New Research on Sialic Acids, Inflammation, & COVID-19
Professor Roger Seheult, MD dives into new research on Neu5Gc, a sialic acid molecule found in meat and dairy, which may contribute to inflammation and more severe COVID-19 symptoms.
Meat, Dairy, & Disease
In this video update, MedCram Co-Founders, Dr. Seheult and Kyle Allred, PA, discuss the mechanisms of sialic acids, specifically the roles of Neu5Ac and Neu5Gc in humans and other animals, as detailed in this 2005 study.
Neu5Gc is not produced by humans, but occurs in red meat (beef, lamb, pork, etc.) and can cause various inflammatory symptoms when consumed by people. Dr. Seheult explains recent research demonstrating this, such as this 2020 French NutriNet-Sante study, which examines the link between high red meat consumption and cancer risk by creating a scale (called the “Gcemic Index”) of amounts of Neu5Gc and its protective antibodies in various meat and dairy products.
Dr. Seheult also interprets studies on xenosialitis and serum sickness, the role of BMI, plant-based diets, meat consumption, and biologic therapy all in relation to the connection of sialic acids, inflammation, and risk of disease.
Watch the full video here, or read through the transcript below.
What are sialic acids and why are they important?
Kyle Allred: Dr. Seheult, you spent a lot of time recently looking into something called sialic acids, and this is something that I have very little familiarity with. Tell us about why these are important and what you’re going to talk about in this video.
Dr. Roger Seheult: Yeah, thanks, Kyle. So sialic acids are a very important compound. Sometimes we can see that sialic acids in certain foods that we eat can lead to an inflammatory condition, and that inflammatory condition could lead to chronic inflammation or even more severe COVID-19, so we’re going to learn more about that. And I’d like to tell you a little bit more about specifically what sialic acids are, and that’ll help explain exactly where we’re going in this video.
So sialic acids are a family of more than 50 members of nine carbon sugars that coat proteins throughout the body. I mean, if you were to look at proteins in the human body, you might not even recognize the fact that they are coated with so many sugar molecules because the animations that we’re all used to seeing. For instance, the spike protein and the ACE-2 inhibitor, whenever we see those being depicted on cartoons, there’s never any coding for sialic acids.
But, in fact, sialic acids are sort of like the Christmas tree decorations on the Christmas tree. If the Christmas tree is the protein, the decorations are the sialic acids. One of those sialic acids is something known as N-Acetylneuraminic acid, or Neu5Ac, and you can see that there, the chemical structure of that. Above that is the one that is primarily in the human body. Now, what is the reason for that being there? The quote is a “major function of sialic acids and glycans on different cell types is to help the innate immune system discriminate between self and non-self; as a result, different tissues express tens to hundreds of millions of glycan chains per cell that are capped by sialic acids.”
And so here’s a picture that demonstrates that. You can see here in humans in this area on the surface of the cell are a number of different sugars. That’s why they’re known as “glycans,” and you can see that these green dots are what we call mannose. And then finally when we get to the very end here when we have galactose, what we want to look at are the very fingertips, if we will, of these sugar molecules that are coating the cell.
Neu5Gc & Neu5Ac
And in this case, in the human situation, what we have encoded with is Neu5Ac in non-human mammals. However, they are coated with five Neu5Ac, but also can be coated with galactose and can also be coated with this white diamond, which is Neu5Gc, which actually is only one atom off of Neu5Ac. We’re going to talk more about that and why that is important. Here’s a blow-up version of it. Again, the white diamonds, Neu5Gc, we never see that on humans; we only see Neu5Ac, and the reason for that, the reason why humans can’t make Gc is because they lack the enzyme that converts the Neu5Ac into Neu5Gc.
And those molecules are so similar to each other; in fact, they only differ by one oxygen molecule. That’s important, because in humans as humans get older from birth, because they lack the Neu5Gc, they start making antibodies against Neu5Gc, and so by the time human beings are two, three four, five years of age, they already have circulating antibodies against this substance, Neu5Gc, which it can’t make on its own. Now you might be asking, “well, why is this important?”
