In this post I want to clarify that the model that I am using is re-entrant (a computer term). This means simply that you can stop at any time and restart at any point later without a problem as long as you are rotating probiotic and anti-infection agents (herbs, antibiotics, etc).

Some people report a smooth progression with greater energy and activities. Other people have severe reaction from a probiotic or herb or vitamin that very few have problems with. Your DNA and your very unique microbiome determines that.

There is NOT a protocol that you must keep religiously too. There is no magical path of taking a set of supplements. Many supplements have studies reporting that the average person improved / reduced symptoms. When you read the studies, you will find that 80% improve, 15% have no change and 5% had adverse reactions. Your odds are 16:1 that any change will be to the better, not worst. Worst does happen… so what should you do?

The answer using the model is simple — significantly  cut back on everything (even stopping everything is fine). Give your system an opportunity to stabilize itself, then add back one item at a time  — no more than one a week. Yes, you are impatient for recovery but going too fast may sabotage your recovery. 

The approach that I would use for myself after stabilizing is to resume with the last item added. I would take this in the evening –likely with an evening snack.  Then I would note if there are any of the following changes:

• Longer or shorter sleep
• Dreams – more often or less often
• Night sweats
• Do I wake up more or less refresh.

There is no preferred answer to the above — the important thing is that a change occurred. My preferred scenario is deeper more solid sleep, with night sweats and waking refresh. Other times, I went to a shorter deep sleep and notices more energy and alertness in the morning. There is no magic set of symptoms to look for — what is important is the change.

If the response is uncomfortably too severe, then I would stop. In 6 months, I may try again because my microbiome may have changed enough that this response may not happen then.  Effectively we are dealing with a constantly moving target and responses.

Re-entrant

Let me take a look at some simple examples.

• Vitamin D
  • if you supplement at 10,000 IU or more, you should have your levels check every three months — some people report that their level stayed low and suddenly jump high – why, I do not know.
  • this accumulate in the body — stopping supplement simply stops the level building (and it may naturally reduce)
• Minocycline
  • Our goal is not to eliminate all of one bacteria with this — it is reduce those that are sensitive to it.
  • The next herb or antibiotic will likely work better in eliminating those left than more of the same antibiotic. It’s mechanism will likely be different and the bacteria will have to adapt again.

There is an excellent article in the Economist explaining what antibiotic resistance is

“The genes needed for resistance can thus be quite readily available. But like any biological attribute, resistance is not a free good. Building extra bacterial bilge pumps or special drug-smashing enzymes costs a micro-organism energy and materials; changing the shape of molecules to make them drug-proof is likely to leave them working less well than they did. Simply copying the DNA of the resistance gene imposes a metabolic load. And different antibiotics require different resistance genes; the more a bug needs to use, the greater the costs.”

By frequently changing the anti-infection agent (antibiotics, herbs, probiotics) we attempt to saturate it’s defense mechanisms.

Bottom Line

Be kind and nice to yourself, herx only to the degree that you are comfortable with — ideally for only part of the day. Herbs and antibiotics are likely to have a peak herx within an hour and then reduce to nothing. Probiotics may keep going if the probiotics successfully establishes itself.

There is nothing that is required.  I look for items with good odds, but nothing has perfect odds.

In 2013, I looked at whether some bacteria may be causing  postural orthostatic tachycardia syndrome in this [post] where Clostridium septicum is one species associated with tachycardia and another CFS symptom, hypotension (low blood pressure). In early 2016, I wrote about Ivabradine, a medicine that looked promising in this [post] as well as some vacines that can cause POTS in this [post].

