Neuroinflammation is defined by Wikipedia as “inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury,^[1] toxic metabolites, or autoimmunity.^[2 “

Neuroinflammation is defined as an inflammatory response within the brain or spinal cord. This inflammation is mediated by the production of cytokines, chemokines, reactive oxygen species, and secondary messengers. These mediators are produced by resident CNS glia (microglia and astrocytes), endothelial cells, and peripherally derived immune cells. There are immune, physiological, biochemical, and psychological consequences of these neuroinflammatory responses. Moreover, the degree of neuroinflammation depends on the context, duration, and course of the primary stimulus or insult (Figure 1)

Neuroinflammation: The Devil is in the Details [2016]

In terms of ME/CFS where stress is a very common cause/contributor

• “the response to chronic or traumatic stressors. Traumatic or chronic stressors appear to promote a more neuroinflammatory profile that involves both resident microglia and bone marrow-derived macrophages (Wohleb et al. 2014a) ” [2016] Which leads to removal of chronic stress as a key treatment choice (sometimes called, re-adjusting expectations or giving the finger to those with high expectations of you!)
• “Neuroinflammation is present in widespread brain areas in CFS/ME patients and was associated with the severity of neuropsychologic symptoms.” [2014]

For more technical details, read the article cited above.
I would also advocate bookmarking the Journal of Neuroinflammation

• ” Chronic noise exposure is associated with neuroinflammation and gut microbiota dysregulation ” [2018] – move to the country
• Porphyromonas gingivalis, a periodontitis causing bacterium, induces memory impairment and age-dependent neuroinflammation in mice.[2018]

Neuroinflammation and the Microbiome

Review studies on pubmed we find:

• These findings indicated that Clostridium butyricum [probiotic] treatment could attenuate microglia-mediated neuroinflammation via regulating the GM-gut-brain axis, which was mediated by the metabolite butyrate. [2019]
• Oral Administration of the Probiotic Strain Escherichia coli Nissle 1917 Reduces Susceptibility to Neuroinflammation and Repairs Experimental Autoimmune Encephalomyelitis-Induced Intestinal Barrier Dysfunction. [2017]
• Alcohol shifts gut microbial networks and ameliorates a murine model of neuroinflammation in a sex-specific pattern. [2019] ” Surprisingly, alcohol-fed males experienced significantly greater disease remission compared to alcohol-fed females and control-fed counterparts. “
• Bee pollen and propolis improve neuroinflammation and dysbiosis induced by propionic acid, a short chain fatty acid in a rodent model of autism. [2019]
• ” the first report about the immunomodulatory effect of the common nutrient, capsaicin [a.k.a. Chili Peppers] ” [2018]
• Paricalcitol alleviates lipopolysaccharide-induced depressive-like behavior by suppressing hypothalamic microglia activation and neuroinflammation. [2019]
• Combating Neurodegenerative Diseases with the Plant Alkaloid Berberine: Molecular Mechanisms and Therapeutic Potential. [2019]
• Resolving neuroinflammation, the therapeutic potential of the anti-malaria drug family of artemisinin. [2019] a.k.a. Wormwood
• Regulation of neuroinflammation by herbal medicine and its implications for neurodegenerative diseases. A focus on traditional medicines and flavonoids. [2014] Full text

Bottom Line

There are many items that will help with reducing neuroinflammation. In terms of priorities, removing contributors should be a high priority. “Plug the hole in the dyke, do not send for more buckets!” This likely include some significant items:

• Removal of personal stress (letting go, ” Que Sera, Sera -what will be, will be”)
• Removal of environment stress
• Work on oral health

All of these can be challenging. For me, we have moved to 25 acres in the country, local organic food, no work email on my phone or home computer, blocked all phone numbers except for a few, employer has no issue with my cutting hours as needed – 20% of the staff just work 4 days a week by choice.

A friend is Spain would love to get some of the old rural monasteries or nuneries re-purpose as sanatoriums for ME/CFS people. I very much agree with her — that would be awesome.

A reader shipped me a link to Antivirals for the Gut? Study Points To Potential New Gut (and Brain) Treatment and asked for comments.

