Re: Re: Article on Vitamin D

[Guest guest]

I think that there would be a lot of negation in the science community to that article. But I think it is important that we maintain hethy d levels. I remember reading once (a few years ago) that mesalamine meds tend to lower folic acid levels. I wish I had copies of all the articles I have ever read. I wonder if for some reason the treatment of CD or UC tends to lower vitamin levels. ShaulPSC UCSent via BlackBerry by AT&TFrom: "shawnee618" Date: Mon, 29 Dec 2008 16:08:51 -0000To: < >Subject: Re: Article on Vitamin D I am having trouble with Adobe right now, so I can't read it yet. However, after breastfeeding 4 kids I have done a fair amount of research on how to get vitamin D, and why we are lacking in it in recent years. One major cause is the American diet, as well as the dangers of sunlight and the avoidance of exposure. It's true that a well balanced diet, complete with all nutritional requirements, should not leave one lacking in Vit D, but how many of us really get that? As for suppressing my immune system, I have Crohn's which is caused by an over active immune system. Logic seems to say this would noet be so detrimental to me. In fact, my CD went into overdrive several years back when I was taking supplements to *boost* my immune system (before I knew I had CD). And if Vit D deficiencies are the result of disease, not the cause, well then what the author propose we do for that? It would be nice if we could just erase PSC huh? ee > > http://trevormarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf > > This is a a somewhat contrarian article about vitamin D... it seems to > be saying that vitamin D suppresses the immune system, among a lot of > other things that run counter to current thought about vitamin D (such > as that sunlight isn't necessary for adequate vitamin D levels, and > neither are supplements, and that low vitamin D levels are the result of > disease, not a cause and that supplements just make things worse!) > > I tend to think that I'll need to see a lot more evidence to convince me > that he's right, since there seems to be a lot of evidence to the > contrary, but I would be be interested in any thoughts about it > (especially from , who can probably understand it much > better than I can! > > athan >

[Guest guest]

I think that there would be a lot of negation in the science community to that article. But I think it is important that we maintain hethy d levels. I remember reading once (a few years ago) that mesalamine meds tend to lower folic acid levels. I wish I had copies of all the articles I have ever read. I wonder if for some reason the treatment of CD or UC tends to lower vitamin levels. ShaulPSC UCSent via BlackBerry by AT&TFrom: "shawnee618" Date: Mon, 29 Dec 2008 16:08:51 -0000To: < >Subject: Re: Article on Vitamin D I am having trouble with Adobe right now, so I can't read it yet. However, after breastfeeding 4 kids I have done a fair amount of research on how to get vitamin D, and why we are lacking in it in recent years. One major cause is the American diet, as well as the dangers of sunlight and the avoidance of exposure. It's true that a well balanced diet, complete with all nutritional requirements, should not leave one lacking in Vit D, but how many of us really get that? As for suppressing my immune system, I have Crohn's which is caused by an over active immune system. Logic seems to say this would noet be so detrimental to me. In fact, my CD went into overdrive several years back when I was taking supplements to *boost* my immune system (before I knew I had CD). And if Vit D deficiencies are the result of disease, not the cause, well then what the author propose we do for that? It would be nice if we could just erase PSC huh? ee > > http://trevormarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf > > This is a a somewhat contrarian article about vitamin D... it seems to > be saying that vitamin D suppresses the immune system, among a lot of > other things that run counter to current thought about vitamin D (such > as that sunlight isn't necessary for adequate vitamin D levels, and > neither are supplements, and that low vitamin D levels are the result of > disease, not a cause and that supplements just make things worse!) > > I tend to think that I'll need to see a lot more evidence to convince me > that he's right, since there seems to be a lot of evidence to the > contrary, but I would be be interested in any thoughts about it > (especially from , who can probably understand it much > better than I can! > > athan >

[Guest guest]

I think that there would be a lot of negation in the science community to that article. But I think it is important that we maintain hethy d levels. I remember reading once (a few years ago) that mesalamine meds tend to lower folic acid levels. I wish I had copies of all the articles I have ever read. I wonder if for some reason the treatment of CD or UC tends to lower vitamin levels. ShaulPSC UCSent via BlackBerry by AT&TFrom: "shawnee618" Date: Mon, 29 Dec 2008 16:08:51 -0000To: < >Subject: Re: Article on Vitamin D I am having trouble with Adobe right now, so I can't read it yet. However, after breastfeeding 4 kids I have done a fair amount of research on how to get vitamin D, and why we are lacking in it in recent years. One major cause is the American diet, as well as the dangers of sunlight and the avoidance of exposure. It's true that a well balanced diet, complete with all nutritional requirements, should not leave one lacking in Vit D, but how many of us really get that? As for suppressing my immune system, I have Crohn's which is caused by an over active immune system. Logic seems to say this would noet be so detrimental to me. In fact, my CD went into overdrive several years back when I was taking supplements to *boost* my immune system (before I knew I had CD). And if Vit D deficiencies are the result of disease, not the cause, well then what the author propose we do for that? It would be nice if we could just erase PSC huh? ee > > http://trevormarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf > > This is a a somewhat contrarian article about vitamin D... it seems to > be saying that vitamin D suppresses the immune system, among a lot of > other things that run counter to current thought about vitamin D (such > as that sunlight isn't necessary for adequate vitamin D levels, and > neither are supplements, and that low vitamin D levels are the result of > disease, not a cause and that supplements just make things worse!) > > I tend to think that I'll need to see a lot more evidence to convince me > that he's right, since there seems to be a lot of evidence to the > contrary, but I would be be interested in any thoughts about it > (especially from , who can probably understand it much > better than I can! > > athan >

[Guest guest]

There are conflicting arguments on both sides of a lot of things (drinking coffee, drinking wine, political parties, religion, evolution, global warming, etc.), One tends to pick your side and figure the other side is manipulating facts, manufacturing fake facts or ignoring the facts.

Ian

I think that there would be a lot of negation in the science community to that article. But I think it is important that we maintain hethy d levels. I remember reading once (a few years ago) that mesalamine meds tend to lower folic acid levels. I wish I had copies of all the articles I have ever read. I wonder if for some reason the treatment of CD or UC tends to lower vitamin levels.

ShaulPSC UCSent via BlackBerry by AT & TFrom: " shawnee618 " Date: Mon, 29 Dec 2008 16:08:51 -0000

To: < >Subject: Re: Article on Vitamin D

I am having trouble with Adobe right now, so I can't read it yet. However, after breastfeeding 4 kids I have done a fair amount of research on how to get vitamin D, and why we are lacking in it in

recent years. One major cause is the American diet, as well as the dangers of sunlight and the avoidance of exposure. It's true that a well balanced diet, complete with all nutritional requirements, should

not leave one lacking in Vit D, but how many of us really get that? As for suppressing my immune system, I have Crohn's which is caused by an over active immune system. Logic seems to say this would noet be so

detrimental to me. In fact, my CD went into overdrive several years back when I was taking supplements to *boost* my immune system (before I knew I had CD). And if Vit D deficiencies are the result of disease,

not the cause, well then what the author propose we do for that? It would be nice if we could just erase PSC huh? ee > > http://trevormarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf > > This is a a somewhat contrarian article about vitamin D... it seems to

> be saying that vitamin D suppresses the immune system, among a lot of > other things that run counter to current thought about vitamin D (such > as that sunlight isn't necessary for adequate vitamin D levels, and

> neither are supplements, and that low vitamin D levels are the result of > disease, not a cause and that supplements just make things worse!) > > I tend to think that I'll need to see a lot more evidence to

convince me > that he's right, since there seems to be a lot of evidence to the > contrary, but I would be be interested in any thoughts about it > (especially from , who can probably understand it much

> better than I can! > > athan >

-- Ian Cribb P.Eng.

