Phage Therapy to Treat ME/CFS and Bacterial Dysbiosis

Hip

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What Is Phage Therapy?

Bacteriophage therapy (phage therapy for short) is a means of fighting bacterial infections or dysbiosis using phages. Bacterial organisms can catch viral infections just as humans do, and the viruses which infect bacteria are called bacteriophages. These phages infect and can kill bacteria, but cannot infect humans or animals.

Bacteriophages have certain advantages over antibiotics, as each phage only kills the specific species of bacteria it targets. Such precision targeting can be useful in gut dysbiosis, as phages can selectively kill pathogenic bacteria, leaving the beneficial bacteria in the gut unharmed.

Using phage therapy to fight bacterial infections has a 100 year history, and is used today in places like Russia, Georgia, the Ukraine and Poland.



Where Can You Obtain Phage Therapy?

Phage therapy comes in two forms: you can buy inexpensive off-the-shelf phage products online, or you can get custom-selected phages that specifically target the bacterial species and strain of that species causing your health problems. Such custom-selected phages are obtained from clinics possessing a large library of thousands of different phages.

Off-the-shelf phages have the advantage of being inexpensive (as little as $30), but they are not guaranteed to work against the particular strain of bacteria that you may have, because phages are bacterial strain-specific.

You may be lucky, and the off-the-shelf product you buy contains a phage that targets your strain of bacteria. Or you may not be so lucky, and find your phage product does not work against the strain of bacteria you have. In which case, you could try a different off-the-shelf product, or you could opt for custom-selected phages which are guaranteed to target and kill your strain of bacteria.

Custom-selected phage therapy is offered at some clinics in the Republic of Georgia (the Phage Therapy Center, the Eliava Phage Therapy Center, and by the company Caucasus Healing).

Unfortunately the total cost of custom phage treatment in Georgia is expensive, in the ballpark of $3000 to $6000 (see here and here).

There is also a Phage Therapy Unit at the Ludwik Hirszfeld Institute, Poland.

These clinics possess a large library of many different phages, and they can usually find one in their library able to target your strain of bacteria. Treatment involves either visiting a clinic in Georgia or Poland, or becoming a remote patient of a clinic (sending your bacterial samples to the clinic, so that they can select and ship to you the appropriate phages in solution). At these clinics, the initial analysis to find a phage which can target your bacteria costs around $200.

Because of their low cost and ease of access, off-the-shelf phages may be a good place to start any experiments in phage therapy. Below we list many websites and pharmacies that have recently sprung up selling off-the-shelf phage products.

Only a few years ago, it was very hard to buy off-the-shelf phages from the countries which specialize in them (which includes the Republic of Georgia, Russia, the Ukraine and Poland). But now there are around a dozen websites/pharmacies selling off-the-shelf phages for the international market.

There is also increased interest in phages in the West, with a new phage therapy center at the University of California, San Diego, which is focusing on clinical trials of phage therapy.



Can Phage Therapy Treat ME/CFS?

The Phage Therapy Center in Georgia have a page on ME/CFS, and they say that phage therapy is sometimes effective for ME/CFS:
Our Opinion

Sometimes patients who believe they have chronic fatigue syndrome are actually suffering from a toxin overload that is produced by a particular strain of pathogenic bacteria. By clearing the treatable bacterial infections and utilizing various techniques to help reduce the toxin loads, there can be much improvement in the patient's overall condition.

Our Experience with Chronic Infections

Patients who have or who have had long term bacterial infections and who have taken antibiotics for extended periods may have serious damage to their immune systems, making them more susceptible to infection. Chronic infections are biofilms, they are colonies of a number of bacteria that together form colonies in various parts of the body - the sinuses, urinary tract, prostate and elsewhere that are inherently more resistant to antibiotics. While in-vitro lab tests may show sensitivity to various antibacterials, such infections typically do not respond to antibiotics. Dr. Tim Lu (MIT), a professor at MIT, explains why biofilms are antibiotic resistant, and why bacteriophage therapy can be effective:


If you have dysbiosis and/or an infection that is caused by one of the treatable genuses (Staphylococcus spp., Streptococcus spp., Enterococcus spp., E. coli, Proteus spp., Pseudomonas aeruginosa, Salmonella spp., Shigella spp., Clostridium difficile (C.Diff), Klebsiella spp., Morganella spp. and several others) there is a good chance we can help - but NO GUARANTEE. You will need to test for the presence of these treatable pathogens and even if they are cleared, sometimes symptoms will persist.

