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.