[Guest guest]

There are conflicting arguments on both sides of a lot of things (drinking coffee, drinking wine, political parties, religion, evolution, global warming, etc.), One tends to pick your side and figure the other side is manipulating facts, manufacturing fake facts or ignoring the facts.

Ian

I think that there would be a lot of negation in the science community to that article. But I think it is important that we maintain hethy d levels. I remember reading once (a few years ago) that mesalamine meds tend to lower folic acid levels. I wish I had copies of all the articles I have ever read. I wonder if for some reason the treatment of CD or UC tends to lower vitamin levels.

ShaulPSC UCSent via BlackBerry by AT & TFrom: " shawnee618 " Date: Mon, 29 Dec 2008 16:08:51 -0000

To: < >Subject: Re: Article on Vitamin D

I am having trouble with Adobe right now, so I can't read it yet. However, after breastfeeding 4 kids I have done a fair amount of research on how to get vitamin D, and why we are lacking in it in

recent years. One major cause is the American diet, as well as the dangers of sunlight and the avoidance of exposure. It's true that a well balanced diet, complete with all nutritional requirements, should

not leave one lacking in Vit D, but how many of us really get that? As for suppressing my immune system, I have Crohn's which is caused by an over active immune system. Logic seems to say this would noet be so

detrimental to me. In fact, my CD went into overdrive several years back when I was taking supplements to *boost* my immune system (before I knew I had CD). And if Vit D deficiencies are the result of disease,

not the cause, well then what the author propose we do for that? It would be nice if we could just erase PSC huh? ee > > http://trevormarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf > > This is a a somewhat contrarian article about vitamin D... it seems to

> be saying that vitamin D suppresses the immune system, among a lot of > other things that run counter to current thought about vitamin D (such > as that sunlight isn't necessary for adequate vitamin D levels, and

> neither are supplements, and that low vitamin D levels are the result of > disease, not a cause and that supplements just make things worse!) > > I tend to think that I'll need to see a lot more evidence to

convince me > that he's right, since there seems to be a lot of evidence to the > contrary, but I would be be interested in any thoughts about it > (especially from , who can probably understand it much

> better than I can! > > athan >

-- Ian Cribb P.Eng.

[Guest guest]

There are conflicting arguments on both sides of a lot of things (drinking coffee, drinking wine, political parties, religion, evolution, global warming, etc.), One tends to pick your side and figure the other side is manipulating facts, manufacturing fake facts or ignoring the facts.

Ian

I think that there would be a lot of negation in the science community to that article. But I think it is important that we maintain hethy d levels. I remember reading once (a few years ago) that mesalamine meds tend to lower folic acid levels. I wish I had copies of all the articles I have ever read. I wonder if for some reason the treatment of CD or UC tends to lower vitamin levels.

ShaulPSC UCSent via BlackBerry by AT & TFrom: " shawnee618 " Date: Mon, 29 Dec 2008 16:08:51 -0000

To: < >Subject: Re: Article on Vitamin D

I am having trouble with Adobe right now, so I can't read it yet. However, after breastfeeding 4 kids I have done a fair amount of research on how to get vitamin D, and why we are lacking in it in

recent years. One major cause is the American diet, as well as the dangers of sunlight and the avoidance of exposure. It's true that a well balanced diet, complete with all nutritional requirements, should

not leave one lacking in Vit D, but how many of us really get that? As for suppressing my immune system, I have Crohn's which is caused by an over active immune system. Logic seems to say this would noet be so

detrimental to me. In fact, my CD went into overdrive several years back when I was taking supplements to *boost* my immune system (before I knew I had CD). And if Vit D deficiencies are the result of disease,

not the cause, well then what the author propose we do for that? It would be nice if we could just erase PSC huh? ee > > http://trevormarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf > > This is a a somewhat contrarian article about vitamin D... it seems to

> be saying that vitamin D suppresses the immune system, among a lot of > other things that run counter to current thought about vitamin D (such > as that sunlight isn't necessary for adequate vitamin D levels, and

> neither are supplements, and that low vitamin D levels are the result of > disease, not a cause and that supplements just make things worse!) > > I tend to think that I'll need to see a lot more evidence to

convince me > that he's right, since there seems to be a lot of evidence to the > contrary, but I would be be interested in any thoughts about it > (especially from , who can probably understand it much

> better than I can! > > athan >

-- Ian Cribb P.Eng.

[Guest guest]

,

Thanks very much for explaining all of that! Wow, It will take awhile for me to absorb. What a blessing it is to have your help.

Lori A.

"Aggressively Pursuing Solutions To Your Real Estate Needs!"

First Weber Group

Cell:

1507 E. Sunset Drive

Waukesha, WI 53189

LoriUSA@...

www.Lori.FirstWeber.com

To: Sent: Tuesday, December 30, 2008 10:39:35 PMSubject: Re: Article on Vitamin D

>> http://trevormarsha ll.com/BioEssays -Feb08-Marshall- Preprint. pdf> > I would be be interested in any thoughts about it Hi athan;There are some things in the article by Trevor Marshall that I do agree with, and others that I don't. I'll try to explain as best as I can, and I hope that I don't loose you (and other readers) in the process.First, I do agree that vitamin D is not only a vitamin, but also an important hormone with lots of biological effects, including causing changes in the expression of a huge number of genes. The number of changes in gene

expression regulated by the active metabolite (1,25-dihydroxyvitamin D) binding to the vitamin D receptor (VDR) is much too large for the human brain to comprehend .... we need a computer model of all the interactions to begin to accurately predict all the biological responses.Because vitamin A (retinol) does something similar ... i.e. is metabolized in two steps to compounds (retinoic acids) that bind to receptors (retinoic acid receptor (RAR) and retinoid X receptor (RXR)) that then bind to a whole bunch of other receptors (including VDR, PXR, LXR, PPAR) that affect expression of a multitude of genes .... shouldn't we also call vitamin A a hormone? And why stop there, since beta-carotene is metabolized in 2 steps to retinoic acid, should we call carrots a hormone? And since docosahexaenoic acid (DHA) (found in fish oil) binds to RXR and PPAR, causing a large number of changes in gene

expression, should we call DHA a hormone? Shouldn't FDA also be regulating how many carrots we eat or how much fish we eat, or fish oil supplements we take? The bottom line is that a lot of nutrients have a marked effect on gene expression, and there is not really a need to single-out vitamin D.Second, I do agree that low values of 25-hydroxyvitamin D (the form of vitamin D that is usually measured) CAN be the result of the disease process. In the case of inflammatory bowel disease and cholestatic liver diseases like PSC and PBC, there is good evidence that absorption of vitamin D from the digestive system is impaired. In the case of inflammatory bowel disease the level of 25-hydroxyvitamin D (the main storage form of vitamin D) tends to be reduced, and this level correlates with bone mineral density (especially in males). Not surprisingly, then, supplementation with vitamin D (and calcium)

tends to rectify the metabolic bone disease associated with IBD. This would not be expected if you believe everything said in the Marshall article! Could vitamin D deficiency tend to make the disease worse? Sure! Because vitamin D plays an important role not only in bone metabolism and the immune system (including how T cells migrate to various sites in the body, and how much anti-bacterial peptides are produced, and how strong the epithelial barrier is in the gut, and how much of the inflammatory cytokine tumor necrosis factor alpha is produced), deficiency of vitamin D would not be good for you in the long run. Similarly, prolonged vitamin A deficiency would not be good for you because vitamin A also regulates how and where T cells migrate, how strong the epithelial barrier is in the gut, and how much IgA is produced in the gut. The best way to rectify any deficiencies is through

