More on Bile Acids (an important piece of the MC puzzle?)

[dfpowell]

Jonas,

After 7 years of many diet changes, this is the only thing that has given me some consistent symptom relief. I am taking the lowest dose possible , and extra amounts of the fat soluble vitamins. Also, I will be doing a nutrient profile with my integrative MD, so I should have an idea how safe it is for me.

[tex]

I read about cholestyramine on "swedish fass" that all swedish doctors use.

Be especially careful with Questran

- If you have inflammatory bowel disease.

- The very long-term treatment because it may decrease the absorption of fat-soluble vitamins and vitamin K can increase the tendency to bleed. Vitamins A , D, and K may in some cases need to be given prevention.

- If you have constipation.

Is this safe to take if you have MC?

Jonas,

Someone made a mistake when they posted the information that you quoted, or maybe there was a problem with the translation, because vitamin K actually promotes blood clotting, thereby preventing excessive bleeding.

But it is true that Questran can cause constipation, so bile acid sequestrants definitely should not be taken by patients who are already constipated.

If it works to resolve the D, taking Questran is far safer than taking a corticosteroid to treat MC. You just have to remember to take any vitamin supplements or other medications several hours before taking the Questran, or at least 4 hours afterward. As long as you do that, it can't affect the absorption of any vitamins.

It will not help to resolve any inflammation that may be present, but the purpose of the diet changes is to resolve the inflammation, so if Questran stops the D, that can make life a lot easier.

Tex

[DebE13]

I was so excited to take my first pill before bed last night... Pretty sad, huh? Haha. I only made three trips to the bathroom this morning instead of my usual 4-5 so it's a start. I know one dose isn't going to work a miracle but it made a good start to the day. The transit time out seemed to be slower too whereas it normally seems like one big rush out and then done. Consistency more like mudd than WD. I have hope but will see- I'm a bit ahead of myself but the idea of finding one more piece to the puzzle is very uplifting.

I've been on entocort since 2011 so the idea of getting off of it is a bonus. I've been taking about one pill every fifth day and would love to not take it all.

[tex]

So far, so good.

Tex

[Polly]

Hi Deb,

Just returned from vacation and the first thing I wanted to do when I logged on here is to see how you are doing. Sounds encouraging! I had the same experience - the D went from watery to mud and then to soft/formed over some days. Hang in there - it may take a few weeks to see full effect if it is going to work. Also, you may have to back off some if you get constipated. It may take a while to find the perfect dose and timing. Don't be afraid to experiment. BTW, there is a Facebook site for Bile Acid Malabsorption that you may be interested in checking out. I am following your progress with great interest! Good luck!

Tex,

You say that the sequestrant will not help to resolve any inflammation, but I am not so sure about that. I have a hunch that the bile acids are actually a CAUSE of colonic inflammation. If, normally, at least 95% of the bile acids are rebsorbed in the terminal ileum, then very little acid should ever make it to the colon. In the case of bile acid diarrhea (BAD), when a large amount of bile acid does make it into the colon, I can imagine how irritating and corrosive that must be to the colonic mucosa. Binding up that acid with a sequestrant would help protect the colon from inflammation, I would guess. And I can tell you from experience that huge amounts of yellow, watery, burning bile acid D at any time day or night are not unusual when you have this condition. (BTW, bile acids also increase the colonic motility, so it makes sense that Deb has felt that maybe her gut has slowed down a bit with the pill).

Love,

Polly

[tex]

Hi Polly,

I thought that the figure was up to 90 % (rather than at least 95 %), but that probably depends on the source of the information, and the difference would be irrelevant, anyway.

But you are surely correct that the bile acids would probably cause some inflammation. I was thinking about the T-cell inflammation normally listed as the cause of the inflammation associated with IBDs, and the effects of the bile acidity passed completely under my radar.

You know, now that you've forced me to think about this a little, I'm amazed that I don't have bile acid malabsorption, since a length of my terminal ileum is missing. Everyone talks about all the things that are absorbed in the "terminal ileum". But exactly how much of the ileum is actually considered to be the "terminal ileum". Do you have any idea. I don't.

But I have never noticed that I have ever had more than a slight amount of bile acid malabsorption, even when I've had rare MC flares. And with an ileostomy, it should be difficult to overlook the problem (if it exists). I'm certainly not complaining, but now that I think about it, it seems odd that I don't have some sort of bile problem.

This makes me wonder if BAM might be caused by excessive bile output. As if the liver is receiving corrupt input data about actual needs.

And here's a question to ponder: Why do bile salts cause D in the colon, but not in the small intestine? The terminal ileum is the caboose of the small intestine. So all but the caboose is exposed to the same bile salts. Why would they never cause problems in the small intestine, but commonly cause problems in the colon? Surely they do not change form simply because they pass from the small intestine into the colon. No processing is done in the cecum.

