A reader forwarded me a copy of a 2019 patent application Therapeutic agent for chronic fatigue syndrome. Patents are an interesting mining source because often they come from unpublished studies. The last time that I did a patent review, I found some interesting stuff.

On the flip side, the inclusion of ME/CFS in the patent application rarely means that the focus is ME/CFS. Patents are written to be ascribe every possible use just in case someone later discover a use. I have several patents and have written over a half dozen of them.

This is a quick review of a few of the more interesting patent applications that mentions ME/CFS:

• Therapeutic agent for chronic fatigue syndrome – agent is Japanese horseradish (wasabi)
• FMT Related
  • Compositions for Fecal Floral Transplantation and Methods for Making and Using Them and Devices for Delivering Them
  • Microbiota restoration therapy (MRT), compositions and methods of manufacture
  • Compositions for the restoration of a fecal microbiota and methods for making and using them
  • Freeze dried fecal microbiota for use in fecal microbial transplantation
  • Compositions and Methods for Transplantation of Colon Microbiota
  • Microbiota restoration therapy (mrt), compositions and methods of manufacture
• Cyclopropanamine compound and use thereof  a lysine-specific demethylase-1 inhibitor
• Probiotic recolonisation therapy ”  The compositions further comprise one or more additional viable non-pathogenic or attenuated pathogenic microorganisms selected from the group consisting of Bacteroides, Eubacteria, Fusobacteria, Propionibacteria, Lactobacilli, anaerobic cocci, Ruminococcus, E. coli, Gemmiger, Desulfomonas, Peptostreptococcus,  ” – sounds like a fishing expeditions to get a patent.
• Methods of Populating a Gastrointestinal Tract
• Disease treatment composition comprising a combination of microbiota-derived bioactive molecules ” A composition having an effect of inducing tolerance, enhancing intestinal barrier integrity, and reducing inflammation, comprising: (a) one or more short-chain fatty acids or short-chain fatty acid derivatives; (C) at least one GPR43 ligand; (d) at least one histone deacetylase (HDAC) inhibitor; (e) one or more clostridial cluster IV, clostridial cluster XIVa, or clostridial cluster XVIII (F) a flagellin polypeptide; or (g) a combination of at least one of (a) to (d) and one of (e) to (f) ” – in short, extracting select chemicals that some bacteria produces.
• Topical macqui berry formula
• Methods and compositions relating to microbial treatment and diagnosis of disorders
• Modulation of blood brain barrier permeability

Bottom Line

Only one was CFS specific, Japanese horseradish (wasabi) . There were many dealing with FMT — I enjoyed seeing the “Fecal Floral Transplant” – A shit by any other name (to paraphrase Shakespeare)

Looking at wasabi or horseradish, I found no significant literature on it’s impact on the microbiome. I found just 140+ studies citing wasabi

• Wasabia japonica is a potential functional food to prevent colitis via inhibiting the NF-κB signaling pathway. [2017]
• Administration of Wasabia koreana Ameliorates Irritable Bowel Syndrome-Like Symptoms in a Zymosan-Induced Mouse Model. [2017]
• Antibacterial Activities of Wasabi against Escherichia coli O157:H7 and Staphylococcus aureus. [2016]
• Food Intolerance: Associations with the rs12212067 Polymorphism of FOXO3 in Crohn’s Disease Patients in New Zealand. ” We identified 17 foods with beneficial effects in our study which were significantly associated with the G allele of the FOXO3 rs12212067 polymorphism. Of these, sweet potatoes had the highest reported frequency of beneficial responses. We also identified 4 foods with detrimental effects in more than 25% of our study population. These were mustard, wasabi, and raw and cooked tomatoes, which again were significantly associated with the G allele in FOXO3. “
• Molecular Mechanisms Underlying Anti-Inflammatory Actions of 6-(Methylsulfinyl)hexyl Isothiocyanate Derived from Wasabi (Wasabia japonica). [2012]
• Bactericidal activity of wasabi (Wasabia japonica) against Helicobacter pylori. [2004]
• Suppressive effect of wasabi (pungent Japanese spice) on gastric carcinogenesis induced by MNNG in rats. [1991]

Since the western diet is relatively devoid of deeply-colored fruits, vegetables and other plant-derived culinary items (e.g., turmeric, ginger, seaweeds, purslane, wasabi, Brassica-family sprouts, and regional spices) this represents a loss of complex phytochemicals that would otherwise make their way into the gastrointestinal tract

The Microbiome and Mental Health: Looking Back, Moving Forward with Lessons from Allergic Diseases [2016]

Wasabi does appear to have significant benefit for a variety of stomach ailments. It is likely beneficial for many digestive issues — NOTE: that it may be harmful for people with the FOXO3 mutation (we are back to the DNA-Microbiome interaction complexities).

