nutrient diffusion, reduced compliance, and loss of coordinated smooth‑muscle excitability. The same process may contribute to thickening of perivascular fascia, including the median arcuate ligament and peri‑coeliac tissue, thereby coupling microvascular pathology to macroscopic compression syndromes.(Brandeis et al. Am Surg 2025)

Hypoxia‑Inflammation Feed‑Forward LoopMicrovascular congestion and pericyte loss create a self‑sustaining cycle of hypoxia and inflammation:

1. Capillary rarefaction limits oxygen delivery, stabilizing HIF‑1α. (Da Silva et al. Int J Mol Sci 2025) (Iosef et al J Transl Med 2023)

2. HIF‑1α induces VEGF and RAGE, promoting endothelial leak and further interstitial hypoxia. (Da Silva et al. Int J Mol Sci 2025) (Iosef et al J Transl Med 2023)

3. RAGE–NF‑κB–STAT3 activation perpetuates cytokine release (IL‑6, TNF‑α, CCL2) and mitochondrial oxidative stress. (Michalak et al Front Immunol 2025)

4. Endothelial–pericyte uncoupling leads to heterogeneous perfusion and localised ischaemia of gastric smooth muscle, enteric neurons, and interstitial cells of Cajal (ICCs). (Khan et al. Cardiovascular Research 2022)(Nunn et al. Biomedicines 2022)

This loop explains the patchy gastric dysmotility and variable symptom severity seen in POTS and Long COVID patients. Mitochondrial dysfunction (PDH inhibition, MAS blockade) compounds these effects, further reducing ATP availability and nNOS‑dependent nitrergic signalling.

Implications for the Median Arcuate Ligament and Coeliac Axis

Within the MAL and adjacent fascia, the same pericyte‑driven fibrotic process may account for the observed ligament thickening and stiffening post‑COVID. (Brandeis et al. Am Surg 2025)( Abu-Hilal et al. J Investig Med. 2023) Hypoxia and chronic RAGE activation promote collagen cross‑linking and loss of ligament elasticity, converting a benign anatomic variant into symptomatic coeliac compression. Thus, the microvascular hypoxia model extends seamlessly from the gastric wall to the ligamentous and vascular structures that govern splanchnic flow.

Summary

Microvascular and endothelial hypoxia underlie both the functional and structural progression of gastroparesis in POTS and Long COVID. Pericyte injury and hypoxia‑driven fibrosis provide a biological bridge between microangiopathy and macro‑mechanical compression syndromes such as MALS, reinforcing the hydraulic–neuroimmune continuum described in this model.

6. Lymphatic and Fascial Dynamics: The Hydraulic Off-Ramp

The lymphatic system forms the drainage arm of the vascular–interstitial continuum, responsible for clearing inflammatory exudate, cytokines, and metabolites. (Tuckey et al. Front Pain Res 2021)  In POTS and Long COVID, mounting evidence suggests that lymphatic flow is impeded both mechanically—by fascial restriction and venous congestion—and biologically—by viral and immune-mediated endothelial injury within lymphatic channels and nodes.

Evidence of Lymphatic Involvement in SARS-CoV-2

SARS-CoV-2 RNA and nucleocapsid protein have been detected in lymph nodes and spleen, accompanied by follicular depletion, sinus histiocytosis, and lymphopenia (Chen et al., Clin Infect Dis 2021; Roldán-Santiago et al., Cell Signal 2024).(Xiang et al Front Immunol 2021)  Autopsy and immunohistochemical studies identify viral tropism for CD169⁺ macrophages in nodal sinuses, suggesting direct viral entry into the lymphoid–lymphatic interface. These structural disruptions plausibly impair immune cell trafficking and fluid clearance, promoting persistent interstitial inflammation and fibrotic remodelling. (Murgola et al PLos Pathog 2021)

Fascial–Lymphatic Coupling

The fascial network surrounding the thoracic inlet, diaphragm, and coeliac axis provides mechanical scaffolding for major lymphatic trunks. (Tuckey et al. Front Pain Res 2021)   Fascial contracture, post-infectious collagen cross-linking, and TGF-β–driven fibroblast activation (as seen in pericyte-derived myofibroblast transition) can constrict these lymphatic conduits. (Plaut Front Med 2023)

