Re: Cocoa-Related Flavonoids Inhibit CFTR-Mediated Chloride Transport across T84 Human Colon Epithelia1

[Guest guest]

Hi athan;

These are really interesting questions! I would suspect that the

further inhibition of CFTR would not be good for PSCers, but I don't

want to be responsible for banning chocolate from the diet!

I've been reading a lot about CFTR lately, and one thing I have

noticed is that in the gut CFTR is responsible for secreting

bicarbonate (HCO3-) to make the pH sufficiently alkaline (i.e. less

acidic) for the enzyme intestinal alkaline phosphatase to function

properly. CFTR patients have a low activity of intestinal alkaline

phosphatase. It has recently been shown that intestinal alkaline

phosphatase is responsible for removing phosphate groups from the

nasty compound lipopolysaccharide (LPS) produced by many bacteria.

This removal of phosphate groups from LPS makes the copound much less

toxic. Bottom line ... low intestinal alkaline phosphtase activity =

high levels of LPS.

LPS can be detoxified further by being bound to

bacterial/permeability increasing protein (BPI). But in cystic

fibrosis patients this system also becomes overwhelmed; increased

levels of circulating BPI-LPS complexes lead to production of anti-

BPI antibodies which further exacerbate the problem of LPS

detoxification. Interestingly, the other disease with a high

percentage of patients with anti-BPI antibodies is PSC! High levels

of LPS can cause gut inflammation, and a leaky gut. This can lead to

LPS transport to the liver via the portal vein causing further

inflammation and cholestasis. One study shows that LPS is

subtantially elevated in livers of PSC patients.

So, inhibition of CFTR ---> acid pH ---> low intestinal alkaline

phosphatase activity ---> high LPS ---> BPI-LPS complexes --> anti-

BPI antibodies ---> high LPS ---> liver inflammation & cholestasis

Best regards,

Dave R.

>

> Link to full text:

> http://jn.nutrition.org/cgi/content/full/135/10/2320

>

> *ABSTRACT

> Cocoa beans have historically been used as a treatment for

diarrhea,

> leading us to hypothesize that polyphenols contained in cocoa

inhibit

> intestinal Cl†" secretion. In this study, the dose-dependent

effects of

> flavonoid compounds present in cocoa, or molecularly closely

related

> compounds, were tested on forskolin-stimulated cystic fibrosis

> transmembrane conductance regulator (CFTR)-mediated Cl†" secretion

across

> T84 colonic epithelia in Ussing chambers. Addition of cocoa extract

or

> cocoa flavanols to the mucosal side of tissues caused partial

inhibition

> following is-Menten kinetics and resulted in a rank order of

> maximum blocker effects as follows: epicatechin > catechin ≥

> standardized cocoa preparation ≥ procyanidin B2. Half-maximal

blocker

> concentrations (Ki) were not substantially different between the

tested

> preparations and were in the range of 100 µmol/L. For comparison,

the

> structurally related flavonoids, quercetin and luteolin, caused a

total

> block of Cl†" currents with Ki values similar to the cocoa

flavanols

> tested. Morin and baicalein were less effective blockers. Effects

of

> test compounds on mucosal redox potential did not correlate with

blocker

> activity. These data indicate that cocoa flavanols target

intestinal

> CFTR Cl†" transport and may serve as mild inhibitors of cAMP-

stimulated

> Cl†" secretion in the intestine.*

>

>

> I noticed this article, and the fact that it involves CTFR raised

some

> questions in my mind. First, if the research linking PSC to CFTR

> deficiency is correct, does this mean that chocolate which seems to

> further inhibit CFTR might cause additional problems for us? Or

does it

> mean that since many of us suffer from diarrhea we should eat more

> chocolate (since inhibiting CFTR may help with diarrhea)? Or is

there

> another conclusion, or no conclusion to be drawn from this?

>

> Just curious!

>

> athan

>

[Guest guest]

wrote:

> So, inhibition of CFTR ---> acid pH ---> low intestinal alkaline

> phosphatase activity ---> high LPS ---> BPI-LPS complexes --> anti-

> BPI antibodies ---> high LPS ---> liver inflammation & cholestasis

Very interesting! Maybe I shouldn't go binge on dark chocolate after all!

Thanks for your insight!

athan