So the Phage Therapy Center in Georgia are saying in their experience, ME/CFS sometimes turns out to be caused by an overload of a bacterial toxin, produced by the pathogenic bacteria living in your body, and their phage therapy may then be able to address this bacterial infection, which may improve your ME/CFS.

This is very interesting, because Dr Igor Markov in the Ukraine also posits that ME/CFS is caused by an overload of bacterial toxins in the body. Dr Markov believes it is the kidneys which may harbor a low-level dysbiosis bacterial infection, which constantly secretes potent bacterial toxins into the systemic bloodstream, causing ME/CFS.

Dr Markov treats this this kidney bacteria dysbiosis with autovaccines (which stimulate the immune system to fight the pathogenic bacteria), and he claims a 93% success rate in curing ME/CFS.

The Phage Therapy Center also have a page on Lyme disease. The center have previously said there are no therapeutic phages for Lyme bacteria. However, they say that patients who are diagnosed with chronic Lyme disease (both those who have Lyme, as well as those with a false positive Lyme diagnosis) sometimes turn out to have a bacterial toxin overload caused by a phage-treatable species of bacteria.

So it sounds like phage therapy is not a treatment which will help all ME/CFS patients, but might have benefits for a small subset, possibly those patients who have had a stool analysis (like the Genova Diagnostics Stool Profiles) which indicates a gut dysbiosis involving a bacterial pathogen.



The Bacteria Targeted by Phages to Treat ME/CFS

There are off-the-shelf phage products available for many pathogenic bacterial species that are common inhabitants of the human gut and urinary tract microbiome, including: Staphylococcus aureus, Streptococcus pyogenes, Proteus mirabilis, Proteus vulgaris, Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, Klebsiella pneumoniae, Klebsiella oxytoca.

Some off-the-shelf phage product will target a specific bacterium, such as this Klebsiella phage product made by Microgen, and these products will contain a set of phages that are effective against the different species in the genus (like Klebsiella pneumoniae, Klebsiella ozaenae, Klebsiella rhinoscleromatis in this case), as well as contain phages which target different strains of these species.

Then there are other off-the-shelf phage products that contain phages which target a broad spectrum of different bacterial species, such as for example the Pyobacteriophage Complex product from Microgen, which targets many common gut pathogens, including Staphylococcus, Streptococcus, Enterococcus, Pseudomonas, Proteus, Klebsiella, Escherichia coli.



How Are Phages Administered?

Phages in solution are usually taken orally, but can also be administered as a rectal suppository, and in trials have been instilled intravesically into the bladder to treat urinary tract infections.



Tips for Successful Phage Treatment

Note that phage products which target a particular bacterium, but which are bought from different companies, will not usually contain exactly the same phages. Each company has its own phages.

So if you have a particular bacterial infection or dysbiosis, and an off-the-shelf phage product from one company did not have any efficacy against the bacterium, it is still possible that a phage product from another company might work for you.

Because phages are species-specific and strain-specific, the first product you bought might not contain a phage which targets your particular strain of bacterium. But a phage product from a second or third company may contain a phage that does the trick.

In the case of phage products from the Russian company Microgen, this company is actually a conglomerate which has 3 different phage-producing subsidiaries, and even when these subsidiaries make products which target the very same bacterium (and sold under the Microgen label), they contain different phages! So these three Microgen subsidiaries should be treated as different companies using different phages.

Microgen is a conglomerate resulting from the merger of several independent once local businesses. Some products that have the same name and target the same bacteria are manufactured at two different sites and do not necessarily contain the same phage according to the website.
Information about which of the 3 Microgen subsidiaries make which Microgen products is found here.



There is some concern about stomach or urinary tract acidity killing phages, but the information is somewhat contradictory:
Several sources indicate that bacteriophages dislike acidity: according to pcfarm.ro for the successful treatment of urinary tract, it is necessary that the urine be not too acidic. Therefore, two days before treatment, four times a day, the site recommends taking a pinch of baking soda diluted in water.

Then, daily during the treatment period, it recommends a pinch of sodium bicarbonate in the morning with empty stomach, and after about 20 minutes, to take the bacteriophage. Then remain still fasting for 1/2 hour.
Source: here.

This paper explains how many phages are sensitive to acid environments, but says that stomach acidity neutralizers like sodium bicarbonate have not shown to be helpful:
Bacteriophages are generally considered to be acid‐sensitive, but they differ strongly in their response to acidity. There are phages that are highly sensitive even to moderate pHs, but others which are quite resistant to even very low pHs.
....
However, stomach acidity neutralizers have not been revealed by the systematic analysis conducted herein as capable of significantly improve phage travel through the alimentary tract.


The above paper also notes that oral administration is not the best for getting phages into the systemic blood circulation:
Delivery route had a major effect on phage ability to penetrate into the system. Among all routes of administration, oral delivery was the worst. It was the least effective among other, namely intraperitoneal (IP), intravenous (IV), or intramuscular (IM) routes.
Judging by figure 3 though, intranasal administration is effective for getting phages into the systemic circulation.

To address bacterial infections or dysbiosis in organs like the kidneys or prostate, one would imagine this will require phages to enter the systemic circulation.



Websites/Pharmacies Selling Off-The-Shelf Phage Products

The following websites sell off-the-shelf phage products:

Russian and Ukrainian Phages:

Georgian Phages:

• MyBacteriophage — Search Bacteriophages — Eliava and BioChimPharm.​
• MyPhages — Search BacteriophagesBioChimPharm — Eliava and Biopharm L.​
• Phage Mart — Search Bacteriophage — Eliava and BioChimPharm.​



Manufacturers of Phage Products

These are the main producers of off-the-self phage products:

Russian Phage Suppliers:
  • Microgen (Микроген) — Russian pharmaceutical company that makes immuno-biological products. Phage products they make detailed ➤ here.
  • Mikromir — Russian company which researches and makes phages.
Ukrainian Phage Suppliers:
  • Phagex — Ukrainian company. Phage products they make detailed ➤ here.
  • Pharmex — Ukrainian company.
Georgian Phage Suppliers:
Other Phage Suppliers:
  • Bohemia Pharm — Czech pharmaceutical company.
  • Aziya — Uzbekistani company. Phage products they make detailed ➤ here.


Manufacturer Logos

Microgen.jpg

Mikromir.jpg

Phagex.jpg

Eliava.jpg

Biochimpharm.jpg

BiopharmL.jpg




History of Phage Therapy

The first hint of the existence of phages came from English bacteriologist Ernest Hankin, who when in India observed that water from the river Ganges could kill cholera bacteria within hours. He hypothesized that some organism in the Ganges water was able to destroy cholera. We now know that the Ganges river has a particularly high level of phages.

Bacteriophages were later discovered by two scientists independently: by English bacteriologist Frederick Twort in 1915 (who did not pursue his discovery further), and by French microbiologist Felix D'Hérelle in 1917.

The idea of using phages to fight bacterial infection was first proposed by d'Hérelle, who suggested that the phages which were observed to kill bacteria in test tubes might be used to treat disease.

The first recorded case of human phage therapy occurred in 1919, when d'Hérelle and colleagues made a phage preparation for a 12-year-old boy with severe dysentery. After fully testing the preparation on himself for safety, he gave it to the boy, who fully recovered within days. D'Hérelle went on to set up phage therapy clinical trials around the world.

In 1933 D'Hérelle moved to Georgia to work at the Eliava Institute on phage research, with his Georgian microbiologist friend, George Eliava. This was done with Stalin's approval, who wanted phages to keep his army healthy, and welcomed D'Hérelle to the Soviet Union as a hero.

A few years later, George Eliava fell out with the Soviet authorities (unfortunately Eliava and the head of the secret police fell in love with the same woman) and was promptly executed. D'Hérelle then fled, but the Eliava Institute survived, and became the world's leading phage research center.



