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.