This topic for me is old hat, since I read the report of Philippe Bottero, MD in 2000, Role of Rickettsiae and Chlamydiae in the Psychopathology of Chronic Fatigue Syndrome (CFS) Patients, Journal of Chronic Fatigue Syndrome. In it he mentions several groups with results:

• “59 psycho-somatic cases; 5 schizophrenia; 3 borderline; 10 children with agressivity, excitement; 1 autistic child; 1 delirium with relapses.”
• “Group two: 82.3% good and very good results; 2.5% fairly good; 15.2% failed.”
• In addition, “other psychopathological states (300): Sydney 98 CFS Conference, Australia.” reported similar results.

How was this obtained? Using long term antibiotics — a very well known way of altering the microbiome.

Jumping ahead two decades

There are multiple articles for neurological issues having a strong statistically significant association to the microbiome..

• Autism
• ADHD
• Alzheimer’s Disease
• Autism
• Chronic Fatigue Syndrome
• Depression
• Epilepsy
• Mood Disorders
• Schizophrenia
• Stress / Post Traumatic Stress Disorder

For other conditions, we find similar findings just looking at recent studies:

• Gut microbial clues to bipolar disorder: State-of-the-art review of current findings and future directions [2020]
• The Gut Microbiome in Bipolar Disorder and Pharmacotherapy Management.[2020]
• Sleep and Microbiome in Psychiatric Diseases. [2020]
• “Alterations of the gut microbiome in anorexia nervosa have been demonstrated, but their clinical relevance remains unclear. ” [2020]
• “We have recently reported specific fecal metabolomic changes in acute and short-term weight restored patients with anorexia nervosa (AN). In this study we explored the association between those metabolomic changes and patients’ gut microbiome” [2020]

The Microbiome is only a Part — but the easiest to modify

For almost all of the above conditions there are known DNA mutations associated (SNPs). We know that there is an interaction between the DNA and the microbiome — effectively the microbiome is an organ. Organs have compatibility issues when transplanted. A similar failure to take has been observed with Fecal Matter Transplant.

The simplest model to understand what is happening is this: the DNA favors bacteria that favors the DNA desired behavior (be it good or bad). Basic self-serving “microbiome forming” by the DNA. Over time, the DNA may alter its behavior due to environmental factors like stress (epigenetics) and in a few cases, RNA from a virus may be taken up into the DNA. In reality, it is estimated that up to 50% of your DNA originated from a virus [Src 2020]… ongoing incorporation of new virus fragments remains a possibility.

The question is how do you stop the undesirable behavior? You could attempt to alter the DNA — that is very experimental with considerable risk. You could use drugs that appear to inhibit the undesirable behavior — drugs tried at random on a population in a study with positive results. Often we do not know the mechanism of the drug — simply that they worked.

My more unconventional approach is to “strong arm” the bacteria. Yes, DNA is encouraging one pattern — but with food, diet, supplements it appears possible to alter the pattern. I have seen my own SPECT scan go from appearing to be early Alzheimer’s disease back to normal by this method.

Is 100% recovery expected — no, improvement is expected. Often very significant improvement. Is there actual evidence? FMT or Fecal Matter Transplant is the clearest demonstration… you change the gut bacteria and see if there are changes!

Clinical trials with FMT have been performed in patients with autism spectrum disorder and showed beneficial effects on neurological symptoms. For multiple sclerosis and Parkinson’s disease, several animal studies suggested a positive effect of FMT, supported by some human case reports. For epilepsy, Tourette syndrome, and diabetic neuropathy some studies suggested a beneficial effect of FMT, but evidence was restricted to case reports and limited numbers of animal studies. For stroke, Alzheimer’s disease and Guillain-Barré syndrome only studies with animal models were identified. These studies suggested a potential beneficial effect of healthy donor FMT. … Whether positive findings from animal studies can be confirmed in the treatment of human diseases awaits to be seen. Several trials with FMT as treatment for the above mentioned neurological disorders are planned or ongoing, as well as for amyotrophic lateral sclerosis.

Fecal Microbiota Transplantation in Neurological Disorders [2020]

My Garage Project

The above was the spark that launched me on a project that resulted in https://microbiomeprescription.com/. Using studies from the National Library of Medicine National Center for Biotechnology Information and 16s microbiome samples (from American Gut, uBiome, Biome Sight with “MICRO” as discount code , and Thryve Inside) I applied my Data Science, Artificial Intelligence, Software developer skills to generate suggestions on what may alter the microbiome in a positive way.

I have written about antivirals in the past, and thought that it was time to do an update.