supplementation .... and I am certainly all for this except that this has to be done with caution to avoid potential toxicity from over-doses. The article by Trevor Marshall has some strong points. I like his Figure 1, showing that the pregnane X receptor (PXR) is involved in regulating not only 25-hydroxyvitamin D synthesis, but also 1,25-hydroxyvitamin D catabolism. Because PXR is markedly down-regulated in ulcerative colitis, this probably means that in ulcerative colitis there would be impaired conversion of dietary vitamin D (or sunshine generated vitamin D) to 25-hydroxyvitamin D. In principle, this metabolism could be restored by taking rifampin, which is a PXR activator (and used to control pruritus in PSC and PBC patients). However, the long-term effects of rifampin therapy on 1,25-hydroxyvitamin D catabolism are a concern to me [my son is taking rifampin]. Will long-term treatment

with rifampin require higher vitamin D intakes to prevent depletion of vitamin D reserves? ... I don't know.While the article by Marshall is a bit controversial, it does get us all thinking about what differences we might make to our long-term health if we make sure we don't become nutrient/vitamin/ hormone deficient, and avoid taking too much of any one nutrient/vitamin/ hormone. Something that Marshall did not really elaborate on was that the VDR actually pairs up with RXR to effect changes in gene expression. What's the activator of RXR? Many suggest that it is 9-cis retinoic acid, a metabolite of vitamin A. But others point out that this metabolite cannot be reproducibly measured, and that the best candidate 'natural' ligand for RXR is actually docosahexaenoic acid (DHA). Regardless of who is right on this specific point, does this mean that in order for VDR to function properly, you

also need either DHA of vitamin A? It's not just one hormone/vitamin/ nutrient that matters, but rather it's best to have a good balance for everything to work properly!I love Marshall's idea that certain bacteria might actually be producing compounds that bind to VDR and prevent it from working. In fact that's essentially the same idea that I have had about PSC, namely that some as yet unidentified bacteria in the gut produces a retinoic acid derivative that binds to RXR and prevents it from working properly, disrupting bile, lipid, xenobiotic and bone metabolism, bile transport, and the immune system. Best regards,Dave (father of (23); PSC 07/03; UC 08/03)P.S. I tried to avoid using references this time, but would be glad to provide any if anyone is interested in more detail.

[Guest guest]

,

Thanks very much for explaining all of that! Wow, It will take awhile for me to absorb. What a blessing it is to have your help.

Lori A.

"Aggressively Pursuing Solutions To Your Real Estate Needs!"

First Weber Group

Cell:

1507 E. Sunset Drive

Waukesha, WI 53189

LoriUSA@...

www.Lori.FirstWeber.com

To: Sent: Tuesday, December 30, 2008 10:39:35 PMSubject: Re: Article on Vitamin D

>> http://trevormarsha ll.com/BioEssays -Feb08-Marshall- Preprint. pdf> > I would be be interested in any thoughts about it Hi athan;There are some things in the article by Trevor Marshall that I do agree with, and others that I don't. I'll try to explain as best as I can, and I hope that I don't loose you (and other readers) in the process.First, I do agree that vitamin D is not only a vitamin, but also an important hormone with lots of biological effects, including causing changes in the expression of a huge number of genes. The number of changes in gene

expression regulated by the active metabolite (1,25-dihydroxyvitamin D) binding to the vitamin D receptor (VDR) is much too large for the human brain to comprehend .... we need a computer model of all the interactions to begin to accurately predict all the biological responses.Because vitamin A (retinol) does something similar ... i.e. is metabolized in two steps to compounds (retinoic acids) that bind to receptors (retinoic acid receptor (RAR) and retinoid X receptor (RXR)) that then bind to a whole bunch of other receptors (including VDR, PXR, LXR, PPAR) that affect expression of a multitude of genes .... shouldn't we also call vitamin A a hormone? And why stop there, since beta-carotene is metabolized in 2 steps to retinoic acid, should we call carrots a hormone? And since docosahexaenoic acid (DHA) (found in fish oil) binds to RXR and PPAR, causing a large number of changes in gene

expression, should we call DHA a hormone? Shouldn't FDA also be regulating how many carrots we eat or how much fish we eat, or fish oil supplements we take? The bottom line is that a lot of nutrients have a marked effect on gene expression, and there is not really a need to single-out vitamin D.Second, I do agree that low values of 25-hydroxyvitamin D (the form of vitamin D that is usually measured) CAN be the result of the disease process. In the case of inflammatory bowel disease and cholestatic liver diseases like PSC and PBC, there is good evidence that absorption of vitamin D from the digestive system is impaired. In the case of inflammatory bowel disease the level of 25-hydroxyvitamin D (the main storage form of vitamin D) tends to be reduced, and this level correlates with bone mineral density (especially in males). Not surprisingly, then, supplementation with vitamin D (and calcium)

tends to rectify the metabolic bone disease associated with IBD. This would not be expected if you believe everything said in the Marshall article! Could vitamin D deficiency tend to make the disease worse? Sure! Because vitamin D plays an important role not only in bone metabolism and the immune system (including how T cells migrate to various sites in the body, and how much anti-bacterial peptides are produced, and how strong the epithelial barrier is in the gut, and how much of the inflammatory cytokine tumor necrosis factor alpha is produced), deficiency of vitamin D would not be good for you in the long run. Similarly, prolonged vitamin A deficiency would not be good for you because vitamin A also regulates how and where T cells migrate, how strong the epithelial barrier is in the gut, and how much IgA is produced in the gut. The best way to rectify any deficiencies is through

supplementation .... and I am certainly all for this except that this has to be done with caution to avoid potential toxicity from over-doses. The article by Trevor Marshall has some strong points. I like his Figure 1, showing that the pregnane X receptor (PXR) is involved in regulating not only 25-hydroxyvitamin D synthesis, but also 1,25-hydroxyvitamin D catabolism. Because PXR is markedly down-regulated in ulcerative colitis, this probably means that in ulcerative colitis there would be impaired conversion of dietary vitamin D (or sunshine generated vitamin D) to 25-hydroxyvitamin D. In principle, this metabolism could be restored by taking rifampin, which is a PXR activator (and used to control pruritus in PSC and PBC patients). However, the long-term effects of rifampin therapy on 1,25-hydroxyvitamin D catabolism are a concern to me [my son is taking rifampin]. Will long-term treatment

with rifampin require higher vitamin D intakes to prevent depletion of vitamin D reserves? ... I don't know.While the article by Marshall is a bit controversial, it does get us all thinking about what differences we might make to our long-term health if we make sure we don't become nutrient/vitamin/ hormone deficient, and avoid taking too much of any one nutrient/vitamin/ hormone. Something that Marshall did not really elaborate on was that the VDR actually pairs up with RXR to effect changes in gene expression. What's the activator of RXR? Many suggest that it is 9-cis retinoic acid, a metabolite of vitamin A. But others point out that this metabolite cannot be reproducibly measured, and that the best candidate 'natural' ligand for RXR is actually docosahexaenoic acid (DHA). Regardless of who is right on this specific point, does this mean that in order for VDR to function properly, you

also need either DHA of vitamin A? It's not just one hormone/vitamin/ nutrient that matters, but rather it's best to have a good balance for everything to work properly!I love Marshall's idea that certain bacteria might actually be producing compounds that bind to VDR and prevent it from working. In fact that's essentially the same idea that I have had about PSC, namely that some as yet unidentified bacteria in the gut produces a retinoic acid derivative that binds to RXR and prevents it from working properly, disrupting bile, lipid, xenobiotic and bone metabolism, bile transport, and the immune system. Best regards,Dave (father of (23); PSC 07/03; UC 08/03)P.S. I tried to avoid using references this time, but would be glad to provide any if anyone is interested in more detail.

[Guest guest]

,

Thanks very much for explaining all of that! Wow, It will take awhile for me to absorb. What a blessing it is to have your help.

Lori A.

"Aggressively Pursuing Solutions To Your Real Estate Needs!"

