The 2015-2020 United States Dietary Guidelines for Americans (USDG) recommended limiting consumption of red meat. The USDG suggested that both processed and unprocessed meat be limited to approximately 1 weekly serving (1). However, a recent article in the October 2019 Annals of Internal Medicine evaluated four systematic reviews that focused on both observational studies and clinical trials that had addressed the health effects associated with red meat and processed meat consumption, and also one systematic review that addressed people's health-related values and preferences regarding meat consumption. The expert panel of 14 US and international nutrition experts came to a very different conclusion than prior reviews and so, perhaps not surprisingly,  that conclusion was widely reported to the general public. After a systematic review, this expert panel stated: “…. adults continue current unprocessed red meat consumption. Similarly, the panel suggests adults continue current processed meat consumption.” However, the panel did note these recommendations were based on “weak evidence” (2). However, this article has drawn sharp criticisms from other researchers and many clinicians who say that the methodology used to grade the existing research misrepresents the vast data that shows red meat’s many known and suspected adverse metabolic effects and health outcomes, including heart disease, some cancers, and type 2 diabetes. Nonetheless, the meat industry is helping to spread this “good news” for those who enjoy processed and unprocessed red meat.Should Nutrition Professionals Stop Advising Less Red Meat?Certainly this review of reviews does little to eliminate the well-established and suspected potentially-detrimental adverse metabolic effects of consuming red meats -- especially those high in fat and processed. Red meats are generally high in saturated fat and cholesterol. We have long known that increasing the consumption of both saturated fat and/or cholesterol in the diet elevates LDL-C and non HDL-C in the blood (3). And no one doubts that higher LDL-C and non HDL-C levels promote more coronary artery disease (CAD) (4).For example, a large prospective study from nine European countries (European Heart Journal Trial) followed middle-aged and older subjects for 12.6 years and showed that heart attacks are strongly associated with eating mammal meat and processed meats (5). Many previous studies have shown that a more vegetarian diet is associated with reduced heart attack risk (6). For more than 70 years, scientists have blamed dietary saturated fat and cholesterol intake as responsible for causing heart attacks, but there is growing evidence that red meats may promote heart disease in other ways too.Other Possible Adverse Metabolic Effects from Red MeatTriMethylAmine oxide is another possible metabolite increased by a steady diet of red meat. Foods that contain choline or L-carnitine are converted to a gas called trimethylamine (TMA) by gut bacteria. This gas is absorbed into the bloodstream and passes to the liver, where a liver enzyme converts TMA to TMAO. Choline and carnitine are found in large amounts in red meat and are also found in poultry, fish, dairy, and egg yolks, but in far lower amounts in plants. However, red meat raises blood levels of TMAO much higher than does poultry, and it also changes the bacteria in your colon to the ones that make more TMA. People who switch from eating red meat to eating primarily chicken and plants see their blood levels of TMAO drop markedly along with the concentrations of the colon bacteria that make TMA (7). The European Heart Journal Trial suggested that elevated blood levels of TMAO may increase risk of heart attacks in several ways:

• Reducing cholesterol clearance from the bloodstream
• Increasing the cytokines that promote inflammation to form plaques.
• Increasing clotting that is the ultimate cause of heart attacks (8)

