Re: A hypothesis on UC/PSC

[Guest guest]

Dave,

Are you going to send this idea to a researcher? You should.

Love, Judy

A hypothesis on UC/PSC

Dear All;After reading the literature on PSC, IBD and immunology for the last 4 years, I would now like to propose a hypothesis on UC/PSC, based in part on my two previous posts this evening.I hypothesize that an as yet unidentified gut bacterium catalyzes asymetric cleavage of beta-carotene (the normal dietary source of vitamin A), to produce a retinoic acid derivative (apo14) that inhibits the retinoid X receptor:________________Mol Endocrinol. 2007 Jan;21(1):77-88. Asymmetric cleavage of beta-carotene yields a transcriptional repressor of retinoid X receptor and peroxisome proliferator-activated receptor responses.Ziouzenkova O, Orasanu G, Sukhova G, Lau E, Berger JP, Tang G, Krinsky NI, Dolnikowski GG, Plutzky JCardiovascular Division, Brigham and Women's Hospital, Havard University, Boston, Massachusetts 02115, USA.beta-Carotene and its metabolites exert a broad range of effects, in part by regulating transcriptional responses through specific nuclear receptor activation. Symmetric cleavage of beta-carotene can yield 9-cis retinoic acid (9-cisRA), the natural ligand for the nuclear receptor RXR, the obligate heterodimeric partner for numerous nuclear receptor family members. A significant portion of beta-carotene can also undergo asymmetric cleavage to yield apocarotenals, a series of poorly understood naturally occurring molecules whose biologic role, including their transcriptional effects, remains essentially unknown. We show here that beta-apo-14'-carotenal (apo14), but not other structurally related apocarotenals, represses peroxisome proliferator-activated receptors (PPAR) and RXR activation and biologic responses induced by their respective agonists both in vitro and in vivo. During adipocyte differentiation, apo14 inhibited PPARgamma target gene expression and adipogenesis, even in the presence of the potent PPARgamma agonist BRL49653. Apo14 also suppressed known PPARalpha responses, including target gene expression and its known antiinflammatory effects, but not if PPARalpha agonist stimulation occurred before apo14 exposure and not in PPARalpha-deficient cells or mice. Other apocarotenals tested had none of these effects. These data extend current views of beta-carotene metabolism to include specific apocarotenals as possible biologically active mediators and identify apo14 as a possible template for designing PPAR and RXR modulators and better understanding modulation of nuclear receptor activation. These results also suggest a novel model of molecular endocrinology in which metabolism of a parent compound, beta-carotene, may alternatively activate (9-cisRA) or inhibit (apo14) specific nuclear receptor responses. PMID: 17008383.________________Because the retinoid X receptor is required for the activity of a large number of other receptors in the liver, including PXR, PPARs, VDR, RAR, and FXR, its inhibition by a compound like apo14 would cause massive disruption of bile transport and detoxification, lipid metabolism, and vitamin D signaling. As mentioned before, down-regulation of PXR would lead to down-regulation of MDR1 and hence increased susceptibility to xenobiotics, and increased inflammation, and cholestasis. Because docosahexaenoic acid (DHA) can substitue for 9-cis retinoic acid as an activator of RXR, then fish oils rich in DHA could potentially counteract the inhibitory action of apo14.It's possible that a compound like apo14 could also interfere with immune regulation in the gut, causing accumulation of inflammatory Th17 cells at the expense of anti-inflammatory Tregs (see my earlier posts this evening), perpetuating the inflammation, and eventually causing vitamin A deficiency (common in IBD and PSC). But a hypothesis should not be treated as fact. Rather it should be subject to critical research and experimentation to prove it is either right of wrong. Best regards,Dave (father of (22); PSC 07/03; UC 08/03)

[Guest guest]