First Weber Group

Cell:

1507 E. Sunset Drive

Waukesha, WI 53189

LoriUSA@...

www.Lori.FirstWeber.com

To: Sent: Tuesday, December 30, 2008 10:39:35 PMSubject: Re: Article on Vitamin D

>> http://trevormarsha ll.com/BioEssays -Feb08-Marshall- Preprint. pdf> > I would be be interested in any thoughts about it Hi athan;There are some things in the article by Trevor Marshall that I do agree with, and others that I don't. I'll try to explain as best as I can, and I hope that I don't loose you (and other readers) in the process.First, I do agree that vitamin D is not only a vitamin, but also an important hormone with lots of biological effects, including causing changes in the expression of a huge number of genes. The number of changes in gene

expression regulated by the active metabolite (1,25-dihydroxyvitamin D) binding to the vitamin D receptor (VDR) is much too large for the human brain to comprehend .... we need a computer model of all the interactions to begin to accurately predict all the biological responses.Because vitamin A (retinol) does something similar ... i.e. is metabolized in two steps to compounds (retinoic acids) that bind to receptors (retinoic acid receptor (RAR) and retinoid X receptor (RXR)) that then bind to a whole bunch of other receptors (including VDR, PXR, LXR, PPAR) that affect expression of a multitude of genes .... shouldn't we also call vitamin A a hormone? And why stop there, since beta-carotene is metabolized in 2 steps to retinoic acid, should we call carrots a hormone? And since docosahexaenoic acid (DHA) (found in fish oil) binds to RXR and PPAR, causing a large number of changes in gene

expression, should we call DHA a hormone? Shouldn't FDA also be regulating how many carrots we eat or how much fish we eat, or fish oil supplements we take? The bottom line is that a lot of nutrients have a marked effect on gene expression, and there is not really a need to single-out vitamin D.Second, I do agree that low values of 25-hydroxyvitamin D (the form of vitamin D that is usually measured) CAN be the result of the disease process. In the case of inflammatory bowel disease and cholestatic liver diseases like PSC and PBC, there is good evidence that absorption of vitamin D from the digestive system is impaired. In the case of inflammatory bowel disease the level of 25-hydroxyvitamin D (the main storage form of vitamin D) tends to be reduced, and this level correlates with bone mineral density (especially in males). Not surprisingly, then, supplementation with vitamin D (and calcium)

tends to rectify the metabolic bone disease associated with IBD. This would not be expected if you believe everything said in the Marshall article! Could vitamin D deficiency tend to make the disease worse? Sure! Because vitamin D plays an important role not only in bone metabolism and the immune system (including how T cells migrate to various sites in the body, and how much anti-bacterial peptides are produced, and how strong the epithelial barrier is in the gut, and how much of the inflammatory cytokine tumor necrosis factor alpha is produced), deficiency of vitamin D would not be good for you in the long run. Similarly, prolonged vitamin A deficiency would not be good for you because vitamin A also regulates how and where T cells migrate, how strong the epithelial barrier is in the gut, and how much IgA is produced in the gut. The best way to rectify any deficiencies is through

supplementation .... and I am certainly all for this except that this has to be done with caution to avoid potential toxicity from over-doses. The article by Trevor Marshall has some strong points. I like his Figure 1, showing that the pregnane X receptor (PXR) is involved in regulating not only 25-hydroxyvitamin D synthesis, but also 1,25-hydroxyvitamin D catabolism. Because PXR is markedly down-regulated in ulcerative colitis, this probably means that in ulcerative colitis there would be impaired conversion of dietary vitamin D (or sunshine generated vitamin D) to 25-hydroxyvitamin D. In principle, this metabolism could be restored by taking rifampin, which is a PXR activator (and used to control pruritus in PSC and PBC patients). However, the long-term effects of rifampin therapy on 1,25-hydroxyvitamin D catabolism are a concern to me [my son is taking rifampin]. Will long-term treatment

with rifampin require higher vitamin D intakes to prevent depletion of vitamin D reserves? ... I don't know.While the article by Marshall is a bit controversial, it does get us all thinking about what differences we might make to our long-term health if we make sure we don't become nutrient/vitamin/ hormone deficient, and avoid taking too much of any one nutrient/vitamin/ hormone. Something that Marshall did not really elaborate on was that the VDR actually pairs up with RXR to effect changes in gene expression. What's the activator of RXR? Many suggest that it is 9-cis retinoic acid, a metabolite of vitamin A. But others point out that this metabolite cannot be reproducibly measured, and that the best candidate 'natural' ligand for RXR is actually docosahexaenoic acid (DHA). Regardless of who is right on this specific point, does this mean that in order for VDR to function properly, you

also need either DHA of vitamin A? It's not just one hormone/vitamin/ nutrient that matters, but rather it's best to have a good balance for everything to work properly!I love Marshall's idea that certain bacteria might actually be producing compounds that bind to VDR and prevent it from working. In fact that's essentially the same idea that I have had about PSC, namely that some as yet unidentified bacteria in the gut produces a retinoic acid derivative that binds to RXR and prevents it from working properly, disrupting bile, lipid, xenobiotic and bone metabolism, bile transport, and the immune system. Best regards,Dave (father of (23); PSC 07/03; UC 08/03)P.S. I tried to avoid using references this time, but would be glad to provide any if anyone is interested in more detail.

[Guest guest]

,

That is a great article. Thanks.

Subject: Re: Article on Vitamin DTo: Date: Tuesday, December 30, 2008, 2:10 AM

Hi athan;Thanks for posting this article. Before adding my own personal comments [it's a very controversial issue!!], I thought it would be good to share some of the correspondence that this article generated in "BioEssays" earlier this year. There were 2 letters followed by a reply by Marshall:____________ _________ _________ ______BioEssays 30:506-507, 2008 Wiley Periodicals, Inc. B. GrantSunlight, Nutrition, and Health Research Center (SUNARC)P.O. Box 641603, San Francisco, CA 94164-1603.E-mail: wbgrant (AT) infionline (DOT) netCedric F. GarlandDepartment of Family and Preventive Medicine 0631CUniversity of California San Diego, La Jolla, CA.For readers wishing additional supporting references please contact Dr GrantThe health benefits of vitamin D greatly outweigh the health

risksSir,In his recent essay, Trevor G. Marshall explores how vitamin D supplementation may be contributing to the current epidemics of obesity and chronic disease.(1) Unfortunately, he has overlooked many important papers that disagree with his hypothesis. This letter points out some of the omissions.The health benefits of vitamin D3 have been reviewed recently.(2) The benefits for bone health have been known for nearly a century. Benefits for cancer, infectious diseases, autoimmune diseases and metabolic diseases have been identified in the past three decades.Starting in the 1980s, largely observational evidence mounted that solar ultraviolet- B (UVB) irradiance and vitamin D reduce the risk of many types of cancer.(3) Based on observational studies, it is estimated that 2500 and 3600 International Units (IU) of vitamin D3 are required daily for a 30-50% reduction in risk of

colorectal and breast cancer, respectively. (4,5) A recent randomized, double-blind, placebo controlled clinical trial that studied post-menopausal women in Nebraska found a 77% reduction in all-cancer incidence between the ends of the first and fourth years,(5) adding strong support to the observational studies.Vitamin D enhances innate immunity through induction of human cathelicidin, LL-37.(1) LL-37 helps control both bacterial and viral infections. A recent post-hoc analysis of vitamin D3 supplementation for post-menopausal women living in New York State found substantial benefits in reducing the common cold and influenza for 800 IU/day, and very strong benefits for 2000 IU/day.(6) Benefits also appear to be strong for septicaemia (Grant, submitted).Many autoimmune diseases appear to arise from an improper immune response to viral infections. Since LL-37 reduces the risk of viral

