Category Archives: Treatment

Unknown's avatar lassesen 2:26 am on March 11, 2014  

Combating an Infection Defense Mechanism: Biofilms

Bio-films are an effective defense mechanism of both bacteria and viruses. A 2010 paper states “these extracellular infectious structures may protect viruses from the immune system and enable them to spread efficiently from cell to cell. “Viral biofilms” would appear to be a major mechanism of propagation for certain viruses. ” [2011 article] If you have reason to suspect that your CFS is related to EBV, HHV6 or other viruses, you should include treatment against biofilms. 60% to 85% of all microbial infections involve biofilms [2010]. Most, if not all, bacteria (and fungi) are capable of forming biofilms [2011]. There is evidence that HHV virus may use existing biofilms[2007]. Microorganisms growing in a biofilm are highly resistant to anti-microbial agents by one or more mechanisms [2002].

If you break down bio-films, more infections may be exposed and symptoms may increase. This is commonly called die-off or a herxheimer reaction. At the same time, having the infection exposed means that both your immune system and anti-infection agents can kill off the infections.

Classic Biofilm Breakers

  • N-acetylcysteine (NAC) is an effective biofilm breaker[Articles].  You should not take acetaminophen (Tylenol,  Anacin-3) with it(it is used for overdoses of acetaminophen). Available as a supplement. It has a half-life of 6 hours suggesting one capsule per  day. Given the long half-life, it may be taken within a few hours of any anti-infection agents.
    • WARNING: This increases histamine release

  • Ethylenediaminetetraacetic acid (EDTA) is another effective biofilm breaker [ Articles]. It can make some antibiotics up to 1000x more effective[2006]. Available as a supplement. This decreases histamine release. It has a half-life (time for the blood concentration to become half) of 45 minutes which suggesting a capsule before each meal. It should be taken with any anti-infection agents.

Why is histamine release relevant? One model of CFS is that it caused by histamine intolerance (due to overproduction).  Both Enterobacter and Klebsiella are known (major) overgrowth bacteria in CFS, and both are known to result in a high conversion of the essential amino acid histidine(found in eggs, chicken, beef, etc) to histamine. If you are interested in this, see my own blog [1] [2].

Always have the dosage and frequency of all supplements reviewed by a knowledgeable health professional before making any changes.

Herbal Biofilm Breakers

There are some herbs that have been demonstrated to inhibit biofilm formation. It appears that they are not as effective as the two supplements listed above.

Pattern for Anti-biofilms and Anti-pathogens

Continuous anti-pathogens is no recommended by same CFS Physicians, in particular, Dr. Cecile Jadin, who applied a treatment protocol to CFS that was originally developed for occult rickettsia infections in Africa half a century ago.  I discovered an interesting article from 2012  entitled “Optimal control strategies for disinfection of bacterial populations with persister and susceptible dynamics”.

“It is well-known that bacteria tend to attach to most surfaces and that this attachment becomes irreversible in the case of a biofilm colony. We have included transient attachment of the bacteria to the walls of the chemostat to incorporate this process. As the attachment rate increases, the time that it takes to eliminate the bacteria increases, which accords with intuition (since fewer bacteria are being washed out per unit time). Our results indicate that this makes constant dosing less effective since preventing growth (or keeping the bacteria in the persister state by never withdrawing the antibiotic) can eliminate the bacteria if they are washed out of the system.”

This is echoed in a 2008 article, Multidrug tolerance of biofilms and persister cells:  “Other approaches to the problem include … cyclical application of conventional antimicrobials.”

Unknown's avatar lassesen 5:43 am on March 8, 2014  

Histamine intolerance – a possible CFS mechanism

In reviewing many sites dealing with histamine intolerance as well as PubMed articles, there is more speculation than fact (especially well constructed studies).

My approach is simple to the issue of reducing histamine levels:

  • Avoid foods that are already high in histamines before entering the mouth (which is the common wisdom out there)
  • Avoid food that with the wrong bacteria in your gut, would generate histamines in the guts (this does not appear to be commonly discussed).