Again, very interesting.Next time my son has blood work maybe he should have his vitamin levels tested.LeeDear All;After reading the literature on PSC, IBD and immunology for the last 4 years, I would now like to propose a hypothesis on UC/PSC, based in part on my two previous posts this evening.I hypothesize that an as yet unidentified gut bacterium catalyzes asymetric cleavage of beta-carotene (the normal dietary source of vitamin A), to produce a retinoic acid derivative (apo14) that inhibits the retinoid X receptor:________________Mol Endocrinol. 2007 Jan;21(1):77-88. Asymmetric cleavage of beta-carotene yields a transcriptional repressor of retinoid X receptor and peroxisome proliferator-activated receptor responses.Ziouzenkova O, Orasanu G, Sukhova G, Lau E, Berger JP, Tang G, Krinsky NI, Dolnikowski GG, Plutzky JCardiovascular Division, Brigham and Women's Hospital, Havard University, Boston, Massachusetts 02115, USA.beta-Carotene and its metabolites exert a broad range of effects, in part by regulating transcriptional responses through specific nuclear receptor activation. Symmetric cleavage of beta-carotene can yield 9-cis retinoic acid (9-cisRA), the natural ligand for the nuclear receptor RXR, the obligate heterodimeric partner for numerous nuclear receptor family members. A significant portion of beta-carotene can also undergo asymmetric cleavage to yield apocarotenals, a series of poorly understood naturally occurring molecules whose biologic role, including their transcriptional effects, remains essentially unknown. We show here that beta-apo-14'-carotenal (apo14), but not other structurally related apocarotenals, represses peroxisome proliferator-activated receptors (PPAR) and RXR activation and biologic responses induced by their respective agonists both in vitro and in vivo. During adipocyte differentiation, apo14 inhibited PPARgamma target gene expression and adipogenesis, even in the presence of the potent PPARgamma agonist BRL49653. Apo14 also suppressed known PPARalpha responses, including target gene expression and its known antiinflammatory effects, but not if PPARalpha agonist stimulation occurred before apo14 exposure and not in PPARalpha-deficient cells or mice. Other apocarotenals tested had none of these effects. These data extend current views of beta-carotene metabolism to include specific apocarotenals as possible biologically active mediators and identify apo14 as a possible template for designing PPAR and RXR modulators and better understanding modulation of nuclear receptor activation. These results also suggest a novel model of molecular endocrinology in which metabolism of a parent compound, beta-carotene, may alternatively activate (9-cisRA) or inhibit (apo14) specific nuclear receptor responses. PMID: 17008383.________________Because the retinoid X receptor is required for the activity of a large number of other receptors in the liver, including PXR, PPARs, VDR, RAR, and FXR, its inhibition by a compound like apo14 would cause massive disruption of bile transport and detoxification, lipid metabolism, and vitamin D signaling. As mentioned before, down-regulation of PXR would lead to down-regulation of MDR1 and hence increased susceptibility to xenobiotics, and increased inflammation, and cholestasis. Because docosahexaenoic acid (DHA) can substitue for 9-cis retinoic acid as an activator of RXR, then fish oils rich in DHA could potentially counteract the inhibitory action of apo14.It's possible that a compound like apo14 could also interfere with immune regulation in the gut, causing accumulation of inflammatory Th17 cells at the expense of anti-inflammatory Tregs (see my earlier posts this evening), perpetuating the inflammation, and eventually causing vitamin A deficiency (common in IBD and PSC). But a hypothesis should not be treated as fact. Rather it should be subject to critical research and experimentation to prove it is either right of wrong. Best regards,Dave (father of (22); PSC 07/03; UC 08/03)

[Guest guest]

Interesting. I eat about a carrot a day (about 150% of MDA), and the high-potency vitamin I've been taking since diagnosis contains 100% MDA of vitamin A. Between the two, I get 200-300% of vitamin A per day. Another factoid I ran across is that in adults, vitamin A reserves are stored in the liver, which may be a problem if your liver has decompensated (http://rnceus.com/ld/lddecomp.html).

Arne

56 - UC 1977, PSC 2000

Alive and (mostly) well in Minnesota

________________________________

From: [mailto: ] On Behalf Of

....beta-Carotene and its metabolites exert a broad range of effects...

[Guest guest]

I was wondering about vitamin A, too. My son had his levels checked

recently and his vitamin A level is too high even though he does not

take any vitamin supplement except for vitamin D with his calcium. He

did have a multivitamin pill a day until calcium+D was prescribed

about 2,5 years ago.

Taru-Mari (mother of Eemeli 10 yrs, PSC 07/2003)

>

> Interesting. I eat about a carrot a day (about 150% of MDA), and

the

> high-potency vitamin I've been taking since diagnosis contains 100%

MDA of

> vitamin A. Between the two, I get 200-300% of vitamin A per day.

Another

> factoid I ran across is that in adults, vitamin A reserves are

stored in the

> liver, which may be a problem if your liver has decompensated

> (http://rnceus.com/ld/lddecomp.html).

>

>

>

> Arne

> 56 - UC 1977, PSC 2000

> Alive and (mostly) well in Minnesota

[Guest guest]

Based on reading earlier threads on this web site, I started taking supplements of fish oil and vitamin D (2000 IU per day). But I wasn't sure that was enough (Von & Tim are taking 50,000 IU), so I asked my doctor if I could have my levels tested. My doctor said that its not a common test and figured the lab probably didn't offer test. I did some research and found out the lab would test the vitamin D levels. My doctor agree to the test and my level came back as 78 (normal considered between 40 and 250). Should I now have my Vitamin A levels tested?? Regardless of what my levels are now (or were when PSC symptoms appeared) some vitamin defiency may have been the trigger that started my problems (long before PSC symptoms appeared). I did have some weird skin rashes in my early twenties, the recommended cure was more sun (vitamin D).

Ian (51) PSC 89

Interesting. I eat about a carrot a day (about 150% of MDA), and the high-potency vitamin I've been taking since diagnosis contains 100% MDA of vitamin A. Between the two, I get 200-300% of vitamin A per day. Another factoid I ran across is that in adults, vitamin A reserves are stored in the liver, which may be a problem if your liver has decompensated (

http://rnceus.com/ld/lddecomp.html

).

Arne 56 - UC 1977, PSC 2000 Alive and (mostly) well in Minnesota

________________________________

From: [

mailto: ] On Behalf Of

....beta-Carotene and its metabolites exert a broad range of effects...

-- Ian Cribb P.Eng.

[Guest guest]

Hello Dave!

And hello everybody again after a summers break (allthough I peeked in few

times).

