Gut microbiome change reverses atherosclerosis

[Hans de Vries]

https://www.sciencedaily.com/releases/2020/06/200615140921.htm

 

Administration of a peptide that changes gut bacteria results in -40% plaque size after 10 weeks although in mice not humans. What do you think of this?

[Doogles31731]

On 6/22/2021 at 3:09 AM, Hans de Vries said:

https://www.sciencedaily.com/releases/2020/06/200615140921.htm

 

Administration of a peptide that changes gut bacteria results in -40% plaque size after 10 weeks although in mice not humans. What do you think of this?

 

I can offer a possible guess as to why that might work. Vitamin K2 is mainly obtained from the gut microbiome in mammals. One would have to postulate that the peptides encourage the growth of micro-organisms that manufacture vitamin K2 or else provide a substrate for such micro-organisms to manufacture vitamin K2.

There is evidence of a deficiency of vitamin K2-MK4 in particular in cases of atherosclerosis.

Jie et al (1995; http://www.sciencedirect.com/science/article/pii/0021915095055377

Luo et al (1997; https://www.ncbi.nlm.nih.gov/pubmed/9052783

Schurgers et al (2001; https://link.springer.com/article/10.1007/s003920170043

Wallin et al (2008; https://www.thrombosisresearch.com/article/S0049-3848(07)00456-2/abstract

Knapen et al (2015; https://www.thieme-connect.de/DOI/DOI?10.1160/TH14-08-0675

Vissers et al (2016; https://www.atherosclerosis-journal.com/article/S0021-9150(16)31216-3/abstract

Lees et al (2018; https://heart.bmj.com/content/105/12/938.abstract

Roumeliotis S et al (2020; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193028/

The above  references collectively suggest that Vitamin K2-MK4 has some therapeutic effect, but that Vitamin K1 (phylloquinone) deficiency is not involved in atherosclerosis.

Just to keep a balance in this post, although the paper by Knapen et al (2015) above, suggests that vitamin K2-MK7 had some therapeutic effect, two more recent papers suggest that vitamin K2-MK7 had no therapeutic effect.  

Zwakenberg et al (2019; https://academic.oup.com/ajcn/article/110/4/883/5544545

De Vriese et al (2020; https://jasn.asnjournals.org/content/31/1/186.abstract

The evidence suggests that vitamin K does not act directly, but by being a co-factor in the activation of raw proteins produced in turn by vitamin D. Unfortunately, extremely few researchers who have set out to assess the therapeutic value of vitamin Ks, have taken any steps to ensure that subjects in trials have had adequate vitamin D concentrations. This could explain the variable results.

[CharonY]

Another possible (or additional) route is the reduction of overall inflammation. The atherosclerotic formation is characterized by local inflammatory responses and it has been shown that certain microbiota compositions are associated with reduced inflammatory responses. The cause-effect relationship is a bit unclear, i.e. whether inflammation changes the microbiota or whether certain gut composition increases inflammation. My gut feeling (heh) is that it is an interaction between these effects and e.g. a pro-inflammatory life style can allow a microbiota to form that in turn increases pro-inflammatory markers. That interaction would explain why fecal transplantation often has relative short term effects.

That being said, both vitamins are involved in suppression of immune responses so the interesting question becomes where it is indeed the main mechanism, and/or part of a more complex network. 

[Doogles31731]

Thanks for adding to the discussion, Charony. That reference, supplied by Hans deVries, to work by Ghadiri et al, was remarkable in my opinion. Like you, my guess was also at the level of ‘gut feeling’, but it was based on two premises -- that much evidence (above) suggests that vitamin K2 improves arteriosclerosis, and that the main source of vitamin K2 in mammals at least is the gut microbiota.

My hypothesis could be checked of course if Ghadiri et al were able  to re-run their experiment and do blood assays for vitamin K2 or matrix-gla-protein.

I notice that the mice treated with the cyclic peptide also had lower cholesterol concentrations. Back in 1997, Kawashima et al (1997; https://www.jstage.jst.go.jp/article/jphs1951/75/2/75_2_135/_article/-char/ja/) produced evidence that “ ... pharmacological dose of vitamin K2 prevents both the progression of atherosclerosis and the coagulative tendency by reducing the total-cholesterol, lipid peroxidation and factor X activity in plasma, and the ester-cholesterol deposition in the aorta in hypercholesterolemic rabbits."

Although inflammatory products are found in atheromas, I haven’t come across any evidence, to date, that anti-inflammatory agents reduce atherosclerosis. I could have missed some literature on it. Can you supply any?

There are statins of course, but the very best reduction in atheromas that they have shown to produce experimentally is of the order of one or two percent. This is why the 40% reduction in the OP reference  is so remarkable.

[CharonY]

There is a bit of lit out there but most is still exploratory. A somewhat outdated but well-written review is  Baeck and Hanssons Nat Rev. Cardiol. 12, 199-211 (2015). I would agree that for the most part there is insufficient data for either assertion. And again, at this point I think that there is more of an interaction which makes causal (rather than correlative) conclusions difficult. That is not to say that the paper is not interesting, quite the contrary, and there are things that I would be interested in looking into eventually.

Another fundamental issue is that mice models only work moderately well compared when it comes to inflammation responses (and the ldl mutant commonly used as a athersclerosis mutant has also issues, but that is a whole other discussion).

In short, it is intriguing but IMO more data is required to decipher the underlying mechanisms.