Colonocyte bioenergetics
The metabolic state of the colon's epithelial cells — particularly their capacity to oxidise butyrate via mitochondrial β-oxidation.
Colonocytes consume oxygen aggressively when bioenergetically intact, holding the lumen near-anaerobic. When iron-sulfur cluster assembly, NAD⁺/SIRT3 signalling, or mitochondrial throughput drop, oxygen leaks into the lumen and downstream changes follow.
Oxygen-gradient instability
The steep epithelial-to-lumen oxygen gradient that gates microbial ecology.
When colonocyte oxygen consumption falls, lumen pO₂ rises and facultative anaerobes (Proteobacteria, Enterobacteriaceae) gain a thermodynamic edge over obligate anaerobes (Firmicutes butyrate producers).
Microbial habitat shift
Re-organisation of community composition and function in response to a changed host environment.
Habitat-driven dysbiosis: communities reassemble around the new oxygen, pH, mucus, and motility regime. The ecology is downstream of host state, not the originating event.
Endotoxin / metabolite stress
The output of a destabilised community: LPS, abnormal SCFA ratios, hydrogen sulfide, methane, ethanol, biogenic amines.
Metabolite stress acts both locally (epithelial irritation, motility effects) and systemically (immune priming, hepatic load, vascular signalling).
Gut barrier strain
Loss of selective epithelial permeability and mucus integrity.
Tight-junction remodelling, mucus thinning, and reduced antimicrobial peptide output let microbial products reach the lamina propria and portal circulation.
Immune & mast-cell activation
Local and systemic immune signalling, including mast-cell mediator release at threshold-crossing intensity.
Persistent low-grade microbial signalling primes Th-skewed responses and lowers the mast-cell activation threshold, producing the symptom volatility characteristic of MCAS-overlap presentations.
Mitochondrial reserve
Whole-organism bioenergetic headroom — the buffer that absorbs metabolic stress before symptoms appear.
Reduced mitochondrial reserve lowers the threshold at which inflammation, hypoxia, or microbial signalling translate into systemic symptoms — a host-side feedback loop with the colonocyte layer.
Motility instability
Altered migrating motor complex and segmental contraction patterns from neuro-immune perturbation.
Mast-cell mediators and microbial metabolites perturb the enteric nervous system, producing both stasis and accelerated transit phenotypes that re-feed the habitat shift.
Systemic symptoms
The clinical surface — fatigue, post-prandial malaise, food reactivity, neurocognitive symptoms, autonomic instability.
These present as discrete diagnoses (SIBO, MCAS, long COVID, IBS) but in complex cases share an upstream substrate: a host that cannot maintain the conditions of a stable epithelial-microbial interface.
Bile-acid signalling (FXR / TGR5)
The bile-acid pool as a signalling system — primary versus secondary bile acids acting on ileal FXR and enteroendocrine TGR5, not merely as fat emulsifiers.
Obligate anaerobes carrying 7α-dehydroxylase (e.g. Clostridium scindens) convert cholic and chenodeoxycholic acid into deoxycholic and lithocholic acid. When host capacity falls and facultative anaerobes expand, that conversion may stall. Primary bile acids are weaker ileal FXR agonists, so FGF19 output can fall, hepatic CYP7A1 is less restrained, and unchecked primary bile acid synthesis may spill into the colon — a detergent load on the barrier and a secretory-diarrhoea driver. In parallel, depleted secondary bile acids leave TGR5 on L-cells under-stimulated, so GLP-1 and PYY release drops and the ileal brake weakens.
Tryptophan partitioning (AhR vs IDO1)
How dietary tryptophan is divided between microbial indole production, mucosal serotonin synthesis, and the host kynurenine pathway.
Microbial indole derivatives activate the aryl hydrocarbon receptor, supporting tight-junction proteins and IL-22-driven antimicrobial peptide output. When colonocyte bioenergetics fail and interferon-γ tone rises, IDO1 upregulation may shunt tryptophan into kynurenine. Enterochromaffin cells can then be substrate-starved for mucosal 5-HT, weakening 5-HT4 signalling to intrinsic primary afferent neurons that initiate peristalsis. Kynurenine metabolites such as quinolinic acid are candidate stressors of enteric glial cells, adding a neuroinflammatory component to motility failure.
Succinate & H₂S mitochondrial pressure
Microbial metabolites that may act directly on host mitochondrial and hypoxia-signalling machinery rather than only on the immune system.
As the oxygen gradient destabilises, Enterobacteriaceae can excrete succinate. Luminal succinate engaging SUCNR1 (GPR91) on mucosal macrophages is a candidate driver of M1 polarisation, while intracellular succinate stabilises HIF-1α and may lock colonocytes into aerobic glycolysis, suppressing OXPHOS recovery. Expansion of sulfate-reducing organisms such as Desulfovibrio raises hydrogen sulfide; at elevated concentration H₂S inhibits cytochrome c oxidase (Complex IV), so the microbial output can itself constrain the host respiration needed to restore the gradient.
Protease & matrix signalling (PAR-2 / MMP-9)
The mast-cell–barrier–connective-tissue interface, where protease signalling meets extracellular matrix integrity.
Mast-cell tryptase cleaves PAR-2 on the enterocyte apical surface; downstream myosin light-chain kinase phosphorylation can mechanically open tight junctions by remodelling occludin and ZO-1 — a barrier breach driven by signalling rather than injury. Chronic activation also releases MMP-9, which degrades collagen and extracellular matrix. Where collagen is already fragile (hEDS-spectrum), that matrix loss may reduce the mechanical scaffold in which vagal afferent terminals sit, blunting mechanosensory feedback and further uncoupling the gut–brain axis.
Vagal tone & villus perfusion
The autonomic and microvascular layer sitting above the epithelium — cholinergic anti-inflammatory control and capillary oxygen delivery to the villus.
