Microbiome in cardiovascular disease

 The gut microbiome is hugely important in many aspects of human well-being. It is a major window through which our environment affects our threshold for developing a wide array of diseases. This blog will focus on some of the cardiovascular effects of a distorted (dysbiotic) microbiome.

 

-- a very recent article assessed the effects of the gut microbiome on cholesterol metabolism, specifically the microbiome's ability to convert cholesterol to coprostanol, a poorly absorbed sterol (https://www.cell.com/action/showPdf?pii=S1931-3128%2820%2930295-X ).  The researchers found that there was a clade of highly prevalent, but previously uncharacterized, IsmA-encoding bacterial species. This research group had previously found that the IsmA enzyme participated in converting cholesterol to coprostanol and identified uncultured Eubacerium species with the ismA gene; this conversion of cholesterol to coprostanol in patients, in 3 studies with paired stool metagenomics and serum cholesterol measures, was associated with a " biologically meaningful decrease in total serum cholesterol", suggesting that the human gut microbiome composition had a significant impact on serums lipids (eg, the Framingham study found a decreased total cholesterol and LDL, along with an increased HDL ). In fact, the Framingham Study found that there were 2 gut microbiome species, Oscillibacter and Eubacterium coprostanoligenes that seem to work synergistically in their effect on cholesterol levels (see microbiome chol lowering bacteria Cell2024 in dropbox, or https://www.cell.com/action/showPdf?pii=S0092-8674%2824%2900305-2)

 

--TMAO (trimethylamine N-oxide) is one of the most atherogenic/prothrombotic chemicals we know, and it induces cytokines and is pro-inflammatory. TMA is synthesized in the gut after eating foods with high carnitine levels, and the TMA is subsequently absorbed into the blood and converted to TMAO, by a two-step process, https://gmodestmedblogs.blogspot.com/2023/10/red-meat-increases-risk-for-diabetes.html:

    -- vegans/vegetarians/tend to have a baseline healthy gut microbiome

    -- vegans/vegetarians typically have lower carnitine levels, but feeding them L-carnitine (an amino acid produced in low levels in the body but leading to very high levels after ingesting foods high in carnitine, especially red meats, and to lesser levels by eating chicken, dairy, fish, beans, avocados). their consuming L-carnitine induces the proliferation of certain microbes but produces essentially no TMAO (the enzyme TMA lyase comes from the Firmicutes species)

    -- BUT, repeated consumption of red meat (or carnitine) leads to high levels of TMAO after their consumption, a response which is obliterated by taking antibiotics that disrupt the microbiome

        -- so, especially consuming red meat or carnitine seem to induce development of not-so-good bacteria that, on further exposure to red meat or carnitine, leads to the production of TMA, which is absorbed into the blood stream and oxidized to the highly atherogenic TMAO

-- TMAO is also associated with the major cardiovascular risk factors:

    -- the development of hypertension: likely from facilitation of angiotensin II-induced vasoconstriction and stiffening of the large arteries; there is strong argument that TMAO itself, along with the associated dysbiosis, is directly associated with the development of hypertension (Trimethylamine N-oxide (TMAO) in human health - PMC (nih.gov) . of note, the microbiome of hypertensive patients leads to hypertension when transplanted into germ-free mice: Gut microbiota dysbiosis contributes to the development of hypertension - PubMed (nih.gov)

    -- the development of diabetes: likely through impaired glucose tolerance, insulin resistance, and oxidative stress. of note, the gut microbiota is strongly associated with both microvascular and macrovascular diabetic complications (eg, 2 bacterial strains have been found to be associated with end-stage diabetic nephropathy, another decreased retinopathy). Again, TMAO and the related dysbiosis seems to play a role in the development of diabetes

    -- the development of obesity: likely through the secretion of inflammatory cytokines (which also contributes to the development of diabetes)

    -- the development of dyslipidemia: likely through the reduction of levels of HDL and reduced expression of cytochrome P450 family 7, the subfamily A member 1 (CYP7A1); this is a key enzyme in cholesterol and bile acid metabolism, which, by inhibiting reverse cholesterol transport by its effects on HDL, leads to more atherosclerosis. This dyslipidemia is associated with  lower levels of the protective short-chain fatty acids of butyrate, acetate, and propionate as mentioned below

        -- of note, TMAO has close buddies that also participate in atherogenesis, such as lipopolysaccharides (which are endotoxins on the surface of Gram-negative bacteria and lead to a pro-inflammatory state by producing TNF-a, IL-1, IL-6 and IL-8, induces endothelial dysfunction, increases reactive oxygen species), changes in the receptors that respond to protective secondary bile acids, and decreased microbial diversity in the microbiome. these changes are associated with eating red meats, which seem to decrease the protective effect of some important short-chain fatty acids (eg butyrate, acetate, and propionate) that are produced by bacteria and protect against obesity and diabetes by improving lipid and glucose homeostasis (eg bifidobacterium, lactobacillus, faecalibacterium prausnitzii and roseburia)