This is very interesting, what you wrote yesterday! In my opinion your

hypothesis touches

and ties together several of the potential major factors involved in the

different forms of

IBD and autoimmunic hepatic deseases: deranged anti-inflammatory mechanisms,

unbalance in gut bacteria, gut permeability and genetic pre-disposition.

Allow me to put some questions around this subject.

> I hypothesize that an as yet unidentified gut bacterium catalyzes

> asymetric cleavage of beta-carotene (the normal dietary source of

> vitamin A), to produce a retinoic acid derivative (apo14) that

> inhibits the retinoid X receptor:

Could this mean in other words, that an unbalance in bacterial flora in the gut

has a role in

the development of these deseases? That would partly explain the help some of us

get

from probiotics.

>

> Because the retinoid X receptor is required for the activity of a

> large number of other receptors in the liver, including PXR, PPARs,

> VDR, RAR, and FXR, its inhibition by a compound like apo14 would

> cause massive disruption of bile transport and detoxification, lipid

> metabolism, and vitamin D signaling.

Does this mean, that the lack of retinoid X receptor makes the bile to become

more toxic

and harmful for the liver?

> It's possible that a compound like apo14 could also interfere with

> immune regulation in the gut, causing accumulation of inflammatory

> Th17 cells at the expense of anti-inflammatory Tregs (see my earlier

> posts this evening), perpetuating the inflammation, and eventually

> causing vitamin A deficiency (common in IBD and PSC).

Could this partly explain the beneficial effect that medications like

prednisolone,

budenoside and azathioprine have in inflammatory bowel diseases and autoimmune

hepatic deseases, when they cut down the activity of T-cells in general?

Could this also mean, that Th17-cells turn against the cells of the gut lining

and so cause

gut permeability and open a pathway for harmful factors to enter the bile

circulation and

liver? And the reason for this damage is the wrong balance between these two

different T-

cells, the unnatural majority of Th-17 cells against Tregs?

These were propably not very clever questions, but dumb questions is better then

no

questions at all, I believe .

I got in August a suspected overlap diagnosis, AIH on the top of previous PSC

and UC,

based on higher transaminases and inflammation in liver biopsy. Recently started

with

budenoside and azathioprine medication (with previous sulfasalazine and UDCA).

Thats

why my own thoughts now circulate round such things you see in my questions.

Keen to see what comes out from your hypothesis, really exciting developement.

Best greetings,

, UC/small duct PSC 83, large duct psc 93, suspected AIH 2007

[Guest guest]

I had the same question, but only Judy can say " Love, Judy " !

Joanne H

(, Ca)

-- In , " Judith " wrote:

>

> Dave,

> Are you going to send this idea to a researcher? You should.

> Love, Judy

> ----- Original Message -----

> From:

[Guest guest]

----- Original Message -----From:

After reading the literature on PSC, IBD and immunology for the last 4

years, I would now like to propose a hypothesis on UC/PSC, based in

part on my two previous posts this evening.

IMHO next years $$$ award from PSC Partners to the best researcher

should go to !

Barb

[Guest guest]

Barb,

I am in total agreement. Dave has my vote!!!

Ricky

From:

[mailto: ] On Behalf

Of barbhenshaw@...

Sent: Sunday, September 09, 2007 5:58 PM

To:

Subject: Re: A hypothesis on UC/PSC

----- Original Message -----From:

After reading the literature on PSC, IBD and immunology for the last 4

years, I would now like to propose a hypothesis on UC/PSC, based in

part on my two previous posts this evening.

IMHO next years $$$ award from PSC Partners to the best researcher

should go to !

Barb

[Guest guest]

Hi ;

Your questions are not dumb at all! They are right on! I'm not sure

that I'll be able to answer them all at once, but I'll try to make a

start.

There is some evidence that there is altered bacterial flora in IBD;

see for e.g.

_______________

Gut. 2006 Dec;55(12):1760-7.

Gut-associated bacterial microbiota in paediatric patients with

inflammatory bowel disease.

Conte MP, Schippa S, Zamboni I, Penta M, Chiarini F, Seganti L,

Osborn J, Falconieri P, Borrelli O, Cucchiara S

Paediatric Gastroenterology Unit, University of Rome La Sapienza,

Viale Regina Elena 324, Rome 00161, Italy.

BACKGROUND: Clinical and experimental observations in animal models

indicate that intestinal commensal bacteria are involved in the

initiation and amplification of inflammatory bowel disease (IBD). No

paediatric reports are available on intestinal endogenous microflora

in IBD. AIMS: To investigate and characterise the predominant

composition of the mucosa-associated intestinal microflora in

colonoscopic biopsy specimens of paediatric patients with newly

diagnosed IBD. METHODS: Mucosa-associated bacteria were quantified

and isolated from biopsy specimens of the ileum, caecum and rectum

obtained at colonoscopy in 12 patients with Crohn's disease, 7 with

ulcerative colitis, 6 with indeterminate colitis, 10 with

lymphonodular hyperplasia of the distal ileum and in 7 controls.

