ALPI (alkaline phosphatase, intestinal) encodes intestinal alkaline phosphatase, a brush border metalloenzyme with critical roles in gut homeostasis and mucosal defense. Primary function: ALPI catalyzes hydrolysis of phosphate groups from various substrates, including the lipid A moiety of lipopolysaccharides (LPS), a Toll-like receptor 4 agonist 1. The gene produces two alternatively spliced transcript variants (aAug10 and bAug10); only the aAug10 variant exhibits detectable alkaline phosphatase activity, while bAug10 lacks the central N-terminal α-helix and critical residues near the active site 2. Mechanism: ALPI functions as a gut mucosal defense factor by detoxifying bacterial LPS and regulating host-microbiota interactions, thereby restraining inflammatory responses 1. Disease relevance: Biallelic ALPI mutations cause inflammatory bowel disease through loss-of-function mechanisms that impair protein stability or catalytic activity, rendering ALPI unable to neutralize LPS signaling 1. Clinical significance: ALPI mutations should be included in screening for monogenic causes of inflammatory bowel disease, and ALPI-based treatments represent novel therapeutic targets for intestinal inflammatory disorders 1. ALPI expression is upregulated by vitamin D, suggesting nutritional regulation of this protective pathway 2.