Doxycycline as a CCI treatment: low-dose doxycycline inhibits the MMP enzymes which break down collagen and elastin in ligaments

Hip

Senior Member
Messages
13,057
Likes
24,256
Summary: low-dose doxycycline 20 mg twice daily inhibits the MMP enzymes which are secreted by immune cells during viral infection, and which can damage connective tissue such as ligaments. So in ME/CFS where craniocervical instability (CCI) and/or atlantoaxial instability (AAI) from weak ligaments is present, low-dose doxycycline may conceivably help strengthen the ligaments and ameliorate the CCI/AAI.

Several other supplements such as fish oil, Q10, ecklonia cava, magnesium and glucosamine sulfate may help further reduce MMPs.

In the CCI survey, around half the ME/CFS patients positive for craniocervical instability (CCI) had a rapid onset to their ME/CFS after an acute infection. It's not clear whether these patients may have had CCI before their ME/CFS onset, or whether CCI only manifested after their ME/CFS started, possibly as a result of the viral infection.

But another small poll found that in the majority of patients, the symptoms of CCI tended to appear after the onset of ME/CFS, rather than before, which suggests that the viral infections of ME/CFS might cause the CCI. And neurosurgeon Dr Fraser Henderson lists infection as a possible cause of CCI (see the slide in this 2012 video at 13:12).

Also, many of these CCI positive ME/CFS patients reported in the survey they experienced sudden-onset connective tissue changes that appeared in the first 3 years of their ME/CFS (such as receding gums, skin wrinkling, and striae stretch marks on the skin). So certainly some factor appears to be attacking the connective tissues in many cases of ME/CFS.

My guess is this factor could be the connective tissue-degrading enzymes called matrix metalloproteinases (MMP) that the immune system secretes in response to infection. If we look at an infection such as coxsackievirus B, studies have shown this induces the secretion of MMP-2, MMP-3, MMP-8, MMP-9 MMP-12 in infected tissues (refs: 1, 2, 3). And herpesvirus infections are shown to stimulate MMP-9 secretion.

These MMPs conceivably might be attacking the connective tissue in ligaments, thus leading to CCI. MMPs might also weaken the dura (the connective tissue membrane surrounding the brain and spinal cord), leading to cerebrospinal fluid leaks.

Which particular MMP enzymes might be responsible for ligament damage? Well, the main collagen in ligaments is collagen type I, which comprises 70% of the dry weight of a ligament. Ref: here

Elastin is also found at 4–9% of the dry weight in ligaments. Ref: here

Collagen has an extremely high tensile strength (approaching that of steel) and is hard to stretch. Whereas elastin has a low tensile strength, and stretching occurs easily. Ligaments which need to stretch more have a higher elastin content.



I would guess that any MMP which can degrade collagen type I might be a suspect for causing the ligament weakening that can lead to CCI. If we look at the list of substrates these various MMP enzymes act on, we see the enzymes capable of degrading collagen type I are: MMP-1, MMP-2, MMP-8, MMP-13 and MMP-14.

And since elastin also contributes the the strength of ligaments, the elastin-degrading enzymes MMP-9, MMP-10, MMP-12 and MMP-20 might also be of significance for CCI or AAI.

Thus since coxsackievirus B infections can induce MMP-2 and MMP-8 which eat away collagen, plus MMP-9 and MMP-12 which eat away elastin, this virus might well be able to weaken ligaments which are in proximity to a chronic tissue infection with coxsackievirus B (note that many ME/CFS patients have a chronic sore throat, a possible infection which is in close proximity to the craniocervical ligaments).



So if virally-induced matrix metalloproteinases such as MMP-2, MMP-8, MMP-9 and MMP-12 might be causing the weakened ligaments of CCI, is there anything that can be done about it?

Well the tetracycline class of antibiotics are good broad-spectrum MMP inhibitors, with doxycycline being one of the most potent inhibitors (doxycycline is also a reasonably safe antibiotic). Doxycycline inhibits MMP-1, 2, 7, 8, 9, 12 and 13.

Furthermore, fortunately even low-dose doxycycline 20 mg twice daily (instead of the normal 100 mg twice a day dose) is still able to inhibit MMPs. Ref: here.

So this means that for long-term use as an MMP inhibitor, you can take these low doses of 20 mg twice daily, and the negative effects on the gut microbiome minimal compared to taking the normal dose (although even with these low doses, it may not be a bad idea to take probiotic). This study found that after taking doxycycline 20 mg twice daily for 9 months, there was no ill effect on the intestinal or vaginal microbiome.