infections, it may also influence the risk of autoimmune diseases such as multiple sclerosis. The well-known increase in prevalence of multiple sclerosis with increasing latitude is consistent with this hypothesis.There is also a growing body of literature that low vitamin D status is a risk factor for many metabolic diseases, including hypertension, type 2 diabetes, and cardiovascular disease.(2) A recent observational study found that vitamin D deficiency is associated with incident cardiovascular disease.(7)There are some diseases where vitamin D supplementation may be contraindicated. These include granulomatous diseases such as sarcoidosis where local production of 1,25-dihydroxyvitam in D (calcitriol) in response to the disease can leak into the serum and dysregulate calcium metabolism.( 8)The current vitamin D3 fortification of food in the United States contributes an

average of 250-300 IU/day to the American diet. This amount is too low to have a substantial beneficial effect on risk of cancer. Intake or production of vitamin D3 of 1000-2000 IU/day seems now to be required for optimal health, and typically will raise serum 25-hydroxyvitamin D (calcidiol) levels to 40-60 ng/mL.(4,6,9)It is possible that the reason that there have not been more clinical trials of vitamin D supplementation clinical trials is that there is little income in selling vitamin D3 (a year's supply of 1500 IU/day costs less than $20 U.S.), and such trials are expensive.The rising prevalence of obesity in the United States has been attributed to over consumption of popular energy-dense foods compared to energy output.(10) Until obesity is eliminated, increased vitamin D3 supplementation and fortification of foods could provide substantial health benefits, including reduced incidence of

several serious diseases.DisclosureWBGreceives funding from the UV Foundation (McLean, VA), the Vitamin D Society (Canada), and the European Sunlight Association.References1. Marshall TG. 2008. Vitamin D discovery outpaces FDA decision making. Bioessays 30:173-182.2. Holick MF. 2007. Vitamin D deficiency. N Engl J Med 357:266-281.3. Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H et al. 2006. The role of vitamin D in cancer prevention. Am J Public Health 96:252-261.4. Garland CF, Grant WB, Mohr SB, Gorham ED, Garland FC. 2007. What is the dose-response relationship between vitamin D and cancer risk? Nutr Rev 65:S91-95.5. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. 2007. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 85:1586-1591.6. Aloia JF, Li-Ng M. 2007. Re: epidemic influenza and

vitamin D. Epidemiol Infect 135:1095-1096; author reply 1097-1098.7. Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, et al. 2008. Vitamin D Deficiency and Risk of Cardiovascular Disease. Circulation [Epub ahead of print].8. Hewison M, Burke F, KN, Lammas DA, Sansom DM, et al. 2007. Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxyla se in human health and disease. J Steroid Biochem Mol Biol 103:316-321.9. Cannell J, Hollis B, Zasloff M, Heaney R. 2008. Diagnosis and treatment of vitamin D deficiency. Expert Opin Pharmacother 9:107-118.10. Pollan M. 2006. The Omnivore's Dilemma; Natural History of Four Meals. New York: Penguin Press. 430____________ _________ _________ ______BioEssays 30:508-509, 2008 Wiley Periodicals,Barbara J. BoucherCentre for Diabetes & Metabolic MedicineBarts & the London Medical & Dental School, London, UKE-mail: bboucher (AT) doctors (DOT) org.ukDOI 10.1002/bies. 20751Published online in Wiley InterScience (www.interscience. wiley.com) .Comment on "Vitamin D discovery outpaces FDA decision making""Before you let the sun in, make sure it wipes its shoes"Dylan , Under Milk Wood. 1954Sir,It is always wise to consider evidence from points of view other than those that are current `received wisdom' so that we can see clearly what we are really looking at. Thus, the above review is of considerable interest.(1) The author postulates that circulating hormonal [activated] vitamin D (calcitriol) concentration is more important than circulating 25-hydroxyvitamin D [25-(OH)D] in the determination of tissue functions that are modulated by vitamin D. He also appears to suggest that changes in circulating 25-hydroxy vitamin D reflect

changes in calcitriol formation and uptake rather than availability of vitamin D and that circulating calcitriol concentration tells us about vitamin D effectiveness. This would indeed be the case if all tissues depended on uptake of calcitriol from the circulation for their supplies of hormonal vitamin D. However, many tissues express the hydroxylase activating vitamin D and several have been confirmed as producers of calcitriol in situ.(2-4) Such tissues must use circulating 25-(OH)D, the substrate for activation by 25-hydroxyvitamin D 1-alphahydroxylase. Thus, for example, in the placenta, calcitriol is produced in large amounts from early in pregnancy with increases in circulating maternal calcitriol and reductions in maternal circulating 25-(OH)D.(4) However, to suggest that all variation on serum 25-(OH)D concentrations in different disease processes reflects changes in local tissue vitamin D

activation to the exclusion of variations due to the amount of vitamin D in the body would be to ignore the massive changes in serum 25-(OH)D seen within hours of exposure to UVB, without any changes in circulating calcitriol(5) and would not explain the remarkable seasonal variations in serum 25-(OH)D seen with variation in available effective UVB from sunlight, with variations in dietary intake of vitamin D and with supplement use. In Sweden for example, in a group of 116 women in the winter, an average serum 25(OH)D of 69 nmol/l was accounted for by the following: (1) daily intake of normally fortified Swedish foods, 6.2 nmol/l, (2) three fish meals/week, 25.5 nmol/l, (3) regular vitamin supplement use, 11.0 nmol/l and (4) a vacation in the sun within the last 6 months, 14.5 nmol/l, which leaves 11.8 nmol/l of 25-(OH)D to be accounted for the balance between incoming vitamin D and the amount of

25-(OH)D being consumed by local vitamin D activating tissues.(6,7) In addition, however much ultraviolet B effective for induction of vitamin D synthesis [effUVb] one is exposed to, vitamin D toxicity does not develop because of feed-back mechanisms in the skin itself.(8) Similarly, feedback mechanisms ensure that circulating calcitriol is virtually unchanged in the face of reductions in serum 25-(OH)D in the circulation until there is clinically obvious vitamin D deficiency with bone disease such as rickets or osteomalacia when calcitriol does eventually fall, though even then, in some case, serum calcitriol is found to be increased.(9) These findings challenge the argument that vitamin D modulation of tissue function depends predominantly on circulating calcitriol and explain why vitamin D repletion continues to be judged at present by circulating concentrations of the storage adduct, 25-(OH)D,

acting as it does as the substrate for local tissue activation throughout the body and not just in the kidney. In support of this position, it is well known that measurement of circulating calcitriol [hormonally active 1,25dihydroxyvitami n D] is unhelpful in the assessment of vitamin D repletion since its concentrations are normally so tightly regulated across a wide range of concentrations of 25-(OH)D.(10) Finally, the fact that vitamin D activation has been demonstrated in several of the extrarenal human tissues known to express specific vitamin D activating 1-alpha hydroxylase supports the view that assessment of substrate availability of vitamin D, as reflected by serum 25-(OH)D, is likely to be of importance in the assessment of vitamin D repletion in humans.References1. Marshall TG. 2008. Vitamin D discovery outpaces FDA decision making. BioEssays 30:173-182.2. Hewison M,

Burke F, KN, Lammas DA, Sansom DM, et al. 2007. Extra-renal 25-hydroxyvitamin Da-1alpha-hydroxyla se in human health and disease. J Steroid Biochem Mol Biol 103:316-321.3. Merke J, Milde P, Lewicka S, Hugel U, Mangelsdorf DJ, et al. 1989. J Clin Invest. 83:1903-1915.4. KN, Bulmer JN, Kilby MD, Hewison M. 2004. Vitamin D and placental-decidual function. J Soc Gynecol Investig 11:263-271.5. Landin-Wilhelmsen K, Wilhelmsen L, Wilske J, Lappas G, Rosen T, et al. 1995. Sunlight increases serum 25(OH) vitamin D concentration whereas 1,25(OH)2D3 is unaffected. Results from a general population study in Goteborg, Sweden (The WHO MONICA Project). Eur J Clin Nutr 49: 44-407.6. Engelsen O, Brustad M, Aksnes L, Lund E. 2005. Daily duration of vitamin D synthesis in human skin with relation to latitude, total ozone, altitude, ground cover, aerosols and cloud thickness. Photochem Photobiol

