Tuesday, April 9, 2013

Meaty "News": Choline, Carnitine & "Bacteria Poop" Make (Red) Meat Unhealthy. Learn Why the Latest Revelations Are Neither New, Nor Meat-Specific And Still Made the News

Personally, I eat meat and will continue to do so, but the above is not meat. That's junk, for which there is evidence that it precipitates heart disease (Micha. 2012).
Actually I did not really want to "blog" about the latest hypothesis on a mechanism by which red meat could give contribute to atherosclerosis and heart disease, but since it's all over the news I feel inclined to provide you with some information to (a) find the happy medium between the scaremongering media hype and the similarly misplaced assessment that "we have been made to eat meat, so it cannot be bad for us" and (b) understand how science news are made.

I am not 100% sure which approach would be most appropriate, but I guess, it would be prudent to start the whole discussion by taking a peak at the actual paper, the publication, or rather the media coverage of which has sparked the whole turmoil.

Why does everybody and his mama talk about the study?

As a SuppVersity reader you probably belong to small number of people who actually care about scientific research. Being such a person myself, I know that people like us are hard-pressed to find anyone who will not answer questions like "have you heard about the latest results from the XYZ study" with a blank stare. So why on earth are there studies like the one Robert A Koeth et. al. just published (in fact the study is not even officially published, as of now it's only an e-paper!) that spread faster than the Hollywood-caliber flu scenarios that are supposed to "encourage" you to get vaccinated? Personally I feel like there are a couple of factors coming together here:
  • Familiarity & ostensible tangibility: The concept that red meat was bad for your heart is something everyone has heard about. You just have to add the words "bacteria poop" and even the average consumer of the Oz-show will feel like he/she knew all about the latest scientific evidence.
  • Personal concernment: Whether we do, or don't eat meat, news like these concern all of us. The meat-eaters will question, whether they may be hurting their health and/or get upset about the "vegan propaganda", while the vegetarians and vegans will celebrate how smart they are not to eat meat and point with a finger at the dumb omnivores, who will soon be suffering the consequences of their "unsustainable and cruel" dietary habits ;-)
  • The vegetarian / vegan lobby: Despite the fact that the "paleo movement" has gathered some momentum, vegetarianism and veganism still have a huge lobbying with sympathizers at many key positions of the society - esp. in the media business. With all "bad news about meat" being "good news for vegetarianism", it should be obvious that the "hurdle" a press release like the one Laura Ambro wrote for the Cleveland Clinic (read what all the "science mags" just copied and pasted here) does not have to pass a similarly high hurdle as the press release from the Michigan Diabetes Research and Training Center which does assert that lifting weights could help keep blood glucose levels under control (read it)
  • The Nature factor: Before I started reading scientific papers on a regular basis I would have been impressed by the words "a recent article published in the prestigious journal Nature", these days I ignore statements like that. Good science will prevail, whether it is published in Nature or in an open journal like PLOS-1.
  •  "Only bad news are good news" Let's be honest, we all know that bad news spread way more rapidly than good news. Imagine the study would have found that "no risk [increase of coronary arthery disease in type II diabetics] is seen with unprocessed meat consumption" (as a 2012 review of the evidence says; cf. Micha. 2012), who would have cared?
    "[...] the generally recognized tendency of the popular media to publish mostly negative aspects of news items is driven by the demand of their audience, rather than by inherent preferences of the media itself. To understand this, consider for a moment that there are two types of stories: positive stories or “good news” (and negative stories or “bad news”. Think of good news as stories about happy endings, in which people made the right choices. Bad news stories are about unhappy endings, in which people made the wrong choices. When consumers read good news stories, they can make similar choices to increase their incomes. When they read bad news stories, they can choose to avoid bad outcomes and the resulting income losses." (Swinnen. 2005)
    You see, according to science it's your own fault that you are fooled by the media... and let's be honest, it in fact is. If people did not click on the "bad news" first, those would generate lower page impressions and ad revenues and the media would have to revise their policy.
Now these are five reasons that may explain why you've already heard about the study. There is yet at least another sixth reason that's missing from the list above - and that despite the fact that I already mentioned it in the introduction.
  • The more publicity a study receives the more idiots like me will deem it necessary to blog about it, so that after bazillions of shares on Facebook (I got three on my Facebook, alone) and a couple of thousand blogposts, all the world knows exactly what the study is about (why are you laughing?)
In essence these would be 5 + 1 good reasons not to delve any deeper into the matter, but now that I am at it, I won't let you go without at least some additional rambling. 

What's the main message of the article?

Apropos evidence: I wonder how the "choline is the bad guy hypothesis" that's at the heart (all puns intended) of the new "red meat causes heart disease" hypothesis is compatible with statements like "the long-term consumption of [dietary choline and betaine] have been shown to prevent CVD mortality by decreasing inflammation and other risk factors." (Rajaie. 2011) And why are they going after red meat specifically, if soy and particularly Miso have been shown to have similar effects on TMAO concentrations and - in human beings, by the way (Solanky. 2005). Plus: Isn't it surprising that the exact same (or almost the same) results have been reported by Wang et al. for phosphatidylcholine (best dietary source = soy lecithin!) and without the words "red meat" in the title in 2011 already and nobody cared? Just sayin'...
Choline and choline-like/-based substances such as l-carnitine and phosphatidylcholine that are found at comparably high concentrations in (red) meat, eggs and all the other usual subjects are converted to trimethylamine by certain bacteria in your gut and metabolized to trimethylamine-N-oxide (TMAO) in your liver.
  • Epidemiological evidence -- Concomitant elevations of serum l-increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events carnitine and TMAO levels.
  • Experimental evidence --Tthe chronic administration of l-carnitine to rodents increased the incidence atherosclerosis. A process that was probably mediated by the reduction of reverse cholesterol transport from the arteries to the liver the scientists observed, when they kept their rodents on a carnitine, choline or TMAO supplemented chow. The extent to which the TMAO load explains variations in the risk of heart disease in rodent studieshas been estimated by Bennett et al. in another recently published study to be 11% (Bennett. 2013)
As mentioned before these are valid scientific findings that cannot be "discussed away" by stating that "we evolved to eat meat" or "that's just rodents, and I am no rodent!"

Which bacteria are to blame?

In view of the fact that scientists usually have a genuine interest in developing means to prevent (in this case) heart disease and not like the media and certain lobbyists to generate hype, acquire readers or rather advertisement consumers or reduce the consumption of meat, the most significant finding of the study at hand actually is that the use of a broad spectrum antibiotic does not only kill all bacteria, it also prevents the ill-health effects that come with the ingestion of large amounts of choline and l-carnitine (please mind my wording: "ill health effects of dietary choline and carnitine - not red meat).
"Discovery of a link between l-carnitine ingestion, gut microbiota metabolism and CVD risk has broad health-related implications. Our studies reveal a new pathway potentially linking dietary red meat ingestion with atherosclerosis pathogenesis. The role of gut microbiota in this pathway suggests new potential therapeutic targets for preventing CVD." (Koeth. 2013)
Against that background it is pretty intruiging that none of the articles I have read mentions that the scientists do already have preliminary evidence of who exactly those bad guys may be (only stat. sign. associations):
    sign. associations with high TMAO concentrations 
    • Tenericutes Mollicutes
    • Tenericutes Mollicutes Anaeroplasmatales
    • Tenericutes Mollicutes Anaeroplasmatales Anaeroplasmataceae
    sign. associations with high TMA concentrations  >
    • Bacteroidetes Bacteroidia Bacteroidales Prevotellaceae
    • Bacteroidetes Bacteroidia Bacteroidales Prevotellaceae Unclassified
    • Bacteroidetes Bacteroidia Bacteroidales Prevotellaceae Prevotella
    • Deferribacteres Deferribacteres
    • Deferribacteres Deferribacteres Deferribacterales
    • Deferribacteres Deferribacteres Deferribacterales Deferribacteraceae
But things get even better there is more than a handful of potential "good guys" who appear to be associated with lower than average levels of TMAO in the blood on the scientists' radar, already. Fostering the growth or directly supplementing with each of the following bacterial strains could thus mitigate if not nullify the ill health effects of carnitine & co. These potentially protective bacteria are bacteriodetes and firmicutes certain strains of protobacteria (* denotes statistical signficance)
    If the connection of choline, meat & co and a certain enterotype is news to you, you can learn more about it in a previous post
  • Bacteroidetes Bacteroidia
    • Bacteroidia Bacteroidales
    • Bacteroidales Porphyromonadaceae*
  • Firmicutes Erysipelotrichi
    • Erysipelotrichales
    • Erysipelotrichales Erysipelotrichaceae
  • Proteobacteria Betaproteobacteria
    • Proteobacteria Deltaproteobacteria
    • Deltaproteobacteria Desulfovibrionales
It is still preliminary to say, whether or not it would be a viable and more importantly practical strategy to constantly suppress the nutrient-dependent (see article referenced in the image above) rise in "bad bacteria" by using antibiotics or probiotics, but it would certainly be good to see the research zoning in on that instead of trying to find new explanations for epidemiologically non-sustainable claims such as "all red meat is bad for you".

A final word on the potential involvemend of the liver, bile and dietary fiber?