• EBV, HHV5 and other virus in CFS
• Valganciclovir, HHV-6, EBV and CFS
• Valganciclovir antiviral and CFS
• Valacyclovir, EBV and CFS
•  Valacyclovir which reported some patients with complete resolution of symptoms). 
• Myths of Chronic EBV and Lyme

Viral re-activation is common with ME/CFS [2017]. It’s a chicken and the egg scenario. Did the viral re-activation cause ME/CFS or did ME/CFS cause viral re-activation. Most people do not ask about the third leg of this stool: Was there something else that contributed to both viral re-activation and ME/CFS (or the contemporary “Long Haul Covid” syndrome).

My model for ME/CFS is a microbiome dysfunction. So the question becomes, can a microbiome dysfunction also account for viral re-activation? Latest research says yes and identifies some bacteria involved!

Correlation analyses between the microbiome and viral titers revealed a positive correlation with Gracilibacteria, Absconditabacteria, and Abiotrophia and a negative correlation between Oribacterium, Veillonella, and Haemophilus. There was also a significant positive correlation between microbiome richness and EBV viral titers.

The influence of spaceflight on the astronaut salivary microbiome and the search for a microbiome biomarker for viral reactivation [2020]

It appears to be a two way street: “Our study is the first to report the impact of long-term subclinical CMV infection on host immunity and gut microbiota” [2018]

It also extends to the food that is consumed and microbiome interaction (i.e. production of short- and medium-chain fatty acids by some bacteria consuming the food).

Our studies of the differential activities of SCFAs and MCFAs as inducers or inhibitors of viral reactivation have implications for oncolytic strategies. The HDAC inhibitors butyrate, phenylbutyrate, and VPA have been investigated as lytic activators in cells, mice, and patients (31, 85,–89). One risk of applying lytic induction therapy is that incomplete inhibition of viral replication by antiviral drugs could allow secondary infection and disease progression

Activation and repression of Epstein-Barr Virus and Kaposi’s sarcoma-associated herpesvirus lytic cycles by short- and medium-chain fatty acids [2014]

Vitamin D levels are usually low, very low with ME/CFS patients. “vitamin D deficiency can be considered as a risk factor for CMV reactivation”[2019] “For EBV, viral load was significantly higher when 25(OH)D levels were low, demonstrating an inverse correlation between 25(OH)D levels and EBV load. ” [2018]. Anna Dorothea Hoeck,MD, has had success in putting some ME/CFS patients in remission by using high dosages of Vitamin D (likely those that also has viral reactivation).

Bottom Line

While there is not an abundance of literature, we see that the metabolites produced by the microbiome can activate or deactivate existing latent viral infections. We also know a shift in bacteria is associated with increase viral titers. Last, we know that virus can alter the microbiome.

We end up with three legs on the stool with the microbiome being significant. It is very significant because it is the easiest to change.

Virus reactivation alters the microbiome which then produces metabolites causing fatigue, etc. The altered microbiome then feeds the virus…. I have often used the expression “Viro-forming the microbiome”. It’s a feedback loop that can be hard to break.

A reader from Europe has ME/CFS with severe brain fog. One of the challenges with Microbiome manipulations is that there are many, many approaches that may be taken. We do not have clear evidence on which has better results. Rather than prescribing a magic bullet path, I have made most of these paths available on Microbiome Prescription.

For the brain fog, this presents a dilemma. I have Dr. Jason Hawrelak’s recommendations for quick, ultra-generalized suggestions. In corresponding with this reader, I realized that the loss of executive decision making and brain fog — very common with ME/CFS (and I have experienced it) — left the person as the typical “deer in headlights’ seen with ME/CFS.

This week, I came up with a elegant solution. Using the microbiome sample and the symptoms that have been entered, I crafted some AI to generate suggestions based on the strong statistical relationships we have discovered via citizen science. Preliminary results are looking good.

To use this, you must enter your symptoms when the sample was taken. It uses both the sample and the declared symptoms.

If you do not have any symptoms entered (or the symptoms lacks strong associations with the current data), you will see this display

Your results may look like this:

This reader’s list is much shorted, but with several things in common

You have two choices on getting suggestions…. Clicking the “use this profile for suggestions” OR build out a custom profile. If you are brain-fogged… do the first.

This takes you to the usual suggestion page where you can scope suggestions.

This then takes you to the suggestions page.

For this reader, all of his avoids had less weight than most of the items above… so it is mainly a take this result.

And the list goes on with Apples, magnesium, selenium, oregano being on the positive list by inference.

Feed Back from the EU Reader

“Thank you very much for your help you can use in the future my data to write blog posts if you want no problem. You made me cry of joy in a dark hour.
Interesting return of result so the Jadin Model fits me:”

I used the Jadin antibiotics (following her rotation protocol) with great success in one of mine earlier relapses. He has a cooperative MD that is willing to prescribe them. Rifaximin became available after that protocol became available – it has been cited on several ME/CFS sites [1] [2]. Personally, I would keep to the Jadin protocol and only include if after a couple of cycles there has not been sufficient progress.