Isolation and characterisation were carried out by conventional

culture techniques for aerobic and facultative-anaerobic

microorganisms, and molecular analysis (16S rRNA-based amplification

and real-time polymerase chain reaction assays) for the detection of

anaerobic bacterial groups or species. RESULTS: A higher number of

mucosa-associated aerobic and facultative-anaerobic bacteria were

found in biopsy specimens of children with IBD than in controls. An

overall decrease in some bacterial species or groups belonging to the

normal anaerobic intestinal flora was suggested by molecular

approaches; in particular, occurrence of Bacteroides vulgatus was low

in Crohn's disease, ulcerative colitis and indeterminate colitis

specimens. CONCLUSION: This is the first paediatric report

investigating the intestinal mucosa-associated microflora in patients

of the IBD spectrum. These results, although limited by the sample

size, allow a better understanding of changes in mucosa-associated

bacterial flora in these patients, showing either a predominance of

some potentially harmful bacterial groups or a decrease in beneficial

bacterial species. These data underline the central role of mucosa-

adherent bacteria in IBD. PMID: 16648155.

_______________

The idea behind probiotics is indeed that they may restore a more

normal balance of bacterial flora.

I'm specifically hypothesizing that if a bacterium in the gut made a

compound like apo14 that was an inhibitor of the retinoid X receptor

(RXR), it could specifically wreak havoc on bile transport and

detoxification processes.

I'd like to first point out a good reference on bile transport

systems in the liver, and their control by various nuclear receptors

(these receptors are sort of like switches that turn on and off the

expression of genes that encode bile transport systems and bile acid

detoxification systems). The article is:

Geier A, Wagner M, Dietrich CG, Trauner M 2007 Principles of hepatic

organic anion transporter regulation during cholestasis, inflammation

and liver regeneration. Biochim. Biophys. Acta 1773: 283-308.

I'll post the full text of this article as soon as I'm finished with

this message. This is a really difficult article to read, but it has

some useful illustrations .... several of these show the important

role played by the retinoid X receptor (RXR) in the control of

everything (sort of a 'master switch' if you like). When this

receptor is inactivated, or down-regulated, you would expect this to

have a huge effect on all of bile metabolism. For example, it would

prevent the pregnane X receptor (PXR) from working properly, and this

could lead to high levels of lithocholic acid and other toxic bile

acids. These toxic bile acids could cause bile duct injury, and may

contribute to increased risk of cholangiocarcinoma and colorectal

cancer. It is known that PXR is down-regulated in ulcerative colitis.

Because PXR is an inhibitor of nuclear factor kappa-B (NFkB) (and

vice-versa), then down-regulation of PXR would lead to upregulation

of NFkB, thereby promoting inflammation (as discussed in the article

on Inflammation and Cholestasis in one of our newsletters):

http://www.pscpartners.org/NewsVol-2-4.pdf

NFkB in turn activates tumor necrosis factor-alpha (TNFa) which

further promotes inflammation, and can induce a " leaky " mucosal

barrier:

________________

Ann N Y Acad Sci. 2006 Aug;1072:242-52.

Inflammatory bowel disease and the apical junctional complex.

Bruewer M, Samarin S, Nusrat A

Department of General Surgery, University of Muenster, Muenster

48149, Germany.

A critical function of the intestinal mucosa is to form a barrier

that separates luminal contents from the underlying interstitium.

This intestinal barrier is primarily regulated by the apical

junctional complex (AJC) consisting of tight junctions (TJs) and

adherens junctions (AJs) and is compromised in a number of intestinal

diseases, including inflammatory bowel disease (IBD). In vitro

studies have demonstrated that proinflammatory cytokines, such as

interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-

alpha), that are increased in the intestinal mucosa of patients with

IBD can induce a leaky mucosal barrier. There is a growing evidence

that the increased permeability and altered AJC structure observed in

IBD are mediated by internalization of junctional proteins. This

review summarizes barrier defects observed in IBD and addresses

mechanisms by which proinflammatory cytokines, such as IFN-gamma and

TNF-alpha, modulate AJC structure and epithelial barrier function.

PMID: 17057204.

_________________

Both NFkB and TNFa are upregulated in inflammatory bowel diseases.

Since RXR forms dimers with a lot of the other receptors in the

liver, including the vitamin D receptor, RXR inactivation or down-

regulation could disturb vitamin D signaling, perhaps contributing to

metabolic bone disease in PSC and UC.

I'm further hypothesizing that a compound like apo14 might also

disturb the balance of pro-inflammatory Th cells versus anti-

inflammatory regulatory T cells in the gut. The papers I mentioned

yesterday indicate that the vitamin A metabolite, retinoic acid,

suppresses pro-inflammatory Th17 cells, and promotes anti-

inflammatory Tregs. If a compound like apo14 promoted accumulation of

Th17 cells in the gut, then these cells would start cranking out pro-

inflammatory cytokines like interleukin-17 which would further

stimulate inflammation, resulting in more TNF-a and more mucosal

damage. Eventually, such uncontrolled inflammation could lead to

bacteria entering the bile ducts, and cholangitis.

It is likely that dendritic cells in the gut are the ones that are

initially responding to bacterial products. When the NFkB of these

dendritic cells is activated, these cells than produce

proinflammatory cytokines like interleukin-12 and interleukin-23.

Production of interleukin-23 would represent a major stimulus for

Th17 cells, especially in the absence of retinoic acid. This is

described in our last newsletter:

Commentary on Recent Genetic Studies

http://www.pscpartners.org/NewsVol-3-1.pdf

As I understand it, a major mechanism of action of immunosuppressants

like corticosteroids, is down-regulation of NFkB, and therefore the

suppression of inflammation.

I hope this answers at least some of your questions

Best regards,

Dave

(father of (22); PSC 07/03; UC 08/03)

[Guest guest]

Hi Ian;

I've probably posted this before, but this paper indicates that

vitamin A deficiency is actually the most common fat-soluble vitamin

deficieny in PSC, and so it might be worth testing for:

J Clin Gastroenterol. 1995 Apr;20(3):215-9.

Serum lipid and fat-soluble vitamin levels in primary sclerosing

cholangitis.

nsen RA, Lindor KD, Sartin JS, LaRusso NF, Wiesner RH

Mayo Clinic, Rochester, MN 55905, USA.

We reviewed the initial lipid and fat-soluble vitamin levels in 56

patients with primary sclerosing cholangitis (PSC) enrolled in a

randomized, placebo-controlled trial evaluating ursodeoxycholic acid.

We also evaluated lipid and vitamin levels in a group of 87 patients

with advanced PSC being evaluated for liver transplantation. Of the

patients entering the therapeutic trial, 41% had total serum

cholesterol levels greater than the 95th percentile, whereas only 20%

had high-density lipoprotein cholesterol levels above normal, and

only one (2%) had an elevated triglyceride level. Total cholesterol

levels were correlated with serum bilirubin levels and were lower in

early versus later histologic stages (206 +/- 61 vs. 248 +/- 79, p =

0.04). Of the 87 pretransplant patients, 29% had elevated serum

cholesterol levels and 17% had elevated serum triglyceride levels.

Total serum cholesterol levels correlated inversely with total serum

bilirubin levels in this group. In patients in the therapeutic trial,

vitamin A deficiency was seen in 40%, vitamin D deficiency in 14%,

and vitamin E deficiency in 2% of those tested. More prominent

deficiencies of fat-soluble vitamins occurred in the pretransplant

group of patients, with 82% deficient in vitamin A, 57% deficient in

vitamin D, and 43% deficient in vitamin E. We conclude that

hypercholesterolemia and fat-soluble vitamin deficiencies are

frequent in patients with PSC and are more common with more severe

disease. Patients with PSC, especially with advanced liver disease,

should be screened for fat-soluble vitamin deficiencies and

supplemented accordingly. PMID: 7797830.

But as Von pointed out, excessive levels can be toxic to the liver,

so you don't want to over do vitamin A supplements!

You might also take a look at the file called " Nutrition.pdf "

http://health.groups.yahoo.com/group//files/Research/

in the files/Research folder. This article (Alnounou M, Munoz SJ

(2006) Nutrition Concerns of the Patient with Primary Biliary

Cirrhosis or Primary Sclerosing Cholangitis. NUTRITION ISSUES IN

GASTROENTEROLOGY, SERIES #37 PRACTICAL GASTROENTEROLOGY • APRIL 2006,

p 92-100.) has a lot of useful information on vitamin deficiency

issues in PBC and PSC.

I find it interesting that the American Liver Foundation has just

funded a large grant on retinoic acid and ursodeoxycholic acid

therapy in PBC (but I don't know anything more about this grant other

than the title!)

http://pbcers.org/ALFgrants.htm

2007

Shi-Ying Cai, PhD, Yale University School of Medicine received

$200,000 over 2 years for Ursodeoxyclolic Acid and Retinoic Acid

Combination Treatment for Primary Biliary Cirrhosis

Best regards,

Dave

> Should I now have my Vitamin A levels tested??

[Guest guest]

Go Dave Go !!

It sounds like you are on the right track so keep racing !

I'm sure you have all our votes, we believe in you!

Lee

[Guest guest]

Hi ,

and thank you for your answers. It seems to me, that the bacterial unbalance

could be

important specially in the initial phase of UC. My own experience from late 70's

in the time

before my UC diagnosis in '83 at least definitely points that way.

The austrian paper is indeed quite tricky, but I think I got the big picture and

I will take a

closer look at it.

And those other papers indeed strongly point to the direction of TH17 cells and

interleukins.

So let's follow, what is coming from this hypothesis. Do you have any idea, what

kind of

medical researchis going on in this field? Or any strategies to get more

research in this

direction?

Best greetings,

>

> Hi ;

>

> Your questions are not dumb at all! They are right on! I'm not sure

> that I'll be able to answer them all at once, but I'll try to make a

> start.

>

> There is some evidence that there is altered bacterial flora in IBD;

> see for e.g.

> _______________

>

> Gut. 2006 Dec;55(12):1760-7.