Well this goes back to a study back in 2005 titled the “Mechanism of Uptake and Incorporation of Non-human Sialic Acid N-Glycolylneuraminic Acid into Human Cells.” This is the Gc that they’re referring to. In other words, is it possible that Gc can get into the human body and the answer to that is yes, and what they showed is that here they have something called “high performance liquid chromatography.”
They can put the sample into a chromatograph and see when the different peaks come off. And Ac here is in blue. That’s what we normally see in humans. And Gc here is in red. And so we can see here that a non-fed or just a Neu5Ac fed human is going to have a spike here with Ac, and then when it is fed Gc, we actually have two spikes.
And what should that tell you? That tells you that if a human being eats an animal that makes Gc, what happens is that Gc is absorbed into the body and that the body utilizes that sialic acid Gc as if it were Ac, and puts it onto the cellular surface and incorporates the Gc into the cells of the human body. It comes in from the diet. It is absorbed through macropinocytosis, goes to the lysosomes. It then goes through into the golgi apparatus, and then it gets placed and put onto the surface of the cells.
So, again, to review, 5Gc is a sialic acid that’s only found in animals, but if a human eats those animals, then the Gc — regardless of how well it is cooked — will be incorporated into the cell surface of the human cells, even though it doesn’t produce its own Gc.
Now why is that important? Because all human adults have varying levels of circulating IgM, IgG, and IgA antibodies against these Neu5Gc glycans, and that human anti-Neu5Gc glycan antibodies can interact with metabolically incorporated Neu5Gc to promote chronic inflammation, likely contributing to tumor inflammation and potentially cancer progression and also vascular inflammation.
Serum Sickness & Xenosialitis
This, by the way, is exactly what they believe is the mechanism for serum sickness, where the serum of animals were put into humans and this caused inflammation. The term that is used here is xenosialitis; xeno- being different animal, -sialitis being a sialic acid mediating inflammation.
And here we have a human who has CMAH-/-. That means he does not have the enzyme to make the Gc from the Ac, so we have loss of Neu5Gc. When he goes out and eats food that has Neu5Gc in it, he gets xenosialitis. Why is that? Because there are antibodies against Gc, which causes inflammation in the epithelium and also in lung and liver and colon tissue, and this can cause issues with atherosclerosis possibly or even cancers that can be related to this.
As they have found, there is Neu5Gc found in the endothelium and atheromas of patients with arteriosclerosis. Here’s a paper that was published in September of 2020, probably lost in the din of COVID-19 news, titled “Association between Neu5Gc carbohydrate and serum antibodies against it provides the molecular link to cancer.” This is a French NutriNet-Santé study, and in the study they looked at 16,000 adults, all of whom had registered a minimum of six dietary records, and the ingestion of Neu5Gc was calculated based on the records of their diet and also the knowledge that scientists had of the food products that they were eating.
I’m thankful that this was in a French population, because they were able to take the dairy products and really break it down in terms of the type of cheese and the amount of Gc in it. It was known as a “Gcemic index,” and I’ve got it listed here for you, where one is the amount of Gc that is in beef As a reference, you can see here that there are many cheeses that have a low amount of Gc and many cheeses that have an even higher amount of Gc in them cheeses such as etorki or roquefort dried cheese, etc. We also have here meat listed, where we can see that there are some that have higher amounts of Gc, like sausage, pate, and liver, whereas there are some meats that have much less Gc in it, as you can see down here.
What meat and dairy products contain Neu5Gc?
Kyle: Just to clarify, is Neu5Gc found in things like poultry, eggs, and fish?
Dr. Seheult: No, Kyle. Neu5Gc is not found in those food products, and even though they have been associated with ischemic heart disease in some studies, the degree and the magnitude is much, much less than some of those other foods that we’ve been talking about that Neu5Gc is in, like red meat, lamb, pork, etc. And that’s what’s so tantalizing about this study and these studies on Neu5Gc is that it seems to explain the differences between those two foods.