On The Gut Club someone asked about a Slovenia Probiotic Mixture. I have great respect for some of the raw probiotics that Eastern Europe produces and often sell on to retail packagers to mix and sell.

Today, there was a mixture which I must described as tossing in the kitchen sink!!! The mixture was literally tossing in anything and everything that could possibly have a health benefit.

What is in it? 20 BCFU consisting of:

Bacillus subtilis	Lactobacillus delbrückii
Bifidobacterium bifidum	Lactobacillus farraginis
Bifidobacterium breve	Lactobacillus gasseri
Bifidobacterium longum	Lactobacillus helveticus
Bifidobacterium infantis	Lactobacillus johnsonii
Bifidobacterium lactis	Lactobacillus paracasei
Bifidobacterium lactis	Lactobacillus parafarraginis
Enterococcus faecium	Lactobacillus plantarum
Lactobacillus acidophilus	Lactobacillus reuteri
Lactobacillus amylolyticus	Lactobacillus rhamnosus
Lactobacillus amylovorus	Lactobacillus salivarius
Lactobacillus bulgaricus	Lactobacillus zeae
Lactobacillus casei	Lactococcus diacetylactis
Lactobacillus casei	Lactococcus lactis
Lactobacillus casei	Streptococcus thermophilus
Lactobacillus crispatus

At least one of these I have never seen for sale in a probiotic before,  Lactobacillus zeae. I found almost nothing about it effects clinically and not a single safety study.

So we toss every strain on the lab kitchen shelf in… BUT WAIT, THERE IS MORE…

• Pineapple,
• Angelica Root,
• Anise,
• Basil,
• Knot,
• Fennel,
• Pomegranate,
• Blueberries,
• Raspberry – Leaves,
• Ginger,
• Olive – Leaves,
• Oregano,
• Peppermint,
• Rosemary,
• Red Tea,
• Red Clover,
• Sage,
• Black Cumin,
• Sweet Root,
• Thyme,
• Maca,
• Pink Root,
• Turmeric,
• Cinnamon,
• Vanilla,
• Cardamom,
• Saffron,
• Grapefruit Extract,
• Terrible Roast Extract (OPC) and
• Ganoderma lucidum

And it’s manufactured in Germany — so this must be good!

Bottom Line

This is the typical pattern that I see with a lot of supplements and probiotics. Toss in whatever marketing studies find are popular and sell it. No medical studies, and literally no science often. Just give the masses what is currently circulating as alternative medicine urban myths.

This is the new snake-oil salesmanship!

Many people have a view of probiotics being a magic bullet that can do no harm and are safe for a 3 month old or a 99 year old. This post attempts to document what we know about the use with infants. The short of it is that there are significant risks.

Probiotics use has been grandfathered in without requiring safety tests in the US.

” The use of probiotics cannot be considered risk-free and should be carefully evaluated for some patient groups. “

Infectious complications following probiotic ingestion: a potentially underestimated problem? A systematic review of reports and case series. [2018]

infections caused by lactobacilli, mainly endocarditis, bacteremia, and pleuropneumonia, occasionally occur. The relevance of Lactobacillus spp. and other members of the LGC as opportunistic pathogens in humans and related risk factors and predisposing conditions are illustrated in this review article with more emphasis on the species L. rhamnosus that has been more often involved in infection cases. 

