Neuro-Immune–Hydraulic Integrative Phenotype Axis (NIHPA): The Conceptual Framework where One Core Engine drives Multiple Phenotypic Variants

Dr Graham Exelby December 2025- in peer review

Preview:

This diagram shows the root network of all chronic immunometabolic diseases:

• hypoxia

• HIF-1α → HIF-2α reprogramming

• ROS / RAGE / NF-κB activation

• STAT3–CCL2 macrophage/microglial loops

• NLRP3 inflammasome

• pericyte dropout

• BBB leak

• mast-cell activation

• mitochondrial failure / PDH shutdown

• glycolytic trap

• autonomic failure

• central sensitisation

This is the “motherboard,” where from this “motherboard,” you can derive variants:

• POTS autonomic phenotype

• Endometriosis hypoxic-fibrotic phenotype

• MCAS phenotype

• Long COVID multi-system phenotype

• Fibromyalgia neuroimmune phenotype

• Migraine / vestibular phenotype

• Pelvic congestion phenotype

• Central sensitisation / chronic pain phenotype

• Breast cancer progression phenotype

• PTSD/mould limbic–HPA variant

They all share the same roots, but different “branches” light up.

We propose that POTS, endometriosis, Long COVID, fibromyalgia, MCAS, and related multisystem disorders represent distinct phenotypic expressions of a single underlying immunometabolic architecture centred on hypoxia–HIF-2α signalling, RAGE/TLR4 activation, STAT3/CCL2 feed-forward loops, mast-cell and microglial activation, and pericyte-driven microvascular instability.

Each clinical condition can be conceptualised as a ‘variant’ arising from this core network, determined by genetic predisposition (PEMT, PTEN, COMT, TLR4, RAGE, STAT3), mechanical factors (venous congestion, lymphatic obstruction, ECM tension), endocrine environment (oestrogen load), mitochondrial flexibility, and immune tone.