Thoracic outlet and Eagle-space restriction increase carotid-sheath tension, distorting vagal and sympathetic fibres and reducing lymph propulsion via negative-pressure gradients during respiration.(Vach et al. Laryngoscope Investig OtoLaryngol 2022)

Hydraulic–Neuroimmune Integration

Lymphatic congestion traps cytokines and danger-associated molecular patterns (DAMPs) within the interstitium, sustaining RAGE–NF-κB–CCL2 activation in adjacent endothelium, glia, and mast cells. (Low et al Front Med 2023) Impaired drainage also limits removal of lactate and oxidized lipids generated under hypoxia, perpetuating redox stress and neuroimmune sensitization. (Holms Immuno 2022)

Manual decompression of cervical and thoracic fascia (Vodder, Watson, or specialized osteopathic techniques) restores lymphatic flow, reduces intracranial and splanchnic pressures, and re-oxygenates the vagal–brainstem axis—explaining the reproducible symptomatic relief observed clinically. (Heald et al Cardiovasc Endocrinol Metab 2022)(Overall et al. Healthcare 2023)

Potential Pharmacologic Modulation

Pharmacologic restoration of microvascular and lymphatic integrity may complement mechanical therapies. Telmisartan (via PPAR-γ activation and RAGE suppression), while at an experimental preclinical stage, and its PPAR-γ role is vascular, with nicotinamide riboside may enhance endothelial-pericyte coupling, while alpha-lipoic acid and vitamin K₂ mitigate oxidative stress within lymphatic endothelium, extrapolated from vascular research.

Although tirzepatide (Mounjaro) remains untested in this setting, its capacity to remodel extracellular-matrix tone and improve fascial compliance in metabolic tissues provides a theoretical rationale for future investigation.

Summary

Lymphatic failure represents the final common pathway through which mechanical, inflammatory, and metabolic stressors sustain autonomic dysregulation in POTS and Long COVID. By reopening this “hydraulic off-ramp,” either through fascial release or vascular–metabolic modulation, interstitial oxygenation normalizes, RAGE signalling abates, and vagal tone can be restored. This places the lymphatic–fascial axis at the centre of recovery from chronic neuroimmune hypoxia.

7.Ehlers-Danlos Syndrome as a Structural Amplifier in the Hydraulic–Neuroimmune Model

Ehlers-Danlos Syndrome represents both a structural and molecular amplifier within the hydraulic–neuroimmune continuum. Connective tissue laxity reduces venous return and lymphatic propulsion, while fibroblast redox stress and mast-cell hyperreactivity sustain low-grade inflammation that further weakens extracellular matrix integrity.

Ehlers-Danlos Syndrome (EDS), a group of hereditary connective tissue disorders affecting collagen synthesis and extracellular matrix integrity, frequently co-occurs with POTS and exacerbates gastroparesis through structural vulnerabilities that amplify hydraulic stress, autonomic dysregulation, and neuroimmune activation. (Wu & Ho. Front Neurol. 2024)  Hypermobile EDS (hEDS), the most common subtype (80–90% of cases), and related Hypermobility Spectrum Disorders (HSD) affect approximately 1 in 5,000 individuals, with a female predominance.(EDS Clinic.2025)

Up to 40% of EDS patients exhibit orthostatic intolerance akin to POTS, while 18% of POTS cohorts have underlying EDS. Gastrointestinal involvement is near-ubiquitous, with up to 98% of hEDS patients meeting Rome IV criteria for functional disorders, and delayed gastric emptying documented in 12–35% of tested cases. This section integrates EDS into the hydraulic–neuroimmune framework, positioning connective tissue laxity as an upstream driver that intersects with preload failure, vascular compressions, lymphatic obstruction, and persistent inflammation—mechanisms that mirror and potentially precede those in Long COVID. (Wu & Ho. Front Neurol. 2024)( Chedid et al. Clin Gastroenterol Hepatolog 2025)