 

-- there have been pretty profound effects of metformin on the microbiome, and these seem to explain at least some of the health benefits of metformin

     -- a part of metformin's mechanism of action may be related to creating a healthier gut microbiome. A study of diabetic mice found that those on metformin improved their glycemic profile (as expected), but there was a significant increase in the gut bacterium Akkermansia. In a parallel experiment, just increasing this bacterium in the gut (in the absence of metformin) also enhanced glucose tolerance and decreased adipose tissue inflammation, suggesting that an additional mechanism of action for metformin may be through its direct effect on the microbiome (see http://gmodestmedblogs.blogspot.com/2014/10/heart-failure-microbiome.html ).  

-- A recent systematic review (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10518565/) evaluated the effects of metformin on the human gut microbiome, finding 13 relevant studies.  They found a remarkable diversity of results, with some finding increases and some decreases in what seemed to be helpful bacteria (eg, Akkermansia).  This brings up several relevant issues:

    -- There actually are several different techniques for identifying the bacteria in the microbiome, and these techniques have differing sensitivities and specificities.  The lack of a consistent validated approach in identifying microbial bacteria limits the validity of combining the results of these studies

    -- The gut microbiome is a remarkably complex structure, composed of over 100 trillion microbial cells, including bacteria, viruses, fungi, and parasites (many more times the number of cells in the rest of the body), and the gut microbe itself weighs 1.5kg 

    -- The health of the gut microbiome depends on many internal and external factors, as is reflected by its level of microbial diversity.  It is clear that exposure to antibiotics, the quality of diet, and the quality and extent of exercise have a direct effect on the microbiome.  In addition, many diseases affect the microbiome's health, including diabetes, obesity, inflammatory bowel disease, irritable bowel syndrome, atopy, depression, situational stress, etc. 

    -- We do tend to be a bit reductionist in our thinking about the human body, looking for the single vitamin or food component that would improve outcomes.  In the case of the microbiome, that would be looking for the single bug that might be associated with decreasing or increasing the risk of disease.  The reality is likely much more complex:

        -- The baseline microbiome composition varies dramatically from person-to-person, depending on many of the factors cited above.  And those microbiomes with less microbial diversity tend to be less healthy and perhaps allow for less augmentation of healthy microbial species if they are poorly represented in the microbiome (eg metformin led to Akkermansia being more abundant in two studies but less prevalent in two others)

        --There are inherent concerns with combining studies such as is done in this systematic review, given significant differences in individual study design, the baseline microbiomes of the participants/differing microbial diversity, the dosing of duration of metformin treatment, the methods of identification of the microbial species, differences in the patients included in the different studies (variations in patients with different underlying diseases such as obesity or depression or other confounding factors such as other medications being given, etc)

        -- There is very likely significant interaction between the microbial species themselves, whereby microbial species that tend to preserve health may well function synergistically together and perhaps even have important interactions with the more harmful species.  And these complex interactions are much harder to elicit in the setting of very different baseline microbiomes in different people

    -- There are clearly also some important differences in the subspecies of a group of microbes (eg, some e. coli are harmful and lead to diarrhea and increased mortality, yet the majority are beneficial).  This also tends to undercut the utility of a superficial analysis of the microbiome

 

-- perhaps related in part to metformin's profound effects on the microbiome,  there seem to be far-reaching benefits of metformin beyond diabetes and heart disease, including neuro-degenerative diseases, cancer (perhaps by improving diabetes control and decreasing diabetes-related cancers), infections (also perhaps by improving diabetes control), anti-aging effects (extending both health span and lifespan), polycystic ovary syndrome (probably from anti-insulin effects): https://gmodestmedblogs.blogspot.com/2022/08/metformin-its-many-faces-and-potential.html

 

-- by the way, I think these overall effects  of metformin really reinforce its use as the primary medication used for diabetes. So, for example, just assessing A1c control as the endpoint in diabetics can lead to the (incorrect, to me) conclusion that perhaps we should be using SGLT-2 inhibitors as first-line therapy (https://gmodestmedblogs.blogspot.com/2022/07/diabetes-sglt-2-inhibitors-as-first.html ). Perhaps we should be prescribing metformin to all people with “prediabetes” to the A1c level down to 5.7%. Perhaps even lower, since men with A1c of 5.5% have increased risk of cardiovascular disease.

