Abstract:
Background: Obesity is a chronic metabolic disease defined by the World Health Organization as excessive fat accumulation risking health, typically diagnosed by a BMI ≥ 30 kg/m2. Globally, it affects over 1 billion people and costs the global economy roughly $2.2 trillion annually (about 2.19% of global GDP) in direct medical expenses and lost productivity, according to World Obesity Federation data(https://www.worldobesity.org/news/economiccost-of-overweight-and-obesity-set-to-reach-3.3-of-global-gdp-by-2060). In the United States, the crisis is acute, with adult obesity prevalence at 40.3% and severe obesity near 10%. As documented in the U.S. Congress Joint Economic Committee's 2025 Economic Report (https://www.jec.senate.gov/public/vendor/_accounts/JEC-R/jerchapters/2025JERChapter4.pdf), managing the disease imposes heavy financial burdens: individual medical costs directly tied to clinical obesity care average an extra $4,043 annually per patient, skyrocketing to $9,895 per year for severe cases. Previously, we observed that mice deficient in intestinal alkaline phosphatase (IAP) are obese (https://pubmed.ncbi.nlm.nih.gov/23569246/), suggesting that IAP may serve as an etiological factor in human obesity. In the current study, we investigated the long-term effectsof IAP deficiency (IAPD) on the pathogenesis of obesity to better understand its underlying role in metabolic dysregulation.
Research Design and Methods: A healthy cohort of participants aged 30–60 years (???? = 574) was followed for 5 years. The cohort comprised 188 individuals without IAPD (normal control; stool IAP ≥ 65 U/g) and 386 individuals with IAPD (stool IAP < 65 U/g). Over the follow-up period, body mass index (BMI) and stool IAP (STAP) levels were longitudinally evaluated.
Results: Based on persistent IAP levels over the 5-year study period, participants were stratified into quintiles: Quintile 1 (< 15 U/g stool), Quintile 2 (15.1 − 33 U/g stool), Quintile 3 (33.1 − 55 U/g stool), Quintile 4 (55.1 − 115 U/g stool), and Quintile 5 (> 115 U/g stool). Sensitivity analyses demonstrated that the longitudinal rate of BMI increase across Quintiles 1 to 5 was 14.1%, 4.1%, 3.1%, 2.8%, and 1.2%, respectively. The difference in BMI acceleration between Quintile 1 (lowest IAP) and Quintile 5 (highest IAP) was statistically significant (???? = 0.040).
Conclusions: These findings indicate that IAPD significantly elevates the risk of developing obesity. Consequently, routine STAP screening could serve as an effective tool to stratify individual metabolic vulnerability, establishing stool IAP as a novel predictive biomarker for obesity. Furthermore, these data suggest that oral IAP supplementation may offer a viable therapeutic strategy for obesity prevention.