To understand the histamine environment, I put together a simple diagram below

histamines

The second approach means reducing eating foods in histidine, an amino acid.  Unfortunately, there is no RDA for histidine, the WHO recommends 700 mg/day. To get this:

  • 33 gm (1/3 serving) of Soy protein isolate (1 oz)
  • 50 gm of Beef (2 oz of beef)

Additionally, encourage the breakdown of histamine by encouraging the DAO reaction on histamine.

Treatment

A 2013 study found that diamine oxidase (DAO) levels are significantly low with histamine intolerance,  “our results showed the benefit of a histamine-free diet because after the diet the majority of symptoms disappeared and the serum DAO activity significantly increased.” More detail is available here. A 1993 study states that “diamine oxidase cannot be supplemented” and describe the low histamine diet as avoiding:

  • “Fish, cheese, hard cured sausages, pickled cabbage and alcoholic beverages had to be avoided.”

A 2007 article in Clinical Nutrition is available as full text and explains the process well and identifies histamine-N-methyltransferase (HNMT)  as another eliminator of histamines. A table of some foods with histamine content as well as troublesome drugs is also included.

  • “histamine intolerance seems to be acquired mostly through the impairment of DAO activity caused by gastrointestinal diseases or through the inhibition of DAO, “ which suggest that gut bacteria may be a factor for DAO levels.

Supplements that were shown effective are:

  • Vitamin C
  • Vitamin B-6 (which leaves the to supplement or to avoid question unclear)
  •  Flavonoids “Fisetin, kaempferol, myricetin, quercetin, and rutin inhibited …histamine release” [2008]

There is table of foods that release histamines (i.e. reduces the body stores of them). This list was actually confusing as several items are included that are the recommended CFS list of foods/supplements:

  • Liquorice,
  • Spices,
  • Chocolate
  • Pineapple (i.e. Bromelain!)
  • My old favorite foods during relapse:
    • nuts and
    • peanut butter!

Doing some further digging, it appears that these have not been confirmed by any clinical studies as having negative impact, rather they appear to be speculative beliefs.

A 2010 study, also available in full text, add further information such as:

  • “Some natural additives like glucose, spices, milk, vanillin, starch, orange juice, ascorbic and citric acids, showed an effective effect on disappearance of histamine and tyramine.”
  • “it was found that tomato showed a decrease in histamine and tyramine concentrations by adding spices. Strawberry and banana showed a clear decrease in histamine and tyramine concentrations by treating them with ascorbic acid [Vitamin C].”

This suggests that a proactive approach may be to soak meats and other foods with a high histamine risk in orange juice to reduce the risk or amount of histamine.

EDTA

An old 1973 article reports: “The characteristics of histamine release induced by human leukocyte lysates were determined. Intact human leukocytes released histamine during incubation with leukocyte lysates. Maximal release occurred under physiological conditions of temperature and pH, and both Ca(2+) and Mg(2+) were required. The addition of ethylenediaminetetraacetic acid abruptly inhibited release.” and this 1976 article: “The activation of human serum complement by incubation with zymosan generates C5a which releases histamine from autologous basophils. The characteristics of the C5a-induced histamine release were investigated. It is similar to IgE-mediated reactions in requiring Ca++ and in being inhibited by EDTA.“

Mangosteen, a Thai medicinal plant

A 2002 article reports: “These results suggest that the 40% ethanol extract of mangosteen has potent inhibitory activities of both histamine release and prostaglandin E2 synthesis.”

Histidine Intake Reduction

Histamine is produced from histidine. This suggests that consuming low histidine foods is beneficial. A low histidine diet with a low histamine diet should be considered. We are fortunate to have detail information of histidine levels available at various sites, including:

Probiotics

In my prior post, it is clear that you wish to avoid Lactobacillus bacteria (typically in yogurt and common probiotics) because they produce L-histidine decarboxylase which converts histidine into histamine.

  • Bifidobacterium infantis and Bifidobacterium longum reduces histamine levels [2008]
  • Bifidobacterium lactis Bb-12 also reduces [2000]

My inference is that the probiotics demonstrated to be effective for IBS are likely also histamine reducers.