 

--it is important to have a context here about the gut microbiome. its effects on the cardiovascular system as above, or on diabetes (also mentioned above) represent only a small part of the potential harms of dysbiosis:

    -- the gut/brain axis (see microbiome gut brain axis JClinInvest2015 in dropbox, or doi:10.1172/JCI76304) has been pretty well described showing that the gut microbiome can affect emotional behavior, stress- and pain-modulation, and brain neurotransmitters (the gut microbiota elaborates many neurotransmitters; animal studies have found major effects on the expression of brain signaling systems; some of these changes could affect appetite/diet/weight as well as the placebo effect (see https://www.frontiersin.org/articles/10.3389/fpsyt.2022.824468/full )

    --many studies have found important effects of gut dysbiosis with the development of cancer (colon, gastric, perhaps prostate), inflammatory bowel disease, local colonic infections (eg C. difficile), systemic infections (gut epithelial disruptions, effects on the overall immune system, microbial translocations, absorption of toxins many of which are broken down in a healthy microbiome), chronic kidney disease, allergic diseases (esp with the respiratory tract microbiome), and generally affecting the maintenance of homeostasis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306068/

        -- the Nurses; Health Study, for example, found that women who used antibiotics for more than 2 months had higher likelihood of colonic adenomas: https://gmodestmedblogs.blogspot.com/2017/04/antibiotics-microbiome-changes-and.html

 

 -- Another large concern in terms of the health of the gut microbiome is the role of emulsifiers in the food (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9331555/ ).  emulsifiers are chemicals that allow for easier " ready-to-eat" foods by allowing immiscible food ingredients (e.g. oil and water) to combine.  They are used frequently in the production of butter, milk, mayonnaise, sauces, ice creams, pastries, margarine, peanut butter,... to make the foods more homogeneous, smoother, and not requiring people to stir the products together to make them homogeneous.  However, they also destroy (emulsify) the mucosal barrier in the gut leading to a leaky gut and increased intestinal permeability as well as directly affecting the microbial communities into being more pro-inflammatory, and this has been found to be associated with increased systemic inflammation. these emulsifiers are found particularly in ultraprocessed foods and may well be of associated with increased incidence of metabolic syndrome and other chronic inflammatory diseases.  Of note, there are oral 100 different emulsifiers used in food processing, and some of them are clearly more harmful than others

-- there are also suggestions that microbiome alterations may be partly responsible for the finding of earlier onset colon cancer (and new recommendations to screen people at an earlier age): https://gmodestmedblogs.blogspot.com/2024/04/colon-cancers-earlier-onset.html , and less microbial diversity has been found in women with breast cancer: https://www.mdpi.com/2076-0817/12/3/468

 

-- and, of course, the medical literature is replete with articles on the association between antibiotic usage and deleterious effects on the microbiome:

     -- a really shocking report by the WHO in 2014 of worldwide dramatic antibiotic-resistant bugs, with some organisms (like gonorrhea) being resistant to all drugs we currently use: http://gmodestmedblogs.blogspot.com/2014/05/who-report-on-antimicrobial-resistance.html 

        --  antibiotic-resistant gonorrhea have been found in the US: https://gmodestmedblogs.blogspot.com/2023/06/antibiotic-resistant-microorganisms-can.html

    -- antibiotic-resistant microorganisms can spread within the community, even to those not exposed to antibiotics: https://gmodestmedblogs.blogspot.com/2023/06/antibiotic-resistant-microorganisms-can.html

    -- there is a huge problem with antibiotic overprescribing (though the current trend is overall more positive): https://gmodestmedblogs.blogspot.com/2019/01/antibiotic-overprescribing-2-more.html

        --this blog has reference to many others, including more blogs on the effects on microbiome changes, the utility of antibiotic stewardship programs, the emergence of untreatable "superbugs" (esp e.coli and klebsiella)

 

-- another blog documents antibiotic overuse in humans and animals (80-90% of antibiotics are used in animal agriculture, a likely very large source of antibiotic resistance in humans), along with case reports of people resistant to essentially all antibiotics: http://gmodestmedblogs.blogspot.com/2018/04/antibiotic-overuse-in-animals-and.html 

    -- the latest report on the extent of antibiotics used in food-producing animals: https://www.fda.gov/industry/animal-drug-user-fee-act-adufa/questions-and-answers-summary-report-antimicrobials-sold-or-distributed-use-food-producing-animals

 

So, though I have not had as many blogs on the microbiome in the past couple of years, I thought that these studies were a useful segue back into that arena. The microbiome is clearly an essential determinant of human health. Our lives have become increasingly complex with increasing exposures to internal and external causes of microbial trauma, varying from less healthy diet/sedentary life/antibiotic use to stress/depression/social isolation to environmental exposures to air pollution (https://www.mdpi.com/2305-6304/10/10/579 )/exposure to microplastics (https://www.nature.com/articles/s41598-021-04489-w ). The good news overall is that the microbiome is pretty responsive to healthful changes: much of the dysbiosis can be improved with improving diet/performing more exercise/mindfulness and relaxation (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8908961/ ), avoiding unnecessary antibiotics, etc. It also reinforces that some foods we consume (eg, red meat) may be particularly harmful to the microbiome, as well as the pretty impressive role of cows in climate change (Quitting Cows Could Have Big Environmental Impacts, but It's Harder Than It Sounds | Scientific American )....

 

geoff

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