Changes in the Gut Microbiome as the Cause of Inflammation and Oxidative Stress Leading to Vascular Dysfunction
Chronic inflammation and oxidative stress disrupt the function of smooth muscle cells in blood vessel walls. This is one of the contributing causes of vascular stiffness with age, alongside cross-links, calcification, and loss of elastin, all of which alter the structural properties of blood vessel tissue to produce a reduction in elasticity. There is the question of the relative importance of these contributions, a question that exists for most aspects of aging at the present time, lacking easy ways to remove only one contributing factor to assess the outcome. Nonetheless, the research results noted here suggest that smooth muscle dysfunction is the most important factor in vascular stiffness, and that - in mice, at least - changes in gut bacteria populations are the cause of this issue. This might make us more optimistic about the prospects for near term therapies in humans.
Stiffening of blood vessels is important because it results in hypertension; the feedback mechanisms controlling blood pressure are disrupted by this type of damage and dysfunction. That in turn produces tissue damage throughout the body due to rupture of capillaries and other pressure-related issues. Hypertension also accelerates the progression of atherosclerosis, and makes it more likely for fatal structural failures in large blood vessels to occur in the later stages of that condition.
Why do blood vessels naturally stiffen and degrade as we age, boosting cardiovascular disease risk? Researchers gave young mice and old mice broad-spectrum antibiotics to kill off the majority of bacteria living in their gut, aka their gut microbiome. Then they assessed the health of their vascular endothelium (the inner lining of their blood vessels) and the stiffness of their large arteries. They also measured blood levels of inflammatory compounds, tissue-damaging free-radicals, antioxidants, and the blood-vessel-expanding compound nitric oxide in both groups. After three to four weeks of the treatment, the young mice saw no change in vascular health. The old mice, however, saw vast improvements on all measures. "When you suppressed the microbiome of the old mice, their vascular health was restored to that of young mice. This suggests there is something about those microorganisms that is causing vascular dysfunction."
To assess what that something may be, the researchers then took fecal samples from another set of mice and had them genetically sequenced, comparing the gut bacteria living in the old mice with that in the young. In the old mice, the researchers saw an increased prevalence of microbes that are pro-inflammatory and have been previously associated with diseases. For instance, the old mice hosted significantly more Proteobacteria, a phyla that includes Salmonella and other pathogens, and pro-inflammatory Desulfovibrio. To drill down further, the researchers measured blood levels of metabolites - small molecules produced by the gut microorganisms and absorbed into the bloodstream - in old and young mice. Old mice had three times as much TMAO (trimethylamine N-oxide), a metabolite shown in previous studies to be linked to increased risk of atherosclerosis, heart attack, and stroke.
"We have long known that oxidative stress and inflammation are involved in making arteries unhealthy over time, but we didn't know why arteries begin to get inflamed and stressed. Something is triggering this. We now suspect that, with age, the gut microbiota begins producing toxic molecules, including TMAO, which get into the blood stream, cause inflammation and oxidative stress and damage tissue." The researchers recently launched a human trial to explore how different diets impact the gut and, in turn, cardiovascular disease risk. They are also studying a compound called dimethyl butanol, which blocks the bacterial enzyme required to produce TMAO. Ultimately, it could be developed into a dietary supplement.
Link: https://www.colorado.edu/today/2019/03/19/fountain-youth-heart-health-may-lie-gut
Hi there ! Just a 2 cents.
This study, is truly the best, it was concorded with a few studies since 2012 or so; this a game changer in my mind because it affects so many elements metabolistically-speaking. TMAO (trimethylamine N-oxide) is really the sereptitious lacking element here; we knew that cholesterol LDL is a major culprit; but what we did not know is that TMAO is the 'contributor' to making LDL 'trapped' and blocking the possibility of HDL foam cells to 'remove' plaque. TMAO, much like 7-ketocholesterol and LDL-ox (oxidized versions) are the main reasons why the oxidation process seems to 'signal' HDL to become null/unactivated or it too, probably, oxidized; as such, dysfunctional, and unable to do its cleaning job in the atherosclerotic lesions.