Green Acres – Information

My last source of information is actually one that often has been very helpful — agriculture research . We find:

  • “higher diamine oxidase activities, transforming growth factor-α, trefoil factor family and MHC-II concentration occurred when feeding 10% wheat bran fibre (WBF) or 10% pea fibre (PF).” [2013]
  • “Tributyrin (TBU) is a good dietary source of butyrate … increases… diamine oxidase” [2014]
  • ” the activities of diamine oxidase .. higher with high fermentable protein (fCP)” [2013]
  • “Zinc … decreases  diamine oxidase” [2013] Zinc dosage: 30-40 mg/day see this post
  • Fish oil ..”decreased plasma diamine oxidase (DAO) activity and increased mucosal DAO activity’ [2012]
  • Copper deficiency associated with low DAO levels [2007] [1998]
  • “Glycinin, the main storage protein in soybean,…indicating that more histamine had been released in glycinin-fed piglets than in control” [2008]

The last study suggests that soy products should be avoided totally.

Major Histamine Producing Bacteria

A 2009 paper lists some species that produces a lot of histamines.

  • Morganella morganii
  • Providencia rustigianii
  • Proteus mirabilis
  • Raoutella planticola
  • R. ornithinolytica
  • Enterobacter aerogenes
  • E. gergoviae
  • Photobacterium damselae
  • Klebsiella oxitoca
  • Hafnia alvei
  • Vibrio alginolyticus
  • Citrobacter freundii

Both Enterobacter and Klebsiella are known overgrowths for CFS.  Streptococcus thermophilus(common in many yogurts)  isolates have the ability to form biogenic amines, especially histamine, and tyramine [2013].

Some Lactobacillus do not produce significant amount, for example Lactobacillus plantarum [2012] used in some cheeses.

The Acid-Basic Connection

  • “The alkalinity of the urine excreted after histamine injection, reaching pH 7.1 to 8.0, was high compared with 5.4 to 6.9 before the injections. ” [1926] This suggests that histamine producing bacteria favors higher (alkaline pH) and suggests that an alkaline biased diet may be beneficial. See this post for more details (the post could be retitled, how does excessive histamine production starts!)
Unknown's avatar lassesen 6:45 pm on March 6, 2014  

The histamine production model of CFS

Some researchers believe that over production of histamines contributes significantly to CFS. The article Freshness Counts: Histamine Intolerance gives a nice simple description with just enough technical details to make me happy, especially since it was written by a MD. One section caught my eye

To turn a garden variety amino acid into a powerful biogenic amine, you need to remove its carboxyl group. To accomplish this you need a special enzyme called a decarboxylase (fancy word for “enzyme that chops off carboxyl groups”).

Many species of bacteria and yeast contain the enzyme histidine decarboxylase(HDC), which turns histidine into histamine. So, when meat (or fish) is not immediately consumed or frozen, bacteria get straight to work breaking down the amino acids within it, and one of the by-products is histamine.

The MD focused on bacteria and yeast before it was consumed – that is, acquired during the storage and preparation process of the food. I find myself asking the opposite question — what about those after it is consumed.  The microbiome (gut bacteria etc) contains bacteria and yeast too!

So over to PubMed, and the first article(2014) was shockingly on target.

“The model probiotic organism Lactobacillus reuteri ATCC PTA 6475 is indigenous to the human microbiome, and converts the amino acid L-histidine to the biogenic amine, histamine.”

Is this why some CFSers have very severe reactions to probiotics? They may increases an already elevated level of histamines? The article continues onward to describe how a specific gene (eriC) is involved. Another 2013 article look at other aspects of L.Reuteri species and histamine production.

This also has been seen with a strain of streptococcus thermophilus as described in this 2012 article. This species is common in yogurt.

Another article(2013) found “species were identified as Bacillus licheniformis A7 and B. coagulans SL5. ” The species Bacillus Coagulans is found in commercial probiotics – however, I do not believe they use this strain.  As a reminder to readers, bacteria is broken down into families, species. strains equivalent to Humans, Italians, Mafia. There are good strains (Michelangelo, Galileo, etc) and bad strains (Mafia god-father).  Be very careful not to think that “All italians are in the mafia” or “All italians are great artists”. Both are incorrect. Similarly, with bacteria:  Some species are very good (like E.Coli Nissle 1917) and some are very bad (many other E.Coli strains).

A 2010 article reports: “Lactobacillus plantarum, L. brevis and L. casei/paracasei, and Enterococcus faecium and Enterococcus faecalis were identified as tyramine/histamine producers in the sausages.” These are all common in typical commercial probiotics.