Another totally neglected yet potentially important factor, I personally feel would be worth investigating is the role of the liver. If you take a look at my slightly modified version of the proposed mechanism in Illustration 1 and remember my elaborations on the TMA => TMOA conversion in the liver, the brown metabolic "waste dump" certainly appears to be at an absolutely crucial position within the proposed etiology of TMAO-induced cardiovascular disease. 
Illustration 1: Modified sketch of the potential mechanism behind the pro-artherogenic effects of dietary carnitine and choline (adapted from Koeth. 2013)
I mean, what is the most common reason for heart disease? Meat consumption? No, if anything it is something that oftentimes correlates with the #1 reason, or I should say reasons for heart disease: the metabolic syndrome. You are very likely to give studies the abstracts of which include statements such as...
"The bile acid receptors farnesoid X receptor (FXR) and TGR5 both regulate lipid, glucose, and energy metabolism, rendering them potential pharmacological targets for MS therapy." (Porez. 2012)
"[Bile acid sequestrants] reduce atherosclerosis in Ldlr-deficient mice, coinciding with a switch from body cholesterol accumulation to cholesterol loss. RUN slightly modulated atherosclerotic lesion formation but the combination of BAS and RUN had no clear additive effects in this respect." (Maissner. 2013)
... a more thorough reading in the future. Especially in view of the fact that the -26% reduction in bile acids (Taurodeoxycholate, Tauroursodeoxycholate, Tauro-β-muricholate, Taurocholate) the scientists observed in the TMAO fed rodents suggest that the provision of bile acid sequestrants that promote the natural adaptation process and lower the intestinal cholesterol absorption even further could at least ameliorate the problem.

Moreover, the natural ability of dietary fiber to bind bile acids leads us back to things of which we already know that they are beneficial for the heart. Things that target both the gut microbiome and the absorption / excretion of cholesterol via bile... oats, for example! A 2010 study by Andersson et al. for example, shows quite conclusively that the bran of the fiber, protein, carb and fat laden powerfood will increase the faecal excretion of cholesterol and bile acids, lower blood lipids and reduce atherosclerotic lesion areas in the descending aorta (-77%) and aortic root (-33%) of LDR(-/-) mice, i.e. mice who lack the ability to "recycle" cholesterol due to the absence of the respective receptors on the liver.

You cannot handpick the several billion lodgers in your intestine, but you can attract the right ones by providing them with the foods they like. Contrary to the current probiotic hype, scientific evidence suggests the key to gut and metabolic health lies in the prebiotics you are stuffing down your piehole (learn more).
Bottom line: The main reason for mentioning the involvement of the liver and the potential role of the FXR (=bile acid receptor) in the etiology of the problem in the end of this post which got much longer than I had intended it to be is to point you to the hilarious over-generalizations that are taking place when the results and implications of studies like these are passed from one person to another before they finally end up at the "Mr. Joe Average Level" in the form of either Meat Kills! or The Vegan Lobby is at it again!

What's lost in all the hysteria is the fact that the study at hand could in fact provide insights into the often-touted involvement of the gut microbiome in the etiology of all sorts of diseases... this, and not the "red meat is fill in whatever you like for you" debate, is what could actually help us to reduce the number of CVD related deaths on both an the large nation- and world-wide, as well as on a personal level.

Ah, and in the mean time, you probably don't have to be all too worried, as long as you eat a varied whole foods diet that's includes different sources of dietary fiber, vegetables and a rational amount of fruits, you can easily keep your gut microbiome in a state where real (=unprocessed meat) is not a problem.

  • Andersson KE, Svedberg KA, Lindholm MW, Oste R, Hellstrand P. Oats (Avena sativa) reduce atherogenesis in LDL-receptor-deficient mice. Atherosclerosis. 2010 Sep;212(1):93-9.
  • Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen SL, Lusis AJ. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013 Jan 8;17(1):49-60.
  • Meissner M, Wolters H, de Boer RA, Havinga R, Boverhof R, Bloks VW, Kuipers F, Groen AK. Bile acid sequestration normalizes plasma cholesterol and reduces atherosclerosis in hypercholesterolemic mice. No additional effect of physical activity. Atherosclerosis. 2013 Feb 26.
  • Micha R, Michas G, Mozaffarian D. Unprocessed red and processed meats and risk of coronary artery disease and type 2 diabetes--an updated review of the evidence. Curr Atheroscler Rep. 2012 Dec;14(6):515-24.
  • Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, Didonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013 Apr 7.
  • Porez G, Prawitt J, Gross B, Staels B. Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease. J Lipid Res. 2012 Sep;53(9):1723-37.
  • Rajaie S, Esmaillzadeh A. Dietary choline and betaine intakes and risk of cardiovascular diseases: review of epidemiological evidence. ARYA Atheroscler. 2011 Summer;7(2):78-86.
  • Solanky KS, Bailey NJ, Beckwith-Hall BM, Bingham S, Davis A, Holmes E, Nicholson JK, Cassidy A. Biofluid 1H NMR-based metabonomic techniques in nutrition research - metabolic effects of dietary isoflavones in humans. J Nutr Biochem. 2005 Apr;16(4):236-44.
  • Swinnen, J. F. M., McCluskey, J. and Francken, N. Food safety, the media, and the information market. Agricultural Economics. 2005; 32: 175–188.