After reading, my first concern is about some naivety about biophages. Biophages are uber specialists in general, often they will address only a very small selection of bacteria. Just like bacteria, there is communications between them.

” Sorek’s team was looking for evidence that a bacterium called Bacillus subtilis might alert other bacteria to phages. The researchers knew that bacteria speak to their brethren through secreting and sensing an array of chemicals. This phenomenon, called quorum sensing, allows the bacteria to adjust behaviours according to the numbers of other bacteria around. For instance, bacteria use quorum sensing to decide whether to divide or when to launch an infection.  Instead, the team found, to its surprise, that a viral invader of Bacillus bacteria — a phage called phi3T — makes a chemical that influences the behaviour of other viruses. …

Sorek’s team found more than 100 different arbitrium(name of this class of chemicals)-like systems, most of them in the genomes of other Bacillus viruses. “Phages broadcast in different frequencies. They speak in different languages and they can hear only the language that they speak,” he adds. “

“Do you speak virus? Phages caught sending chemical messages“[2017].

So conceptually, this sounds nice … a magic silver bullet! The problem is every phage is a different caliber so finding the right gun to shoot it becomes a challenged.

In theory: We need to identify which of the 3000+ bacteria each person has that are associated with the condition. Each person with the same condition will have different taxa involved. Then we need to find the appropriate matching phages for each. Each bacteria will likely need a different phage. In the 2017 study cited above, they found 100’s of phages for bacillus genus. We have years, if not decades, that will need researching.

The article cites Firmicutes being high in ME/CFS and links to the study. I suspect that brain fog has hit the author. I read the opposite

A highly significant separation could be achieved between Norwegian controls and Norwegian patients: patients presented increased proportions of Lactonifactor and Alistipes, as well as a decrease in several Firmicutes populations.

High-throughput 16S rRNA Gene Sequencing Reveals Alterations of Intestinal Microbiota in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients [2013]

Hoping over to my library of studies we find those below. Many of the low items are co-morbid with ME/CFS. (I excluded the above study because results were different for the two sets of ME/CFS patients used)

1. Parkinson’s Disease reported from 1 studies to be High and Low
2. Allergies reported from 1 studies to be High
3. Gastro-esophageal reflux disease (Gerd) including Barrett’s esophagus reported from 1 studies to be High
4. Inflammatory Bowel Disease reported from 1 studies to be High
5. Metabolic Syndrome reported from 1 studies to be High
6. Sjögren syndrome reported from 1 studies to be High
7. Type 1 Diabetes reported from 1 studies to be High
8. Type 2 Diabetes reported from 1 studies to be High
9. Ulcerative colitis reported from 1 studies to be High
10. Acne reported from 1 studies to be Low
11. ADHD reported from 1 studies to be Low
12. Autism reported from 1 studies to be Low
13. Celiac Disease reported from 1 studies to be Low
14. Chronic Kidney Disease reported from 1 studies to be Low
15. Crohn’s Disease reported from 3 studies to be Low
16. Depression reported from 1 studies to be Low
17. Inflammatory Bowel Disease reported from 1 studies to be Low
18. Irritable Bowel Syndrome reported from 1 studies to be Low
19. Juvenile idiopathic arthritis reported from 1 studies to be Low
20. Multiple Sclerosis reported from 1 studies to be Low
21. neuropsychiatric disorders (PANDAS, PANS) reported from 1 studies to be Low
22. Small Intestinal Bacterial Overgrowth (SIBO) reported from 1 studies to be Low
23. Stress / post-traumatic stress disorder reported from 1 studies to be Low
24. Systemic Lupus Erythematosus reported from 1 studies to be Low

The findings suggested to the authors that antibacterials like minocycline and probiotics might be helpful not just in returning the gut to health, but also in reducing the neuroinflammation present in Gulf war Illness and similar disorders.

What is excluded is that success with minocycline and other tetracyclines with GWI and ME/CFS has been known for a while. For example Garth Nicolson, Continuing Research into Gulf War Illness 2001; Philippe Bottero, Co-Infections, 1987; C.L. Jadin, Common Clinical and Biological Windows on CFS and Rickettsial Diseases , 2000

In 2017, Solve ME funded a gut virome study, and a fecal transplant study is underway in Norway.