81:1287-1290.7. Burgaa A, Akesson A, Oster A, sson K, Wolk A. 2007. Associations of diet, supplement use and ultraviolet B radiation exposure with vitamin D status in Swedish women during winter. Am J Clin Nutr 86: 404.8. Bickle DD. 1997. Vitamin D and Skin. Chapter 25 in Vitamin D. Ed. Feldman D, Glorieux FH, Wesley Pike J. 379-394.9. Pettifor JM, s ED. 1997. Vitamin D deficiency and nutritional rickets in children. Chapter 42 in Vitamin D. Ed. Feldman D, Glorieux FH, Wesley Pike J. 663-678.10. Hollis B. 1997. Detection of vitamin D and its major metabolites. Chapter 38 in Vitamin D. Ed. Feldman D, Glorieux FH, Wesley Pike J. 587-606.____________ _________ _________ ______BioEssays 30:510-511, 2008 Wiley Periodicals, Inc.Trevor G. MarshallSchool of Biological Sciencesand Biotechnologyc/o 3423 Hill Canyon AvenueMurdoch UniversityWestern

AustraliaE-mail: trevor.m@autoimmuni tyresearch. orgAuthor's reply to correspondence from Drs Grant, Garland, and BoucherSir,The primary function of calcitriol, 1,25-dihydroxyvitam in-D (1,25-D), is to activate the Vitamin D Nuclear Receptor (VDR), enabling transcription and transrepression of genes. Even pathways previously thought to be 'non-genomic' have been shown to rely upon gene transcription. (1) Thus, the measured level of 25-hydroxyvitamin- D (25-D) is not sufficient to determine "Vitamin D deficiency" or "Vitamin D status". Only the 1,25-D form of Vitamin D has the ability to activate the VDR to transcribe genes, and therefore only measurements including this metabolite can accurately describe the overall homeostasis of the Vitamin D metabolism in man [see Ref. 2, Fig. 1].Dr Boucher has

highlighted many of the difficulties confronting clinical medicine as it expands its knowledge base from the level of tissues, as seen under the microscope, to that of individual genes and proteins, interacting at the submicroscopic scale of the molecule. Even though there are decades of clinical studies attempting to delineate the association between health, disease and the Vitamin D metabolites, any study conducted without reference to genes, or transcription, must necessarily lead to an incomplete characterization.Drs. Grant and Garland correctly note that low levels of 25-D are associated with many diseases. Yet they extrapolate that observation to imply that a causal relationship should be expected between this (largely inactive) metabolite, and those disease states. This is a non sequitur, as our article shows there is not a first-order mass-action relationship between the dosage of

exogenous Vitamin D and the measured level of the 25-D metabolite (see Ref. 2, Fig. 1). Not only are there multiple metabolic feedback control mechanisms, there are control inputs via Protein Kinase A (PKA), in addition to the steroid and xenobiotic ligands of PXR. Our article explains why the observed lower level of 25-D metabolite is a symptom of Vitamin D dysregulation resulting from the disease state, an attempt by the body to bring the level of the active metabolite back into its control range.Exploring the cause of the obesity epidemic, we took the rhetorical question from Bajzer and Seeley,(3) "are gut bacteria a factor in the obesity epidemic", and built a detailed putative pathogenesis, based on our molecular, and clinical, knowledge. Specifically cited were two carefully controlled studies,(4,5) which had failed to show a causal relationship between lifestyle, nutritional choices and

obesity. It would have been helpful if Grant and Garland could have addressed any specific failings they might have seen in those controlled studies, rather than give the citation they chose(6) as the basis for their argument.They suggest that deficiencies in the available clinical trials can be blamed on the low profit potential from sales of the secosteroid itself. Although the direct cost of Vitamin D supplements may not be great, there is money to be made from market positioning, enough to attract the interest of a large multinational. Our article explains how the Coca-Cola Company has petitioned the FDA to be allowed to add a high level of Vitamin D to their brands of orange juice, so that they can claim that it reduces the risk of osteoporosis. (7) There is clearly money available for higher quality studies. However, because this secosteroid is still classified as a vitamin, rather than

as a drug, the FDA has not yet begun insisting that a more rigorous understanding of the underlying biology be brought to bear upon Vitamin D trial design.Grant and Garland accept that sarcoidosis is a chronic inflammatory diagnosis in which Vitamin D supplementation might do harm, but we feel they need to address why other autoimmune diagnoses might not be similarly exacerbated by supplementation. Our 2004 paper "Sarcoidosis succumbs to antibiotics - implications for autoimmune disease"(8) canvassed a homogeneity of inflammatory pathogeneses, a hypothesis that has subsequently been supported by the emerging clinical evidence.(9- 11)We do not disagree with the primary premise of Grant and Garland, that Vitamin D supplementation of the food supply is one of the most important public health issues of our time. Our article is arguing that more sophisticated study designs will be needed if

one is to definitively evaluate the metabolism responsible for expression of at least 913 genes. Only then can we determine if, and to what degree, addition of Vitamin D to the food chain might be beneficial to the public's health.References1. Bravo S, Paredes R, Izaurieta P, Lian JB, Stein JL, et al. 2006. The classic receptor for 1alpha,25-dihydroxy vitamin D3 is required for non-genomic actions of 1alpha,25-dihydroxy vitamin D3 in osteosarcoma cells. J Cell Biochem 99:995-1000.2. Marshall TG. 2008. Vitamin D discovery outpaces FDA decision making. BioEssays 30:173-182.3. Bajzer M, Seeley RJ. 2006. Physiology: obesity and gut flora. Nature 444: 1009-1010.4. Caballero B, Clay T, SM, Ethelbah B, Rock BH, et al. 2003. Pathways Study Research Group. Pathways: a school-based, randomized controlled trial for the prevention of obesity in American Indian schoolchildren. Am J

Clin Nutr 78:904-905.5. Reilly JJ, L, Montgomery C, on A, Fisher A, et al. 2006. Physical activity to prevent obesity in young children: cluster randomised controlled trial. BMJ 333:1041.6. Pollan M. 2006. The Omnivore's Dilemma; Natural History of Four Meals. Penguin Press, New York. 430 pp.7. DHHS Food and Drug Administration. 2007. Food Labeling; Health Claims; Calcium and Osteoporosis, and Calcium, Vitamin D, and Osteoporosis. 21 CFR Part 101 [Docket No. 2004P-0464] Federal Register/Vol. 72, No. 3/Friday, January 5, 2007.8. Marshall TG, Marshall FE. 2004. Sarcoidosis succumbs to antibiotics - implications for autoimmune disease. Autoimmunity Reviews 3:295-3001.9. Waterhouse JC, Marshall TG, Fenter B, Mangin M, Blaney G. 2006. High levels of active 1,25-dihydroxyvitam in D despite low levels of the 25-hydroxyvitamin D precursor - Implications of dysregulated vitamin D for

diagnosis and treatment of Chronic Disease. In: Stoltz VD, editor. Vitamin D: New Research, Vol. 1. New York: Nova Science Publishers.10. Arnson Y, Amital H, Shoenfeld Y. 2007. Vitamin D and autoimmunity: New aetiological and therapeutic considerations. Ann Rheum Dis 66(9):1137-1142.11. Marshall TG. 2006. VDR Nuclear Receptor Competence is the Key to Recovery from Chronic Inflammatory and Autoimmune Disease. Abstractpresentation, Days of Molecular Medicine 2006. Copy available from URL http://autoimmunity research. org/karolinska- handout.pdf.____________ _________ _________ ______Best regards,Dave (father of (23); PSC 07/03; UC 08/03)

