Thursday, November 13, 2014

Fibrolmyaglia and Non-celiac Gluten Sensitivity: Two peas in a pod?

Some newer research looking at remission in fibromyalgia recently caught my eye for a few reasons.  First, I worked on a clinical trial in fibromyalgia at the University of Pennsylvania a few years back and formed several opinions on what I thought may be predisposing factors to the syndrome.  Second, over the course of the last few years I have expanded my knowledge on gut health and gut bacteria to the point where I keep coming back to my thoughts on fibromyalgia and many of the things I thought were potential contributing factors.  This new study renewed my interest because it may be shedding light on potential lifestyle modifications that can send fibromyalgia in to remission.

Before I go in depth in to the research, I have to point out that you really cannot make very many hard scientific conclusions based on this information.  For one, this data is merely a short communication pinpointing clinical findings of the use of a gluten free diet in people with fibromyalgia.  Secondly, this wasn't a random sample of people with fibromyalgia.  These people were selected based on certain criteria, specifically that they did not have Celiac disease, they had intraepithelial lymphocytosis, and their symptoms improved on a gluten free diet.  While this very specific set of symptoms makes it hard to generalize these results to everyone with fibromyalgia, they honestly make this data far more interesting.

In Fibromyalgia and non-celiac gluten sensitivity: a description with remission of fibromyalgia, physicians in Madrid, Spain chronicle their success at putting patients with fibromyalgia in to remission with a gluten free diet.  The study followed 20 patients who met the above criteria for the study and who were willing to try a gluten free diet.  The results found all patients had improvement in their pain with 15 of the 20 patients having complete remission of their pain.  Fatigue, depression, migraines and GI symptoms all improved with their pain and 2 people with psoriatic arthritis and spondylarthritis, 2 autoimmune conditions, saw remission of those conditions as well.

This data is interesting for a few reasons.  First, all but one of the patients had some sort of digestive tract abnormality/issue, and the patient who didn't was the patient who had been diagnosed with fibromyalgia for the shortest period of time(3 years).  Indigestion, IBS, constipation, and GERD were the most commonly reported digestive issues.  Oral aphthae was also an interesting finding in 2 of the patients.  Oral aphthae is essentially recurrent canker sores in the mouth.  I've always thought this condition was a barometer of total GI health, and the presence of immune cells in the intestine provide support for this notion.

Next, none of the patients had villous atrophy, a flattening of the villi associated with Celiac disease, but all had intraepithelial lymphocytosis.  This isn't a finding because this was part of the inclusion criteria, but it provides significant evidence for the existence of non-celiac gluten sensitivity.  Intraepithelial lymphocytosis essentially means something is triggering intestinal inflammation, but it cannot be assumed that gluten is the specific cause just because there is inflammation.  Resolution of the problem via a gluten free diet and re-occurence of symptoms in 7 people who reintroduced gluten indicate gluten may be one of, if not the causative factor.  The picture below illustrates the stages of progression from normal small intestinal tissue to the damaged villi seen in Celiac disease.

Notice how the normal tissue on the left has projections, called villi, that erode over time in to flat tissue.  This is villous atrophy and is caused by intraepithelial lymphocytosis, which is illustrated by the little black dots that slowly infiltrate the intestinal tissue gradually from left to right.  As the villi become flattened, a person's ability to absorb nutrients is decreased and they may eventually become deficient in one or more nutrients.  In addition, inflammation can dump in to the circulation and cause problems elsewhere in the body.  This is where it gets interesting.

For the most part, it has always been assumed that forming antibodies to something called tissue transglutaminase has been the cause of problems outside of the gut due to ingestion of gluten.  In Celiac disease, it is believed that tissue transglutaminase binds with gluten and the immune system recognizes this complex as foreign.  From there it has been assumed that the immune system mistakes other body tissues as foreign because tissue transglutaminase is found in every cell in the body, but the patients in this study were not forming antibodies to tissue transglutaminase.  Therefore, this data does not support the notion that antibodies to tissue transglutaminase is the issue in fibromyalgia, at least not in those who fit the inclusion criteria in this study.  So what could be causing the pain?

Interestingly enough, inflammation is known to induce the release of something called nerve growth factor.  Nerve growth factor(NGF) has many functions in the body, and in response to inflammation that role is to attempt to reduce it under certain circumstances.  NGF is produced locally in tissues but can also be produced by cells of the GI tract and may circulate throughout the body to help maintain homeostasis(1).  However, continually assaulting the body with a food that increases inflammation, in this case gluten, will cause more (NGF) to be produced.

Another one of NGFs functions is that it increases pain sensitivity both acutely and chronically in an inflammatory state(2, 3, 4) and administration of anti-NGF drugs reverses this increased sensitivity rapidly(5, 6).  Notably, the biggest finding in this short communication is that removal of gluten from the diet of these patients reduced or eliminated their widespread pain.  Below is an illustration of the tender points known to be extremely sensitive to touch in people with fibromyalgia.

