Continuation of the endotoxin theme, and links to vitamin A

[Guest guest]

Dear All;

As I've tried to explain in recent postings, one possibility to account for PSC

is that toxic bacterial products in the gut, such as endotoxin

(lipopolysaccharide), are not adequately detoxified, and get through a " leaky

gut " to be transported to the liver, where they cause inflammation. I've

mentioned that there are three lines of defense against endotoxin:

1. Secreted IgA in the gut can bind to endotoxin.

2. Intestinal alkaline phosphatase can clip off a phosphate group from

endotoxin, rendering it less toxic.

3. Bactericidal/permeability-increasing protein (BPI) can bind tightly to

endotoxin, neutralizing it.

Once the endotoxin breaches these defenses, it can bind to CD14, and then to

Toll-like receptors (such as TLR4) triggering inflammation.

Here I'd like to note that the vitamin A metabolite, retinoic acid, is involved

in the regulation of ALL of these components.

Retinoic acid increases IgA secretion in the gut:

Kim CH (2008) Roles of retinoic acid in induction of immunity and immune

tolerance. Endocr. Metab. Immune Disord. Drug Targets. 8: 289-294.

Retinoic acid increases the expression of intestinal alkaline phosphatase (in

participation with the thyroid hormone):

Malo MS, Zhang W, Alkhoury F, Pushpakaran P, Abedrapo MA, Mozumder M, Fleming E,

Siddique A, JW, Hodin RA (2004) Thyroid hormone positively regulates

the enterocyte differentiation marker intestinal alkaline phosphatase gene via

an atypical response element. Mol. Endocrinol. 18: 1941-1962.

Retinoic acid increases the expression of the

bactericidal/permeability-increasing protein (BPI):

Lennartsson A, Vidovic K, Pass MB, Cowland JB, Gullberg U (2006)All-trans

retinoic acid-induced expression of bactericidal/permeability-increasing protein

(BPI) in human myeloid cells correlates to binding of C/EBPbeta and C/EBPepsilon

to the BPI promoter. J. Leukoc. Biol. 80: 196-203.

Retinoic acid reduces gut permeability/leakiness:

Osanai M, Nishikiori N, Murata M, Chiba H, Kojima T, Sawada N (2007) Cellular

retinoic acid bioavailability determines epithelial integrity: role of retinoic

acid receptor alpha agonists in colitis. Mol. Pharmacol. 71: 250-258.

Retinoic acid decreases expression of CD14, and to a lesser extent, TLR4:

Liu PT, Krutzik SR, Kim J, Modlin RL (2005) Cutting edge: all-trans retinoic

acid down-regulates TLR2 expression and function. J. Immunol. 174: 2467-2470.

So retinoic acid (a derivative of vitamin A) seems to be intimately involved in

this pathway. But, as I've also mentioned, vitamin A is not the only dietary

constituent that can affect these processes.

Omega-3 fatty acids found in fish oils can also act to reduce gut

permeability/leakiness:

Jiang WG, Bryce RP, Horrobin DF, Mansel RE (1998) Regulation of tight junction

permeability and occludin expression by polyunsaturated fatty acids. Biochem.

Biophys. Res. Commun. 244: 414-420.

Usami M, Muraki K, Iwamoto M, Ohata A, Matsushita E, Miki A (2001) Effect of

eicosapentaenoic acid (EPA) on tight junction permeability in intestinal

monolayer cells. Clin. Nutr. 20: 351-359.

And the micronutrient zinc is essential for intestinal alkaline phosphatase

activity:

Bortolato M, Besson F, Roux B (1999) Role of metal ions on the secondary and

quaternary structure of alkaline phosphatase from bovine intestinal mucosa.

Proteins 37: 310-328.

My son takes fish oils and a Centrum Silver vitamin supplement which contains

vitamin A, vitamin D, and zinc, to name but a few of the ingredients.

I might add that a lot of my reading in this area is due to the fact that my son

first presented with PSC in conjunction with acne, which is often treated with

retinoic acid:

__________________________

J. Immunol. 174: 2467-2470 (2005)

Cutting edge: all-trans retinoic acid down-regulates TLR2 expression and

function.

Liu PT, Krutzik SR, Kim J, Modlin RL.

Department of Microbiology, Immunology and Molecular Genetics, Geffen

School of Medicine at University of California, Los Angeles, USA.

A major consequence of microbial infection is the tissue injury that results

from the host inflammatory response. In acne, inflammation is due in part to the

ability of Propionibacterium acnes to activate TLR2. Because all-trans retinoic

acid (ATRA) decreases inflammation in acne, we investigated whether it regulates

TLR2 expression and function. Treatment of primary human monocytes with ATRA led

to the down-regulation of TLR2 as well as its coreceptor CD14, but not TLR1 or

TLR4. The ability of a TLR2/1 ligand to trigger monocyte cytokine release was

inhibited by pre- and cotreatment with ATRA; however, TLR4 activation was

affected by cotreatment only. ATRA also down-regulated monocyte cytokine

induction by P. acnes. These data indicate that ATRA exerts an anti-inflammatory

effect on monocytes via two pathways, one specifically affecting TLR2/1 and CD14

expression and one independent of TLR expression. Agents that target TLR

expression and function represent a novel strategy to treat inflammation in

humans.

PMID: 15728448

__________________________

I might also add that since taking fish oils together with Centrum Silver,

urosdiol and rifampin, his acne has improved dramatically.

Best regards.

Dave

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