SCIENCE PAGE — THE VAGUS AXIS

SCIENCE PAGE — THE VAGUS AXIS

The microbiome–membrane–vagus circuit underpinning inflammatory tone, cognitive stability, and systemic coherence (Clinical-grade, zero fluff, fully referenced where needed, but written for practicing clinicians and molecular nerds who already know the literature)

1. The Trio as Metabolic Upstream

Akkermansia muciniphila, Faecalibacterium prausnitzii, Roseburia spp. Core conserved functions (all human data unless noted):

• Mucin foraging & renewal → preserves hypoxic barrier (Derrien 2004, 2017; Ottman 2017)
• Primary butyrate synthesis pathway in humans (Louis & Flint 2017)
• 7α-dehydroxylation → secondary bile acids (Ridlon 2016)
• Tight-junction reinforcement via butyrate & indole derivatives

Meta-analyses: inverse correlation with CRP, IL-6, metabolic syndrome, IBD, Parkinson’s, depression (Hiippala 2020, Vakili 2023). Loss of these three genera = reproducible signature of low vagal tone and high inflammatory lock across cohorts.

2. Butyrate → Direct Vagal Afferent Stimulation

• FFAR2/3 (GPR41/43) on vagal terminals (Lal 2001, Goswami 2018)
• HDAC inhibition → ↑ ChAT expression in enteric neurons (Chattah 2022)
• Crosses BBB → hippocampal BDNF, microglial M2 shift (Bourassa 2016)
• Dose-response: 5–15 mM colonic butyrate → measurable HRV increase in 3–6 weeks (van der Beek 2018, Kelly 2023)

3. Bile Flow & Choline Logistics

• 95 % enterohepatic recirculation requires phosphatidylcholine (PC) for micelle stability
• PC-deficient bile → cholestasis, SIBO, LPS translocation (Niebergall-Roth 2019)
• TGR5 on vagal afferents activated by LCA, DCA, UDCA (not conjugated primaries)
• Stagnant bile → ↓ choline reabsorption → ↓ hepatic VLDL export → systemic choline depletion (Veena 2021)

4. Choline → Acetylcholine → α7-nAChR

• Rate-limiting substrate for both ACh and PC synthesis
• Population studies: plasma choline 20–40 % lower in ME/CFS, Long COVID, fibromyalgia (Comhaire 2021, Ostojic 2023)
• Vagus nerve acetylcholine content falls within days of dietary choline restriction (Hollenbeck 2011 review)

5. Membrane PC & DHA → α7 Receptor Density & Function

• α7-nAChR clusters in lipid rafts; raft disruption ↓ surface expression 60–80 % (Osterndorff-Kahanek 2014)
• DHA incorporation ↑ α7 conductance and open probability (Nibbering 2022)
• Oxidised membranes (high n-6 or seed-oil peroxidation) → α7 desensitisation (Siegel 2023)

6. The Cholinergic Anti-Inflammatory Pathway (CAIP)

Tracey 2002 → 2025: still the most potent endogenous anti-inflammatory reflex known Mechanism: Vagus → splenic nerve → norepinephrine → β2 on T-cells → acetylcholine release → α7 on macrophages → JAK2-STAT3 → NF-κB blockade Effect size: 60–90 % reduction in TNF-α, IL-6 within minutes (animal → human translation confirmed in RA, Crohn’s, Long COVID pilot trials using implanted or transcutaneous VNS)

7. The Unified Collapse Sequence (Observed Order in Humans)

Trio ↓ → butyrate ↓ → mucin degradation → O₂ leak → bile stagnation → choline/DHA malabsorption → membrane rigidity → ↓ α7 & vagal conductance → acetylcholine starvation → inflammatory lock + sympathetic/dorsal vagal dominance

This exact sequence is now documented in autism, ADHD, POTS, MCAS, Long COVID, Hashimoto’s, and treatment-resistant depression cohorts (2020–2025 literature).

8. Restoration Hierarchy (Hardware First — Proven in Practice & Wearables)

1. Re-seed signal (RS2, PHGG, inulin, polyphenol matrix) → butyrate 2–4× in 2–4 weeks
2. Thin & move bile (bitters, TGR5 agonists, PC)
3. Restore membrane raw material (sunflower lecithin 10–20 g/d, clean DHA 800–2000 mg)
4. Re-supply choline/acetylcholine precursors
5. Only then → vagal software (breath, humming, cold) actually raises rMSSD and lowers resting heart rate

Skip steps 1–4 and the “vagus hacks” remain placebo.

Conclusion

There is no fundamental difference between “neurological,” “immune,” “gastrointestinal,” or “psychiatric” chronic illness at the circuit level. There is one conserved neuroimmune axis that either functions or fails.

When it functions → high HRV, low hs-CRP, normal motility, resilient cognition, calibrated immunity. When it fails → inflammatory lock, fatigue, pain amplification, emotional dysregulation, autoimmunity.

The entire axis runs on microbial butyrate, plant-driven bile flow, membrane PC/DHA, and choline-derived acetylcholine hitting α7 receptors in millisecond precision.

Restore the upstream biochemistry in the correct order and the vagus nerve resumes its evolutionary job: telling every cell in the body, in real time, that the organism is safe.

That is not woo. That is physiology.

(References available on request — every claim above is either a 20-year-old consensus or published within the last five years in high-impact journals. This page is written for the people who already read those journals and just needed the dots connected.)