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.

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.

Extended model

9 closed-loop extensions

The linear cascade above describes direction. These 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.

The H₂S threshold loop (SQR bottleneck)

Why the same sulfide load may be fuel in one gut and metabolic arrest in another: the switch is the host's Q-pool redox state, not the sulfide level alone.

1.Electron-transport flux slows; CoQ pool stays reduced
2.SQR loses oxidised CoQ and sulfide oxidation stalls
3.H₂S accumulates in the mitochondrial matrix
4.Complex IV inhibited — respiration falls further
5.Oxygen consumption drops; lumen pO₂ rises
6.Sulfate reducers expand — more H₂S into a less capable epithelium
↺loop closes on host capacity

Candidate leverage points

— Restoring electron-transport flux so SQR regains oxidised CoQ, rather than only lowering sulfide substrate
— Reducing sulfide load as a temporary decompression step where a sulfide pattern is evident
— Recognising the non-linear threshold: dose responses may be state-dependent, not linear

Uncertainty

Human SQR capacity and colonic H₂S concentrations are not clinically measurable; the biphasic threshold is inferred from ex-vivo and animal data.

The nitrosative Fe–S lock-in loop

Why feeding butyrate may not restart hypoxia: peroxynitrite can dismantle the enzymes that burn it.

1.LPS reaches lamina propria; macrophage iNOS raises nitric oxide
2.Strained mitochondria leak superoxide
3.Peroxynitrite forms and attacks exposed 4Fe–4S clusters
4.Aconitase and Complex II inactivated (4Fe–4S → 3Fe–4S)
5.β-oxidation of butyrate cannot proceed
6.Oxygen consumption falls; barrier strains; more LPS translocates
↺loop closes on host capacity

Candidate leverage points

— Lowering nitrosative and endotoxin load before expecting substrate strategies to work
— Supporting Fe–S / CIA assembly cofactors as a candidate enabling step
— Sequencing: repair the machinery before increasing the fuel

Uncertainty

Peroxynitrite and cluster status cannot be measured in practice; this loop is a mechanistic hypothesis built on redox chemistry and surrogate markers.

The HIF-1α fragmentation loop (PHD / succinate)

Why barrier signalling becomes contradictory rather than simply switched off: oxygen and succinate push the same enzymes in opposite directions.

1.Colonocyte oxygen consumption falls; epithelial pO₂ rises
2.PHDs activate and degrade HIF-1α via VHL/proteasome
3.Tight-junction and mucus programmes lose transcriptional support
4.Complex II failure raises intracellular succinate
5.Succinate competitively inhibits the same PHDs
6.Fragmented HIF signalling — barrier repair never fully commits
↺loop closes on host capacity

Candidate leverage points

— Targeting the succinate:α-KG ratio as a candidate lever on barrier stability
— Restoring Complex II function rather than treating the barrier symptomatically
— Reading conflicting barrier markers as signal fragmentation, not measurement error

Uncertainty

Intracellular metabolite ratios are inaccessible clinically; the relative weight of oxygen versus succinate control of PHDs in human colon is unresolved.

The glial bridge loop (ATP → S100B → mast cells)

Why mast-cell reactivity and motility chaos may be one phenomenon: enteric glia translate epithelial energy failure into neuro-immune output.

1.Colonocyte ATP depletion; pannexin release of extracellular ATP
2.Enteric glial P2X7 activation and reactive gliosis
3.S100B secretion; RAGE engagement on mast cells and enteric neurons
4.Mast-cell degranulation threshold lowered — mediator volatility
5.ENS hyper-excitability — alternating stasis and spasm
6.Transit instability re-shapes habitat and re-loads the epithelium
↺loop closes on host capacity

Candidate leverage points

— Treating epithelial bioenergetics as upstream of mast-cell threshold work
— Mediator-stabilising measures as symptom containment, not as the correction
— Motility support timed to glial-inflammatory quiescence rather than applied continuously

Uncertainty

Mucosal S100B and glial activation are research-grade endpoints; human evidence is biopsy- and model-based rather than prospective.

The FXR / FGF19 checkpoint loop

Why bile-acid chemistry may enforce the dysbiosis it followed: the host's antimicrobial programme is commissioned by microbes it no longer has.

1.Oxygen gradient fails; obligate anaerobes decline
2.7α-dehydroxylation drops — secondary bile acids fall
3.FXR signalling quietens on colonocytes
4.Antimicrobial peptide output (angiogenin, RegIIIγ) falls — Proteobacteria expand
5.FGF19 falls; hepatic CYP7A1 unrestrained
6.Primary bile-acid spillover — detergent stress, secretory diarrhoea, further mitochondrial injury
↺loop closes on host capacity

Candidate leverage points

— Restoring habitat for 7α-dehydroxylating anaerobes rather than suppressing overgrowth alone
— Managing bile-acid spillover where it is documented, as decompression while capacity recovers
— Interpreting recurrent Proteobacteria expansion as a checkpoint failure, not a treatment failure

Uncertainty

FGF19 and faecal bile-acid panels are poorly standardised; the antimicrobial-peptide arm of FXR signalling is better established in models than in patients.

The DBH redox trap (dopamine / norepinephrine split)

Why motility and autonomic symptoms may move together: one enzyme, stalled locally by redox collapse, splits the catecholamine pathway in two directions.

1.Chronic mucosal inflammation oxidises local ascorbate
2.DBH loses the co-reductant that recycles its copper centres
3.Microbial HPHPA adds competitive inhibition
4.Dopamine pools in the gut wall
5.D2-receptor inhibition of motility — stasis, SIBO persistence
6.Systemic norepinephrine shortfall — orthostatic and dysautonomic symptoms
↺loop closes on host capacity

Candidate leverage points

— Restoring mucosal redox capacity as a prerequisite to catecholamine balance
— Addressing HPHPA-producing organisms where organic-acid patterns support it
— Reading gut stasis and orthostatic intolerance as one node, not two problems

Uncertainty

Tissue ascorbate redox state and enteric catecholamine ratios are not clinically measurable; this loop is inferred from enzymology and organic-acid patterns.

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.

How the analysis is built

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.