Connective Tissue Laxity and Hydraulic Stress

At the core of EDS pathology are defects in collagen types I, III, and V, leading to reduced tissue tensile strength, hyperelasticity, and fragility. (EDS Clinic.2025) In the abdominal and vascular compartments, this manifests as ligamentous laxity, peritoneal instability, and increased compliance of splanchnic veins and arteries. ( Chedid et al. Clin Gastroenterol Hepatolog 2025)  These changes propagate hydraulic resistance by promoting venous pooling in dependent regions (e.g., lower limbs and pelvis), reducing central venous return, and precipitating orthostatic preload drops—hallmarks of POTS. (Baker et al.JACC Basic Transl Sci.2024)(Wu & Ho. Front Neurol. 2024)(Singh et al. Radiopedia 2025)    Splanchnic hypercapacitance is particularly amplified post-prandially, with mesenteric blood volume increasing up to 300% in susceptible individuals, overwhelming impaired sympathetic vasoconstriction and exacerbating brainstem hypoperfusion within the LC–NTS–PVN axis. (Baker et al.JACC Basic Transl Sci.2024) ( Chedid et al. Clin Gastroenterol Hepatolog 2025)

Structurally, EDS laxity unmasks or worsens compressive syndromes like Median Arcuate Ligament Syndrome (MALS), Nutcracker Syndrome (NCS), and pelvic congestion, as elongated or floppy ligaments fail to stabilize vascular structures. (Wu & Ho. Front Neurol. 2024)(Brandeis et al.Am Surg.2025)   For instance, in hEDS, excessive mobility of the median arcuate ligament can dynamically compress the celiac axis during respiration or posture changes, restricting splanchnic inflow and irritating the celiac plexus—directly linking to vagal dysregulation and gastric hypomotility. (Brandeis et al.Am Surg.2025)(Chedid et al. Clin Gastroenterol Hepatolog 2025)      

Similarly, renal vein compression in NCS, often comorbid with EDS (up to 20–30% overlap),(Sarikaya et al. Ann Vasc Surg.2025) (Singh et al. Radiopedia 2025)  elevates gonadal vein pressures, propagating pelvic venous hypertension and cranio-caudal hydraulic coupling to the brainstem via the valveless vertebral plexus. Lymphatic dynamics are equally impaired: fascial laxity and tissue oedema obstruct thoracic and abdominal lymphatic trunks, trapping cytokines and DAMPs, sustaining RAGE–NF-κB activation, and perpetuating glial–endothelial inflammation.(Tuckey et al.Front Pain Res. 2021) (Chedid et al. Clin Gastroenterol Hepatolog 2025)

Fascial laxity and diminished anchoring filaments reduce lymphatic vessel shear stress and nitric oxide–dependent propulsion. The resulting stagnation perpetuates cytokine accumulation and tissue hypoxia, mirroring the pathophysiology seen in post-viral dysautonomia.

Autonomic and Neuroimmune Intersections

EDS-associated autonomic dysfunction, including POTS, arises from both peripheral (e.g., venous dilation impairing baroreflex) and central mechanisms (e.g., brainstem hypoperfusion biasing LC tonic firing). (Baker et al.JACC Basic Transl Sci.2024) (Wu & Ho. Front Neurol. 2024)  This degrades vagal efferent signalling to the enteric nervous system (ENS), disrupting nitrergic relaxation and interstitial cells of Cajal (ICC) rhythmicity, leading to gastric arrhythmias and delayed emptying.(Travagli & Ansemli.Gatsroenterol Hepatol.2016)(Gillis et al Nat Neurosci.2024) Gastric emptying studies in EDS/POTS cohorts reveal greater post-prandial fluctuations, correlating with symptom severity like nausea and bloating. (Wu & Ho. Front Neurol. 2024) (Chedid et al. Clin Gastroenterol Hepatolog 2025)

Neuroimmune amplification occurs via comorbid Mast Cell Activation Syndrome (MCAS), reported in up to 30–50% of hEDS/HSD patients—higher than the general population. (EDS Clinic.2025)     MCAS triggers histamine and cytokine release, increasing gut permeability, visceral hypersensitivity, and RAGE-mediated inflammation, which intersects with hypoxia-driven HIF-1α pathways to collapse mitochondrial ATP (e.g., PDH inhibition) in gastric smooth muscle.(da Silva et al.Int J Mol Sci.2025) (Chedid et al. Clin Gastroenterol Hepatol.2025)    This forms a feed-forward loop: tissue instability activates mast cells, perpetuating ENS gliosis and vagal irritability, while hydraulic congestion prolongs antigen dwell time, mimicking post-viral persistence in Long COVID.(Peluso et al. Sci Translat Med 2024)((Zuo et al. Lancet Infect Dis 2024)