There is no mention of the massive research being done in Australia — so massive and successful that “Australians are running out of shit” (unbelievable and could not resist!) [News] In The GI microbiome and its role in Chronic Fatigue Syndrome: A summary of bacteriotherapy[2011] found ” Results: 35/60 patients who underwent initial bacteriotherapy responded to treatment. 10/15 patients who failed this course were offered a secondary transcolonoscopic infusion followed by a rectal infusion or an oral course of cultured bacteria. Of these 7/10 responded, giving a total of 42/60 (70%) patients who responded to treatment. “

Bottom Line

I often see the same old concepts being recycled for more funded investigations into these “new” concepts. Often it seems that the researchers are in their own little niche speciality and have not read (beyond a glance) the massive body of literature and studies on ME/CFS.

After some 20+ years in the ME/CFS world and having read everything that I could find multiple times…. I tend towards “Folks, put it together and get on with treating people!” The reality is that there is massive inertia in medical practice, my classic example is that many MDs believed ulcers were caused by stress for over 30 years after it was discovered to be treatable by antibiotics. MDs preached to their patients — “The ulcer is because YOU are stressed, I can’t help with that”…”What!!! Antibiotics, that is not standard of care — sorry, I will not be reckless!”

It’s been six years(2013) since my earlier review on Infrared Sauna and autoimmune conditions. As stated earlier, it is my hypothesis that this alters the microbiome — how, has still to be reported. It kicks start changes whose benefit appears not the same day, but in the week following.

The following additional studies have come out:

Perceived fatigue significantly decreased after therapy, although no significant reductions were observed during therapy. In addition, a negative mood, including anxiety, depression and fatigue, and the performance status significantly improved after therapy. However, the levels of pain and vigor did not change significantly. No patients reported any adverse effects during the therapy.

Effects of Waon therapy on chronic fatigue syndrome: a pilot study. [2015]

• [The influence of general infrared sauna on the antioxidant systems in the blood of volunteers]. [2013]
  • It was shown that the effect of high temperatures promotes the development of oxidative stress that is followed by the formation of adaptive reactions in the form of activation of antioxidant protection, enhancement of non-specific responses of the cells, increase of stability and restoration of structural homeostasis of erythrocyte membranes. 
• Waon therapy improves quality of life as well as cardiac function and exercise capacity in patients with chronic heart failure. [2015]
  •  Mental QOL improved independently of WT-induced improvement of cardiac function and exercise capacity.
• Effects of far-infrared sauna bathing on recovery from strength and endurance training sessions in men.[2015]
• Effects of sauna bath on heart failure: A systematic review and meta-analysis. [2018]
  •  exposure to an infrared sauna bath in 60°C for 15 minutes, followed by a 30-minute rest in warm environment, five times a week for 2 to 4 weeks, was associated with a significant reduction in B-type natriuretic peptide, cardiothoracic ratio, and an improvement in left-ventricular ejection fraction.

Bottom Line

I continue to still use my infrared sauna at least once a week (and likely should do more often). The evidence suggests that it does help with CFS, and potentially may reduce brain fog.

In dealing with ME/CFS I came across a group of supplements/drugs that I continue to use. The main reasons are:

• They are biofilm breakers, thus weaken the defenses of some bacteria
• Blood thinners of diverse mechanisms – I deal with a Prothrombin 20210 A/G defect (85+% of ME/CFS patients are believed to have coagulation defects – often due to epigenetics)
• They make antibiotics more effective because a much (up to 10x ) higher amount of the antibiotics makes it into tissue.
• Last, it reduces my risk of blood clots; remove much of blood vessel fibrin deposits that reduce the amount of oxygen you receive.

This is a short summary of my main ones with their literature.

Serrapeptase 

This in an enzyme derived from silk worms. It is produced for the silkworm to escape it cocoon. It is effective against some types of coagulation.

