The Host Capacity Model, as a dynamical system you can push.
The framework predicts that the gut substrate has two stable equilibria — a healthy attractor (high colonocyte bioenergetics, low lumen O₂, anaerobic core community) and a collapsed attractor (low bioenergetics, oxygenated lumen, facultative-anaerobe dominance). Move the parameters and watch the system find one or the other. Educational only — not a diagnostic instrument.
System is mid-transit. Trajectory depends on which feedback closes first — restoration of substrate or amplification of mast-cell drive.
parameters within the homeostatic envelope
Outcome is contingent on parameter trajectory over the next ~90 simulated days. Current basin pull: 92% toward healthy.
The cascade, step by step.
The same seven nodes the simulator integrates over, laid out so the reader moves through them at reading speed. The map on the right activates as the prose advances.
Inflammatory signalling sets the cascade in motion
Type-I interferons, lipopolysaccharide, IL-6, and the senescence-associated secretory phenotype share a common downstream effect: they upregulate CD38 across tissues that include the colonic epithelium and its underlying mesenchyme.
CD38 is, before anything else, an NADase. Its turnover number is orders of magnitude higher than the sirtuins whose substrate it consumes. The cascade begins not with a microbe but with a signalling tone that the host cannot easily switch off.
Matrix NAD⁺ collapses where CD38 is most induced
Wherever CD38 is strongly induced, the matrix NAD⁺ pool falls. The drop is local, compartmental, and disproportionate — bulk cytosolic measurements miss it.
NAD⁺ is the cofactor that the sirtuins consume to deacetylate the mitochondrial proteome. When it is gone, the sirtuins stop working, regardless of how much protein is present.
SIRT3 substrates hyperacetylate
SIRT3 is the matrix deacetylase that holds β-oxidation, the TCA cycle, and the electron transport chain in their high-flux configuration. Without NAD⁺, its substrates accumulate acetyl marks and shift toward their low-flux states.
This is the regulatory layer that fails before any structural damage. The mitochondria look intact on imaging. The respirometry tells a different story.
Two independent pillars buckle in parallel
On the mitochondrial side, iron-sulfur cluster biogenesis falters under oxidative pressure. Complexes I through III lose flux. β-oxidation of butyrate — the colonocyte's preferred fuel — becomes the rate-limiting step.
On the substrate side, inflammation-driven CpG methylation silences SLC5A8, the high-affinity apical butyrate transporter. Even when luminal butyrate is plentiful, the colonocyte can no longer pull it across the membrane. Demethylation, when it happens at all, takes months.
The colonocyte runs out of ATP for oxygen-sink work
Butyrate β-oxidation in the colonocyte is not just a calorie strategy. It is the engine that consumes apical oxygen and keeps the lumen anaerobic. ATP supply must remain high enough to sustain that consumption against a continuous diffusive load.
When transport, machinery, and regulation all degrade together, ATP production drops below the threshold required for the colonocyte to act as an oxygen sink.
Physiological hypoxia is lost; the aerobic niche opens
Luminal pO₂ rises. The strict anaerobes that produce butyrate — Faecalibacterium, Roseburia, the Lachnospiraceae — lose their habitat. Facultative anaerobes and aerotolerant Proteobacteria, including pathobionts, expand into the new niche.
This is the moment the conventional model finally sees the problem. By then, the upstream substrate has been failing for months.
Dysbiosis, barrier failure, and the mast-cell amplifier
Intestinal alkaline phosphatase falls. LPS detoxification at the brush border becomes inadequate. Endotoxin reaches systemic circulation in its more pro-inflammatory form. The vagal α7nAChR brake on tissue mast cells lifts.
What presents as SIBO, MCAS, or POTS downstream is the same cascade. The feedback arc from this terminal node back to inflammatory drive is what makes the equilibrium bistable — and what makes interventions that only touch the microbiota recur.