Further Info on Phages

An old BBC Horizon Documentary on Phage Therapy (Video) from 1997. The video is slow to load initially, but is fine once it gets going. Among other things, it details the phage therapy center in Georgia.

Recent BBC article on phage therapy

https://www.bacteriophage.news — informative site

http://europhages.com/en/ — informative site

https://bacteriophages.info/en/ — informative site
 
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sometexan84

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Interesting, can you elaborate? ...just kidding

I'm a fan of treating bacterial infections, optimizing microbiome, and clearing out fatigue-inducing toxins.

What I'd like to know is, what the long-term status is of a CFS patient that used Phage Therapy. Because I can totally see why it would improve symptoms. I just can't envision there not being a relapse later on. You should ask them about any long-term follow-up w/ CFS patients they treated. I'd be very curious to know.
 

Hip

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What I'd like to know is, what the long-term status is of a CFS patient that used Phage Therapy. Because I can totally see why it would improve symptoms. I just can't envision there not being a relapse later on. You should ask them about any long-term follow-up w/ CFS patients they treated. I'd be very curious to know.
It would be nice to have more info from them, such their percentage success rate, the degree of improvement obtained on average, and as you say, how long the improvements last.

I don't think phage therapy is going to cure ME/CFS or place patients in to remission. But if you are lucky, maybe you might get some improvements in symptoms.

If we look the Phage Therapy Center's own words, they say:
If you have dysbiosis and/or an infection that is caused by one of the treatable genuses...there is a good chance we can help - but NO GUARANTEE.

But even if you fit the bill, and have a dysbiosis or infection with a bacterium that is phage-treatable, they do not talk about any remission from ME/CFS, but rather say that phage therapy can lead to:
much improvement in the patient's overall condition


So unless you are a billionaire, I think the $3000+ they charge for custom-selected phage treatment is probably not worth the gamble.

However, buying a relatively inexpensive off-the-shelf phage product, like this broad-spectrum Pyobacteriophage Complex 100 ml I bought from otc-online-store.com (an established and reliable pharmacy) for $44, is the kind of gamble I am happy to take. I am going to be trying these phages in a few weeks time.

I will start off taking them orally, and then may try intranasally, to get the phages into the systemic circulation, which should help target bacterial infections/dysbiosis in organs like the kidneys, prostate and of course the nasal cavity, sinuses and nasopharynx.

I wanted to try phages years ago, but I could not find any pharmacies selling phages internationally. Now all of a sudden, there are lots of places which sell them.
 
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Hip

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Do you now prefer phages over Markov's autovaccines?
If we can rely on the reports from the Markov Clinic and the Phage Therapy Center, autovaccine therapy appears superior as well as cheaper. The Markov Clinic reports a 93% permanent cure rate with autovaccines, whereas the Phage Therapy Center does not even talk about a cure for ME/CFS, only improvements, and it does not sound like those improvements from phage therapy occur that often, or that reliably.

Nevertheless, I am hoping off-the-shelf phage therapy might improve my gut health. Some years ago I did a Genova Diagnostic Digestive Stool Analysis, which showed an overpopulation of Proteus mirabilis in my gut (a state of dysbiosis). If I am lucky, the phage product I bought will target that Proteus.


Dr Igor Markov himself uses phage therapy to treat certain conditions like intestinal dysbiosis: see this page of his clinic's website.
 

LINE

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The issue with phage (to be done properly) is to identify the offending pathogen, then the clinic can reference which phage works. Of course, this is expensive and time consuming. The alternative is to buy the available commercial phages and experiment as Hip suggests. There are a couple of phages listed as prebiotics that are available on Amazon: Dr. Tobias Prebiotics lists these 4 phages. If I remember right, this can target e coli species and perhaps some other pathogens.

LH01 Myoviridae
LL5 Siphoviridae
T4D Myoviridae
LL12 Myoviridae

There are some other phage combinations that are available that are specific to gut pathogens. Facebook has a phage group that lists links.
 