People with fibromyalgia have an extreme sensitivity to touch in these areas, the slightest brush to the area can cause tremendous pain.  In the study I ran, we directly measured the amount of pressure with a dolorimeter and the difference in pain tolerance between someone with fibromyalgia and someone without it is pretty striking.  However, these areas tend to be tender for most people indicating that they may have a greater supply of nerve endings than the surrounding tissue.  Fascia, a body-wide matrix of connective tissue that runs throughout muscle tissue, is richly innervated with pain receptors.  Therefore, it is tempting to hypothesize that the fascia may be involved in the widespread pain associated with fibromyalgia.  A recent study found pain receptors in the fascia to be highly prone to the pain sensitizing effects of NGF, and this effect lasted up to 2 weeks(7).

When I worked on the AT101 clinical study on fibromyalgia at UPENN, researchers elsewhere were looking at levels of something called Substance P in the cerebrospinal fluid of people with fibromyalgia as a way to diagnose the syndrome as it is elevated in patients with fibromyalgia.  In an interesting twist of fate, Substance P levels in cerebrospinal fluid appear to be associated with cerebrospinal NGF levels and cerebrospinal NGF levels have been shown to be 4x higher in people with primary fibromyalgia than in healthy controls and 2x higher than people with other pain conditions(8).

I have yet to find anything on how blood levels of NGF relate to levels of NGF in cerebrospinal fluid, and NGF appears to play a dual role in inflammation, acting as pro-inflammatory or anti-inflammatory depending on the situation.  However, in LPS induced sepsis, NGF appears to have a pro-inflammatory role(9) and this state is similar to what one would experience in non-celiac gluten sensitivity with LPS-containing bacteria from the intestine leaking in to the bloodstream due to a leaky gut.  Whether NGF functions as pro- or anti-inflammatory is irrelevant, however, since an increase in NGF that accompanies inflammation likely induces increased sensitivity to pain, the hallmark of fibromyalgia.

I would love to go more in depth with the science aspect in this blog, but it gets pretty dry.  The take-home message is that a gluten free diet is a potential therapeutic approach that most people with fibromyalgia likely don't use to their advantage.  Even in those who have tried it, the results are variable and can take some time.  I've worked with people to eliminate gluten and it's hard enough to get them to go without it for a week, let alone for several months.  Another issue is that, for some people, gluten may not trigger intraepithelial lymphocytosis or at least may not be the sole instigator.  We are all different and have different sensitivities to food.  One of the more important things to consider is not whether or not you should be eating gluten, but whether or not gastrointestinal health should be a central variable in what you consider to be a healthy diet.

In the short communication discussed in this blog, some patients saw quick relief over the course of a few months while others took much longer and the results came along much more slowly.  I have a feeling this may have to do with how damaged their GI tract was, how strictly they followed the diet, or whether other foods also triggered a reaction specific to the individual.  In addition, other foods such as eggs, coffee, oats, and dairy may have cross-reactivity with gluten, meaning that some of the proteins are similar enough to gluten to give the body the impression that you are eating gluten.  Even a small dose of gluten can be problematic for someone who is reacting to it, and a diet containing something the body senses as foreign with a structure similar to gluten may have the same effect as eating gluten itself.  For more on gluten cross-reactivity go here.  A study looking at a gluten free diet found persistent intraepithelial lymphocytosis in people with Celiac disease despite a long term gluten free diet.  The offending nutrient was oats(10), which do not contain the problematic proteins associated with wheat and barley. Cross-contamination may be a potential contributing factor in this study.

Another confounding dietary issue could be the presence of small intestinal bacterial overgrowth, or SIBO.  A recent study found that 100% of the people enrolled in the study(42 out of 42) who had fibromyalgia also had SIBO(11).  We do not know if this is cause or effect, but eating a reduced FODMAP diet is likely a good idea to help normalize the gastrointestinal flora as SIBO can induce intestinal inflammation.  Finally, consumption of foods that contain or cause the release of histamine may be problematic due to the inflammatory effects of histamine.  For more information on histamine, check out this blog.

Now, to the bottom line.  If you have fibromyalgia, the autoimmune paleo protocol low in FODMAPs and histamine containing and releasing foods is likely the best dietary protocol to help calm down the immune activation in the gut.  Below are a couple of links to foods that fit the FODMAP and histamine criteria.  After a couple of weeks the hope is that the pain sensitizing effects of NGF will wear off, but it wouldn't surprise me if results took longer.  There are other strategies that have to do with exercise, stretching and physical activity that would speed up the process, but we'll save that blog for another day.

A final interesting note on this study.  The predominant theory is that once an autoimmune process starts, it will continue throughout life if the environmental trigger is reintroduced.  In other words, it would mean lifelong elimination of gluten from the diet.  However, this study does not support fibromyalgia as a classic autoimmune disease in that antibodies are not being produced, at least not to tissue transglutaminase.  In theory, this means that once the gut is healed, a person may be able to eat gluten in sane quantities provided their gut is healthy and the majority of their diet is centered on maintaining a healthy gut.  This would mean that once their gut is healed, it would be beneficial to gradually increase FODMAPs and other types of fiber to promote a more acidic GI tract and to limit inflammation once the SIBO is cleared.  However, there is the potential that people with fibromyalgia are forming different antibodies when they ingest gluten, but I don't imagine the science will pick up on that for quite some time.

Histamine in foods

Foods low in FODMAPS