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  #1   ^
Old Wed, Jul-05-17, 06:29
teaser's Avatar
teaser teaser is offline
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Default gut bacteria/obesity

Quote:
Altering gut bacteria pathways may stimulate fat tissue to prevent obesity

Cleveland Clinic researchers have uncovered a biological link between gut bacteria metabolism and obesity. The team showed that blocking a specific intestinal microbial pathway can prevent obesity and insulin resistance, as well as cause fat tissue to become more metabolically active. The study was recently published in Cell Reports.

The research team, led by J. Mark Brown, Ph.D., of Cleveland Clinic's Lerner Research Institute, studied the metabolic pathway that creates trimethylamine oxide (TMAO), a chemical produced by gut bacteria during digestion of key nutrients -- choline, lecithin and carnitine -- found abundantly in animal products, such as red meat, processed meats, egg yolks and liver.

Dr. Brown's colleague on the current study -- Stanley Hazen, M.D., Ph.D. -- previously showed that high levels of TMAO are associated with a higher risk of severe cardiovascular events, such as heart attack and stroke.

Since cardiovascular disease and obesity are so closely linked, the team hypothesized that TMAO may also be involved in metabolic pathways that lead to obesity. They focused on a host enzyme called flavin-containing monooxygenase 3(FMO3), which converts TMAO into its active form. They discovered that mice that had a missing or deactivated FMO3 gene were protected from obesity, even when fed a high-fat, high-calorie diet. Furthermore, the FMO3-negative mice showed higher expression of genes associated with beige or brown fat cells, which are more metabolically active than white fat cells.

The study confirmed in 435 patients that high levels of TMAO are associated with higher incidence of Type 2 diabetes.

"Obesity, diabetes and cardiovascular disease are strongly linked. While the microbiome has been shown to affect cardiovascular disease, there is as yet no concrete evidence of precisely how gut bacteria influence obesity," Brown said. "These findings shed light on a possible way to manipulate the microbiome with therapeutics to combat our obesity and diabetes epidemic."

Brown is a member of the scientific staff in the Lerner Research Institute's Department of Cellular & Molecular Medicine. Rebecca Schugar, PhD, is first author on the publication in Cell Reports.

"Given the numerous strong associations of the gut microbe-driven TMAO pathway with human disease, this work has broad implications for drug discovery efforts targeting gut microbes themselves," said Dr. Hazen, chair of the Department of Cellular & Molecular Medicine for the Lerner Research Institute and section head of Preventive Cardiology & Rehabilitation in the Miller Family Heart & Vascular Institute at Cleveland Clinic. "However, additional work is needed to better understand the entire pathway and the links between TMA, FMO3, TMAO and human health."

TMAO is a byproduct of bacterial digestion of choline, lecithin and carnitine, nutrients that are especially abundant in animal products such as red meat, processed meats and liver. Dr. Hazen, who also holds the Jan Bleeksma Chair in Vascular Cell, has previously linked TMAO to an increased risk of cardiovascular disease and has shown it can be a powerful tool for predicting future heart attacks, stroke and death in multiple patient populations. Dr. Hazen is an inventor of a test for TMAO that was licensed to Cleveland HeartLab, Inc., a Cleveland Clinic spin-off company. Dr. Hazen and Cleveland Clinic would benefit financially from sales of the test.


This is a fun area. A vegan might be tempted to just accept that these nutrients that meat is rich in are bad for you. Low carbers might be tempted to point out that the likely outcome of deficiency in these nutrients is fatty liver.

There is some evidence that choline deficiency can protect mice from diet induced diabetes, but they do get fatty liver in the process. And there's this;

https://www.hindawi.com/journals/jobe/2012/319172/

Abstract

Quote:
Previous studies demonstrated that choline supply is directly linked to high-fat-diet-induced obesity and insulin resistance in mice. The aim of this study was to evaluate if choline supply could also modulate obesity and insulin resistance caused by a genetic defect. Eight-week-old male ob/ob mice were fed for two months with either choline-deficient or choline-supplemented diet. Tissue weight including fat mass and lean mass was assessed. Intracellular signaling, plasma glucagon and insulin, and glucose and insulin tolerance tests were also investigated. The choline-deficient diet slowed body weight gain and decreased fat mass. Choline deficiency also decreased plasma glucose level and improved glucose and insulin tolerance although fatty liver was exacerbated. Increased adipose lipolytic activity, decreased plasma glucagon and reduced expression of hepatic glucagon receptor were also observed with the choline-deficient diet. Our results demonstrate that a choline-deficient diet can decrease fat mass and improve glucose tolerance in obese and diabetic mice caused by a genetic defect.