Low-dose doxycycline is actually sold as an MMP inhibitor under the brand name of Periostat, which effective for reducing receding gums (this periodontal disease is linked to elevated levels of MMP enzymes which eat the gum tissue, and Periostat works by inhibiting these MMPs). Periostat tablets are just a 20 mg dose of doxycycline.

Periostat is in fact the only MMP inhibitor approved by the FDA. But rather that buying Periostat, it may be cheaper to buy normal 100 mg doxycycline tablets, and cut the tablets into four pieces of 25 mg each.

For those ME/CFS patients positive for craniocervical instability (CCI) and/or atlantoaxial instability (AAI), treatment with low-dose doxycycline might possibly help strengthen the ligaments. And for those with cerebrospinal fluid leaks, which result from holes in the dura connective tissues, perhaps low-dose doxycycline might also be useful.

I imagine any benefits would only emerge after several months of doxycycline treatment.

However, I could not find any studies or articles about MMP inhibitors being used in the context of CCI or AAI. But this rodent study discovered that for damaged tendons, combining platelet-rich plasma (PRP) injections with broad-spectrum MMP inhibitors had better results than the individual treatments used alone. And this paper discusses MMP inhibition as a potential method to augment the healing of tendons.

As an adjunct to low-dose doxycycline, some of the supplements and drugs listed below may also help reduce MMPs.



Compounds Which Inhibit MMPs In Vivo:

Fish oil supplementation at 9.6 grams per day reduced MMP-9 secretion from immune cells by 58% after 3 months in multiple sclerosis patients. Ref: here. So these high doses of fish oil might be a useful adjunct to low-dose doxycycline.

Q10 at 500 mg daily reduced MMP-9 in multiple sclerosis patients, a study found. Q10 is also known to help periodontal disease, which is linked to elevated MMPs. So Q10 might also be useful to add to low-dose doxycycline protocol.

Ecklonia cava inhibits MMP-2 and MMP-9 and in a rat study reduced periodontitis. Ecklonia cava is an edible marine brown alga available as a supplement.

This study found the angiotensin-converting enzyme (ACE) inhibitor captopril inhibits serum MMP-9 in patients with Kawasaki disease (this disease is likely caused by infection).



Compounds Which Inhibit MMPs In Vitro:

This in vitro study found magnesium reduces MMP-2, suggesting that the beneficial effect of magnesium supplementation on the cardiac disease may be due, at least in part, to the inhibitory effect on MMPs. Thus a magnesium supplement may be useful to add to the protocol.

This study found glucosamine sulfate inhibits MMP-2 and MMP-9 expressions in human fibrosarcoma cells in vitro, probably explaining, say the authors, why glucosamine is effective in relieving the symptoms of osteoarthritis. So adding glucosamine sulfate into the protocol might be worthwhile.

Vitamin K2 — inhibits MMP-1 in vitro.
Q10, N-acetyl-cysteine, myricetin — inhibit MMP-2 in vitro.
Triphala herbal formula, sulforaphane, propolis, alpha lipoic acid — inhibit MMP-9 in vitro.
Blueberry flavonoids, quercetin, chondroitin sulfate, EGCG, aloe vera, neem — all inhibit MMP-2 and MMP-9 in vitro.

Not that these are in vitro studies, so whether these compounds are effective in vivo, and whether they can specifically inhibit the MMP enzymes secreted by the immune response to viral infection, is another question.
 
Last edited:

MTpockets

Senior Member
Messages
160
Likes
431
Location
AZ, USA
I couldn't read the whole thing so sorry in advance if this was information already given. Isn't doxycycline one of the main treatments for Lyme and doesn't Lyme degrade collagen? Also would you think it would be couterintuitive to take a collagen supplement? I wonder if it would be fanning the flames so to speak, or if it would help your body repair the damage faster. Has anyone tried it?
 