There are 200+ article on pubmed dealing with this area.

So how to deal with this issue?

A 2013 article looked at the use of spices and found clove oil, lemongrass and sweet basil oil were effective against one species. A 1996 study found “Cinnamon and clove exhibited a significant inhibitory effect,  whereas turmeric and cardamom had a moderate effect.”

How does this relates to the Microbiome Model?

It actually agrees completely. If the stable dysfuctional gut bacteria is rich in strains that produces histidine decarboxylase(HDC) we are in complete agreement. The model states that the symptoms are due to a stable dysfunction (which will vary from person to person). This is just such a subset where histamines are the inducer of the symptoms.

Unknown's avatar lassesen 11:07 am on February 11, 2014  

Gut Bacteria Testing — the harsh reality

Please read also a more detail analysis of test results done in March 2014, start here.

There are many companies offering gut bacteria testing. Unfortunately, the families of bacteria covered by commercial tests are just a fraction of those in the human gut. A recent study was blunt “The proportion of the human gut bacterial community that is recalcitrant to culture remains poorly defined.” [2011] or to put it in the common tongue: “We have no idea of what percentage of the gut bacteria that we can culture (and thus test)”

This is the root of the problem – the best, most funded researchers in the world are literally in a bacterial fog! If you having a good cognitive mind day, you should read Extending Our View of Self: the Human Gut Microbiome Initiative (HGMI)

Today, the best hope for meaningful test results in likely the http://americangut.org/ project. They are clear in expectations “The bad news is that much of this information is still mysterious because we don’t know the complete genomes of most of the microbes in there, but the good news is that you can get an insight into the gene functions, not just which microbes are there.”[*].

  • Will my MD know what it means? I really doubt it, the experts do not!
  • What is the benefit? My hope is that by enough CFS patients doing it and sharing their results, we may identify some common aspects. No immediate benefit to you.

With no testing available, how can you propose a model?  Honestly, my model lacks the amount of technical, detailed, hard supporting studies that I would prefer. A model is, or should be, the best (and simplest) fit to all of the data available. It is your best guess. A model also should have predictive abilities — in this case, taking things that reduce the known overgrowth and other things to increases the known undergrowth should reduce symptoms. For me it has. For some of my readers, it has too.

We will likely not get the type of data that I would like for another 10 years, getting specific probiotics for another 20-30 years. I am just trying to work off the best that we currently know and what is commercially obtainable….

Unknown's avatar lassesen 12:24 am on February 3, 2014  

Buteyko (and other) Breathing Theraphies

There is a fourth factor that can impact hypoxia that I did not mention in my last post: The ability of oxygen to be carried by the blood. This gets a little complicated so I will approach it backwards: from the method to why the method works.

During my 1999 CFS episode, I tried Teresa Hale’s Breathing (which was popular and new then). It caused some improvement but did not lead to remission. Today, Buteyko is what is often popular with some CFS patients. It appears to be effectively the same.

Cochrane’s review in 2013 found no evidence to support that it is effective in general. Some reports indicate some subjective improvement for asthma[2013].

The rationale for the improvement was the change of pH of the blood which also altered the pH of the digestive system. There is a Ying-Yang relationship between these two when it comes to pH. At that time. I recall that there was debate whether you want to increase or decrease the pH. Today — I have a good answer.

Yes.

It may be unimportant if it increases or decreases — what is important is that it changes. Why? The acidity (pH) has a very significant impact on the microbiome (gut bacteria). The core of the model is that we have a dysfunctional cartel of bacteria and need to change them. We do not have tests for or knowledge of which bacteria are in the cartel.

Blood pH issue

For details, see http://en.wikipedia.org/wiki/Blood but the simple form is shown below. I read this as saying:

  • higher blood pH increases oxygen levels
  • lower temperature increases oxygen levels (is this why CFS patients often have temperatures < 98.6, even down to 96F?)

Oxyhaemoglobin dissociation curve

So what is the expected result: symptom reduction because you are reducing the degree of hypoxia.

If you are interested in following up on this, you may wish to read:

IMHO: It will help reduce some symptoms, it will not lead to remission. There is no harm in trying it (and it may provoke a placebo effect – which is always good).