Mycobacterium vaccae vaccine reduces microglial priming, which could treat ME/CFS

[Hip]

A team at the University of Colorado have shown that Mycobacterium vaccae subcutaneous vaccinations can prevent obesity caused by Western diet, reduce microglial priming, and reduce neuroinflammation in the brain (in mice at least, the next step is testing in humans). Mycobacterium vaccae is a beneficial bacterium naturally found in the soil. Article here, study here.

From the ME/CFS perspective, the reduction in microglial priming is the most interesting, as it has been theorised (by Prof Hugh Perry and Dr Jarred Younger) that microglial priming could be the basis of ME/CFS. Amy Proal recently tweeted about microglial priming.

Microglial priming is where microglia in the brain have become "trigger happy", which is to say that the microglia have become over-sensitive, so they activate strongly for even the slightest hint of infection, thereby creating unnecessary neuroinflammation in the brain.

If you can reverse microglial priming, you may be able to ameliorate ME/CFS. So the fact that this Mycobacterium vaccae vaccine reduced microglial priming in mice suggests it could be an effective treatment for ME/CFS.

There is a commercially-available Mycobacterium vaccae made by Chinese firm Anhui Zhifei Longcom. Their vaccine is called Vaccae, and is used to treat latent tuberculosis infection.

There is also an immune-stimulating heat-killed Mycobacterium vaccae supplement available, see this post.



A previous 2017 study by the same team found injecting mice with heat-killed Mycobacterium vaccae boosted brain serotonin, making the mice less anxious and more stress resilient. They theorise that treatment with this bacterium could help a whole range of inflammatory diseases, including psychiatric disorders (which often involve neuroinflammation). Article here.



Unrelated to the Mycobacterium vaccae study is the fact that complement system C3 appears to drive microglia priming. See this study. So inhibiting C3 might help ME/CFS. One supplement which is a potent C3 inhibitor is the supplement fucoidan (also called fucans) from brown seaweed. See this study.

When I have taken the brown seaweed supplement Ecklonia cava which contains fucoidan, I've generally found my ME/CFS feels slightly better.

 

[jasperZA]

I find the idea of microglia priming very interesting as it can explain why crashing in a crash can lead to permanent baseline worsening.

Renz-Polster:
> Also, once repetitively stimulated by challenges, the “activation” threshold may decrease and with it the ability of the glial cells to revert to homeostatic physiological functions.

Microglia depletion might be another way to reset microglia priming. The microglia are replaced after a few weeks.
I don't think that peripheral inflammation and pathogens drive microglia priming, so it wouldn't just come back, because it's not so much about the grade of inflammation/microglial triggers but about how strongly the microglia react to them - based on their previous exposure.

 

[Hip]

I don't think that peripheral inflammation and pathogens drive microglia priming, so it wouldn't just come back, because it's not so much about the grade of inflammation/microglial triggers but about how strongly the microglia react to them.

From what I have read, when immune cells like macrophages or microglia are exposed to an inflammatory stimulus like interferon gamma, this sensitives these cells (primes them), so that if they are later exposed to a second inflammatory stimulus like LPS, these immune cells react much more quickly and much more strongly the second time round.

This paper explains it:

In macrophages that have previously been exposed to IFN-γ (the priming stimulus), exposure to a triggering stimulus, such as LPS, leads to an exaggerated production of pro-inflammatory cytokines. Priming of macrophages involves several molecular mechanisms, including upregulation of Toll-like receptors (TLRs).

I believe it can also work the other way around, where the priming stimulus is LPS, and the second stimulus is interferon gamma.

This makes me think that prior to catching the viral infection that triggers most people's ME/CFS, people may have already been exposed to an inflammatory stimulus, maybe a bacterial toxin like LPS coming from a leaky gut. Or maybe some inflammatory stimulus from a mould infestation in their home.

So their immune cells might have already been primed via this inflammatory stimulus. Then when they catch a viral infection, since this normally triggers the interferon gamma response, it acts as the second inflammatory stimulus.

 

[Hip]

Microglia depletion might be another way to reset microglia priming. The microglia are replaced after a few weeks.

Yes, I've come across a few drugs in development which can deplete microglia. Though I wonder what risks might be involved? Flair up of dormant viruses in the brain might be one.

 

[jasperZA]

Thank you for the response.

I am wondering:
- would the microglia quickly become active again after depletion (or the vaccine you mentioned), because they are chronically stimulated (pathogens, inflammatory mediators)?
- or would they only become active again in a crash, and you would have to stimulate them another time wirhin a short timeframe (weeks?) to lower their activation threshold?

 

[Hip]

would the microglia quickly become active again after depletion (or the vaccine you mentioned), because they are chronically stimulated (pathogens, inflammatory mediators)?

Hard to say, but my guess is that new microglia would become primed also.

Microglia are slowly replaced all the time. This paper says:

Human microglia renewed at a median rate of 28% per year and the average lifespan was 4.2 years.

Yet we don't see improvements over time in diseases involving chronic neuroinflammation. So that suggests new microglia might get primed as well.

I think a more promising approach might be to look at the factors which promote microglial priming, seeing if any of those can be inhibited. Complement system C3 is one such priming factor that can be inhibited.

Interestingly, the blood anticoagulant heparin inhibits complement system C3 (see here).

Heparin was used by Dr David Berg treat ME/CFS, with some success cases. His theory was that heparin might address the blood hypercoagulation found in ME/CFS. But maybe the success cases were actually due to heparin's inhibition of C3.

And as mentioned above, the supplement Ecklonia cava inhibits C3.



Toll-like receptors are also implicated in priming: this paper says that TLR2, TLR3 and TLR4 are involved in microglial priming. The paper says that:

TLR3 specifically engages double-stranded RNA, indicating a role in host defence against viruses.

TLR2 shows affinity for a wide range of PAMPs originating from bacteria, virues, fungi and parasites.

TLR4 is triggered not only by lipopolysaccharides (LPS) from Gram-negative bacteria, but also recognizes danger-associated molecular patterns released by injured tissue

Naltrexone blocks TLR4 on microglia, so this drug might help reverse microglial priming. This might explain why some ME/CFS patients benefit from low-dose naltrexone. Those who benefit might get further benefits by adding the supplement Ecklonia cava, which inhibits complement system C3.

 

[Wishful]

I find the idea of microglia priming very interesting as it can explain why crashing in a crash can lead to permanent baseline worsening.

I don't think that fits with the abrupt switching of state possible with ME. Would microglia become non-primed over the space of minutes, then abruptly switch back to primed some hours later?

I suppose it's possible for some molecule to temporarily block activation of primed microglia, but then why doesn't that same molecule keep working, rather than stop working after the first dose or two?

 

[Hip]

It looks like you can buy a heat-killed Mycobacterium vaccae supplement called Müd+ for £30.

Whether the immune stimulation achieved from this oral supplement would match that of an injected Mycobacterium vaccae vaccine is open to question. As an oral supplement, it would act as a mucosal vaccine, stimulating mucosal immunity via its contact with the gut mucous membranes.

But it may require systemic immune stimulation to have an effect on the brain.

As the table below indicates, if a mucosal vaccine is applied intranasally or sublingual, this stimulates systemic immunity (in the table, "blood" means systemic immunity). So if this Müd+ product were applied sublingually, it may get results.



The table shows which areas of the body have their immunity stimulates by administering a mucosal vaccine to different areas (areas like nasal, sublingual, oral, etc).

Source: here.

The same table as above can be found in this paper: Buccal and sublingual vaccine delivery, in table 1.

 

[Florida Guy]

I find the concept of priming and later triggering to very interesting as well. Could it be that many cases of ME were first primed by an infection, or some trauma. Then later another infection or trauma causes it to turn on. I wonder how many had some problem before the onset of ME that made it more likely to happen?

 

[datadragon]

I posted this before that m vaccae activated the anti inflammatory ppar-a pathway. Lowering inflammation can subsequently lower ifn-y which is one contributor toward higher wasf3 levels and /me cfs symptoms.

10(Z)-hexadecenoic acid is found in Mycobacterium vaccae bacteria in soil and the natural environment which our ancestors would have had more interaction with than people today. Mycobacterium vaccae (NCTC 11659) is an environmental saprophytic bacterium with anti-inflammatory, immunoregulatory, and stress resilience properties. So even a different environment and interaction with the soil can contribute to our health. Recent studies also demonstrate that immunization with M. vaccae prevents stress-induced exaggeration of proinflammatory cytokine secretion from mesenteric lymph node cells stimulated ex vivo, prevents stress-induced exaggeration of chemically induced colitis in a model of inflammatory bowel disease, and prevents stress-induced anxiety-like defensive behavioral responses. Furthermore, immunization with M. vaccae induces anti-inflammatory responses in the brain and prevents stress-induced exaggeration of microglial priming. https://pubmed.ncbi.nlm.nih.gov/31119329/

10(Z)-hexadecenoic acid activated PPARα signaling, but not PPARγ, PPARδ, or retinoic acid receptor (RAR) α signaling (showing PPAR-a is what is giving the effect). The effects of 10(Z)-hexadecenoic acid of LPS stimulated secretion of IL-6 were prevented by PPARα antagonists and absent in PPARα-deficient mice.
https://link.springer.com/article/10.1007/s00213-019-05253-9

Posted before here
https://forums.phoenixrising.me/thr...herapy-of-negative-voltage.91160/post-2448638

 

[Cipher]

Mycobacterium vaccae's immunomodulating effects are very interesting. I remember seeing a documentary about it many years ago. I managed to find a copy of it that I had saved, it was a short segment in a documentary called Life on Us: A Microscopic Safari (2014). It's an interesting documentary about the human microbiome from a lot of different perspectives.