Love,
Tex

[Polly]

Good questions, Tex!

I'll give you my take on them, FWIW.

You don't have a problem, probably because more than 100 cm. of ileum has to be removed before an impact is seen. Apparently, remaining ileum is very good at taking up the functions of any removed part.

The main role of the terminal ileum is to absorb sodium chloride and bile salts. When it is not doing its job for whatever reason, the non-absorbed bile acids cause watery D in this way: they irritate the colonic mucosa because the colon is impermeable to LCFAs (long chain fatty acids). These LCFAs, which were not absorbed properly in the ileum, increase the osmotic load, which as we know, leads to D. There is a second reason for the D....apparently the LCFAs have an additional effect on the colon - they exert a direct stimulatory effect on colonocyte electrolye secretion, which leads to D too.

The answer, then, is to be found not at the anatomical level, but at the cellular level. The colonic mucosa may look the same in the ileum and the colon - each having the same 4 layers, etc.; however, the difference lies in their cellular functions.

At least that's how I see it.

Love,

Polly

[louis]

dont you think it could also be the opposite for some of us. That their is not enough bile acid produced, maybe the liver runs on limit, and the food leaves the colon undigested?

[tex]

Louis,

Yes, that could certainly cause digestive problems because of undigested fats (which can cause D), but it wouldn't cause bile acid malabsorption (because there wouldn't be any surplus of bile acids to not be absorbed).

So in that case bile acid sequestrants should just make the problem worse.

Tex

[tex]

Polly,

Thank you for that enlightening explanation. I see what you're saying, but LCFAs cannot be absorbed (at least not into the bloodstream) in the small intestine either. IOW they are not released into the intestinal capillaries, and that was where I always got side-tracked when thinking about this problem.

But (until I looked it up) I wasn't aware that LCFAs utilize a unique process whereby they are absorbed into the fatty walls of the villi in the small intestine, and reassembled again into triglycerides. Obviously that can't happen in the colon, since the colon has no villi (even though, as you point out, the mucosal layers are similar, otherwise). This process involves a unique passageway into the circulatory system, and perhaps this is where the problem exists for those who have BAM. Here is how the process is described in simple form, in Wikipedia:

Short- and medium-chain fatty acids are absorbed directly into the blood via intestine capillaries and travel through the portal vein just as other absorbed nutrients do. However, long-chain fatty acids are not directly released into the intestinal capillaries. Instead they are absorbed into the fatty walls of the intestine villi and reassembled again into triglycerides. The triglycerides are coated with cholesterol and protein (protein coat) into a compound called a chylomicron.

From within the cell, the chylomicron is released into a lymphatic capillary called a lacteal, which merges into larger lymphatic vessels. It is transported via the lymphatic system and the thoracic duct up to a location near the heart (where the arteries and veins are larger). The thoracic duct empties the chylomicrons into the bloodstream via the left subclavian vein. At this point the chylomicrons can transport the triglycerides to tissues where they are stored or metabolized for energy.

Fatty acid

So looking at this and thinking about it (and considering my own physical symptoms while I was reacting) perhaps the problem (the cause of BAM) lies in obstructed lymphatic passageways, because swollen lymph glands were a very common problem for me, and apparently this is a common problem for many of us when our MC is active. But the thoracic duct (aka the left lymphatic duct), is the largest of the body's lymphatic ducts, and it collects almost all of the lymph that circulates throughout the body, and from there, the lymph flows back into the bloodstream. Could it be possible that the functioning of such a major lymph duct could be compromised because of MC? That doesn't seem likely.

Love,
Tex

[Polly]

Mornin' Tex!

Yes, you have definitely described the accepted mechanism for fat absorption. Your lymphatic system idea is interesting, but I think the key here is the bile acid synthesis/resorption mechanism (enterohepatic circulation).

Normally, bile synthesis occurs in the liver and bile acid is released into the gut by the gallbladder in the presence of a fatty meal. (Bile acids are absolutely necessary for digesting LCFAs, although the short and medium chain ones can often break down with lipase alone). These bile acids work throughout the small intestine to promote fat absorption. Then, about 95% of the bile acids are absorbed from the terminal ileum and enter a unique recycling system, known as enterohepatic circulation. This system has a down-regulated feedback mechanism. IOW, if the body perceives that there is not enough bile acid in the recycling system, then it will instruct the body to make more (from cholesterol, basically).