[Guest guest]

Hi ;

Perhaps the simplest approach would be to write this hypothesis up in

the PSC Partners Seeking a Cure Newsletter, with all the " i's " dotted

and " t's " crossed, with illustrations, and complete reference

citations. Some researchers have been reading our newsletter, and we

havn't received any negative feedback on its contents (yet). Perhaps

once the article is written, it could then be mailed to certain

researchers who have an interest in retinoic acid and the control of

bile transport systems, and researchers interested in the role of

retinoic acid in T cell development and " gut homing " and IBD? Supposing

that the ideas are not " shot down " by said researchers, then perhaps it

could be fleshed out further in a paper submitted to a peer-reviewed

Journal like " Medical Hypotheses " to reach a broader audience? I think

it is a bit premature yet to ask any researcher to pursue this line of

study, but it's O.K. to get the idea out there and subject to critical

comments and discussion, or ridicule. Perhaps in the next few months

some further research will be published which is either consistent or

inconsistent with the ideas?

But, I should add that it would not be a good idea for anyone to start

taking vitamin A supplements without having their doctor's O.K. I do

need to mention again that vitamin A excess can be toxic, and it can be

particularly toxic when taken with alcohol:

______________

Nat Rev Cancer. 2007 Aug;7(8):599-612.

Molecular mechanisms of alcohol-mediated carcinogenesis.

Seitz HK, Stickel F

Department of Medicine and Laboratory of Alcohol Research, Liver

Disease and Nutrition, Salem Medical Centre, University of Heidelberg,

Heidelberg, Germany. helmut_karl.seitz@...

Approximately 3.6% of cancers worldwide derive from chronic alcohol

drinking, including those of the upper aerodigestive tract, the liver,

the colorectum and the breast. Although the mechanisms for alcohol-

associated carcinogenesis are not completely understood, most recent

research has focused on acetaldehyde, the first and most toxic ethanol

metabolite, as a cancer-causing agent. Ethanol may also stimulate

carcinogenesis by inhibiting DNA methylation and by interacting with

retinoid metabolism. Alcohol-related carcinogenesis may interact with

other factors such as smoking, diet and comorbidities, and depends on

genetic susceptibility. PMID: 17646865.

______________

So here's yet another interaction with retinoid metabolism that needs

to be taken into account. Retinoids and alcohol don't mix well in terms

of cancer risk, and could potentially further increase cancer risk in

PSC patients!

Yes, if you are found to have a deficiency in vitamin A, do take

supplements according to your doctor's directions, but please don't mix

these with alcohol.

Best regards,

Dave

(father of (22); PSC 07/03; UC 08/03)

>

> So let's follow, what is coming from this hypothesis. Do you have any

idea, what kind of medical research is going on in this field? Or any

strategies to get more research in this direction?

[Guest guest]

Do you recommend taking fish-oil high in HDA?

Chaim Boermeester, Israel

[Guest guest]

Hi ,

I once more try to simplify for me the " evil chain " described in your hypothesis

to check, if

I have understud the things correctly. I use kind of a C.I.A Miami setting with

characters to

get a story to follow easily. In Finland we had lot of old sequencies of that

TV-serie going

on this summer.?

The damage in PSC in the biliary system inside the liver and in the biliary tree

is caused by

the " bile turning bad " . The guys responsible to keep the bile clean and good are

very much

the receptors PXR, PPARs, VDR, RAR, and FXR. The main man for these receptors,

kind of a

controller or boss, is retinoid X receptor.

Apo14 is the bad guy, who beats down the good boss, retinoid X receptor. The

growth of

this apo14-population is made possible by asymmetric cleavage of betacarotene.

Betacarotene so to say turns bad, becomes apo14 (among other apocarotenals)

instead of

good ( 9-cisRA).

But who is the guy making betacarotene turn bad? That is the question. And your

hypothesis is, that he is this " yet unknown bacteria " .

Apo14 could also be responsible to make T-cells go crazy, or actually in letting

the Th17-

cells become too many. Th17-cells have important things to do, but if they are

too many,

it is bad, and there should be enough Treg-cells to fix the job properly.

------------------------

I was rereading several of your recent posts and try now to put some more

questions

hoping, that they could be helpful in some way.

A-vitamin deficiency in IBD is propably measured in the blood and according to

the

hypothesis more likely due to reasons of lack in absorption then lack in the

nutrition?

The same goes for PSC.

There seems to be some variation in PSC. Some times with UC, sometimes without.

Sometimes with other autoimmune diseases, sometimes without. Sometimes more

vigorous, sometimes less. I would think, that this " apo14-mechanism " could be

responsible in several different variants. Our bodies are though different, some

have

" stronger guts " , that can fight the attack, but the biliary system gets easier

attacked, and

vice versa.

But could the immunological attack on the system come sometimes another way?

Endresult probably would be the same, even if the reason would be different?

And sometimes the UC gets very calm and the gut almost normal, but the PSC goes

on

slowly. When the system is out of balance, it is very hard to get back.

Some keys fit better then others, when we try to find the right way towards a

cure. The

cure could be also a combination of different things, like it seems to be for

many of us.

But your hypothesis seems like a strong, good key for major questions.

Not necessary to answer all these questions, I was asking them, because the more

questions, the more you can find angles to shed light on these matters.

I will put another mail about that research-theme, sorry about the length of

this one. But I

find this really interesting ?.

Best greetings

[Guest guest]

Hi ,

some comments on this research theme.

