Active inquiry
Open mechanistic questions
Each entry states the question, the measurements needed to answer it, the confounders that would spoil the answer, and — most importantly — the result that would count against the Host Capacity Model. Nothing on this page is a claim, and nothing on it is clinical advice.
Falsifiable registry
Stable identifiers. Cite an individual question by its own URL.
- BL-RQ-001 · Open
Does restoring colonocyte butyrate oxidation lower luminal oxygen availability in humans, as it does in mouse models?
The mouse epithelial-oxygenation work is the mechanistic backbone of the ecology argument. Its human quantitative status is unknown.
What would count against the model: Human mucosal oxygenation shows no relationship with butyrate availability or facultative anaerobe expansion.
- BL-RQ-002 · Open
Is stool short-chain fatty acid concentration interpretable as a measure of colonocyte fuel supply?
Many commercial reports present stool SCFA as a functional readout. Concentration reflects production minus absorption, so the direction of a low value is ambiguous.
What would count against the model: Stool concentration is shown to track colonocyte supply reliably, making the measurement caveat unnecessary.
- BL-RQ-003 · Open
Do people with recurrent SIBO-pattern breath tests differ in host epithelial or motility measures from people with a single episode?
Recurrence is usually attributed to incomplete eradication. A host-capacity explanation predicts measurable host differences instead.
What would count against the model: No host-side difference is detectable between recurrent and single-episode groups.
- BL-RQ-004 · Open
Is there a human measurement that distinguishes mast-cell mediated barrier disruption from barrier disruption of other causes?
Without a discriminating measurement, mast-cell involvement in barrier failure remains untestable in individuals.
What would count against the model: No measurement separates them, so the distinction stays theoretical.
Also tracked, per concept
Shorter open problems tracked against individual concept pages. These are not part of the falsifiable registry above and carry no decision criteria yet.
- Actively tracked
Do colonic bioenergetic markers (mucosal SIRT3, lactate/pyruvate, stool SCFA) prospectively predict relapse risk in functional gut disease?
If they do, the Host Capacity Model gains a clinically actionable readout for staging recovery and timing intervention.
Candidate experiments
- Prospective cohort with serial mucosal biopsies + SCFA before / after relapse.
- Bioenergetic-stratified RCT comparing intervention orders.
- Open
Does restoring colonocyte bioenergetics shift microbial ecology back toward obligate-anaerobe dominance without targeted antimicrobials?
Direct test of dysbiosis-as-adaptation versus dysbiosis-as-primary-lesion.
Candidate experiments
- Bioenergetic-only intervention arm with longitudinal 16S + metabolomics.
- Open
Under what bioenergetic conditions does exogenous butyrate help, do nothing, or worsen mucosal stress?
Resolves a clinically common contradiction and lets clinicians stop using butyrate empirically.
Candidate experiments
- Stratified trial by baseline mucosal β-oxidation capacity.
- Actively tracked
Is MCAS-pattern symptomatology a primary mast-cell disorder or a downstream amplification of upstream gut, mitochondrial, or connective-tissue lesions?
Determines whether mast-cell stabilisation is curative or merely symptomatic in most cases.
Candidate experiments
- Sequential intervention trial: upstream-first vs. mast-cell-first.
- Partially answered
Are lactulose / glucose breath tests clinically useful as a stand-alone SIBO diagnostic, or only when combined with mechanistic context?
Has direct implications for over- and under-treatment of suspected SIBO.
Candidate experiments
- Blinded comparison of test result vs. mechanism-grounded clinical pattern.
- Open
Does aromatase / oestrogen modulation measurably affect MCAS-pattern severity in humans?
Mechanistically plausible but human evidence is still thin; confirmation would justify a hormonal axis in MCAS staging.
Candidate experiments
- Cycle-phased symptom tracking with concurrent oestrogen + tryptase profiles.
- Open
Does sulfide (H₂S) burden gate colonocyte recovery independently of SCFA supply?
If yes, sulfide-targeted strategies become a parallel axis to SCFA-restoration in HCM.
Candidate experiments
- Sulfide-stratified bioenergetic recovery trial.
- Actively tracked
Does intestinal mitochondrial dysfunction propagate systemically to skeletal muscle and immune compartments in chronic gut disease?
Would unify post-viral / ME-CFS / chronic-gut overlap under a shared bioenergetic frame.
Candidate experiments
- Multi-tissue mitochondrial-function profiling in cohorts with gut + systemic symptoms.
- Open
Do shifts in primary/secondary bile-acid ratios track recovery from host-capacity failure independently of microbial composition?
Bile-acid signalling is a candidate readout that's cheaper than mucosal biopsies.
Candidate experiments
- Longitudinal bile-acid profiling alongside bioenergetic markers.
- Open
Is increased intestinal permeability a primary lesion or a downstream consequence of bioenergetic failure?
Determines whether barrier-targeted therapies should sit upstream or downstream of bioenergetic restoration.
Candidate experiments
- Permeability + bioenergetic co-measurement across recovery timepoints.
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