The Host Capacity Model.

The inversion

The dominant clinical narrative places microbial composition at the center of chronic gut dysfunction. Dysbiosis is treated as the disease, and antimicrobials, prebiotics, and probiotics become the levers of intervention.

The Host Capacity Model inverts this hierarchy. The microbial signature is downstream. The upstream lesion is the colonocyte's loss of bioenergetic capacity to maintain physiological hypoxia at the epithelial surface. When that capacity collapses, oxygen leaks into the lumen, obligate anaerobes lose their niche, and a facultative-anaerobe-skewed community becomes the predictable outcome.

The mechanism in compressed form

Colonocyte beta-oxidation of butyrate depends on functional iron-sulfur clusters across Complexes I, II, and III of the mitochondrial electron transport chain. Iron-sulfur cluster biogenesis is itself dependent on adequate matrix NAD⁺, intact frataxin, and an intracellular environment not under sustained inflammatory pressure.

Two upstream insults dominate the clinical picture. The first is CD38 induction — driven by chronic low-grade inflammation, post-infectious immune activation, or aging — which depletes NAD⁺ at a rate that mitochondrial biosynthesis cannot match. The second is SLC5A8 epigenetic silencing, which closes the colonocyte's principal route for butyrate uptake even when luminal butyrate is adequate.

The microbiome is not the disease. It is the readout of a host substrate that has lost capacity.

Downstream consequences

Once the colonocyte loses bioenergetic capacity, several recognizable clinical signatures follow with predictable regularity:

• H₂S Complex IV poisoning. Sulfide-producing taxa expand and chemically inhibit Complex IV at the colonocyte surface, deepening the lesion.
• Intestinal alkaline phosphatase feedback failure. LPS detoxification falters, producing low-grade endotoxemia and reinforcing the inflammatory loop that drives CD38.
• Cholinergic anti-inflammatory pathway collapse. Vagal tone falls, mast cell thresholds drop, and the host loses one of its principal anti-inflammatory levers.
• Mast cell activation pattern shift. Antigen flux across a compromised barrier, combined with neuroimmune dysregulation, produces the constellation recognized clinically as MCAS — but with mechanistically distinct subtypes that respond to different interventions.

Why this matters clinically

The Host Capacity Model produces specific predictions. Recurrent SIBO is not a failure of antimicrobial choice — it is the predictable outcome of antimicrobial intervention without restoration of host substrate. MCAS interventions that ignore which subtype dominates will produce inconsistent results. Fertility interventions in the absence of mitochondrial restoration target a fixed substrate and cannot move outcomes beyond a hard ceiling.

Further reading

Individual mechanisms within the framework are developed at length in the articles. The most important entry points:

• The Host Capacity Model: an introduction
• The CD38–NAD⁺–SIRT3 cascade in chronic illness
• H₂S Complex IV poisoning in recurrent SIBO
• Stratifying MCAS: not all activation patterns are the same