Efferent vagal acetylcholine acting on α7-nicotinic receptors on resident macrophages restrains TNF-α release. In post-viral states, sustained afferent vagal firing from local gut inflammation may exhaust central vagal tone, removing that brake from macrophages and mast cells. Separately, microvascular injury or micro-thrombosis can produce villus-tip ischaemia; enterocytes starved of the oxygen they need to oxidise fuel may enter precisely the bioenergetic failure state that opens the cascade — meaning the model can be entered from the top as well as the bottom.
H₂S biphasic switch (SQR / CoQ)
The mitochondrial sulfide-oxidising unit — sulfide:quinone oxidoreductase (SQR) with rhodanese — that decides whether hydrogen sulfide is a fuel or a poison.
At low luminal concentration, colonocytes appear to oxidise H₂S through SQR, passing electrons directly to coenzyme Q and detoxifying sulfide to thiosulfate via rhodanese. SQR depends on a supply of oxidised CoQ. When electron-transport flux slows — systemic stress, mild hypoxia, early iron–sulfur cluster damage — the Q pool stays reduced (CoQH₂) and SQR throughput may stall. H₂S then backs up into the matrix and can inhibit cytochrome c oxidase (Complex IV) in a cyanide-like manner. This is a candidate explanation for the threshold behaviour seen clinically: the same sulfide concentration may be buffered and used as fuel by an energetically intact epithelium, yet arrest respiration in a strained one.
Nitrosative stress & Fe–S cluster disassembly
The chemistry that may physically dismantle the enzymes required to burn butyrate — peroxynitrite attack on solvent-exposed 4Fe–4S clusters.
As the barrier strains, LPS reaching the lamina propria induces iNOS in resident macrophages, raising nitric oxide. Strained mitochondria simultaneously leak superoxide. NO and O₂⁻ combine to form peroxynitrite (ONOO⁻), which preferentially attacks exposed 4Fe–4S clusters in aconitase (TCA cycle) and succinate dehydrogenase (Complex II), converting them to inactive 3Fe–4S forms. The practical consequence is a candidate bioenergetic lock-in: supplying butyrate may not restore hypoxia if the enzymatic hardware needed to oxidise it has been structurally degraded. Recovery in this reading depends on lowering nitrosative load and supporting Fe–S/CIA assembly (frataxin, cysteine sulfur donors) before respiration can resume.
PHD / succinate–α-KG switch on HIF-1α
The oxygen-sensing enzymes that decide whether HIF-1α survives long enough to maintain tight junctions, mucus, and antimicrobial peptide output.
Prolyl hydroxylases (PHDs) hydroxylate HIF-1α and mark it for VHL/proteasomal destruction. They require oxygen, Fe²⁺, and α-ketoglutarate, and are competitively inhibited by succinate. Loss of colonocyte oxygen consumption raises epithelial pO₂ and can activate PHDs, collapsing HIF-1α and with it the barrier programme. But when Complex II is impaired, intracellular succinate accumulates and may inhibit those same PHDs. The result is fragmented, internally contradictory HIF signalling rather than a clean on/off state — and it makes the intracellular succinate:α-KG ratio a mechanistically defined candidate target for stabilising the barrier even while the lumen remains relatively hyperoxic.
Enteric glia, ATP/P2X7 and S100B
The cellular translator between epithelial energy failure and neuro-immune pathology — reactive enteric glial cells.
Severely ATP-depleted colonocytes release extracellular ATP as a danger signal through pannexin channels. Enteric glial cells sense this via P2X7 receptors and may enter reactive gliosis, secreting S100B. S100B binds RAGE on both mucosal mast cells and enteric neurons: it appears to lower the mast-cell degranulation threshold and to hyper-excite the ENS. Read this way, mast-cell reactivity and the alternating stasis/spasm motility phenotype are not separate diseases sitting beside the gut problem — they are candidate neuro-glial responses to epithelial ATP depletion, which places them squarely downstream of colonocyte bioenergetics.
FXR / FGF19 antimicrobial checkpoint
The host-side control loop through which secondary bile acids commission antimicrobial defence and shut off primary bile-acid synthesis.
Obligate anaerobes convert primary bile acids into deoxycholic and lithocholic acid, the main endogenous ligands for FXR and TGR5 on colonocytes. FXR activation is associated with antimicrobial peptide output (angiogenin, RegIIIγ) that constrains Proteobacteria, and with FGF19 release that signals the liver to stop synthesising primary bile acids. When the oxygen gradient fails and obligate anaerobes decline, secondary bile acids fall and FXR may go quiet: antimicrobial pressure on facultative anaerobes drops, while loss of the FGF19 stop-signal can leave hepatic CYP7A1 unrestrained, delivering caustic primary bile acids into an already damaged colon — a candidate driver of bile-acid diarrhoea, oxidative stress, and further mitochondrial injury.
DBH redox trap (dopamine ↔ norepinephrine)
The copper- and ascorbate-dependent step converting dopamine to norepinephrine, and why it may fail locally in an inflamed gut.
Dopamine β-hydroxylase is copper-dependent and requires ascorbate as a co-reductant to re-reduce its copper centres after each catalytic cycle. Microbial HPHPA and genetic variation are only part of the picture: in chronic mucosal inflammation, local ascorbate is rapidly oxidised to dehydroascorbate, producing what amounts to a functional, localised scurvy in the enteric nervous system. DBH may then remain stalled through electron deficiency even if HPHPA is cleared. The candidate consequence is dopamine pooling in the gut — inhibiting motility through D2 receptors and sustaining stasis — while systemic circuitry is left norepinephrine-poor, a pattern consistent with the dysautonomia and POTS overlap seen in these presentations.