Evidence and Clinical Correlates

EDS patients often present with orthostatic intolerance, reflux, bloating, and dysmotility that are misattributed to anxiety or “functional GI disorders.  Dynamic echocardiography and duplex studies can reveal venous capacitance failure and coeliac compression even in the absence of overt herniation.

Prevalence data underscore the overlap: A Mayo Clinic review of 687 EDS patients found 12% with confirmed gastroparesis on scintigraphy, rising to 46% in symptomatic subsets. (Chedid et al. Clin Gastroenterol Hepatol.2025)     In hEDS, GI symptoms (e.g., reflux in 69%, nausea in 71%) often precede diagnosis, with POTS comorbidity increasing disability risk. Autonomic testing (e.g., tilt-table) in EDS reveals parasympathetic impairment associated with delayed emptying, while imaging (e.g., CT angiography) confirms vascular compressions in 20–40% of dysautonomic cases. (EDS Clinic.2025) (Brandeis et al.Am Surg.2025)(Sarikaya et al. Ann Vasc Surg 2025) 

Therapeutic Implications

Management in EDS/POTS gastroparesis emphasizes addressing structural amplifiers alongside the model's multi-axis interventions. Non-pharmacologic strategies include pelvic floor therapy to stabilize lax tissues, dietary modifications (low-FODMAP, small frequent meals) to mitigate post-prandial pooling, and lymphatic decompression (manual techniques) to restore fascial compliance and oxygenation.(Tucket et al. Front Pain Res.2021)(Heald et al. Cardiovacs Endocrinol Metab.2022)

Pharmacologically, mast cell stabilizers (e.g., cromolyn, H1/H2 blockers) suppress neuroimmune loops, while prokinetics (e.g., domperidone) and neuromodulators (e.g., low-dose amitriptyline) target vagal tone and motility. (Chedid et al. Clin Gastroenterol Hepatol.2025)       Surgical decompression (e.g., MAL release) yields 70–80% improvement but requires caution due to poor wound healing in EDS.

Emerging therapeutic options for biochemical scaffolding include:

• Nicotinamide riboside and vitamin K₂ (matrix γ-carboxylation)

• Proline, lysine, ascorbate, copper, zinc (collagen synthesis)

• Telmisartan (experimentally for PPARγ-mediated antifibrotic and anti-inflammatory effects)

• Tirzepatide for fascial elasticity and metabolic reprogramming.

Tirzepatide may remodel fascial extracellular matrix via TGF-β modulation, offering potential in laxity-driven compressions—hypotheses warranting trials.(Batiha et al. Immunopharmacology 2023) Integrating EDS screening (e.g., Beighton score) into POTS/Long COVID evaluations could enable precision approaches, measuring endpoints like gastric transit and perfusion. (Chedid et al. Clin Gastroenterol Hepatol.2025)       

In summary, EDS reframes gastroparesis in POTS and Long COVID as a structurally amplified disorder, where connective tissue laxity bridges hydraulic, neuroimmune, and metabolic deficits. This underscores the need for multidisciplinary care, aligning with the model's emphasis on reversibility through targeted decompression and stabilization.

Within this continuum, Ehlers-Danlos Syndrome exemplifies how connective tissue fragility and impaired mechanotransduction amplify both hydraulic and neuroimmune dysfunction. Collagen disarray, venous capacitance loss, and lymphatic inertia create a permissive environment for hypoxia and RAGE activation. This overlap explains why EDS phenotypes are disproportionately represented among POTS and Long COVID cohorts — not merely as comorbidity, but as structural terrain predisposing to neurovascular dysautonomia.

7. Direct Viral Persistence and ENS/Vagal Neuropathy—Integration with the Hydraulic Model

Multiple lines of evidence now support persistent SARS-CoV-2 antigen/RNA within gut tissues months after acute infection, with antigens detected in intestinal mucosa and lamina propria immune cells and associated with ongoing symptoms. (Davis et al. Nat Rev Microbiol 2023)(Peluso et al Sci Transl Med 2024)(Zuo et al Lancet Infect Dis 2024) 

This establishes a plausible reservoir capable of maintaining mucosal interferon signalling, epithelial–neuronal cross-talk, and dysmotility via ENS sensitization. (Deffner et al. 2020. Front Neuropath.)(Jollner et al 2022. Yale J Biol Med)( Balasubramaniam et al 2023. Biomolecules)(Woo et al 2023 Acta Neuropathol )(Moyano et al 2021.IDCases)

Neuroanatomically, ENS neurons and glia express viral entry machinery (ACE2/TMPRSS2) and are positioned for epithelial-neuronal signalling; experimental systems show infected epithelia driving VIP release and transporter dysregulation in enteric neurons—mechanisms that favour secretion, dysrhythmia, and nausea.( Valdetaro et al. Am J Physiol Gastrointest Liver Physiol.2023) (Deffner et al. 2020. Front Neuropath.)(Jamka & Gulbransen. Neurogastroenterol Motil. 2025)  In parallel, vagus nerve inflammation/neuropathy has been documented in COVID-19 and PCC, providing a proximal explanation for gastroparesis-range symptoms when efferent nitrergic control fails.(Elbeltagi et al. World J Clin Cases. 2023)(Khan et al. Infect Med.2024)(Nascimento et al. Mucosal Immunol.2024)

These viral/neuropathic mechanisms do not compete with the hydraulic model; they intersect with it at three chokepoints:

1. Perfusion sensitivity—infected/activated ENS and vagal fibres become exquisitely sensitive to hypoperfusion (orthostatic preload loss) and microvascular hypoxia (pericyte–endothelial injury), lowering the threshold for dysmotility. (Stein et al. Nature.2022)

2. Lymphatic trapping—cervico-thoracic and splanchnic lymphatic stasis impedes antigen/cytokine clearance, extending the dwell time of viral proteins that sustain local interferon/RAGE–NF-κB tone. Decongestion thus functions as a biophysical “antigen-washout” that complements immunometabolic therapies. (Liu et al. Clin TransL Med.2024)

3. Serotonergic–vagal coupling—gut antigen persistence is linked to tryptophan malabsorption and serotonin depletion, which in turn reduces vagal activity and degrades phasic autonomic control of gastric accommodation; restoration of mucosal homeostasis tracks with symptom improvement. (Harris.JAMA 2023)( Jollner et al 2022. Yale J Biol Med)(ong et al 2023 Cell)

Synthesis: We therefore propose gastroparesis in POTS/Long-COVID as a tripartite loop:

1. Viral/antigen persistence driving ENS/vagal neuroinflammation,

2. Hydraulic stressors (preload failure, coeliac/pelvic congestion, lymphatic stasis) that amplify hypoxia and antigen dwell time,

3. Metabolic-redox failure (PDH/MAS block) that collapses nitrergic tone.

Breaking any one limb helps, but the most durable responses are expected when lymphatic decompression and microvascular re-oxygenation are combined with immune-metabolic normalization, and—where present—targeting of viral reservoirs.(Camici et al. Front Cell Infect Microbiol. 2024)(Liu et al. Clin TransL Med.2024)

8 Discussion

This framework reconceptualizes gastroparesis in POTS and Long COVID as a reversible neurovascular–neuroimmune disorder where mechanical, metabolic, and infectious drivers intersect. While preload failure, hypoxia, and inflammation remain upstream amplifiers of vagal dysregulation, accumulating evidence indicates that persistent SARS-CoV-2 within the gastrointestinal mucosa can induce direct enteric and vagal neuropathy.

Viral entry via ACE2/TMPRSS2 in epithelial and enteric neurons leads to ACE2 depletion, RAS imbalance, and sustained glial activation, fostering localized inflammation and fibrosis that blunt motility. These mechanisms complement rather than compete with hydraulic factors—each amplifying the other through shared hypoxia–RAGE–NF-κB–STAT3 signalling.

