This is a mechanism module, not a specific disease. It models one conserved mechanism - substrate-specific failure of an apical digestive or absorptive step producing luminal osmotic solute retention - and deliberately does NOT cover the other congenital-diarrhea mechanism classes, which have different rate-limiting steps and are separated from this one in the current CODE nosology (PMID:29654747). In particular it excludes electrolyte-transport-related diarrhea (congenital chloride diarrhea/SLC26A3, congenital sodium diarrhea/SLC9A3 and GUCY2C), where the lost transport step handles ions rather than an ingested nutrient and the stool osmotic gap is low rather than high - that class is modelled by the sibling module electrolyte_transport_related_diarrhea, and a disorder must not conform to both this module and that one for the same node; it excludes the enterocyte structural/trafficking enteropathies (microvillus inclusion disease, congenital tufting enteropathy), where villus architecture itself is abnormal and diarrhea does not remit on dietary substrate withdrawal; and it excludes immune-mediated enteropathy (IPEX, autoimmune enteropathy) and barrier injury, which are covered by intestinal_barrier_dysfunction. Note that this module and intestinal_barrier_dysfunction reach a superficially similar "absorptive failure -> diarrhea" endpoint from opposite directions: there, malabsorption is a downstream consequence of mucosal injury and villus blunting; here, the mucosa is histologically normal (a normal villus-to-crypt ratio is the diagnostic hallmark of this class) and the lesion is a single missing molecular step. A disorder should not conform to both for the same node. Key disease-specific substitutions conforming entries make: congenital lactase deficiency substitutes LCT/lactase-phlorizin hydrolase and lactose; congenital sucrase-isomaltase deficiency substitutes SI and sucrose (with variable isomaltose/starch involvement); trehalase deficiency substitutes TREH and trehalose; glucose-galactose malabsorption substitutes SLC5A1/SGLT1 and dietary glucose plus galactose, and is the one conformer whose lesion is a transporter rather than a hydrolase - fructose absorption via GLUT5 is spared, which is what makes a fructose-based formula therapeutic. The module carries two complementary treatment patterns on different nodes: dietary elimination of the offending substrate INHIBITS luminal solute retention, and oral enzyme replacement (sacrosidase in CSID) BYPASSES the missing brush-border digestive step. Modules bind GO and CL terms only and do not use chemical (CHEBI) or disease (MONDO) term bindings; substrate chemistry is described in prose, except in the treatments block where the therapeutic agent carries an NCIT/CHEBI identifier per the treatment schema.
Loss of a Substrate-Specific Brush-Border Digestive or Absorptive Step
trigger
The shared upstream lesion. A biallelic loss-of-function defect removes one substrate-specific activity from the apical brush border of the small-intestinal enterocyte, while leaving the rest of the absorptive machinery and the villus architecture intact. Two molecular classes of lesion produce the same functional result. In the hydrolase class, a brush-border disaccharidase is absent, catalytically dead, or - as demonstrated for sucrase-isomaltase - synthesised but blocked in the endoplasmic reticulum or Golgi and never delivered to the apical membrane, so the dietary disaccharide is never cleaved to absorbable monosaccharides. In the transporter class, the apical sodium-coupled monosaccharide carrier is present but non-functional, so hydrolysis proceeds normally yet the liberated monosaccharide cannot cross the apical membrane. Because each lesion removes exactly one step, the defect is silent until the corresponding substrate is fed, and the specific enzyme or transporter substituted differs by disorder.
Downstream
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Unabsorbed Dietary Solute Retention in the Intestinal Lumen
Unabsorbed Dietary Solute Retention in the Intestinal Lumen
central effector
The rate-limiting, disorder-agnostic node and the key conformance target. Whatever the specific missing step, its consequence is identical: the ingested substrate is neither reduced to an absorbable form nor taken up, so it remains in the small-intestinal lumen as an osmotically active solute at a concentration set by dietary load rather than by absorptive capacity. This is the point at which the disorder-specific molecular lesions converge, and the point at which both therapeutic strategies act - removing the substrate from the diet, or hydrolysing it in the lumen with a replacement enzyme, each empties this node without repairing the underlying genetic defect. Its clinical signature is a high stool osmotic gap, which is what separates this class from the electrolyte-transport-related congenital diarrheas.
Downstream
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Osmotic Water Influx and Luminal Distension
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Colonic Microbial Fermentation of the Malabsorbed Substrate
Osmotic Water Influx and Luminal Distension
amplifier
Retained luminal solute exerts an osmotic force that draws water across the intestinal epithelium into the lumen. The resulting increase in luminal volume distends the small bowel and accelerates propulsion of fluid and unabsorbed substrate into the colon, shortening the time available for any residual absorption or for colonic salvage. This is the step that converts a biochemical malabsorption into a fluid-volume problem.
Downstream
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Substrate-Dependent Watery Diarrhea and Nutritional Consequences
Colonic Microbial Fermentation of the Malabsorbed Substrate
amplifier
A parallel branch rather than an obligatory step in the chain to diarrhea. Substrate delivered to the colon is fermented by the resident microbiota to hydrogen, carbon dioxide, methane, lactate and short-chain fatty acids. This branch has two opposing effects, which is why it is modelled separately. Gas production causes the bloating, distension and flatulence that dominate the milder phenotypes, and is what the hydrogen and 13C breath tests used to diagnose these disorders actually measure. At the same time, short-chain fatty acids are absorbed by the colonic mucosa and drive concomitant salvage of water and electrolytes, partially offsetting the osmotic load. The balance between fermentative production and this reabsorptive reserve, rather than the primary enzymatic defect alone, determines the substrate dose at which an affected individual becomes symptomatic - which is why partial-deficiency phenotypes are dose-dependent while complete congenital deficiencies are not.
Downstream
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Substrate-Dependent Watery Diarrhea and Nutritional Consequences
Substrate-Dependent Watery Diarrhea and Nutritional Consequences
consequence
The clinical output. Osmotic fluid loss that exceeds colonic salvage capacity produces watery, often explosive and acidic diarrhea, accompanied by abdominal distension, flatulence and pain from the fermentative branch. In the complete congenital deficiencies the diarrhea begins with the first feed containing the offending substrate and, if unrecognised, causes dehydration, electrolyte disturbance, failure to thrive and malnutrition, historically with substantial mortality. The defining feature of this node - and of the whole module - is its strict substrate dependence: symptoms remit completely when the offending nutrient is removed from the diet and recur on rechallenge, without any repair of the underlying molecular defect. That reversibility is the clinical evidence that the chain runs through luminal solute retention rather than through mucosal damage.