• From Mayo clininc “Only 33 (19%) respondents reported complete resolution of symptoms… 2-10 years after diagnosis.” [2016]
• “POTS can be mistaken for panic disorder, inappropriate sinus tachycardia, and chronic fatigue syndrome.” [2016]
• “Apart from symptoms of orthostatic intolerance, there are many other comorbid conditions such as chronic headache, fibromyalgia, gastrointestinal disorders, and sleep disturbances. Dermatological manifestations of POTS are also common and range widely from livedo reticularis to Raynaud’s phenomenon….The most commonly reported symptom was rash (77%). Raynaud’s phenomenon was reported by over half of the patients, and about a quarter of patients reported livedo reticularis. The rash was most commonly found on the arms, legs, and trunk. ” [2016]
• “Many patients with POTS also report symptoms not attributable to orthostatic intolerance, including those of functional gastrointestinal or bladder disorders, chronic headache, fibromyalgia, and sleep disturbances. In many of these cases, cognitive and behavioral factors, somatic hypervigilance associated with anxiety, depression, and behavioral amplification contribute to symptom chronicity.” [2012]
• “Numerous symptoms such as excessive tachycardia, lightheadedness, blurry vision, weakness, fatigue, palpitations, chest pain, and tremulousness are associated with orthostaticintolerance. Other co-morbid conditions associated with POTS are not clearly attributable to orthostatic intolerance. These include chronic headache, fibromyalgia, functional gastrointestinal or bladder disorders, cognitive impairment, and sleep disturbances.” [2015]
• ” Other observed dermatological manifestations of this systemic disease include Raynaud’s phenomenon, koilonychia, onychodystrophy, madarosis, dysesthesia, allodynia, telogen effluvium, increased capillary refill time, and livedo reticularis. The treatment of this disease poses a great challenge. The author reports the unprecedented use of an oral angiotensin II type 1 receptor antagonist [Losartan] resulting in remarkable improvement.” [2014]

And the gut bacteria aspect is clear:

• “The most commonly reported GI symptoms were nausea (86%), irregular bowel movements (71%), abdominal pain (70%), and constipation (70%). Additionally, 82% of patients reported having GI symptoms more than once per week, and 71% reported having seen a GI specialist, and symptoms did not improve with changes in position….GI disturbances are common, frequent, and prolonged in patients with POTS, likely impacting quality of life. Given the importance of the enteric nervous system to normal GI functioning, the same autonomic impairment leading to POTS may result in abnormal gut motility and ultimately subjective GI discomfort.” [2015]
• “Over 70 % of patients had nausea and/or vomiting, which was the most common GI symptom; other common symptoms were abdominal pain (59 %), bloating (55 %), and postprandial fullness/early satiety (46 %). Over one-third of patients had abnormal [i.e., rapid (27 %) or delayed (9 %)] gastric emptying.” [2013]
• “Two-thirds of patients with POTS and GI symptoms had abnormal, most frequently rapid gastric emptying.” [2015]
• “Nonorthostatic symptoms included dry eyes or mouth, gastrointestinal complaints of bloating, early satiety, nausea, pain, and alternating diarrhea and constipation. Half of the patients reported an antecedent illness presumed to be of viral origin.” [1999]

And mast cell involvement in some patients:

• “Mast cell activation+POTS patients were characterized by episodes of flushing, shortness of breath, headache, lightheadedness, excessive diuresis, and gastrointestinal symptoms such as diarrhea, nausea, and vomiting. Triggering events include long-term standing, exercise, premenstrual cycle, meals, and sexual intercourse.” [2005]
• ” POTS is a “final common pathway” for a number of overlapping pathophysiologies, including an autonomic neuropathy in the lower body, hypovolemia, elevated sympathetic tone, mast cell activation, deconditioning, and autoantibodies. Not only may patients be affected by more than one of these pathophysiologies but also the phenotype of POTS has similarities to a number of other disorders, e.g., chronic fatigue syndrome, Ehlers-Danlos syndrome, vasovagal syncope, and inappropriate sinus tachycardia.” [2015]

Microbiome Data is Still Lacking

“POTS, which often accompanies ME/CFS, is a fainting disorder associated with an abnormal increase in heart rate and low blood pressure. The mechanism is unknown, but some people develop it after contracting viral or bacterial infections like mononucleosis, pneumonia or Lyme disease…. found two blood-borne microbes — Human Herpesvirus-4 and the coxsackie virus — known to cause chronic disease and POTS. Though Montoya wasn’t sure if these viruses were at the root of Erin’s illness or merely collateral infections, he started her on a high dose of the antiviral drug famciclovir.” [Stanford 2014]

Losartan is cited in one study as being effective, it has risks to it. This drug has a major impact on S. Aureus (the bacteria that keeps showing up connected to CFS!!), but zero impact on E.Coli. [2002] In other words, it’s antimicrobial profile matches what my model would deem to be a very good candidate.

 
On my wish list is for a research MD to do microbiome analysis of a large set of POTS patients, and have this data, with co morbid conditions analyze by a good machine learning program – the results may give a nice bacteria strain to symptoms mapping.

I periodically review news releases on probiotics. For example Sjögren Syndrome has a distinctive shift of bacteria. There is a lot of research going on and knowledge increases often.