The latest thinking about the cause of bile acid D is this: there appears to be a deficiency of fibroblast growth factor 19 (FGF 19) in the terminal ileum. And this factor apparently has a role in promoting the absorption of bile acids. Studies have found a deficiency of FGF 19 in some people with BAD. This deficiency means that less absorption occurs, and as a result, the feedback mechanism perceives a need for the production of more bile acids and the liver begins making them (from cholesterol). This causes an excess of bile acids in the small intestine, with the resulting overflow into the colon, with resulting inflammation and BAD. This explains how the sequestrants (like cholestyramine) work. They are marketed as cholesterol lowering meds - in fact, their use for diarrhea is still off-label. They bind up the bile acids, and the body perceives the need to make more, so it uses up the available cholesterol in the bloodstream to make more. Studies have shown that those with high cholesterol who use sequestrant can lower it by up to 40%.

All of the above is explained much better in this article I have cited before: http://www.medicine.virginia.edu/clinic ... Oct_12.pdf

I am intrigued by the issue with the terminal ileum. Of course we know that people who have actual damage to, or removal of more than 100 cm of, the ileum, are at risk for BAD. But the largest group with BAD have no obvious damage to the ileum, although, of course, something is going on at the cellular level. I wonder what causes the deficiency in FGF 19? Could it be an autoimmune reaction....i.e. that antibodies are being made to FGF 19? Or maybe an issue with SIBO - maybe certain bacteria (or their toxins) somehow cause damage to FGF 19? Or, perhaps FGF 19 is sensitive to environmental insults, like infection or antibiotics? And it is possible that other as yet unknown factors combine with the FGF 19 deficiency to prevent adequate absorption of bile acids. Who knows? But I think we are getting closer to some real answers. I shared the article in my first post on this thread about some current research that is finding that obeticholic acid (OCA) seems to be able to increase FGF 19 levels.

As we know, another function of the terminal ileum (besides absorption of bile acids and sodium chloride) is the absorption of vitamin B 12. Several months ago, I had a B12 level drawn, and although it was still in the normal range, it had fallen to the lower limit. Interesting.......especially since my vitamin D level has always remained above 70 (vit. D is absorbed elsewhere). Again, something is going on with the distal part of the ileum.

I don't believe I have had a major problem with BAD until more recently. For many of the 15 years since diagnosis my MC was in fairly good control, although never perfect. So, I may have had a slight BAD problem. However, this changed last Jan. when the watery urgent D hit with a bang. I went back to my GI, and she performed a ton of tests - serum gastrin, pancreatic function, the works! All negative. That's when she suggested cholestyramine....it is a regular part of her MC protocol now. It is working well for me at present. And here is an interesting aside: I have been experimenting with adding foods back into my diet and am having some success. I am also doing the low FODMAPs diet, which greatly reduces bloating, gas, etc. But I have been able to add in some of the foods that used to bother me - like tomato, white potato, etc. And wonder of wonders, I have also been able to tolerate some cheese. But I am being very cautious with all of this experimenting. The one thing I will NOT test is gluten!

Love,

Polly

[tex]

Hi Polly,

This is interesting stuff. I agree that you clearly have something going on that compromises the functioning of your terminal ileum.

I wonder about the prognosis for long-term use of bile acid sequestrants, though. Given how the feedback system works for bile salts recycling, it appears to me that interrupting the recycling process by sequestering part of the"feedstock" would result in the sending of even more aggressive feedback signals, which would call for additional bile production. Of course, if the liver is already producing at maximum levels, than more demand would be a moot point. But could that unresolved demand add to the background level of physical stress in our body? We have no way of measuring that.

Sure, bile acid sequestrants lower cholesterol levels, because they prompt the liver to work overtime to grab all the cholesterol it can get its little hands on to produce more bile. (Many people probably aren't even aware that the liver has little hands. ). But is it a good idea to work the liver at max output? And I'm not convinced that it's healthy to deplete cholesterol levels to the range that is considered "ideal" by the medical community in the first place. Research shows this to be a risky range as we grow older, and yet it's treated as a one-size-fits-all recommendation. This is not unlike the "body mass index" touted as a way to gauge relative health. Statistics show that longevity is associated with BMIs above the so-called "ideal" range, especially as we age, suggesting that the recommendations are skewed. Anyway, the point is, we are all aware that there are no "free" lunches — all medications carry some unwanted side effects.

But none of that helps to shed light on the problem at hand. It only suggests that we need a better way to deal with BAM. And like so many parameters that are mistakenly identified by overzealous researchers, I have a sneaking suspicion that the FGF 19 deficiency issue associated with BAD might be a symptom, rather than a cause of the problem. But who knows? This time they might be right.