Of course if you approach this from the gut bacteria side rather than as a "bad nutrients" thing, this might yield approaches where people aren't trying to decide whether they'd rather have obesity and diabetes, or a fatty liver.

Another question is whether there's a sweet-spot for these nutrients. Also meal-timing might make a difference, keeping tmao elevated throughout the day vs. a smaller window. Since these approaches can be protective vs. diabetes and obesity, it's probably reasonable to suspect they might be protective against this potential mechanism.
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  #2   ^
Old Wed, Jul-19-17, 15:13
VLC.MD VLC.MD is offline
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Quote:
Originally Posted by teaser
Dr. Brown's colleague on the current study -- Stanley Hazen, M.D., Ph.D. -- previously showed that high levels of TMAO are associated with a higher risk of severe cardiovascular events, such as heart attack and stroke.


Ahem.
Let's see the reference.

(EDIT) Found one.
http://www.acc.org/latest-in-cardio...-n-oxide-in-acs

Interpretation: TMAO as some biomarker for CVD risk may have merit. What causes it to go up ?

----- Wikipedia ------
https://en.wikipedia.org/wiki/Trimethylamine_N-oxide

Microbiotic associations
The order Clostridiales, the genus Ruminococcus, and the taxon Lachnospiraceae are positively associated with TMA and TMAO levels.[8] In contrast, proportions of S24-7, an abundant family from Bacteroidetes, are inversely associated with TMA and TMAO levels.[8]

The concentration of TMAO in the blood increases after consuming foods containing carnitine[10] or lecithin[9] if the bacteria that convert those substances to TMAO are present in the gut.[11] High concentrations of carnitine are found in red meat, some energy drinks, and some dietary supplements; lecithin is found in soy, eggs,[11] as an ingredient in processed food and is sold as a dietary supplement.

The link between cardiovascular diseases and TMAO is disputed by other researchers.[13] Clouatre et al. argue that choline sources and dietary L-carnitine do not contribute to a significant elevation of blood TMAO, and the main TMAO source in the diet is fish.[14]

Another source of TMAO is dietary phosphatidylcholine, again by way of bacterial action in the gut. Phosphatidyl choline is present at high concentration in egg yolks and some meats.

Inhibition of TMAO
Vegan and vegetarian diets appear to select against gut flora that metabolize carnitine (in favor of other gut flora more coordinated with their food supply). This apparent difference in their microbiome is associated with substantially reduced gut bacteria capable of converting carnitine to trimethylamine, which is later metabolized in the liver to TMAO.[10]

3,3-Dimethyl-1-butanol (DMB), a structural analog of choline, inhibits microbial TMA formation in mice and in human feces, thereby reducing plasma TMAO levels after choline or carnitine supplementation.[8] It is found in some balsamic vinegars, red wines, and some cold-pressed extra virgin olive oils and grape seed oils.[8]

Summary: put some Olive oil based Chipotle Mayo on your Hamburger patty. (Personal opinion: I'm adding mustard, pickles, hot peppers, jalapenos, pepper as well).

Last edited by VLC.MD : Wed, Jul-19-17 at 15:49.
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  #3   ^
Old Wed, Jul-19-17, 15:47
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teaser teaser is offline
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  #4   ^
Old Wed, Jul-19-17, 16:00
teaser's Avatar
teaser teaser is offline
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Plan: ketosis/IF
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127123/

Trimethylamine N-Oxide: The Good, the Bad and the Unknown

Quote:
Abstract
Trimethylamine N-oxide (TMAO) is a small colorless amine oxide generated from choline, betaine, and carnitine by gut microbial metabolism. It accumulates in the tissue of marine animals in high concentrations and protects against the protein-destabilizing effects of urea. Plasma level of TMAO is determined by a number of factors including diet, gut microbial flora and liver flavin monooxygenase activity. In humans, a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events and death is reported. The atherogenic effect of TMAO is attributed to alterations in cholesterol and bile acid metabolism, activation of inflammatory pathways and promotion foam cell formation. TMAO levels increase with decreasing levels of kidney function and is associated with mortality in patients with chronic kidney disease. A number of therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that utilize TMAO as substrate and the development of target-specific molecules with varying level of success. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies examining the cellular signaling in physiology and pathological states in order to establish the role of TMAO in health and disease in humans.