Bacteria that make brain chemicals[article]

Source: T.G. Dinan et al/J. Psych. Res. 2015

• Altered Mucosal Microbiome Diversity and Disease Severity in Sjögren Syndrome..Stool from SS subjects had greater relative abundances of Pseudobutyrivibrio, Escherichia/Shigella, Blautia, andStreptococcus, while relative abundance of Bacteroides, Parabacteroides,Faecalibacterium, and Prevotella was reduced compared to controls. The severity of SS ocular and systemic disease was inversely correlated with microbial diversity. These findings suggest that SS is marked by a dysbiotic intestinal microbiome driven by low relative abundance of commensal bacteria and high relative abundance of potentially pathogenic genera that is associated with worse ocular mucosal disease in a mouse model of SS and in SS patients.” [article]. This often is co-morbid to CFS/FM.
• “antibiotic-induced gut microbiota disturbance can impair novel object recognition in mice.” [2016] “Antibiotic treatment strongly disrupted and diminished the microbial community in the colon of antibiotic-treated mice. Also, microbial metabolite levels were markedly decreased in the colonic luminal contents of antibiotic-treated mice. Particularly, the colonic levels of the short-chain fatty acids acetate, butyrate and propionate as well as of trimethylamine, adenine and uracil were significantly diminished by antibiotic treatment.Circulating metabolite levels were also markedly altered by antibiotic treatment.”
• “a team led by researchers at Shanghai Jiao Tong University, China, have found that the severity of dandruff is linked to the composition of those microbes-in particular, bacteria-offering potential opportunities for treatment.” [2016]
• “The Spanish firm Biosearch Life has filed for a health claim linking a probiotic strain with the reduced risk of painful inflammation of the breast during breastfeeding.”[2016]
• “MESSAGE RECEIVED A microbe called Bacteroides fragilis (left image, boxed) sends out messages that calm the immune system, quelling inflammation in mouse intestinal cells (left, bottom half). These messages rest in pouches called outer membrane vesicles (yellow bubbles in reconstruction of microbe at right). Defective genes linked to Crohn’s disease might make it hard for people to get such messages.”[2016]
• “Autoimmune disease in children could be caused by gut bacteria that inhibit immune development. Surface lipopolysaccharide (LPS) is made by microbes such as Escherichia coli and helps immune cells to mature.” [2016]
• “Heat-killed Pediococcus pentosaceus LP28 derived from the longan fruit may help trim waist lines and reduce body fat, say results from a double-blind, randomized, placebo-controlled study.” [2016]
• “Researchers at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and their colleagues sequenced the DNA of bacterial strains in patients with metabolic syndrome who each received an FMT, finding that donor strains persisted in the recipients’ guts for up to three months following the procedure…
  Bork also noted that new strains of bacteria transferred more easily than new species….Rather, the success of the transplant appears to depend on the compatibility between the donor and the recipient.
  ” [2016] – FMT does not make a permanent change, it gives an opportunity for normalization; this may be why FMT does not work always for CFS.
• “The United States Food and Drug Administration’s (FDA) regulation of products containing probiotics is complex and largely depends on the claims that are made for the product. For example, they can be regulated as foods, dietary supplements, cosmetics, or drugs/biologics. This article is the first of a four part series about the regulation of probiotics in the USA, and we start with foods.” [article]
• “Intestinal bacteria play a key role in causing and preventing obesity and neurodegeneration and a study has suggested they could also reduce cancer risk.” [article]
• Mouth Bacteria
  • “The mix of bacteria living in the oral cavity is related to a person’s risk of developing pancreatic cancer, according to a study…”We found that Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, two species of bacteria linked to periodontal disease, were associated with a more than 50 percent increased risk of pancreatic cancer,” [Apr 2016] I suspect this may also apply to FM and CFS!
  • “In the journal Medicine comparing patients on dialysis who received periodontal treatment with those who did not. Those getting treatment had an almost 30 percent lower risk of pneumonia and hospitalization from infections. Another study published earlier this year found that gum disease is associated with a roughly 10 percent higher mortality over 10 years among patients with kidney problems…Cognitive decline among Alzheimer’s patients with gum disease versus those with healthy gums 2.5 times greater” [article]
  • “One study concluded that L.Reuteri reduced both gingivitis and plaque in patients with moderate to severe gingivits in 14 days. …in another study no significant difference [article]
• “Unexpected phage-bacteria interactions in a simplified murine gut environment Lately gut microbiota scientists have been paying more attention to phages-bacterial viruses-in the gut environment, to uncover how they interact with bacteria to affect activities in the gut.”[article]

I noticed today on facebook that someone posted a link to a NewScientist article Antibody wipeout found to relieve chronic fatigue syndrome (1 July 2015) dealing with the use of Rituximab. This is an anti-cancer drug. Since 2002, I have personally met physically several CFSers that went into full remission of CFS after treatment for cancer. The results are very believable that  “Eleven of the 18 responders were still in remission three years after beginning the treatment, and some have now had no symptoms for five years”.