I think PSC Partners Seeking a Cure News is a fine idea. Just doing like you say

it, getting it

well in right shape with references and other material. And propably stressing

out, that

this is a hypothesis to be checked, so that none of us non-scholars start to

think, that this

is how it is.

And then get an opinion from some scholars to test the logic in the conclusions,

that

would be important, I believe. Is this a step before getting it to these people

-

>certain researchers who have an interest in retinoic acid and the control of

> bile transport systems, and researchers interested in the role of

> retinoic acid in T cell development and " gut homing " and IBD?

- maybe.

With this following I definitely agree:

>I think

> it is a bit premature yet to ask any researcher to pursue this line of

> study, but it's O.K. to get the idea out there and subject to critical

> comments and discussion, or ridicule.

But only by asking the questions we get the answers. With this question one

should

proceed (they may be on the track already, like you say.) If somebody says, this

is a stupid

question and tells us why, then we know. But if somebody with the help of this

question

finds substantial help for this desease - what a great thing it would be.

Wishing all the best,

> >

> > So let's follow, what is coming from this hypothesis. Do you have any

> idea, what kind of medical research is going on in this field? Or any

> strategies to get more research in this direction?

>

[Guest guest]

Sorry, some unwanted questionmarks in this earlier mail due to copying from

Word.

>

> Hi ,

>....

> I once more try to simplify for me the " evil chain " described in your

hypothesis to check,

> on this summer.?

.... angles to shed light on these matters.

> I will put another mail about that research-theme, sorry about the length of

this one. But I

> find this really interesting ?.

[Guest guest]

Hi ;

I like your " evil chain " theme and C.I.A. Miami analogy. I think you

have pretty much grasped the main points ... I'm trying to think of a

way that one " bad-guy " might cause some of the features of both

ulcerative colitis (UC) and PSC ... and a disturbance in normal

retinoic acid metabolism might fit the bill.

Vitamin A is formed mostly in the gut from dietary beta-carotene,

giving rise to retinoic acid and 9-cis retinoic acid. Retinoic acid

keeps the pro-inflammatory Th17 cell population low, and favors the

accumulation of anti-inflammatory regulatory T cells (Tregs)

with " gut-homing " properties. 9-cis Retinoic acid maintains activity

of several of the receptors that keep bile metabolism and transport

working in the liver (via RXR). So inhibition of Treg formation and

inhibition of bile transport and metabolism might possibly result in

both gut inflammation (UC) and liver damage (PSC). Likely, the gut

inflammation could be controlled by corticosteroids, but not the

liver damage. And the prediction would be that the liver damage due

to inhibition of RXR would be more severe in males than in females:

Cai Y, Dai T, Ao Y, Konishi T, Chuang KH, Lue Y, Chang C,

Wan YJ 2003 Cytochrome P450 genes are differentially expressed

in female and male hepatocyte retinoid X receptor alpha-deficient

mice. Endocrinology 144: 2311-2318.

But it is difficult to know whether this could all be brought about

simply by vitamin A deficiency, or might be triggered by a bacterium,

or something else? Perhaps there are several mechanisms that we don't

yet understand. Certainly the recent association of IBD with the use

of isotretinoin (accutane) a retinoic acid analog used for the

treatment of acne, hints that IBD can be caused by ingesting a

foreign retinoid:

Reddy D, Siegel CA, Sands BE, Kane S (2006) Possible association

between isotretinoin and inflammatory bowel disease. Am. J.

Gastroenterol. 101: 1569-1573.

We can't rule out that oral isotretinoin may not itself be toxic but

is metabolized to a more active inhibitor by gut associated bacteria.

Then there is the business of " genetic susceptibility " . Perhaps those

individuals with an altered level of PXR, RXR, IL-23, or IL-17, or

tumor necrosis factor [or a host of other genetic factors], would be

more susceptible to this " evil chain " .

Best regards,

Dave

(father of (22); PSC 07/03)

[Guest guest]

Hi , and thank you for your answers. And happy to hear, that you liked the

C.I.A.

Miami allegory . I still put some comments, all though maybe is about time

for me to

take a rest from this topic, before you and everybody else gets drowned by my

questions

and comments.

>

> Hi ;

>

> I like your " evil chain " theme and C.I.A. Miami analogy. I think you

> have pretty much grasped the main points ... I'm trying to think of a

> way that one " bad-guy " might cause some of the features of both

> ulcerative colitis (UC) and PSC ... and a disturbance in normal

> retinoic acid metabolism might fit the bill.

I was thinking little bit the other possibilities: could one also think, that

PSC allways is

something, that follows UC or Morbus Crohn or other similar, but milder

conditions? Even

though there are cases of PSC where the patients do not have IBD (and of IBD

without PSC),

it could be, that there is some kind of damage on the gut in any case. The

damage is not

that strong, that it can give reason for a IBD diagnosis, but strong enough to

break te

protective barrier of the gut and in that way to let the damage in the liver and

in the biliary

system to happen.

Genetic differences then explain the differences in different variations of

PSC/IBD. But

despite all this, in research one will have to make the choice of which line to

follow and

the idea of one factor, the " bad-guy " disturbing the retinoic acid metabolism

indeed

sounds a likely and good candidate. This is a line, which indeed should be

followed to

clear the role of one factor. And the different desease types due to genetic

differences can

also be explained that way also in this case.

