Intestinal Alkaline Phosphatase Deficiency Is Associated with Ischemic Heart Disease

Abstract

Background. We have previously shown that the deficiency of the gut enzyme intestinal alkaline phosphatase (IAP) is associated with type 2 diabetes mellitus (T2DM) in humans, and mice deficient in IAP develop the metabolic syndrome, a precipitant of T2DM and ischemic heart disease (IHD). We hypothesized that IAP deficiency might also be associated with IHD in humans. We aimed to determine the correlation between the IAP level and IHD in humans. Methods and Results. The IHD patients were recruited from the National Institute of Cardiovascular Diseases (NICVD), Dhaka, Bangladesh, and the control healthy participants were recruited from a suburban community of Dhaka. We determined the IAP level in the stools of 292 IHD patients (187 males, 105 females) and 331 healthy control people (84 males, 247 females). We found that compared to controls, IHD patients have approx. 30% less IAP (mean±SEM: 63.7±3.5 vs. 44.9±2.1 U/g stool, respectively; p<0.000001), which indicates that IAP deficiency is associated with IHD, and a high level of IAP is probably protective against IHD in humans. The adjusted generalized linear model (GLM) of regression analysis predicted a strong association of IAP with IHD (p=0.0035). Multiple logistic regression analysis showed an independent inverse relationship between the IAP level and the IHD status (odds ratio, OR=0.993 with 95% CI 0.987-0.998; p<0.01). Conclusions. IAP deficiency is associated with IHD, and a high level of IAP might be protective against IHD.

Alkaline Phosphatase: An Old Friend as Treatment Target for Cardiovascular and Mineral Bone Disorders in Chronic Kidney Disease

“…In contrast to the other ALP isozymes, IALP may be protective against CVD, in addition to its protective effect on metabolic syndrome and diabetes discussed above. In fact, a case-control study on 623 patients showed that ischemic heart disease was associated with lower fecal IALP activity [ 91 ]. This could be due to the increase in chronic systemic inflammation, with subsequent endothelial damage, which has previously been observed in studies on IALP-deficient mice.…”

Targeting the Intestinal Barrier to Prevent Gut-Derived Inflammation and Disease: A Role for Intestinal Alkaline Phosphatase

“…Recent studies have found an obvious correlation between IAP deficiency and ischemic heart disease (IHD) [55, 59, 60]. Here, IHD patients had approximately 30% lower levels of IAP in stool samples in comparison to the healthy controls.…”

“…Furthermore, in that study, IAP-KO mice put on a high-fat diet (HFD) exhibited T2DM symptoms such as higher fasting glucose levels and an abnormal glucose tolerance. An HFD is known to lead to a higher proportion of LPS-containing microbiota [54], and that LPS binds to fatty acids which lead to more LPS absorption in the context of HFD [55]. In return, absorbed LPS can cause local intestinal inflammation and increase intestinal permeability, resulting in increased translocation [54].…”

“…The generalized linear modeling verified a strong association of IAP with IHD. Multiple logistic regression analysis controlling for physical and biochemical characteristics showed an independent inverse relationship between the IHD status and levels of IAP [55]. The authors discuss the pathogenesis of IHD caused by IAP deficiency as follows: IAP deficiency increases intestinal permeability and intraluminal bacteria-derived LPS concentration [52, 61], both of which contribute to excessive translocation of LPS into the systemic circulation, causing varying degrees of endotoxemia.…”

Intestinal alkaline phosphatase modulation by food components: predictive, preventive, and personalized strategies for novel treatment options in chronic kidney disease

“…In some intestinal diseases such as colitis and inflammatory bowel disease, IAP mRNA expression is reduced and related to gut inflammation, with a consequent increase of LPS and TLR-4 expression [46,47]. IAP deficiency also has been associated with ischemic heart disease and type 2 diabetes mellitus [48,49]. Upon activation by LPS, TLR-4, or MyD88, a standard adaptor downstream of TLRs, mediates the release of proinflammatory cytokines, including IL-6, IL- 1, and TNF through the nuclear-kappa B factor (NF-kB) pathway [50][51][52].…”