Fatty dairy products and egg yolks are high in saturated fat and cholesterol. Egg yolks and fatty dairy products also contain choline. Fish can contain carnitine and choline that raise blood levels of TMAO and some cold deep-water fish also contain TMAO, which they appear to use as an anti-freeze. However, eating fish is generally not associated with an increased risk for heart attacks (9), perhaps because the omega-3 fatty acids in deep-water fish may help to reduce inflammation and clotting that increase heart attack risk, thus countering or blunting the adverse metabolic effects of TMAO.Last May 22nd, the Journal of the American Medical Association contained a detailed article by Jennifer Abbasi, who wrote: "Researchers at Stanford University are already studying the effects of plant-based meat alternatives on TMAO levels in a clinical trial. But short of going full-on herbivore, people can substantially reduce TMAO levels within as little as a month by eliminating or reducing red meat, according to the European Heart Journal Trial that compared protein sources."Another possible CAD Risk Factor is Neu5GcBack in 1982, Professor Ajit Varki of the University of California San Diego discovered a sugar-protein complex molecule (called Neu5Gc) that appears in the tissues of almost every mammal except humans (10). Two to three million years ago, our pre-human ancestors had a single genetic mutation in their CMAH gene that apparently helped protect them from a deadly form of malaria in Africa. Apes, gorillas, chimpanzees, and other human progenitors were dying from a type of malaria called Plasmodium reichenowi. Then along came a pre-human ancestor with a CMAH gene mutation. Instead of making a cell surface sugar-protein complex called Neu5Gc, this mutation resulted in another molecule called Neu5Ac (11). As a result, that pre-human ancestor did not die from malaria like other apes, monkeys and gorillas, so his or her children lived and proliferated. The result is that today all humans have Neu5Ac instead of Neu5Gc. Chimpanzees share more than 99 percent of their genes with modern humans, but the CMAH gene is one of the areas of difference. As often happens in nature, the malaria parasite then modified its own genetic makeup into a variant called Plasmodium falciparum, which can infect humans, but not chimpanzees, so today humans can be infected only with Plasmodium falciparum while chimpanzees and other great apes can be infected only with Plasmodium reichenowi. Since no other mammal developed this genetic mutation, only humans make Neu5Ac and so have an immune system that reacts to Neu5Gc.When people eat mammal meat, some of the Neu5Gc from that meat is absorbed into their bloodstream. It appears that with red meat, Neu5Gc triggers the immune system of people because their immune system responds to this sugar-protein in much the same way it responds to infecting microbes. The human immune system recognizes germs by the sugar-proteins on the surface of their cells. If the surface proteins are the same as those on your own cells, your immune system lets the protein enter you cells, but if the surface proteins on membranes are different from those on your cells, your immune system tries to kill what it mistakes as invading germs. It appears that eating red meat turns on one’s immune system just as germs do, and if one eats red meat regularly, one’s immune system may stay overly active all the time. This can lead to chronic inflammation. The same cells and chemicals that attack and kill germs can damage arteries, making it easier for nonHDL-C particles to deliver more cholesterol to the artery wall. Chronic inflammation may also destabilize cholesterol-rich atherosclerotic plaques that can rupture and lead to a heart attack. People who have the most markers of an overactive immune system and inflammation are the ones most likely to suffer, and die from, heart attacks (12). Researchers have identified a gene (CMAH) that produces Neu5Gc, the potentially harmful component in red meats (13).Neu5Gc, Neu5Ac, and Heart DiseaseHeart disease causes about one-third of the deaths in North America, and while well-established risk factors for heart attacks include high blood cholesterol, high blood sugar, high blood pressure, obesity, smoking, or lack of exercise, there are about 15 percent of people who suffer heart attacks and yet do not have elevated any these risk factors (14). Other mammals can suffer heart attacks when they have these risk factors (often caused by human lifestyle habits), but they seldom suffer heart attacks if they do not have any these risk factors as some people do (15). When mice were genetically modified to have the same CMAH gene mutation, these CMAH gene-modified mice suffered double the risk of atherosclerosis compared to unmodified mice when fed red meat. Like humans, they also experience an increased risk for inflammation, heart attacks, strokes, diabetes, and some types of cancers.Bottom Line: For many years, this reviewer has been recommending that people should limit their intake of red meat (meat from mammals). Continuing research on TMAO and Neu5Gc add yet more evidence as to why a steady diet of red meat may promote serious ills over the long term and the evidence grows stronger still. Processed and red meat intake has been linked to increased risk for diabetes, some types of cancers, and other diseases. Certainly we need more research to establish more precisely how TMAO and Neu5Gc from eating red meat appear to promote chronic inflammation and other adverse metabolic effects that promote disease. However, when added to the fact that red meat is high in saturated fat and cholesterol, this new data suggests that most people would likely be better off in the long run if they limited red meat and especially fatty processed red meat intake. There seems to be adequate data showing that people who regularly eat red meat are indeed more likely to have an increased risk for heart attacks, strokes, diabetes,  and cancers (16). However, there is not enough data at this time to conclude that even eating small amounts of red meat on occasion is dangerous to one’s health.By James J. Kenney PhD, FACNReferences:

1. U.S. Department of Health and Human Services 2015-2020 Dietary Guidelines for Americans. Washington, DC, U.S. Department of Health and Human Services. December 2015.
2. https://annals.org/aim/fullarticle/2752328/unprocessed-red-meat-processed-meat-consumption-dietary-guideline-recommendations-from.
3. https://academic.oup.com/ajcn/article-abstract/29/11/1184/4649703/
4. file:///C:/Users/PritiKin1330/AppData/Local/Packages/Microsoft.MicrosoftEdge_8wekyb3d8bbwe/TempState/Downloads/316.full%20(1).pdf
5. Circulation, April 22, 2019
6. Am J of Clin Nutr, July 1, 2014;100(suppl 1):320S–328S
7. Eur Heart J, Feb 14, 2019;40(7):583–594
8. Cell, March 24, 2016;165(1):111-124.
9. Microbial Ecology in Health and Disease, May 19, 2017:28(1)
10. Proc Nat Acad of Sciences, Sept 29, 2003
11. Proc Natl Acad Sci USA, Sept 6, 2005;102(36): 12819–12824
12. J of Nutr, May 22, 2019
13. Genome Biol Evol, Jan 1, 2018;10(1):207-219
14. CDC, NCHS, Underlying Cause of Death, 1999-2013
15. Evol Appl, 2009 Feb; 2(1): 101–112
16. Genome Biol Evol, Jan 1, 2018;10(1):207-219