>

> Vitamin A is formed mostly in the gut from dietary beta-carotene,

> giving rise to retinoic acid and 9-cis retinoic acid. Retinoic acid

> keeps the pro-inflammatory Th17 cell population low, and favors the

> accumulation of anti-inflammatory regulatory T cells (Tregs)

> with " gut-homing " properties. 9-cis Retinoic acid maintains activity

> of several of the receptors that keep bile metabolism and transport

> working in the liver (via RXR). So inhibition of Treg formation and

> inhibition of bile transport and metabolism might possibly result in

> both gut inflammation (UC) and liver damage (PSC). Likely, the gut

> inflammation could be controlled by corticosteroids, but not the

> liver damage.

With this I am in interesting situation personally taking corticosteroids

(after the AIH

overlap diagnosis) and waiting, if the corticosteroid medication will pull the

hepatic

inflammation down. Not that I am specially happy to having got the AIH overlap

as a

" bonus-track " so to say.

And the prediction would be that the liver damage due

> to inhibition of RXR would be more severe in males than in females:

>

> Cai Y, Dai T, Ao Y, Konishi T, Chuang KH, Lue Y, Chang C,

> Wan YJ 2003 Cytochrome P450 genes are differentially expressed

> in female and male hepatocyte retinoid X receptor alpha-deficient

> mice. Endocrinology 144: 2311-2318.

Interesting. Could there be something similar behind PBC, which is more common

in

females then males? Or something different, which then would cast more light on

the PSC-

mechanism?

>

> But it is difficult to know whether this could all be brought about

> simply by vitamin A deficiency, or might be triggered by a bacterium,

> or something else? Perhaps there are several mechanisms that we don't

> yet understand. Certainly the recent association of IBD with the use

> of isotretinoin (accutane) a retinoic acid analog used for the

> treatment of acne, hints that IBD can be caused by ingesting a

> foreign retinoid:

>

> Reddy D, Siegel CA, Sands BE, Kane S (2006) Possible association

> between isotretinoin and inflammatory bowel disease. Am. J.

> Gastroenterol. 101: 1569-1573.

>

> We can't rule out that oral isotretinoin may not itself be toxic but

> is metabolized to a more active inhibitor by gut associated bacteria.

>

> Then there is the business of " genetic susceptibility " . Perhaps those

> individuals with an altered level of PXR, RXR, IL-23, or IL-17, or

> tumor necrosis factor [or a host of other genetic factors], would be

> more susceptible to this " evil chain " .

>

> Best regards,

>

> Dave

> (father of (22); PSC 07/03)

>

I found the following article interesting, because the role of bacterial

inflammation as a

tgriggering factor in UC is partly taken under discussion here. It also mentions

the role of

more common use of antibiotics as a new factor, which has changed globally and

specially

in western societis during the last decades. As a factor strongly affecting

bacterial balance

in the gut it also could partly explain the increase of IBD (and PSC) in the

western societies.

Something that in my opinion would also fit the theory about the role of the

unbalance of

the retinoid metabolism due to wrong kind of bacteria in the gut.

Best greetings,

BMC Gastroenterol. 2005; 5: 3.

Published online 2005 January 24. doi: 10.1186/1471-230X-5-3.

Copyright © 2005 Miner et al; licensee BioMed Central Ltd.

Steroid-refractory ulcerative colitis treated with corticosteroids,

metronidazole and

vancomycin: a case report

Miner,1,2 M Monem Gillan,2 Philip ,1,2 and Centola1,2

1University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104 USA

2Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104 USA

Corresponding author.

Miner: Jminer@...; M Monem Gillan: mmgillan@...; Philip

:

palex@...; Centola: centolam@...

Received April 20, 2004; Accepted January 24, 2005.

This is an Open Access article distributed under the terms of the Creative

Commons

Attribution License (http://creativecommons.org/licenses/by/2.0), which permits

unrestricted use, distribution, and reproduction in any medium, provided the

original work

is properly cited.

Abstract

Background

Increasing evidence elucidating the pathogenic mechanisms of ulcerative colitis

(UC) has

accumulated and the disease is widely assumed to be the consequence of genetic

susceptibility and an abnormal immune response to commensal bacteria. However

evidence regarding an infectious etiology in UC remains elusive.

Case presentation

We report a provocative case of UC with profound rheumatologic involvement

directly

preceded by Clostridium difficile infection and accompanying fever, vomiting,

bloody

diarrhea, and arthritis. Colonic biopsy revealed a histopathology suggestive of

UC.

Antibiotic treatment eliminated detectable levels of enteric pathogens but did

not abate

symptoms. Resolution of symptoms was procurable with oral prednisone, but

tapering of

corticosteroids was only achievable in combination therapy with vancomycin and

metronidazole.

Conclusions

An infectious pathogen may have both precipitated and exacerbated autoimmune

disease

attributes in UC, symptoms of which could be resolved only with a combination of

corticosteroids, vancomycin and metronidazole. This may warrant the need for

more

perceptive scrutiny of C. difficile and the like in patients with UC.