Benefits:

• break down atherosclerotic plaques [src]
• improves carpal tunnel syndrome (decreased pain) [1999]
• effective with inflammatory venous diseases (thrombophlebitis) [1996]
• effective as a booster for antibiotics, overcoming drug resistance (like bromelain) [1993]
• concentration of antibiotic in tissue increased by :[1980]
  • ciclacillin – 8.5 fold (850%)
  • ampicillin – 5.7 fold (570%)
  • cephalexin – 3 to 5 fold (300-500%)
  • minocycline – 2.2 fold (220%)
• “anti-inflammatory, anti-oedemic and fibrinolytic activity and acts rapidly on localized inflammation” [1990]
• ” Using biofilm busters, such as stevia and serratiopeptidase, could lead to bacterial blood release,  ” [2018]
• Serratiopeptidase reduces the invasion of osteoblasts by Staphylococcus aureus. [2017]
• Serrapeptase and nattokinase intervention for relieving Alzheimer’s disease pathophysiology in rat model. [2013]
• Combination therapy including serratiopeptidase improves outcomes of mechanical-antibiotic treatment of periimplantitis. [2013]

Nattokinase

This is an enzyme that exhibits strong fibrinolytic activity. Natto is a kind of fermented soy bean-cheese used in Japan. This characteristic is not from the soy but the fermentation (produced from Bacillus subtilis Natto).

• appear to reduce lipid peroxidation and improve lipid metabolism. [2002]
• enhancement of the fibrinolytic activity, increase production of tissue plasminogen activator. [1990]
• “inactivates plasminogen activator inhibitor type 1 and then potentiates fibrinolytic activity” [2003]
• having four times greater fibrinolytic activity than plasmin. [2003]
• help to prevent arteriosclerosis, as they appear to reduce lipid peroxidation and improve lipid metabolism [2003]
• Increased activated factor VII levels[1997]
• Nattokinase Crude Extract Inhibits Hepatocellular Carcinoma Growth in Mice. [2019]
• Acute toxicity and genotoxicity evaluations of Nattokinase, a promising agent for cardiovascular diseases prevention. [2019]
• Attenuation of neurobehavioral and neurochemical abnormalities in animal model of cognitive deficits of Alzheimer’s disease by fermented soybean nanonutraceutical. [2018]
• Nattokinase: An Oral Antithrombotic Agent for the Prevention of Cardiovascular Disease. [2017]
• Consumption of nattokinase is associated with reduced blood pressure and von Willebrand factor, a cardiovascular risk marker: results from a randomized, double-blind, placebo-controlled, multicenter North American clinical trial. [2016]
• A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles. [2015]
• Mechanisms of Nattokinase in protection of cerebral ischemia. [2014]
• Nattokinase improves blood flow by inhibiting platelet aggregation and thrombus formation. [2013]

Lumbrokinase

This is strong fibrinolytic enzyme was readily obtained in saline extracts of the earthworm.

• digested fibrinogen and inhibited platelet adhesion [1991]
• fibrinogen decreased significantly. Inhibition of intrinsic coagulation pathway and the activation of fibrinolysis via an increase of t-PA activity.  [2000]

Bromelain 

This is an extract from pineapple stem.

• Increased penetration of antibiotics [1986] [1978] [1973] [1972][1967]
• Benefits of a Food Supplement Containing Boswellia serrata and Bromelain for Improving the Quality of Life in Patients with Osteoarthritis: A Pilot Study. [2019]
• The potential use of bromelain as a natural oral medicine having anticarcinogenic activities. [2019]
• Antibacterial activity of papain and bromelain on Alicyclobacillus spp. [2019]
• Bromelain has paradoxical effects on blood coagulability: a study using thromboelastography. [2016]
• Fibrinolytic and antithrombotic action of bromelain may eliminate thrombosis in heart patients. [1980]
• Bromelain Degrades Aβ1-42 Monomers and Soluble Aggregates: An In Vitro Study in Cerebrospinal Fluid of Alzheimer‘s Disease Patients. [2018]

Bottom Line

These should not be taken continuously.

Warning 1:Most are anticoagulants which means that the risk of easy bruising and failure of the blood to clot is high.

Warning 2: With antibiotics, they can change a minor herx into needing to crawl on the floor herx. With 10x the concentration, you are effectively increasing the antibiotic dosage 10x!

Appropriate dosage and duration should be done in consultation with your medical professional.

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).