So why would your ileum begin to malfunction, 10 to 15 years after adopting the GF diet? Some would probably point out that this proves that the health "experts" are right, that cutting gluten out of the diet is unhealthy. But that's hogwash of course. There has to be a reason though, because everything happens for a reason. Your GI doc certainly checked out all of the logical possibilities. What on earth could we be overlooking?

Also, please remember that just because we can "tolerate" something, does not mean that it is a "safe" food for us. The question is, "What is our definition of 'safe'?" I can "tolerate" dairy products just fine (without any adverse GI symptoms), but I produce antibodies to them. That couldn't be good. And I suspect that they cause osteoarthritis, in the long-term. The big question in my mind is, "What are the consequences of antibody production in the absence of antigens?" I totally avoid dairy products because of that unknown. But research statistics indicate that asymptomatic celiacs are at no higher risk of non-Hodgkin's lymphoma than someone in the general population. Of course that doesn't mean that inflammation is not present.

My EnteroLab kit arrived yesterday. I hope to shed a little light on the issue of "antibodies without antigens", but to be honest, I fully expect my results to show antibodies to at least casein and gluten. Casein is much easier to avoid, and I have no doubt that I have been totally keeping it out of my diet for the last 3+ years since my last test.

But gluten is another matter. Wheat has been hailed as an exalted diet staple for thousands of years. The air has been contaminated with wheat flour dust ever since the first loaf of bread was baked. I'll bet that if sufficiently-sensitive measuring devices were available, one could detect low gluten levels in the atmosphere over most developed countries, at any time of day or night. That implies that all of our food, and probably everything we touch, very likely contains trace residues of gluten. IMO, gluten truly meets the definition of "ubiquitous".

I doubt that these miniscule amounts are a problem for many of us (in terms of clinical symptoms), but they may be for some of us. And the big question is, "Why couldn't these tiny amounts result in the production of antibodies?" The answer is, IMO, "They can." But most of the time the antigen levels are below the threshold at which typical clinical symptoms will be triggered. So now I'm wondering if this effect (combined with additional trace amounts picked up restaurants, and/or processed foods) might be a factor in the development of malabsorption issues in the terminal ileum that result in symptoms associated with BAM. But because antigen levels are so low, the T-call reactions associated with IBDs would not be triggered, at these low exposure levels.

We know from research that with MC, the terminal ileum is a focal point for inflammation (the terminal ileum and the ascending colon typically contain the highest average levels of inflammation markers). So I'm not convinced that BAM is disassociated from MC. It might appear to be, but it's probably just another satellite issue.

Sorry for all the off-topic rambling. These were just some of the random thoughts wandering through my deranged brain this morning.

Love,
Tex

[Tor]

For people with MC, I think BAM/BAD is secondary to inflammation. It has been shown that budesonide normalize bile acid reuptake in CC. For example, look at this free article: http://onlinelibrary.wiley.com/doi/10.1 ... 828.f03t04.

For a more detailed account on how excess bile acids increases colon permeability, I think this thesis is a good read:
http://liu.diva-portal.org/smash/get/di ... TEXT01.pdf.

Andreas Münch is the head of the European Microscopic Colitis Group, and he sent me one of his published articles on this theme. Interesting work!

IMHO Münch and Bajor are two of the best scientists when it comes to MC. This new article by Bajor et. al. is also a good read on BAM/BAD: http://gut.bmj.com/content/64/1/84.long

-- Tor

[dfpowell]

Seven weeks ago I started cholestyramine because my most recent diet changes, followed for the previous 2 months, of eating only turkey, lamb, well cooked vegetables, and a small amount of banana did not eliminate my symptoms of WD, gurgling, and frequent bms. Over the past 2 years I have made many diet changes and have not seen the results that I have gotten with cholestyramine, by the second day I had normal bms, and no gurgling or gas. I am very surprised at the lack of gas in my intestine and how the gurgling stopped.

Over the past 6 months I have been tracking all my food and supplements on cron-o-meter, so I am very sure of what I am eating, my nutrient intake, and what changes I have made, which I find helpful.

Recently I have been able to decrease the cholestyramine to 1/2-3/4 dose twice a day, and continue to be free of WD and gurgling. At first I noticed bile in my bm, but I have not noticed much recently as my bms look very normal.

[DebE13]

I have been taking cholestyramine for four days now and am quite surprised at the immediate results. I noticed there is considerably less gas which is great since I'm up around 4:30 each morning and often wish for a sound proof bathroom. It's still to early to make a firm comment on how things are going but two visits to the toilet in the morning is much better than my 3-6 with additional visits after my morning break and lunch.

Reading some of the potential side effects doesn't give me any comfort but I haven't been wild about the entocort either and it's working much better. If it is a bile acid issue is it then something I would expect to take long term? Would that be a good idea for someone who has no cholesterol problems?