JenB

Senior Member
Messages
221
Likes
1,705
I couldn't read the whole thing so sorry in advance if this was information already given. Isn't doxycycline one of the main treatments for Lyme and doesn't Lyme degrade collagen? Also would you think it would be couterintuitive to take a collagen supplement? I wonder if it would be fanning the flames so to speak, or if it would help your body repair the damage faster. Has anyone tried it?
It could help your body repair the damage faster. Aloe vera also looks awesome: https://www.me-pedia.org/wiki/Aloe_vera
 

Hip

Senior Member
Messages
13,057
Likes
24,256
Last edited:

Hip

Senior Member
Messages
13,057
Likes
24,256
Isn't doxycycline one of the main treatments for Lyme and doesn't Lyme degrade collagen?
Yes, but here doxycycline is not used for its antibiotic effects, but because this drug is also able to lower levels of enzymes called MMPs — enzymes which break down collagen and elastin. So if you slow the breakdown process using doxycycline, then the ligaments may be better positioned to rebuild themselves.
 

valentinelynx

Senior Member
Messages
1,031
Likes
2,720
Location
Tucson
My joints, especially hand joints, got a lot better on minocycline & doxycycline, taken for presumed Lyme. But that was about the extent of the response. I take a lot of the supplements you list (Fish oil in high dose, CoQ10, K2, N-AC and others I used to take, e.g. quercetin). I don't think they make much difference, really, but I take them on theory of their anti-inflammatory and other benefits (e.g. N-AC for liver and for dry eyes, Coq10 for mitochondrial and cardiac function). Perhaps I'd be way worse now if I hadn't taken this stuff for years. Or maybe it's just depleted my bank account. If I were brave, I'd stop taking them and reintroduce one at a time. Perhaps I'll try that; I'll have to think on it!
 

gbells

Improved SEIDs from 2 to 4
Messages
524
Likes
519
Location
Eastern NC USA
Of course long term off-label rx for doxycycline puts you at risk for anti-biotic resistant superbugs. You'd also be killing off your bacterial flora so you couldn't self-generate antidepressant neurotransmitters and be at risk for depression and anxiety. Also it would weaken your immune system. So not a good idea.
 

Hip

Senior Member
Messages
13,057
Likes
24,256
My joints, especially hand joints, got a lot better on minocycline & doxycycline, taken for presumed Lyme. But that was about the extent of the response.
My feeling is that if doxycycline dose have any benefits for the weak ligaments of CCI/AAI (or for the weak dura of CSF leaks), then it will be a mild effect. But if someone is trying treatments such as prolotherapy for weak craniocervical ligaments, low dose doxy might be an add-on to consider.

That's not to say that there's any evidence low-dose doxy will work for the weak ligaments of CCI/AAI; it's only a theoretical possibility that it might.



Of course long term off-label rx for doxycycline puts you at risk for anti-biotic resistant superbugs.
Low-dose doxy (Periostat) is not off-label in terms of treating periodontal disease (receding gums). It is an FDA approved MMP inhibitor used for periodontal disease which is caused by MMP enzymes destroying gum tissue.

Several ME/CFS patients in the CCI survey reported they got sudden-onset receding gums once their ME/CFS started, or some other connective tissue changes like sudden-onset skin wrinkling or striae, which suggests that elevated levels of MMPs can occur in ME/CFS.
 
Last edited:

Hip

Senior Member
Messages
13,057
Likes
24,256
I wonder if certain strains of probiotics could impact MMPs:

‘A combination of the antibiotic minocycline and the probiotic E. coli Nissle 1917 was shown to improve recovery form DSS induced colitis in mice including improved ratio of beneficial/harmful bacteria and reduced MMP-9 expression’

https://www.hindawi.com/journals/mi/2015/964131/
Probiotics might impact MMPs to a small degree, but maybe not always favorably: I just came across this animal study which found that probiotics increased MMP-9 in the oral cavity.
 

gbells

Improved SEIDs from 2 to 4
Messages
524
Likes
519
Location
Eastern NC USA
My feeling is that if doxycycline dose have any benefits for the weak ligaments of CCI/AAI (or for the weak dura of CSF leaks), then it will be a mild effect. But if someone is trying treatments such as prolotherapy for weak craniocervical ligaments, low dose doxy might be an add-on to consider.





Low-dose doxy (Periostat) is not off-label in terms of treating periodontal disease (receding gums). It is an FDA approved MMP inhibitor used for periodontal disease which is caused by MMP enzymes destroying gum tissue.

Several ME/CFS patients in the CCI survey reported they got sudden-onset receding gums once their ME/CFS started, or some other connective tissue changes like sudden-onset skin wrinkling or striae, which suggests that elevated levels of MMPs can occur in ME/CFS.
Actually the receeding gums was one an early SEIDs symptom I noticed myself. It was followed by reinfection of past root canals requiring extractions. I lost six teeth.
After I treated with Gcmaf and the right supplements I improved and both problems stopped.
 