In the Mycobacterium vaccae segment they talked about research where it was tested as a vaccine against leprosy. The researcher, John Stanford, and his wife tested the vaccine on themselves before giving it to anyone else. Incidentally, his wife's lifelong Raynaud's disease disappeared. There was a test subject in India that got the vaccine to prevent leprosy, and their psoriasis got better.

When googling now I found a documentary from 2002 that goes into this in more detail, and it's available on YouTube:

Spoiler

When it comes to psoriasis they did a small placebo-controlled study with intradermal injections showing improvements relative to placebo:

A placebo-controlled study of immunotherapy with Mycobacterium vaccae for chronic plaque psoriasis showed improvement in the psoriasis area severity index in 19 of 21 immunotherapy recipients (P<0.005). Minor improvement, not reaching statistical significance for the group, occurred in nine of 14 placebo recipients.

The Müd+ product is very interesting. It contains the same strain of M. vaccae (NCTC 11659) that John Stanford isolated and used in his research. I wonder how potent its 10 μg dose is.

A company that John Stanford started, Bioeos, seems to offer a heat-killed oral M. Vaccae supplement in two different strengths, but it's out of stock, so I don't know if it has been discontinued or something. I couldn't find the dose listed on the website.

I found a mice study showing that intragastric administration of heat-killed Mycobacterium vaccae increased regulatory T-cells:

Here we show in mice exposed to the chronic subordinate colony housing (CSC) paradigm that repeated intragastric (i.g.) administrations of a heat-killed preparation of Mycobacterium vaccae NCTC 11659, a saprophytic microorganism with immunoregulatory properties, protected against the stress-induced reduction in systemic Tregs, increase in basal and LPS-induced in vitro splenocyte viability, as well as splenic in vitro GC resistance.

These data highlight the potential for use of oral administration of M. vaccae NCTC 11659 to prevent stress-induced exaggeration of inflammation, a risk factor for development of stress-related psychiatric disorders.

Another study found that intragastric M. vaccae administration was as effective as subcutaneous injections in downregulating symptoms of allergic inflammation in mice:

Results: A single intragastric administration of M. vaccae induced a transient increase in the production of IL-10 and IFN-gamma by mesenteric lymph nodes cells and splenocytes. In addition, in a mouse model of pulmonary allergic inflammation, a single treatment with M. vaccae by gavage not only diminished the total cellular infiltrate and the eosinophilic component induced by subsequent intratracheal allergen challenge, but also biased local and systemic cytokine production towards IL-10. Delivery of M. vaccae by gavage was as effective as subcutaneous treatment.

Conclusion: This is the first report to suggest that heat-killed mycobacteria can down-regulate symptoms of allergic inflammation by the intragastric route. These data suggest an alternative route of treatment with M. vaccae for patients with allergic conditions.

I found two other supplements sold by other companies that doesn't contain M. vaccae but other, related bacteria; one containing Mycolicibacterium aurum called immy (10 μg) and one containing Mycobacterium smegmatis called IMBXX (250 mg). I couldn't find any research on the immunomodulating effects of these bacteria, but since they are related the effects might be similar to M. vaccae. If IMBXX's stated dose actually refers to pure bacteria then the dose is much higher than the others. Their website is very clickbaity though which is a bit offputting.

The Chinese Vaccae injection vaccine seems to be a lysate:

Vaccae® was approved by Chinese FDA in 2001 for adjunct therapy of tuberculosis. The vaccine contains 22.5 μg of antigen per dose and is administered intramuscularly once per week or every two weeks for 6 mo. M. vaccae was grown on solid agar media, harvested; cells were broken with a press and autoclaved as per Longcom procedure.

John Stanford seems to have done research on both irradiation-killed and heat-killed Mycobacterium vaccae vaccines. In the psoriasis study they used intradermally injected 1 mg autoclaved Mycobacterium vaccae suspension.

 

[bad1080]

- would the microglia quickly become active again after depletion (or the vaccine you mentioned), because they are chronically stimulated (pathogens, inflammatory mediators)?

since EBV can hide in the CNS i believe this is one of the pathways in me-cfs.

This makes me think that prior to catching the viral infection that triggers most people's ME/CFS, people may have already been exposed to an inflammatory stimulus, maybe a bacterial toxin like LPS coming from a leaky gut. Or maybe some inflammatory stimulus from a mould infestation in their home.

a hit to the head can be enough to reactivate dormant viruses located in the brain and prime the glia cells.

It looks like you can buy a heat-killed Mycobacterium vaccae supplement called Müd+ for £30.

that site just redirects me to google and idk why (tested on multiple browsers and multiple links). maybe it's my country? gonna try it with VPN tomorrow...