Members of the Lactobacillus Genus Complex (LGC) as Opportunistic Pathogens: A Review. [2019]

• ” Three patients were given a diagnosis of B. longum bacteremia: 2 patients in a neonatal unit in which 17 patients were given oral probiotics and 1 patient in a neonatal unit in which 31 patients were given oral probiotics…  Thus, the incidence of Bifidobacterium bacteremia is theoretically underestimated. ” [2016] So risk of developing bactermia is 3/48 or at least 6%
• Are probiotics safe? Bifidobacterium bacteremia in a child with severe heart failure. [2019]
• necrotising enterocolitis (NEC) –  NEC was significantly reduced in probiotic group infants fed any breastmilk [20/179 (11.2%) vs. 10/183 (5.5%); P = 0.027]. No benefits were noted in exclusively formula‐fed infants [4/54 (7.4%) vs. 6/44 (13.6%); P = 0.345] (Repa et al., 2015). [2019]
• Probiotic sepsis: The reports of probiotic sepsis and the death of one preterm infant due to fungal sepsis from a contaminated probiotic product justify the concern about probiotic supplementation in preterm infants (Centers for Disease Control and Prevention, 2014; Bertelli et al., 2015; Esaiassen et al., 2016).
• ” This is the largest trial to date of a probiotic intervention. It shows no evidence of benefit and does not support routine use of probiotics for preterm infants. “[2016]
• Prophylactic administration of B.clausii to preterm neonates did not result in a significant difference in the incidence of LOS as compared with placebo. [2015]
• Our observational data support the use of Lactobacillus acidophilus/Bifidobacterium infantis probiotics to reduce the risk for gastrointestinal morbidity but not sepsis in very low birth weight infants. [2014]

General Studies

• Genomic and epidemiological evidence of bacterial transmission from probiotic capsule to blood in ICU patients. [2019]
• Meningoencephalitis caused by Lactobacillus plantarum – case report. [2019]
• Breaking Bad: a case of Lactobacillus bacteremia and liver abscess. [2019]
• Probiotic related Lactobacillus rhamnosus endocarditis in a patient with liver cirrhosis. [2018]
• Mitigating risk of bloodstream infection related to inpatient probiotic use. [2018]
• Are Probiotic Really Safe for Humans? [2018]
• Lactobacillus: the not so friendly bacteria. [2017]
• The evidence for benefit of probiotics in infantile colic is strong but limited to the L. reuteri DSM 17938 strain and to breast-fed infants. [2019]

Bottom Line

If there is a risk/indications of necrotising enterocolitis or sepsis for an infant, studies indicate that the risk/benefit for an infant is improved with probiotics [2018, 2017]. ”  Introduction of probiotics was associated with a reduced adjusted odds for ‘NEC or sepsis or death’ in exclusively breastmilk-fed infants (OR 0.43, 95% CI 0.21-0.93, p = 0.03) only. [2016]”

My advice is to not use probiotics for a child or in fact unless there is a serious health risk that the right probiotics have been documented to actually help.

Any probiotic claiming that it is designed for children — demand that they share the clinical studies for their formulation. They are likely pissing urine to make sales (excuse my language). If you get such a study and have a sick child — you really should be asking for studies with similarly sick children.

“The bacteria in your gut may reveal your true age” [2019] We actually see age specific patterns with citizen science.

It is fine for an adult to make a decision to take or not to take; but with a risk of sepsis being established with no certain benefit – IMHO, it’s inappropriate for a parent to make that decision for a child.

Addendum: More Information on Age and the microbiome

Functional microbiome deficits associated with ageing: Chronological age threshold. [2019]

• The gut microbiota and healthy aging [2018]
• Role of gut microbiota in aging-related health decline; insights from invertebrate models [2017]
• Identification of gut microbiome signatures associated with longevity provides a promising modulation target for healthy aging [2019]

I have done a few prior post on this, listed below. At a high level, this does not mean that ME/CFS is a DNA disease instead of a microbiome dysfunction, rather it paints a richer picture.

The microbiome and your DNA interact with each other. Your microbiome is actually much richer/more complex than your DNA. There is evidence that the microbiome and DNA cooperate with each other. So, ME/CFS is a “perfect storm” scenario. You need the right DNA mutations to coincide with the right microbiome dysfunction. To the best of my knowledge, no studies have been done combining the two 😦 .

I focus on the microbiome because it is much more actionable then DNA. You can change the microbiome, i.e. pull your ship caught in the perfect storm into a sheltered harbor…. The ship may still have its defect (DNA) issues, but without the storm beating on it, it won’t sink.