[Guest guest]

DaveLove the commentary as well as your insight!ShaulPSC UCSent via BlackBerry by AT&TFrom: " " Date: Wed, 31 Dec 2008 04:39:35 -0000To: < >Subject: Re: Article on Vitamin D > > http://trevormarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf > > I would be be interested in any thoughts about it Hi athan; There are some things in the article by Trevor Marshall that I do agree with, and others that I don't. I'll try to explain as best as I can, and I hope that I don't loose you (and other readers) in the process. First, I do agree that vitamin D is not only a vitamin, but also an important hormone with lots of biological effects, including causing changes in the expression of a huge number of genes. The number of changes in gene expression regulated by the active metabolite (1,25- dihydroxyvitamin D) binding to the vitamin D receptor (VDR) is much too large for the human brain to comprehend .... we need a computer model of all the interactions to begin to accurately predict all the biological responses. Because vitamin A (retinol) does something similar ... i.e. is metabolized in two steps to compounds (retinoic acids) that bind to receptors (retinoic acid receptor (RAR) and retinoid X receptor (RXR)) that then bind to a whole bunch of other receptors (including VDR, PXR, LXR, PPAR) that affect expression of a multitude of genes .... shouldn't we also call vitamin A a hormone? And why stop there, since beta-carotene is metabolized in 2 steps to retinoic acid, should we call carrots a hormone? And since docosahexaenoic acid (DHA) (found in fish oil) binds to RXR and PPAR, causing a large number of changes in gene expression, should we call DHA a hormone? Shouldn't FDA also be regulating how many carrots we eat or how much fish we eat, or fish oil supplements we take? The bottom line is that a lot of nutrients have a marked effect on gene expression, and there is not really a need to single-out vitamin D. Second, I do agree that low values of 25-hydroxyvitamin D (the form of vitamin D that is usually measured) CAN be the result of the disease process. In the case of inflammatory bowel disease and cholestatic liver diseases like PSC and PBC, there is good evidence that absorption of vitamin D from the digestive system is impaired. In the case of inflammatory bowel disease the level of 25- hydroxyvitamin D (the main storage form of vitamin D) tends to be reduced, and this level correlates with bone mineral density (especially in males). Not surprisingly, then, supplementation with vitamin D (and calcium) tends to rectify the metabolic bone disease associated with IBD. This would not be expected if you believe everything said in the Marshall article! Could vitamin D deficiency tend to make the disease worse? Sure! Because vitamin D plays an important role not only in bone metabolism and the immune system (including how T cells migrate to various sites in the body, and how much anti-bacterial peptides are produced, and how strong the epithelial barrier is in the gut, and how much of the inflammatory cytokine tumor necrosis factor alpha is produced), deficiency of vitamin D would not be good for you in the long run. Similarly, prolonged vitamin A deficiency would not be good for you because vitamin A also regulates how and where T cells migrate, how strong the epithelial barrier is in the gut, and how much IgA is produced in the gut. The best way to rectify any deficiencies is through supplementation .... and I am certainly all for this except that this has to be done with caution to avoid potential toxicity from over-doses. The article by Trevor Marshall has some strong points. I like his Figure 1, showing that the pregnane X receptor (PXR) is involved in regulating not only 25-hydroxyvitamin D synthesis, but also 1,25- hydroxyvitamin D catabolism. Because PXR is markedly down-regulated in ulcerative colitis, this probably means that in ulcerative colitis there would be impaired conversion of dietary vitamin D (or sunshine generated vitamin D) to 25-hydroxyvitamin D. In principle, this metabolism could be restored by taking rifampin, which is a PXR activator (and used to control pruritus in PSC and PBC patients). However, the long-term effects of rifampin therapy on 1,25- hydroxyvitamin D catabolism are a concern to me [my son is taking rifampin]. Will long-term treatment with rifampin require higher vitamin D intakes to prevent depletion of vitamin D reserves? ... I don't know. While the article by Marshall is a bit controversial, it does get us all thinking about what differences we might make to our long-term health if we make sure we don't become nutrient/vitamin/hormone deficient, and avoid taking too much of any one nutrient/vitamin/hormone. Something that Marshall did not really elaborate on was that the VDR actually pairs up with RXR to effect changes in gene expression. What's the activator of RXR? Many suggest that it is 9-cis retinoic acid, a metabolite of vitamin A. But others point out that this metabolite cannot be reproducibly measured, and that the best candidate 'natural' ligand for RXR is actually docosahexaenoic acid (DHA). Regardless of who is right on this specific point, does this mean that in order for VDR to function properly, you also need either DHA of vitamin A? It's not just one hormone/vitamin/nutrient that matters, but rather it's best to have a good balance for everything to work properly! I love Marshall's idea that certain bacteria might actually be producing compounds that bind to VDR and prevent it from working. In fact that's essentially the same idea that I have had about PSC, namely that some as yet unidentified bacteria in the gut produces a retinoic acid derivative that binds to RXR and prevents it from working properly, disrupting bile, lipid, xenobiotic and bone metabolism, bile transport, and the immune system. Best regards, Dave (father of (23); PSC 07/03; UC 08/03) P.S. I tried to avoid using references this time, but would be glad to provide any if anyone is interested in more detail.

[Guest guest]

