Systems map

The Host Capacity Model, as a systems map.

The same cascade as the canonical framework page, presented as a clickable systems-biology map. Each node opens a short definition, mechanism summary, related articles, and the uncertainty associated with that layer. For a dynamical view of the same model — phase portrait, basin pull, and the cascade step by step — open the living simulator.

Linear cascade with feedback loops. Dashed arcs mark host-side feedbacks: inflammation increasing energy demand, dysbiosis increasing metabolite stress, mast-cell activation worsening motility, and mitochondrial stress lowering host capacity.

Systems map

The Host Capacity Model — interactive

Click a node to read its definition, mechanism summary, related articles, and the uncertainty associated with it. This is an educational systems-biology map, not a diagnostic tool.

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.

Extended model

Three closed-loop extensions

The linear cascade above describes direction. These three loops describe why the state can persist: each one closes back on an upstream node. Educational systems-biology reasoning — hypotheses and mechanisms, not diagnostic criteria.

The motility / bile-acid loop

Why SIBO may recur after successful eradication: the signal that sets transit time is itself microbially produced.

1.Host capacity falls
2.Community shifts toward facultative anaerobes
3.7α-dehydroxylation declines — secondary bile acids deplete
4.TGR5 on enteroendocrine L-cells under-stimulated
5.GLP-1 / PYY release drops — ileal brake weakens
6.MMC phase III disrupted, stasis
7.SIBO recurrence
↺loop closes on host capacity

Candidate leverage points

— Restoring colonocyte substrate capacity so obligate anaerobes regain habitat
— Addressing FXR–FGF19–CYP7A1 dysregulation where bile-acid spillover is documented
— Motility support as a bridge rather than a stand-alone answer

Uncertainty

Bile-acid panels are poorly standardised and transit time confounds the profile; this loop is a mechanistic hypothesis, not a validated clinical pathway.

The mitochondrial-pressure loop

Why the cascade may become self-sustaining: the metabolites produced by the shifted community can constrain the host respiration needed to reverse it.

1.Oxygen gradient destabilises
2.Enterobacteriaceae and Desulfovibrio expand
3.Succinate and H₂S rise in the lumen
4.Complex IV inhibition; HIF-1α stabilisation
5.Colonocytes locked toward aerobic glycolysis
6.OXPHOS recovery suppressed — gradient cannot be restored
↺loop closes on host capacity

Candidate leverage points

— Lowering sulfide substrate load where a sulfide pattern is evident
— Supporting mitochondrial cofactor availability alongside, not instead of, ecology work
— Sequencing: antimicrobial pressure alone does not address the bioenergetic constraint

Uncertainty

Luminal succinate and H₂S concentrations are rarely measured clinically, and human thresholds for Complex IV inhibition are not well defined.

The matrix / neuroimmune loop (MCAS & hEDS)

Why the MCAS–hypermobility overlap may be mechanistic rather than coincidental: protease signalling acts on both the barrier and the scaffold.

1.Microbial antigen translocation
2.Mast-cell degranulation — tryptase release
3.PAR-2 cleavage → MLCK phosphorylation → tight junctions pulled open
4.MMP-9 release degrades collagen and extracellular matrix
5.Vagal afferent terminals lose mechanosensory context
6.Gut–brain uncoupling; further immune disinhibition
↺loop closes on host capacity

Candidate leverage points

— Reducing the translocating antigen load upstream of mast cells
— Recognising hEDS-spectrum collagen fragility as a modifier, not the primary lesion
— Autonomic work where cholinergic anti-inflammatory tone is clearly depleted

Uncertainty

Tryptase and MMP-9 measures are timing-sensitive and non-specific; the hEDS–MCAS association is well described clinically but mechanistically unsettled.

Deep dive

Layer 1 at biophysical resolution

The motility node resolved to the level of ion channels, junction geometry, motor proteins, and chromatin state — the SIP syncytium, ANO1 pacing and Cx43 uncoupling, the IP₃R–ANO1 nano-junction, Piezo2 and S-nitrosylation, muscularis macrophage–ENS crosstalk, neuropod synaptic shearing, and c-Kit niche silencing.

Read Layer 1: Neuro-Mechanical Motility & Transit Vectors →

Where to go next

Read the Host Capacity Model

View the canonical diagram

Simple and advanced visual model, downloadable.

See the fictional sample report

Gate 1 is only a fit screen. No labs or files are required.

Educational systems-biology consulting. Not diagnosis or treatment. Designed to work alongside your licensed medical team.