It was demonstrated that TMAO contributes to dramatic formation of atherosclerotic plaques, almost Regardless of HDLLDL ratio. Well it does alter it, and promotes cholesterol formation in the liver, mostly LDL and triglycerides formation. TMAO inhibitors block farnesoid X receptor (And I suspect Liver receptor X gets activated), in doing so, it stops TMA from being converted to TMAO inside liver (it stays as trimethylamine...Not oxidized; the culprit is the N-oxide (TMA(O)) of TMA). Mice that were fed 'western-junk cholesterol diet' And a TMAO inhibitor showed dramatic protection of their arteries (not as good as the mice have normal diet..but still dramatic reduction of the effects of hypercholesteremic junkfood consumption)...some bad foods: Eggs, Fish, Burgers...all them high in cholesterol, but, specifically, all having high carnitine levels, cartinitine accelerates TMAO formation in liver. Carnitine is fatty oxidation activator (a good thing) except, it's not so good with micro-flora in your intestine. It increases negative bacterias that inflammatory causing (mostly the 'coccus' varieties (enterococcus, streptococcus, helicobacter...All these - TMAO producers), while a TMAO inhibitor creates intestinal gut microbiota flora landscape transformation - towards that of people that live a 100 years (centenarians). Mainly, blocking the coccus ones..and increasing the Bacteroides bifido ones/lactose 'illus' (Lactobacillus, Bifidobacterium, Bacteroides), These Specific bacterias are very anti-inflammatory and act completely inverse of the others ones (with age they reduce and you have gut dysbiota where there is Far more 'coccus' variety - creating inflammation - creating excess blood levels of TMAO; when you increase thes benefitial lactobifidos you stop this Whole conversion of TMA -to - TMAO in the liver and there is much more bile production from the liver (bile is protective), and also higher fecal excretion of TMAO - very important, and also, through urine, it was shown high urinal excretion of TMAO when the gun biota changed; in doing so it was demonstrated that in just a few weeks, there was Reversal of plaques in the arteries).
The best TMAO inhibitors: meldonium, (not eating eggs,fish, junkfood), Resveratrol (a very powerful TMAO inhibitor..now I am understanding the whole 'French Paradox' of French people eating foie gras and living still...made no sense..they drink red wine (resveratrol negates Much of these problems - since it reshapes the gut biota and blocks TMAO; same thing with centenarians like Jeanne Calment whom drank Porto/Pino noir and red wine - she got her fair share of resveratrol changing her gut biota) yogurt with Exactly Lacto/bifido nothing else - trust me I consumed yogurt for my atherosclerosis - it did not help because I most likely cause dybiosis in my gut creating More TMAO) - thus, you need Only the Benefitial ones but it's dangerous hence it's better alternate ways since you could be increasing the 'coccus variety which cause TMAO/I'm positive I created microbial loadExcess/bacterial overload and then high blood TMAO causing ischemic events and arterial narrowing/fatty plaque formation),
TMAO causes, heart attack, kindkey failure, atherosclerosis, stroke, T2D, brain stroke, ischemia, angina, CVDs, and ton of others..including - cancer, I'm sure Alzheimer's too (for TMAO is blood born and goes to brain/circulates). It's down to it's 'N-oxide' ROS, bacterias produce So much of it that it causes constant N-oxide exposition in blood (thus blood microbial toxin TMAO). Unlike, Nitric oxide, N-oxide ends up as peroxidation causing effect and is messes the liver and arterial cholesterol signaling - cascading atheroscleorsis and plaque formation.
So for anyone suffering of ahterosclerosis, this is Biggest thing ever yet that can Reverse atherosclerosis (as seen in mice arterial slice scans showing plaques in western-fed diet; while little plaques (Regressing) in same diet + TMAO inhibitor).
Just a 2 cents.
PS: I should add another one, is soluble fiber - definitely blocks TMAO formation for soluble fibers reorder gut flora towards more lacto/bifidos and increase fecal excretion (fiber in stool/bulkier stool/more fecal TMAO excretion).