LINE

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I have used a number of therapies to kill the gut pathogen (not phage though). I used an array of biofilm attackers which brought my gut down (inflammation). I also engage in natural antibiotics (after having issues with pharmaceutical abx) and focus on resistance stoppers. I have been able to make an impact.
 
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I have used a number of therapies to kill the gut pathogen (not phage though). I used an array of biofilm attackers which brought my gut down (inflammation). I also engage in natural antibiotics (after having issues with pharmaceutical abx) and focus on resistance stoppers. I have been able to make an impact.
Could you share what you have taken/done?
 

Hip

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Yes I’m also very interested because of this:
I did not see Bilophila wadsworthia when I was looking through the various phage products sold at the above-listed pharmacies, so I am not sure if you would be able to find an off-the-shelf phage product which targets this bacterium.

The phage therapy clinics might have a phage for this bacterium in their library of phages, but of course you are then talking costs of $several thousand for treatment.
 

Hip

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So I think it will be more about balancing the whole microbiome over time to correct this.
This article about treating Bilophila wadsworthia says prebiotics (like inulin) and probiotics can reduce Bilophila populations, and says that Bilophila loves bile, so high fat diets which induce bile secretion lead to an overgrowth of Bilophila. It says lots of dairy products can also stimulate Bilophila growth.

It also says that although Bilophila wadsworthia is a hydrogen sulfide-producing bacterium, it does not produce this toxic gas in the normal sulfate-reducing manner of H2S bacteria, but creates H2S by acting on taurine. So it might be an idea to avoid taurine-containing drinks like Red Bull.
 
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This article about treating Bilophila wadsworthia says prebiotics (like inulin) and probiotics can reduce Bilophila populations, and says that Bilophila loves bile, so high fat diets which induce bile secretion lead to an overgrowth of Bilophila. It says lots of dairy products can also stimulate Bilophila growth.

It also says that although Bilophila wadsworthia is a hydrogen sulfide-producing bacterium, it does not produce this toxic gas in the normal sulfate-reducing manner of H2S bacteria, but creates H2S by acting on taurine. So it might be an idea to avoid taurine-containing drinks like Red Bull.
Thanks! So a keto diet would be very much contraindicated I think?!
 

Hip

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So a keto diet would be very much contraindicated I think?!
With these things, it is always hard to know the degree of the effect. It's possible that by taking prebiotics and probiotics, this reduces Bilophila populations, and helps reduce other bad bacteria in the gut, but whether that translates to noticeable improvements in symptoms is another question.

Years ago, I found probiotics and especially prebiotics noticeably improved my energy, depression and anxiety (see an old thread from 2010). However some ME/CFS patients actually feel worse with probiotics.

Same with cutting down on dietary fat: whether that would translate into noticeable improvements in symptoms by reducing Bilophila populations is hard to say. If it does not, then it suggests the degree of effect of dietary fat on your gut health is small, and so your consumption of dietary fat is not something you would want to worry about.

This study on the effects of dietary fat on Bilophila growth suggests there is some effect. Interestingly that paper says Bilophila actually has an unknown means to stimulate bile secretion in the host, presumably for its own survival purposes, and so those with Bilophila can have higher than normal intestinal bile levels. Perhaps it would be useful to avoid supplements which stimulate bile (choleretics and cholagogues) — some details about choleretics and cholagogues in this post.
 
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With these things, it is always hard to know the degree of the effect. It's possible that by taking prebiotics and probiotics, this reduces Bilophila populations, and helps reduce other bad bacteria in the gut, but whether that translates to noticeable improvements in symptoms is another question.

Years ago, I found probiotics and especially prebiotics noticeably improved my energy, depression and anxiety (see an old thread from 2010). However some ME/CFS patients actually feel worse with probiotics.

Same with cutting down on dietary fat: whether that would translate into noticeable improvements in symptoms by reducing Bilophila populations is hard to say. If it does not, then it suggests the degree of effect of dietary fat on your gut health is small, and so your consumption of dietary fat is not something you would want to worry about.