I know that cancer treatment results in a massive change of the microbiome (exactly what my model asks for!). For example:

• Chemotherapy-driven dysbiosis in the intestinal microbiome[2015]. “We found that faecal samples collected after chemotherapy exhibited significant decreases in abundances of Firmicutes (P = 0.0002) and Actinobacteria (P = 0.002) and significant increases in abundances of Proteobacteria (P = 0.0002) compared to samples collected before chemotherapy.”
• Effect of chemotherapy on the microbiota and metabolome of human milk, a case report[2014]. “Chemotherapy caused a significant deviation from a healthy microbial and metabolomic profile, with depletion of genera Bifidobacterium, Eubacterium, Staphylococcus and Cloacibacterium in favor of Acinetobacter, Xanthomonadaceae and Stenotrophomonas.”
• 16S rRNA gene pyrosequencing reveals shift in patient faecal microbiota during high-dose chemotherapy as conditioning regimen for bone marrow transplantation[2014]. ” Chemotherapy was associated with a drastic drop in Faecalibacterium and accompanied by an increase of Escherichia.”
• Oral microbiota distinguishes acute lymphoblastic leukemia pediatric hosts from healthy populations [2014]. “patients who developed subsequent bacteremia, or bloodstream infection exhibited decreased overall diversity and decreased abundance of taxa including Barnesiellaceae, Coriobacteriaceae, Faecalibacterium, Christensenella, Dehalobacterium, Desulfovibrio, and Sutterella. Using machine-learning methods, we developed a BSI risk index capable of predicting BSI incidence with a sensitivity of 90 % at a specificity of 90 % based only on the pretreatment fecal microbiome.”
• Fecal microbiota diversity in survivors of adolescent/young adult Hodgkin lymphoma: a study of twins [2013]. “Adolescent/young adult Hodgkin lymphoma survivors appear to have a deficit of rare gut microbes.”
• Also, very intersting: Lymphoma caused by intestinal microbiota[2014]. “While there are not a plethora of studies demonstrating a connection between microbiota and lymphoma development, we believe that animal models are a system which can be exploited in the future to enhance our understanding of causation and improve prognosis and treatment of lymphoma.”

So, we have Staphylococcus decrease and Escherichia increase – which is precisely the type of shift that I have been advocating….

What does PubMed say for CFS?

There are just 12 studies at the moment, newspaper reports tend to often tilt results to sell newspaper.

• “Recently, two clinical trials of B cell depletion therapy with rituximab (anti-CD20) reported convincing improvement in symptoms.” [2016]
• “In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses.” [2015]
• “The delayed responses starting from 2-7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses.” [2011]

Bottom Line

We have a drug that causes remission in a subset of CFS patients [Fact]. The drug causes multiple effects: B-lymphocyte depletion and shift of the microbiome. Which effect (or a third unknown one) is the cause of remission?

IMHO the shift of the microbiome is more likely, many people have reported on this site (and by private email), significant improvement of symptoms by shifting the microbiome by just probiotics and supplements. There is no apparent link to B-lymphocyte with that treatment.

The model also predicts that any treatment will only be effective on subsets because the success is determined by the effectiveness of the treatment against the very specific strains that a person has. This is what is reported in the above literature — effective for a subset.

If you can get this prescribed by your MD, covered by insurance, and you fully understand the risks (see official literature), then give it a try. For myself, I would exhaust the appropriate probiotics and appropriate antibiotic paths first.

A reader left a comment on probiotic herxheimer reaction page, and wrote:

“The day after a Fecal Microbiota Transplant (FMT) [In Northern Europe] I woke up very constipated, but no other worsening than that. But two days after I became very sick and I just get worse and worse. All my symptoms are worse. A lot of extreme pain, inflammation, neurological symptoms, can’t almost walk etc. I know very well about herx reactions.. I have had a lot of them. …

I just wonder.. Do you think a single (or I’ll do a second one a week after the first one) FMT treatment can produce extreme herx for a really long time if you have a really bad flora as I have? Can it actually last until most of the foe species are gone, if the species from the FMT really has colonized my gut?”