Past Posts

• 2013 – Is CFS in your DNA?
• DNA: Irritable Bowel Syndrome’s SNPs
• Fibromyalgia DNA SNP’s
• A Serotonin SNP in CFS
• Methylation Testing via 23andMe
• Case Study on Using DNA: Multiple Chemical Sensitivity

Extracts from Recent Studies

• MtDNA population variation in Myalgic encephalomyelitis/Chronic fatigue syndrome in two populations: a study of mildly deleterious variants [2019]
  • Role of mitochondrial DNA damage and dysfunction in veterans with Gulf War Illness. [2017]
  • Mitochondrial dysfunction in a family with psychosis and chronic fatigue syndrome. [2017]
  • Association of mitochondrial DNA variants with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms.[2016]
  • Is chronic fatigue syndrome truly associated with haplogroups or mtDNA single nucleotide polymorphisms? [2016]
  • Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome. [2016]
• Genetic Predisposition for Immune System, Hormone, and Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study. [2019]
• Single nucleotide polymorphisms and genotypes of transient receptor potential ion channel and acetylcholine receptor genes from isolated B lymphocytes in myalgic encephalomyelitis/chronic fatigue syndrome patients. [2016]
• A targeted genome association study examining transient receptor potential ion channels, acetylcholine receptors, and adrenergic receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. [2016]
• Natural killer cells and single nucleotide polymorphisms of specific ion channels and receptor genes in myalgic encephalomyelitis/chronic fatigue syndrome. [2016]
• Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome. [2016]
• Maintenance of Chronic Fatigue Syndrome (CFS) in Young CFS Patients Is Associated with the 5-HTTLPR and SNP rs25531 A > G Genotype. [2015]
• Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome. [2015]
• Use of single-nucleotide polymorphisms (SNPs) to distinguish gene expression subtypes of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). [2014]
• A possible genetic association with chronic fatigue in primary Sjögren’s syndrome: a candidate gene study. [2014]
• Meta analysis of Chronic Fatigue Syndrome through integration of clinical, gene expression, SNP and proteomic data. [2011]
• Polymorphisms of adrenergic cardiovascular control genes are associated with adolescent chronic fatigue syndrome. [2011]
• Convergent genomic studies identify association of GRIK2 and NPAS2 with chronic fatigue syndrome. [2011]
• A functional polymorphism in the disrupted-in schizophrenia 1 gene is associated with chronic fatigue syndrome. [2010]
• Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome. [2006]

Someone care to extract a summary?

In the past, I have walked thru each article and produced a checklist of SNPs cited with the matching 23andMe item (if they reports it) and even recall creating a template on a 3rd party analysis site. I do not have the time for this at present.

If a reader care to do this and write up a guest post, I would love it!

In time, I would love to add these SNPs to the microbiome site to try to detect which dna-bacteria-symptoms combinations are significant. It will be another step into being uber-specific on why you have certain symptoms and thus have specific treatment based on your DNA, microbiome and symptoms.

I have added maternal haplotypes to the symptoms list now — if you know yours, please associate it with your sample. The types entered are the common one from this page.

I just pushed out an update to http://microbiomeprescription.com/ that may help you understand what various prescription, over the counter and some supplements may be doing to your microbiome.

Select any of the links highlighted below

The next page will show some choices at the top:

Compare Impact

This is intended to allow you to better choice between alternatives – for example Aspirin versus  Paracetamol (acetaminophen). I am sure people will find more uses for it.

The process is simple, search for each item, and put a check beside it. Select the Compare Impact radio button and then click the submit button below it.
Hint: Pick Complete List, and then do Ctrl-F to search for each drug.

This will take you to a page listing the impact side by side. In this case we see that their impacts are similar, but different on a few items. At the family level there are a few differences

Compensate

This is intended when you are prescribed drugs to treat some conditions and wish to reduce the impact on the microbiome by counteracting the drug or drugs impact on the microbiome.

For this example, we pick lovastatin (a statin), Famotidine (Pepcid AC).

We may wish to first see how much impact they have together (do they reinforce or counteract each other)

Just pressing back, and changing radio buttons, and submit produces suggestions.

The suggestions are done by creating a virtual microbiome report based on the above shifts and running that through our AI engine.

The suggestion page is the new format with the long lists hidden until you ask to see them.

The Take or Avoid list is defaulted to 100 items (which is one reason that I toggle visibility). Remember – none of these items are guaranteed to work, nor do you need to take all of them. Each item increases your odds…

The avoid list values are a lot higher, and thus you may wish by reducing any of these items that you are taking.

As always, these are suggestions that must be reviewed by a knowledgeable medical professional before doing.