Something that leaps out to confirm my bias;

Quote:
Indeed, TMAO generated by gut microbiome exacerbates impaired glucose tolerance, inhibits hepatic insulin signaling, and promotes adipose tissue inflammation in mice that are maintained on a high-fat high-sugar diet
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  #5   ^
Old Wed, Jul-19-17, 16:04
VLC.MD VLC.MD is offline
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3414418/

(1) Infarction itself causes TMAO to go up.

Quote:
To extend beyond ischemia, Lewis and colleagues have utilized an artificial infarction human model in the setting of alcohol septal ablation for obstructive hypertrophic cardiomyopathy to examine the temporal changes in metabolomic profiling during the course of myocardial infarction. Interestingly, the plasma signature of aconitic acid, hypoxanthine, trimethylamine-N-oxide (TMAO), and threonine differentiated with high diagnostic accuracy between infarcted subjects and patients undergoing coronary angiography.

https://www.ncbi.nlm.nih.gov/pubmed/18769631/

So in the OP original study, TMAO was pointing out the people having a heart attack. TMAO is a product of a heart attack. Not a cause. This study shows TMAO goes up in a heart attack, not that TMAO from food sources causes heart attacks.


(2) TMAO is higher in diabetics and patients with poor kidney function.

Quote:
These metabolites were subsequentally identified through a variety of chemical approaches and isotope tracer studies as TMAO, choline, and betaine – all being involved in phosphatidylcholine (choline) metabolism. We subsequently determined that oral ingestion of phosphatidylcholine was directly linked to systemic levels of TMAO and choline, and that intestinal microflora were intricately involved in the production of TMAO with direct causal association with the development of atherosclerosis in animal models. Systemic levels of TMAO were also shown to be higher in patients that are at increased risk of developing coronary artery disease, such as those with diabetes mellitus and with renal insufficiency. Interestingly, phosphatidylcholine is predominatley found in eggs, milk, fish, shell fish, poultry, red meat, and liver – many food groups abundant in fat and cholesterol, and that physicians have long been advising their patients to avoid in reducing cardiovascular risks.


So the subjects in the study in the OP could have high TMAO associated with their diabetes or poor renal function. The study did not correct TMAO levels for renal function or diabetes. TMAO is a marker for diabetes and reduced renal function. But that not helpful we have A1c and Creatinine levels already !

of course, everyone should know that low carb diets prevent or cure diabetes.

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  #6   ^
Old Wed, Jul-19-17, 16:12
VLC.MD VLC.MD is offline
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The TMAO produced when I eat meat gets cleared quickly with my good kidneys

Quote:
Missailidis et al. measured plasma concentration of TMAO in 80 controls and 179 CKD patients and reported that that elevated TMAO levels are strongly associated with degree of renal function [27]. Kaysen et al. measured serum levels of TMAO in 235 hemodialysis patients and reported that serum TMAO concentrations (median 43, (25th–75th percentile 28–67 μM/L)) were elevated in these patients compared to persons with normal or near normal kidney function (1.41 ± 0.49 μM/L) [8]


Mental note: Eat more chicken and less red meat when I am on dialysis.


Quote:
Originally Posted by teaser
it is questioned whether TMAO is the mediator of a bystander in the disease process.

Typo: or
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  #7   ^
Old Wed, Jul-19-17, 16:28
VLC.MD VLC.MD is offline
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Plan: Atkins/LCHF
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Quote:
Reduced intake of dietary precursors of TMAO is a potential approach. Dietary l-carnitine has been shown to induce gut microbiota-dependent production of TMA and TMAO in an animal study [3]. Thus, decreased consumption of l-carnitine and choline could decrease TMAO levels [3]. A systematic review and meta-analysis of 13 controlled trials showed that l-carnitine is associated with a 27% reduction in all-cause mortality, a 65% reduction in ventricular arrhythmias and a 40% reduction in anginal symptoms in patients experiencing an acute myocardial infarction compared to controls [59].


Huh ?

L-carnitine (which is associated with the eventual production of TMAO) is good for you ?

Uhhh ?
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