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
-
Unabsorbed Dietary Solute Retention in the Intestinal Lumen
Show evidence (3 references)
"our data demonstrate that, in contrast to common adult-type hypolactasia (lactose intolerance) caused by a variant of the regulatory element, the severe infancy form represents the outcome of mutations affecting the structure of the protein inactivating the enzyme"
Establishes the hydrolase class of this trigger: coding-region LCT mutations that inactivate the lactase enzyme protein itself, as opposed to the regulatory downregulation that causes common lactase non-persistence. This is the distinction that makes congenital lactase deficiency a Mendelian conformer of this module and adult-type hypolactasia not one.
"The results suggest that different, probably small, mutations in the sucrase-isomaltase gene lead to the synthesis of transport-incompetent or functionally altered enzyme which results in congenital sucrose intolerance."
Shows that the trigger node covers trafficking failure as well as loss of catalytic activity: transport-incompetent sucrase-isomaltase never reaches the brush border, which is functionally equivalent to absence of the enzyme. Evidence source is IN_VITRO because the phenotypes were resolved by antibody-based subcellular and protein analysis of patient material.
"Sequence analysis of the amplified products has revealed a single missense mutation in SGLT1 which cosegregates with the GGM phenotype and results in a complete loss of Na(+)-dependent glucose transport"
Establishes the transporter class of this trigger - a single SGLT1 missense mutation abolishing sodium-dependent glucose transport - showing that the module's trigger admits an apical carrier defect as well as a hydrolase defect. Evidence source is IN_VITRO because the transport loss was measured in Xenopus oocytes injected with the mutant cRNA.
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
-
Osmotic Water Influx and Luminal Distension
-
Colonic Microbial Fermentation of the Malabsorbed Substrate
Show evidence (2 references)
"Diet-induced diarrhea is characterized by an elevated stool osmotic gap (>100 mOsm). Examples include glucose or disaccharide malabsorption."
Defines the class this module models and names its measurable signature - an elevated stool osmotic gap produced by retained unabsorbed nutrient - with glucose and disaccharide malabsorption given as the examples, i.e. exactly the module's conformers. Evidence source is OTHER because this is a review proposing the current CODE classification.
"Infants with CODEs resulting from defects in digestion, absorption, transport of nutrients and electrolytes, or enteroendocrine cell development or function have normal villi to crypt ratios; defects in enterocyte structure or immune-mediated conditions result in an abnormal villus to crypt..."
Supports the module's scope boundary: the digestion/absorption defects modelled here leave villus architecture normal, which is what distinguishes them from the structural and immune-mediated enteropathies that this module explicitly excludes and that intestinal_barrier_dysfunction covers instead.
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
-
Substrate-Dependent Watery Diarrhea and Nutritional Consequences
Show evidence (1 reference)
"Carbohydrate malabsorption can provoke an osmotically driven influx of fluid into the small bowel, leading to intestinal distension and rapid propulsion into the colon"
States this node directly: malabsorbed carbohydrate osmotically drives fluid into the small bowel, distending it and accelerating delivery to the colon. Evidence source is OTHER because this is a review.
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
-
Substrate-Dependent Watery Diarrhea and Nutritional Consequences
Show evidence (2 references)
"unabsorbed carbohydrates are rapidly fermented by colonic microbiota, generating gas, lactate, and short-chain fatty acids that have effects on gastrointestinal function"
Establishes the fermentative branch - colonic microbiota rapidly ferment unabsorbed carbohydrate into gas, lactate and short-chain fatty acids. Evidence source is OTHER because this is a review.
"The short-chain fatty acids are rapidly absorbed by the colonic mucosa, favouring the concomitant absorption of water and electrolytes"
Supports the offsetting arm of this branch: short-chain fatty acid uptake by the colonic mucosa drives water and electrolyte salvage, which is why fermentation is modelled as a branch with two opposing effects rather than as a step that simply worsens the diarrhea. Evidence source is OTHER because this is a review.
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.
Show evidence (2 references)
"The consequent severe diarrhoea and dehydration are usually fatal unless these sugars are eliminated from the diet."
States both halves of this node in one sentence: the severity of the outcome (fatal diarrhea and dehydration) and its strict substrate dependence (reversed by eliminating the offending sugars), which is the module's defining clinical signature.
"Congenital lactase deficiency (CLD) is a severe gastrointestinal disorder characterized by watery diarrhea in infants fed with breast milk or other lactose-containing formulas."
Shows the substrate-triggered onset that characterises this node - watery diarrhea appearing specifically on feeding with a lactose-containing milk, not from birth independent of diet.
Elimination of the Offending Dietary Substrate
Platform:
Behavioral / lifestyle
The foundational treatment for every disorder conforming to this module, and the intervention that demonstrates the module's causal chain. Removing the substrate the patient cannot handle - a lactose-free formula in congenital lactase deficiency, sucrose and starch restriction in sucrase-isomaltase deficiency, trehalose avoidance in trehalase deficiency, a fructose-based formula in glucose-galactose malabsorption, where GLUT5-mediated fructose uptake is spared - empties the luminal solute pool without correcting the genetic lesion. Symptoms resolve and recur predictably on rechallenge. In the complete congenital deficiencies this is life-saving rather than symptom-relieving.
Oral Enzyme Replacement (Sacrosidase)
Platform:
Protein replacement
The complementary treatment pattern, acting on the trigger node rather than the central effector. Sacrosidase is a liquid sucrase preparation derived from Saccharomyces cerevisiae, taken with meals so that it hydrolyses sucrose in the intestinal lumen in place of the missing brush-border enzyme. It bypasses the defective apical digestive step, allowing patients with congenital sucrase-isomaltase deficiency to eat a normal sucrose-containing diet. Its effectiveness is direct interventional evidence for the module's trigger-to-central-effector link. This pattern is specific to the hydrolase class of trigger and is not inherited by conformers whose lesion is a transporter: no equivalent luminal replacement exists for SGLT1, because the defective step is membrane transport rather than luminal hydrolysis.