This study on the effects of dietary fat on Bilophila growth suggests there is some effect. Interestingly that paper says Bilophila actually has an unknown means to stimulate bile secretion in the host, presumably for its own survival purposes, and so those with Bilophila can have higher than normal intestinal bile levels. Perhaps it would be useful to avoid supplements which stimulate bile (choleretics and cholagogues) — some details about choleretics and cholagogues in this post.
Thank you, these are very useful information
 

Cipher

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So if you have a particular bacterial infection or dysbiosis, and an off-the-shelf phage product from one company did not have any efficacy against the bacterium, it is still possible that a phage product from another company might work for you.

Because phages are species-specific and strain-specific, the first product you bought might not contain a phage which targets your particular strain of bacterium. But a phage product from a second or third company may contain a phage that does the trick.
However, buying a relatively inexpensive off-the-shelf phage product, like this broad-spectrum Pyobacteriophage Complex 100 ml I bought from otc-online-store.com (an established and reliable pharmacy) for $44, is the kind of gamble I am happy to take. I am going to be trying these phages in a few weeks time.
It might be interesting to test the phage susceptibility of the bacteria that you've isolated on your agar plates (context for others). I think phage solutions usually contains some sort of preservative that might kill the bacteria on the agar plate, but if you dilute it for example 1:100 the preservative probably becomes inactive, but the dilution still contains enough phages to kill the bacteria if they are vulnerable.

A few years later, George Eliava fell out with the Soviet authorities (unfortunately Eliava and the head of the secret police fell in love with the same woman) and was promptly executed.
Damn, talk about bad luck! :eek:
 
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Hip

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It might be interesting to test the phage susceptibility of the bacteria that you've isolated on your agar plates (context for others). I think phage solutions usually contains some sort of preservative that might kill the bacteria on the agar plate, but if you dilute it for example 1:100 the preservative probably becomes inactive, but the dilution still contains enough phages to kill the bacteria if they are vulnerable.
That is a very interesting idea! I believe this is what Dr Markov does in his clinic, when prescribing phages: he checks that the phages are able to kill the patient's isolated bacteria on agar first, and only if the bacteria appear susceptible does he give the patient phage therapy.

I am not clear, though, on how to do this in a reliable way. When I have grown bacteria on the urine dipslide agar, sometimes they will continue to grow more and more each day (as the days go by, the bacteria will occupy more and more area of the agar). Other times the bacteria will just stop growing on the dipslide agar after the first 24 hours, and remain in a small corner of the agar, even though I continue to incubate the agar at 37°C.

I imagine the way you detect bacterial susceptibility to phages is by observing a cessation in bacterial growth once the phages are added to the agar. But if this cessation in growth can occur anyway just on its own, you would not have a reliable way to observe phage susceptibility.


On the chromogenic agar plates, you do not seem to get continued growth at all. I have noticed you will get some growth around the areas where you have transferred some bacteria, but after around 24 hours of incubation, you do not seem to get any further growth. The bacteria remain localized, and do not grow to expand across the plate. Maybe bacteria find it hard to grow on chromogenic agar?

For the nutrient agar slants/slopes (nutrient agar in a small glass test tube), when I add bacteria this does seem to grow to cover the entire surface. But the surface area in these tests tubes is small, so not an ideal place to test for phage susceptibility. But on nutrient agar, the bacteria do seem to grow well,

If I were to buy some nutrient agar plates, I think this might work. You could watch the bacteria grow bit by bit across the nutrient agar plate. Then while the bacteria are still growing across the plate, you could add the phage solution, and observe whether that halts all growth.



A few days ago a started taking the broad-spectrum gastrointestinal phage product called Pyobacteriophage Complex, made by Microgen. I am taking this orally, rectally (administered into the colon using a colon tube), and intranasally (sprayed into the nose with a nasal spray bottle). I noticed some mild twinges in my intestines after a few hours, and then the next day, I woke up feeling more distanced from my ME/CFS. I had a slight glimpse of what it would be like to be healthy without ME/CFS.

So that was a good start. But then for the next two days I went back to my normal ME/CFS state. My dreams have been quite strange and disturbed in the last two days, suggesting there is something going on in my intestines.

I have just started taking a good probiotic, to replace any bad bacteria that may have been killed by the phages. We will see what happens over the next few days.
 
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