Hip

Senior Member
Messages
13,057
Likes
24,256
Actually the receeding gums was one an early SEIDs symptom I noticed myself. It was followed by reinfection of past root canals requiring extractions. I lost six teeth.
After I treated with Gcmaf and the right supplements I improved and both problems stopped.
Wow, that really is a serious impact, losing 6 teeth because of ME/CFS. Which GcMAF brand did you use (and it is still available, as many good GcMAF suppliers have unfortunately been closed down by regulators).
 

gbells

Improved SEIDs from 2 to 4
Messages
524
Likes
519
Location
Eastern NC USA
I used the sublingual drops from FirstImmune. They recommended a treatment with high dose Vit D and GcMAF which I did for six months. I titrated it down as I went through. Shortly after that I developed systemic lupus erythematosis so people doing it should tell their GP to have a rheumatologist handy if they develop SLE symptoms.

Test date Nagalase level (Gcmaf drops sublingual)
5/7/2014 1.8 0
7/9/2014 1.5 6
9/16/2014 1.3 4.5
11/11/2014 1.1 1.5
 
Last edited:

Hip

Senior Member
Messages
13,057
Likes
24,256
Shortly after that I developed systemic lupus erythematosis
Can you have both lupus and ME/CFS? If a patient has lupus, which itself causes a lot of fatigue and ME/CFS-like symptoms, then those ME/CFS-like symptoms will usually be put down to lupus.
 

gbells

Improved SEIDs from 2 to 4
Messages
524
Likes
519
Location
Eastern NC USA
Can you have both lupus and ME/CFS? If a patient has lupus, which itself causes a lot of fatigue and ME/CFS-like symptoms, then those ME/CFS-like symptoms will usually be put down to lupus.
The lupus symptoms were very different and new (joint pain, facial rash, nocturnal fever, chills in 2014), they put me in the hospital for three weeks while they figured me out.

I think you can have both. My CFS symptoms preceeded them by six years, starting in 2008.

Lupus treatment fixed the lupus symptoms but not the CFS.
 

wastwater

Senior Member
Messages
1,126
Likes
784
Location
uk
I find this interesting as I saw a connection to my rare condition mentioning doxycycline but didn’t think it was reguarding infection I thought it was something to do with micro glial activation but it might of been this
 

Sarah94

Senior Member
Messages
875
Likes
947
Location
UK
Of course long term off-label rx for doxycycline puts you at risk for anti-biotic resistant superbugs. You'd also be killing off your bacterial flora so you couldn't self-generate antidepressant neurotransmitters and be at risk for depression and anxiety. Also it would weaken your immune system. So not a good idea.
And you would not be doing the human race in general a favour, because you'd be contributing to antibiotic resistance.
 

gbells

Improved SEIDs from 2 to 4
Messages
524
Likes
519
Location
Eastern NC USA
And you would not be doing the human race in general a favour, because you'd be contributing to antibiotic resistance.
This is a major reason why doctors try to avoid overprescription of antibiotics. Also remember that antibiotics are often found in commercial meats because they are growth stimulants. It is a good idea to buy meat labelled antibiotic free.
 
Messages
32
Likes
110
Probiotics might impact MMPs to a small degree, but maybe not always favorably: I just came across this animal study which found that probiotics increased MMP-9 in the oral cavity.
Yes, I saw that one. I would guess it might vary quite a lot depending on the strain? I notice that you posted about high dose fish oil reducing MMPs. I’d like to try that, but I would be concerned about it reducing NK cell function.
 

Hip

Senior Member
Messages
13,057
Likes
24,256
And you would not be doing the human race in general a favour, because you'd be contributing to antibiotic resistance.
Well that's something to take up with the pharmaceutical manufacturers of Periostat, who supply low-dose doxycycline for the long-term treatment of periodontal disease (it says here that "PERIOSTAT is indicated for treatment periods of 3 months. PERIOSTAT should not be administered for more than 3 consecutive three month periods").

Note also that the low doses of doxycycline used in Periostat have no effect on your gut microbiome, even after nine months (the study above demonstrated this). So Periostat does not cause gut dysbiosis. This is because the low doses used have negligible effect on bacteria.

Possibly the fact that doxycycline is bacteriostatic rather than bactericidal plays a role in this (bacteriostatic means the antibiotic while present stops bacteria from reproducing, but does not kill the bacteria).
 
Last edited: