Latest on intestinal alkaline phosphatase and IBD

[Guest guest]

Hopefully, recent background on the role of intestinal alkaline phosphatase in

detoxifying lipopolysaccharide (LPS) (endotoxin) will allow you to interpret

this paper from the March 2009 issue of " Gut " :

____________________

Gut 58: 379-387 (2009)

Role of alkaline phosphatase in colitis in man and rats.

Tuin A, Poelstra K, de Jager-Krikken A, Bok L, Raaben W, Velders MP, Dijkstra G

Department of Pharmacokinetics and Drug Delivery, University Centre for

Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen,

The Netherlands. a.tuin@...

BACKGROUND AND AIMS: Crohn's disease (CD) and ulcerative colitis (UC) are

chronic multifactorial inflammatory bowel diseases (IBDs) with unknown

aetiology, but a deregulated mucosal immune response to gut-derived bacterial

antigens is thought to be involved. Toll-like receptor ligands, especially

lipopolysaccharide (LPS), contribute to the maintenance of the disease. It has

previously been shown that the enzyme alkaline phosphatase (AP) is able to

detoxify LPS, and the aim of this study was to examine a possible role in IBDs.

METHODS: Intestinal AP (iAP) mRNA expression and LPS dephosphorylation in

intestinal biopsies of control subjects and patients with IBD were examined, and

the effect of orally administered iAP tablets on the progression of dextran

sodium sulfate-induced colitis in rats was subsequently studied. RESULTS: In

healthy persons, iAP mRNA and enzyme activity was high in the ileum relative to

the colon. In patients with UC and CD, iAP mRNA expression was found to be

markedly reduced when inflamed tissue was compared with non-inflamed tissue.

Oral administration of iAP tablets to colitic rats resulted in a significant

attenuation of colonic inflammation as reflected by reduced mRNA levels for

tumour necrosis factor alpha, interleukin 1 beta, interleukin 6 and inducible

nitric oxide synthase NOS (iNOS), a reduced iNOS staining and inflammatory cell

influx, and a significantly improved morphology of the intestinal wall.

CONCLUSIONS: The present study shows that epithelial iAP mRNA expression is

reduced in patients with UC and CD. The rat model demonstrates that oral

administration of active iAP enzymes in the intestinal tract results in a

significant reduction of inflammation. This provides new insight on IBD

pathology and a novel treatment approach to this severe inflammatory disease.

PMID: 18852260.

__________________________

They are basically saying that decreased expression of intestinal alkaline

phosphatase occurs in the intestines of UC and CD patients, and this could allow

build up of lipopolysaccharide, contributing to inflammation in the gut. They

are also saying that animals taking intestinal alkaline phosphatase have better

detoxification of lipopolysaccharide and significant reduction of inflammation.

But you may well ask the challenging question .... our alkaline phosphatase is

already elevated, and we want to see our alkaline phosphatase levels go down, so

why should we take extra alkaline phosphatase?

The answer to this paradox is that the alkaline phosphatase measured in the

" liver function tests " is predominantly the biliary/liver isoform; a protein

that is distinct from the intestinal isoform. The liver isoform becomes elevated

when the gut/intestine isoform is not doing its job properly, and permitting

lipopolysaccaride to be transported to the liver (because of poor expression of

the intestinal form and impairment of other defense mechanisms, and/or a leaky

gut).

When LPS hits the liver, it causes an increase in the liver alkaline phosphatase

.... this is a protective mechanism to attempt to detoxify the LPS!

By properly detoxifying LPS in the gut with intestinal alkaline phosphatase, and

by other mechanisms previously described (IgA and BPI), less LPS would be

transported to the liver, and the liver would no longer need to make such high

amounts of liver alkaline phosphatase.

I think this is somewhat explained here:

_____________________________

Am. J. Physiol. Gastrointest. Liver Physiol. 290: G377-G385 (2006)

On the role and fate of LPS-dephosphorylating activity in the rat liver.

Tuin A, Huizinga-Van der Vlag A, van Loenen-Weemaes AM, Meijer DK, Poelstra K.

Department of Pharmacokinetics and Drug Delivery, University of Groningen,

Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. a.tuin@...

Gut-derived lipopolysaccharide (LPS) plays a role in the pathogenesis of liver

diseases like fibrosis. The enzyme alkaline phosphatase (AP) is present in,

among others, the intestinal wall and liver and has been previously shown to

dephosphorylate LPS. Therefore, we investigated the effect of LPS on hepatic AP

expression and the effect of AP on LPS-induced hepatocyte responses.

LPS-dephosphorylating activity was expressed at the hepatocyte canalicular

membrane in normal and fibrotic animals. In addition to this, fibrotic animals

also displayed high LPS-dephosphorylating activity around bile ducts. The enzyme

was shown to dephosphorylate LPS from several bacterial species. LPS itself

rapidly enhanced the intrahepatic mRNA levels for this enzyme within 2 h by a

factor of seven. Furthermore, in vitro and in vivo studies showed that exogenous

intestinal AP quickly bound to the asialoglycoprotein receptor on hepatocytes.

This intestinal isoform significantly attenuated LPS-induced hepatic tumor

necrosis factor-alpha and nitric oxide (nitrite and nitrate) responses in vitro.

The enzyme also reduced LPS-induced hepatic glycogenolysis in vivo. This study

shows that LPS enhances AP expression in hepatocytes and that intestinal AP is

rapidly taken up by these same cells, leading to an attenuation of LPS-induced

responses in vivo. Gut-derived LPS-dephosphorylating activity or enzyme

upregulation within hepatocytes by LPS may therefore be a protective mechanism

within the liver. PMID: 16223948

____________________________

Dave

(father of (23); PSC 07/03; UC 08/03)