Within this integrated model, viral persistence prolongs neuroinflammatory tone and heightens the vulnerability of the vagal–enteric network to perfusion deficits and oxidative stress. Conversely, hydraulic congestion and lymphatic failure impair antigen clearance, permitting continued antigenic stimulation and prolonging dysmotility. Thus, the viral–neuropathic and hydraulic–metabolic axes are reciprocally reinforcing, explaining the chronicity of symptoms and the benefit observed when lymphatic decompression and telmisartan therapy restore perfusion and suppress RAGE-mediated cytokine signalling.

Reconciling with Gastroenterological Perspectives

Gastroenterological practice has traditionally interpreted gastroparesis through a localized lens—either as a primary neuropathy or as a downstream effect of faecal loading and mechanical obstruction. Aperients and coeliac plexus blockade remain standard interventions, yet outcomes are inconsistent in POTS and Long COVID populations, reflecting a gap between local symptom treatment and the systemic neurovascular reality.

While constipation is indeed prevalent (50–90% overlap), it appears increasingly secondary to upstream autonomic dysregulation rather than the primary cause of dysmotility. In this framework, colonic stasis reflects reduced vagal efferent tone and perfusion deficits within the LC–NTS–PVN complex rather than a purely mechanical delay. Aperients may therefore provide short-term relief but risk exacerbating orthostatic intolerance or dehydration when used chronically without addressing preload and autonomic tone.

Coeliac plexus blockade, similarly, offers transient pain relief in non-dysautonomic patients but carries risk of sympathetic denervation in those with pre-existing autonomic instability. This underscores the need for more nuanced approaches that target the drivers of vagal dysfunction rather than its downstream manifestations.

The current model integrates and extends these perspectives by introducing three convergent mechanisms:

1. Hydraulic factors—venous and lymphatic congestion restricting perfusion and antigen clearance;

2. Immune–metabolic dysregulation—HIF-1α–RAGE–STAT3 signalling sustaining oxidative and inflammatory stress; and

3. Direct viral persistence and ENS neuropathy—where SARS-CoV-2 infection of enteric neurons and glia (via ACE2 and RAGE) produces enduring neurogenic dysfunction and mucosal fibrosis.

Recognizing these as interlocking rather than competing explanations allows gastroenterological management to evolve from symptomatic relief toward mechanistic reversal. Aperients and dietary modulation remain valuable adjuncts, but durable recovery depends on re-establishing preload and oxygen delivery, suppressing RAGE-driven inflammation, and restoring enteric–vagal homeostasis.

This synthesis reconciles the gastroenterological and autonomic views of gastroparesis: a condition once viewed as isolated neuropathy now seen as part of a gastro-cranial hydraulic continuum, where viral persistence, hypoxia, and lymphatic stasis converge on a reversible systems disorder.

Conclusion

Gastroparesis in POTS and Long COVID represents a potentially reversible hydraulic–neuroimmune continuum, where viral, vascular, and metabolic lesions converge on impaired vagal control of gastric motility. Orthostatic preload failure and lymphatic congestion reduce oxygen delivery to the LC–NTS–PVN axis and gastric wall, stabilizing HIF-1α and activating RAGE–NF-κB–STAT3 loops that perpetuate inflammation and mitochondrial exhaustion. Persistent SARS-CoV-2 antigens within enteric neurons add a sustained neuropathic component that interlocks with these hydraulic and metabolic deficits.

The model proposed here moves beyond organ-centric interpretations toward a systems-level framework linking brainstem perfusion, lymphatic function, and immune-metabolic signalling. By targeting these axes simultaneously—through vascular decompression, lymphatic rehabilitation, immune modulation and metabolic reconstitution, gastroparesis may transition from a refractory symptom to a measurable and treatable phenotype within dysautonomia.

By acknowledging both viral–neuropathic persistence and hydraulic–metabolic insufficiency as co-equal drivers, this model reframes gastroparesis as a treatable systems disorder rather than an irreversible neuropathy. It provides a path toward precision trials and measurable clinical endpoints integrating perfusion imaging, gastric electrophysiology, and mucosal immunophenotyping.

This unified framework suggests gastroparesis is a systemic rather than localized manifestation of dysautonomia, offering measurable endpoints for interventional trials.

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