As a FYI: I am pleasantly delighted that the antibiotics predictions came out matching Jadin’s protocol and isolated a small number of high value antibiotics to consider.

A reader asked me about this element today. I know that the abundance or absence of some minerals/elements have health impact. A simple introduction is here. A quick summary of interesting studies is shown below

• Comparative psychopharmacology of autism and psychotic-affective disorders suggests new targets for treatment [2019] ME/CFS have neurological issues often and this discusses some possible pathways.
  • Psychotropic treatment of chronic fatigue syndrome and related disorders [1993]
• Lithium’s antiviral effects: a potential drug for CoViD-19 disease? [2020] ME/CFS often have virus re-activation as a contributing factor, sometimes reinforcing ME/CFS.
• The mood-stabilizing drug lithium eases repetitive behaviors seen in mice missing SHANK3, an autism gene, according to a new study. [2020]
• Emotionality is a common problem with ME/CFS. Fortunately, the people are too exhausted to become violent. But this paper raise some speculation: Is violence in part a lithium deficiency state?[2016]
• It is known to lower suicide rates [2020]
• “Trace lithium in water is negatively linked with changes in AD mortality, as well as obesity and type 2 diabetes, which are important risk factors for AD. “[2018] Translation: more lithium means less AD, obesity and diabetes.
• “Long-term increased lithium exposure in drinking water may be associated with a lower incidence of dementia” [2017]

Problems

Lithium increases hypothyroidism [2020] [2020], unfortunately hypothyroidism is common with ME/CFS [2019]. This makes it a high risk experiment if thyroid levels are low. Zinc supplements may reduce the risk [2017]

It’s known impact on the microbiome is below (and has been added to the analysis site)

” Lithium, valproate and aripiprazole administration significantly increased microbial species richness and diversity, while the other treatments were not significantly different from controls. At the genus level, several species belonging to Clostridium, Peptoclostridium, Intestinibacter and Christenellaceae were increased following treatment with lithium, valproate and aripiprazole when compared to the control group. “

Differential effects of psychotropic drugs on microbiome composition and gastrointestinal function [2018]

“Bacterial richness was increased in both treatments compared to vehicle-treated animals; moreover, at the genus level, lithium increased the relative abundance of Ruminococcaceae and decreased Bacteroides“

Psychotropics and the Microbiome: a Chamber of Secrets… [2019]

Bottom Line

It appears that Lithium was tried on ME/CFS patients a few decades ago. We can infer that the results were not significant on the patient population as a whole. On the flip side, it does appear to have positive neurological impact for select conditions, with some risk. For Autism where it is known that the SHANK3 defect is present, we need a well constructed study to determine th benefits to risk factors.

FMTs have been tried for Chronic Fatigue Syndrome/ME with mixed success. The why of failures has been an ongoing interest of mine. We may now have a significant factor that has been ignored in these attempts.

 Fecal microbiota transplantation (FMT) as a special organ transplant therapy, which can rebuild the intestinal flora, has raised the clinical concerns. It has been used in the refractory Clostridium difficile, inflammatory bowel disease, irritable bowel syndrome, chronic fatigue syndrome, and some non-intestinal diseases related to the metabolic disorders. But this method of treatment has not become a normal treatment, and many clinicians and patients can not accept it. 

[Research progress of fecal microbiota transplantation] 2015

This week’s Economist had an extended essay on Viruses and the like: The aliens among us/The Outsider within, this provides good background.

In addition to this, there was a podcast reporting success with FMT was associated with higher Phage Diversity in the donor. Phages are the police of the microbiome.

In this retrospective analysis, FMTs with increased bacteriophage α-diversity were more likely to successfully treat rCDI. In addition, the relative number of bacteriophage reads was lower in donations leading to a successful FMT. These results suggest that bacteriophage abundance may have some role in determining the relative success of FMT.

The success of fecal microbial transplantation in Clostridium difficile infection correlates with bacteriophage relative abundance in the donor: a retrospective cohort study (2019)

My earlier posts on FMT

• Fecal Microbiota Transplantation (FMT)
• An ideal FMT Donor scenario for ME/CFS
• Fecal Transplants – not for the herx adverse!
• A Healthy FMT Donor Microbiome and response to FMT
• uBiomes before and after a Fecal Microbiota Transplant

Bottom Line

This implies that for a greater chance of success and less risk, than DYI fecal transfer, that a lab that tests for possible infections AND for phage state may yield the best results.