Upstream Ecological Control of the IAA-Skatole Branch: A pH-Dependent Triple-Lock Framework for Gut-Derived Uremic Toxin Precursors.

Gut-derived indole metabolites are implicated in the gut-kidney axis, but the factors controlling the intestinal conversion of indole-3-acetic acid (IAA) to skatole remain incompletely defined. We developed a deterministic, hypothesis-generating framework that represents this conversion as a finite-pool allocation process governed by pH-dependent ecological permissiveness, terminal-conversion capacity, precursor availability, spatial progression, and competing loss. The model separates the available-pool scale from a dimensionless integrated conversion exposure, Ψ. Across 5400 loss-free scenarios spanning 10 pH profiles and graded metabolic and host-associated constraints, the distal endpoint normalized to the available pool followed the analytically derived relationship 1-exp-Ψ. Thus, distinct combinations of mechanistically relevant parameters produced the same normalized distal endpoint, demonstrating that this endpoint alone cannot uniquely identify the underlying mechanism. Competing loss further separated absolute, total-pool-normalized, and conditional outputs, showing that mechanistic interpretation depends on endpoint normalization. Analytical and numerical checks supported internal consistency. The framework was not fitted to biological data, and concentration values were used only as technical scaling references. This biologically unvalidated model generates experimentally testable hypotheses regarding the roles of pH, terminal-conversion capacity, precursor availability, and competing loss in intestinal IAA-to-skatole metabolism; it is not intended to provide physiological or clinical predictions.