A new study suggests that the enzyme intestinal alkaline phosphatase (IAP) appears to help to prevent age-related loss of intestinal barrier integrity in mice, fruit flies, and potentially humans.
Improving intestinal barrier integrity
There can now be little doubt that the decline of intestinal barrier integrity and the resulting inflammation play an important role in aging. In fact, some researchers suggest that inflammaging, the low-grade chronic background of inflammation seen in older people, has its origin point in the microbiome, the ecosystem of bacteria living in our guts.
The emerging theory is that aging causes changes to the microbiome that lead to the loss of intestinal barrier integrity and an increase in gut-derived systemic inflammation, as bacterial products pass through the intestinal barrier in greater numbers.
The way this process is regulated is still somewhat unsolved, but a group of researchers from Massachusetts General Hospital have published a study that may help shed light on this mystery using the naturally produced gut enzyme Intestinal alkaline phosphatase (IAP) .
IAP is secreted by enterocytes, epithelial cells that line the inner surface of the small and large intestines. It seems to play a key role in intestinal homeostasis, the balance that allows gut bacteria to function in a healthy rather than harmful pro-inflammatory way.
For the experiment, the team studied both aged mice and fruit flies and found that IAP helped to prevent the loss of intestinal barrier integrity and thus reduced the incidence of gut-derived systemic inflammation. This led to a reduced incidence of frailty and an increase in lifespan.
They tested blood taken from the portal venous system, which connects the GI tract to the liver prior to its journey deeper into the body. This gave them a much more focused measure of what was traveling through the intestinal barrier than blood from elsewhere in the body would give.
The researchers reported that the oral administration of IAP in aged mice helped to improve intestinal barrier integrity and that it had a significant influence in the preservation of healthy gut microbiome function against aging.
They believe that as IAP is a naturally occurring enzyme that is found almost exclusively in the gut, it should prove to be safe for human use and supplementation by people who have low levels of the enzyme, which can often occur with age. They think that as IAP has systemic anti-inflammatory properties, it may help address various conditions such as Crohn’s, ulcerative colitis, and metabolic disorders such as diabetes and obesity.
The research team is now taking the required steps to develop IAP as a supplement to help maintain gut microbiome health.
Gut barrier dysfunction and gut-derived chronic inflammation play crucial roles in human aging. The gut brush border enzyme intestinal alkaline phosphatase (IAP) functions to inhibit inflammatory mediators and also appears to be an important positive regulator of gut barrier function and microbial homeostasis. We hypothesized that this enzyme could play a critical role in regulating the aging process. We tested the role of several IAP functions for prevention of age-dependent alterations in intestinal homeostasis by employing different loss-of-function and supplementation approaches. In mice, there is an age-related increase in gut permeability that is accompanied by increases in gut-derived portal venous and systemic inflammation. All these phenotypes were significantly more pronounced in IAP-deficient animals. Oral IAP supplementation significantly decreased age-related gut permeability and gut-derived systemic inflammation, resulted in less frailty, and extended lifespan. Furthermore, IAP supplementation was associated with preserving the homeostasis of gut microbiota during aging. These effects of IAP were also evident in a second model system, Drosophilae melanogaster. IAP appears to preserve intestinal homeostasis in aging by targeting crucial intestinal alterations, including gut barrier dysfunction, dysbiosis, and endotoxemia. Oral IAP supplementation may represent a novel therapy to counteract the chronic inflammatory state leading to frailty and age-related diseases in humans.
If these results translate to humans, IAP would be a useful aid in maintaining microbiome health and gut homeostasis while combating age-related loss of intestinal membrane integrity and chronic inflammation
 Kühn, F., Adiliaghdam, F., Cavallaro, P. M., Hamarneh, S. R., Tsurumi, A., Hoda, R. S., … & Vasan, R. (2020). Intestinal alkaline phosphatase targets the gut barrier to prevent aging. JCI insight, 5(6).