DaveLove the commentary as well as your insight!ShaulPSC UCSent via BlackBerry by AT&TFrom: " " Date: Wed, 31 Dec 2008 04:39:35 -0000To: < >Subject: Re: Article on Vitamin D > > http://trevormarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf > > I would be be interested in any thoughts about it Hi athan; There are some things in the article by Trevor Marshall that I do agree with, and others that I don't. I'll try to explain as best as I can, and I hope that I don't loose you (and other readers) in the process. First, I do agree that vitamin D is not only a vitamin, but also an important hormone with lots of biological effects, including causing changes in the expression of a huge number of genes. The number of changes in gene expression regulated by the active metabolite (1,25- dihydroxyvitamin D) binding to the vitamin D receptor (VDR) is much too large for the human brain to comprehend .... we need a computer model of all the interactions to begin to accurately predict all the biological responses. Because vitamin A (retinol) does something similar ... i.e. is metabolized in two steps to compounds (retinoic acids) that bind to receptors (retinoic acid receptor (RAR) and retinoid X receptor (RXR)) that then bind to a whole bunch of other receptors (including VDR, PXR, LXR, PPAR) that affect expression of a multitude of genes .... shouldn't we also call vitamin A a hormone? And why stop there, since beta-carotene is metabolized in 2 steps to retinoic acid, should we call carrots a hormone? And since docosahexaenoic acid (DHA) (found in fish oil) binds to RXR and PPAR, causing a large number of changes in gene expression, should we call DHA a hormone? Shouldn't FDA also be regulating how many carrots we eat or how much fish we eat, or fish oil supplements we take? The bottom line is that a lot of nutrients have a marked effect on gene expression, and there is not really a need to single-out vitamin D. Second, I do agree that low values of 25-hydroxyvitamin D (the form of vitamin D that is usually measured) CAN be the result of the disease process. In the case of inflammatory bowel disease and cholestatic liver diseases like PSC and PBC, there is good evidence that absorption of vitamin D from the digestive system is impaired. In the case of inflammatory bowel disease the level of 25- hydroxyvitamin D (the main storage form of vitamin D) tends to be reduced, and this level correlates with bone mineral density (especially in males). Not surprisingly, then, supplementation with vitamin D (and calcium) tends to rectify the metabolic bone disease associated with IBD. This would not be expected if you believe everything said in the Marshall article! Could vitamin D deficiency tend to make the disease worse? Sure! Because vitamin D plays an important role not only in bone metabolism and the immune system (including how T cells migrate to various sites in the body, and how much anti-bacterial peptides are produced, and how strong the epithelial barrier is in the gut, and how much of the inflammatory cytokine tumor necrosis factor alpha is produced), deficiency of vitamin D would not be good for you in the long run. Similarly, prolonged vitamin A deficiency would not be good for you because vitamin A also regulates how and where T cells migrate, how strong the epithelial barrier is in the gut, and how much IgA is produced in the gut. The best way to rectify any deficiencies is through supplementation .... and I am certainly all for this except that this has to be done with caution to avoid potential toxicity from over-doses. The article by Trevor Marshall has some strong points. I like his Figure 1, showing that the pregnane X receptor (PXR) is involved in regulating not only 25-hydroxyvitamin D synthesis, but also 1,25- hydroxyvitamin D catabolism. Because PXR is markedly down-regulated in ulcerative colitis, this probably means that in ulcerative colitis there would be impaired conversion of dietary vitamin D (or sunshine generated vitamin D) to 25-hydroxyvitamin D. In principle, this metabolism could be restored by taking rifampin, which is a PXR activator (and used to control pruritus in PSC and PBC patients). However, the long-term effects of rifampin therapy on 1,25- hydroxyvitamin D catabolism are a concern to me [my son is taking rifampin]. Will long-term treatment with rifampin require higher vitamin D intakes to prevent depletion of vitamin D reserves? ... I don't know. While the article by Marshall is a bit controversial, it does get us all thinking about what differences we might make to our long-term health if we make sure we don't become nutrient/vitamin/hormone deficient, and avoid taking too much of any one nutrient/vitamin/hormone. Something that Marshall did not really elaborate on was that the VDR actually pairs up with RXR to effect changes in gene expression. What's the activator of RXR? Many suggest that it is 9-cis retinoic acid, a metabolite of vitamin A. But others point out that this metabolite cannot be reproducibly measured, and that the best candidate 'natural' ligand for RXR is actually docosahexaenoic acid (DHA). Regardless of who is right on this specific point, does this mean that in order for VDR to function properly, you also need either DHA of vitamin A? It's not just one hormone/vitamin/nutrient that matters, but rather it's best to have a good balance for everything to work properly! I love Marshall's idea that certain bacteria might actually be producing compounds that bind to VDR and prevent it from working. In fact that's essentially the same idea that I have had about PSC, namely that some as yet unidentified bacteria in the gut produces a retinoic acid derivative that binds to RXR and prevents it from working properly, disrupting bile, lipid, xenobiotic and bone metabolism, bile transport, and the immune system. Best regards, Dave (father of (23); PSC 07/03; UC 08/03) P.S. I tried to avoid using references this time, but would be glad to provide any if anyone is interested in more detail.

[Guest guest]

DaveLove the commentary as well as your insight!ShaulPSC UCSent via BlackBerry by AT&TFrom: " " Date: Wed, 31 Dec 2008 04:39:35 -0000To: < >Subject: Re: Article on Vitamin D > > http://trevormarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf > > I would be be interested in any thoughts about it Hi athan; There are some things in the article by Trevor Marshall that I do agree with, and others that I don't. I'll try to explain as best as I can, and I hope that I don't loose you (and other readers) in the process. First, I do agree that vitamin D is not only a vitamin, but also an important hormone with lots of biological effects, including causing changes in the expression of a huge number of genes. The number of changes in gene expression regulated by the active metabolite (1,25- dihydroxyvitamin D) binding to the vitamin D receptor (VDR) is much too large for the human brain to comprehend .... we need a computer model of all the interactions to begin to accurately predict all the biological responses. Because vitamin A (retinol) does something similar ... i.e. is metabolized in two steps to compounds (retinoic acids) that bind to receptors (retinoic acid receptor (RAR) and retinoid X receptor (RXR)) that then bind to a whole bunch of other receptors (including VDR, PXR, LXR, PPAR) that affect expression of a multitude of genes .... shouldn't we also call vitamin A a hormone? And why stop there, since beta-carotene is metabolized in 2 steps to retinoic acid, should we call carrots a hormone? And since docosahexaenoic acid (DHA) (found in fish oil) binds to RXR and PPAR, causing a large number of changes in gene expression, should we call DHA a hormone? Shouldn't FDA also be regulating how many carrots we eat or how much fish we eat, or fish oil supplements we take? The bottom line is that a lot of nutrients have a marked effect on gene expression, and there is not really a need to single-out vitamin D. Second, I do agree that low values of 25-hydroxyvitamin D (the form of vitamin D that is usually measured) CAN be the result of the disease process. In the case of inflammatory bowel disease and cholestatic liver diseases like PSC and PBC, there is good evidence that absorption of vitamin D from the digestive system is impaired. In the case of inflammatory bowel disease the level of 25- hydroxyvitamin D (the main storage form of vitamin D) tends to be reduced, and this level correlates with bone mineral density (especially in males). Not surprisingly, then, supplementation with vitamin D (and calcium) tends to rectify the metabolic bone disease associated with IBD. This would not be expected if you believe everything said in the Marshall article! Could vitamin D deficiency tend to make the disease worse? Sure! Because vitamin D plays an important role not only in bone metabolism and the immune system (including how T cells migrate to various sites in the body, and how much anti-bacterial peptides are produced, and how strong the epithelial barrier is in the gut, and how much of the inflammatory cytokine tumor necrosis factor alpha is produced), deficiency of vitamin D would not be good for you in the long run. Similarly, prolonged vitamin A deficiency would not be good for you because vitamin A also regulates how and where T cells migrate, how strong the epithelial barrier is in the gut, and how much IgA is produced in the gut. The best way to rectify any deficiencies is through supplementation .... and I am certainly all for this except that this has to be done with caution to avoid potential toxicity from over-doses. The article by Trevor Marshall has some strong points. I like his Figure 1, showing that the pregnane X receptor (PXR) is involved in regulating not only 25-hydroxyvitamin D synthesis, but also 1,25- hydroxyvitamin D catabolism. Because PXR is markedly down-regulated in ulcerative colitis, this probably means that in ulcerative colitis there would be impaired conversion of dietary vitamin D (or sunshine generated vitamin D) to 25-hydroxyvitamin D. In principle, this metabolism could be restored by taking rifampin, which is a PXR activator (and used to control pruritus in PSC and PBC patients). However, the long-term effects of rifampin therapy on 1,25- hydroxyvitamin D catabolism are a concern to me [my son is taking rifampin]. Will long-term treatment with rifampin require higher vitamin D intakes to prevent depletion of vitamin D reserves? ... I don't know. While the article by Marshall is a bit controversial, it does get us all thinking about what differences we might make to our long-term health if we make sure we don't become nutrient/vitamin/hormone deficient, and avoid taking too much of any one nutrient/vitamin/hormone. Something that Marshall did not really elaborate on was that the VDR actually pairs up with RXR to effect changes in gene expression. What's the activator of RXR? Many suggest that it is 9-cis retinoic acid, a metabolite of vitamin A. But others point out that this metabolite cannot be reproducibly measured, and that the best candidate 'natural' ligand for RXR is actually docosahexaenoic acid (DHA). Regardless of who is right on this specific point, does this mean that in order for VDR to function properly, you also need either DHA of vitamin A? It's not just one hormone/vitamin/nutrient that matters, but rather it's best to have a good balance for everything to work properly! I love Marshall's idea that certain bacteria might actually be producing compounds that bind to VDR and prevent it from working. In fact that's essentially the same idea that I have had about PSC, namely that some as yet unidentified bacteria in the gut produces a retinoic acid derivative that binds to RXR and prevents it from working properly, disrupting bile, lipid, xenobiotic and bone metabolism, bile transport, and the immune system. Best regards, Dave (father of (23); PSC 07/03; UC 08/03) P.S. I tried to avoid using references this time, but would be glad to provide any if anyone is interested in more detail.