I have an early 2014 post on FMT. My (limited) understanding from reading the literature is that having a herxheimer reaction has been sometimes reported, although usually minor ( cite1). I have located some online journals dealing with more extreme reactions for reference in answering your questions below.

Patient Experience #1

“After the first few transplants I developed die-off… Now I’ve done several cleanses and tried different prescriptions but this die-off did not stop for about 2 weeks straight – It was horrible and severe! So I took a break from the transplants and resumed them several weeks later. The die-off symptoms still remained but became less severe after each transplant. I never did the top-down approach, only bottom up….
After 13 transplants, my donor and I decided to take an extended break for a while and see how things progressed. I could definitely tell a change in consistency and smell. There was definitely less abdominal pain and bloating. However, although I had experienced improvements, my IBS had not been totally eliminated and my CFS symptoms remained.” [cite2]

Patient Experience #2

“Day 2 (after FMT): It’s now Day 2; I ended up holding the solution in all the way through today. The abundance of fiber I ingested yesterday clogged me up a bit, which I do not mind because the longer I can hold it in the longer the bacteria has spread and propagate. I ate an excessive amount of fiber yesterday which normally would make me quite ill; yet it only gave me subtle gas – nothing compared to what it did before. I have not noticed any substantial changes yet however. My diet will be essentially the same as yesterday.

Day 3: Finally went to the restroom at 2 PM today; I had not been able to go since the procedure – this means I held in the solution for 48 hours.The stool was a type 5 on the Bristol stool chart; therefore not in line with healthy stool. I’m not sure whether this is due to die off of the bad bacteria or if it means the procedure does not work, I will have to wait and see. I should know that a heavy amount of fiber is recommended so that the new bacteria can propagate; however if your body is not used to dietary fiber then take it easy the 1st few days or you will constipation yourself – a mistake I made. Today I begin taking Intestinew; a supplement meant to help repair gut lining in order to fix my leaky gut.

Day 4: It’s interesting; I’m actually feeling a bit worse than before I did the procedure. I’m having IBS attacks frequently and my anxiety has risen. I followed the procedure perfectly; so I’m quite dumbfounded on how it could make things worse. Either my problem extends farther than dybiosis or I’m still experiencing die off symptoms; I hope it’s the latter. If anyone has experience with fecal matter transplant die off symptoms please do share what they were. Today I’m continuing with Intestinew and reducing the fiber that I’ve been eating to try to calm the symptoms down.

Day 5: Due to a lack of any results I’m going to discontinue this journal here; I will revisit FMT in about a month and will update my progress then. This specific FMT unfortunately did not yield any results; this may be due to a variety of reasons which will be addressed next time. I still feel FMT is a real means of fixing the bacteria in one’s gut but I can’t say anymore until next month.

[Read the end of this thread, which is page 2, to see what I did following this journal. The FMT’s did work, but it took a much more comprehensive plan.]” [Cite3]

Patient Experience #3

“Once I gave my mom normal functioning bacteria [via FMT], her immune system regained it’s intelligence. She did have severe die off and pain during the FMT’s, but it appears to all have been worth it. Best of luck to all. Search for the best donor! I can even help if you need. Tessnik@yahoo.com” [cite4]

Bottom line

We do not know what the risk(odds) is for a more extreme reaction. We know that it does occur.

• Duration can be expected to be 2-3 weeks. Unlike antibiotics which have a half-life of hours (i.e. the time for half of it to leave the body), organics (bacteria) may not decrease but increase. This applies to both probiotics and fecal transplants.
• Given that this reader is well familiar with herx, it implies that the bacteria that she is fighting likely “explodes” like a suicide bomber when killed, dumping its full load of toxins into the system.

While repeated FMT does work in some, I would suggest considering a slightly different route before the 2nd FMT, namely:

• Myarisan — slowly working up from 1 tablet to normal dosage (18) and then 54 until no herx happens
• Prescript assist — slowly working up to 4x bottle dosage until there is no herx at that dosage
• GeneralBiotics’ Equilibrium — as above

The reasoning is following this idiom”The operation was a success, but the patient died”. Die-off or herxheimer reactions can become life threatening (especially if the MD does not “believe” in them). They can also be exhausting and result in lack of compliance to a treatment plan. If your bacteria produce strong die-off, then you need to move slowly in dislodging them. You want to aim for a state of moderate die off (hopefully with a few hours each day free of it).

Once you have done the above, then try another FMT.

As always, just academic discussion and speculation to discuss with your MD.