Well, what they were able to do is they were able to do a quartile graph of the Neu5Gc intake, and you can see here that as it went up, the amount of meat, dairy cow and dairy sheep, and goat went up. Now, we have men here on the left and women on the right. You can see clearly that the amount of Gc intake was significantly higher in men than it was for women, something that’s interesting when we go back to look at the risk factors for COVID-19.
And then when they looked at the antibodies circulating in these patients and, of course, there’s numerous different types of antibodies to 5Gc because 5Gc can be in many different types of positions on the glycans on the cells, that when you added those up there was definitely a correlation in terms of the amount of antibodies and the amount of food in terms of Gc intake that was seen.
So this for the first time connected together in human beings that the amount of Neu5Gc in their diet caused Neu5Gc antibodies to be elevated, and therefore may be the connection to show that these things are the things in fact that lead to this chronic xenosialitis or chronic inflammation.
What’s the role of BMI?
Kyle: I want to ask you about BMI, body mass index, because when studies come out showing potential benefits of a vegetarian diet or at least reducing the amount of meat and dairy intake, oftentimes it’s easy to try to poke holes in the research by saying “well, meat and and some types of animal dairy are just very caloric dense foods, so people that consume them are more likely to have a high BMI, and therefore if you have a higher BMI, we know the evidence is really solid there that there are a variety of diseases that are more common.” So how do you parse this data here to suggest that these sialic acids may have a role on their own?
Dr. Seheult: Good question. So if we look at the Adventist Health Study – 2, where they looked at almost 100,000 Adventists living in North America, what they were able to show was an association between dietary pattern and BMI. So you had the vegan group with the lowest BMI at around 23, and then you went to the lactoovo-vegetarian which was just north of 25, and then after that was the pescovegetarian, followed by the semivegetarian, and then finally the nonvegetarian.
And at each step there was a stepwise increase in BMI, and this was an association, and the point you bring up is great is “how do we know that they’re just not eating more calories, and that’s the reason why they have a higher BMI?” Well, what they did next was they then looked at the diabetes risk and they found that the same relationship was there for diabetes risk, even after they controlled for BMI.
So in other words, the same pattern going from vegan all the way to non-vegetarian: if you had a vegan and non-vegetarian together with exactly the same BMI, the risk of diabetes was higher in the non-vegetarian than it was in the vegan, even though they had the same BMI. And we know that diabetes, that insulin resistance, that a lot of these things are related to inflammation and related to oxidative stress, and so it’s felt that even though the BMI is the same, and BMI doesn’t take into account everything, but when they did the multi-regression analysis, taking out gender, taking out socioeconomic status, taking out all of these things, there was still a very strong relationship between dietary pattern and risk for diabetes, risk for hypertension, risk for BMI.
Kyle: At the end there, you said “at a higher risk for BMI.” Are you suggesting that inflammation itself can be a driver for a higher BMI, regardless of calorie intake?
Dr. Seheult: Yes, that’s very astute. So that’s exactly what the evidence that is now coming out seems to show is that there is a vicious cycle of inflammation leading to obesity and then obesity leading to inflammation, and this vicious cycle is unfortunately continued. And we don’t know if it’s the chicken or the egg, but yes, both can lead to both.
So the question then becomes “is all of this mediated or at least in part mediated from inflammation?” Well, here’s a very interesting study that was published in 2019 in the Journal of the American Medical Association Cardiology, titled “Association of Biologic Therapy With Coronary Inflammation in Patients With Psoriasis as Assessed by Perivascular Fat Attenuation Index,” and what they did was they looked at patients with autoimmune conditions such as psoriasis who were on biologics.
Now biologics are medications that by antibodies reduce inflammation. This was a prospective study cohort looked at 2013 all the way through 2019 with about 134 subjects. And what they found was there was significant coronary improvement and reduction in coronary inflammation with biologics. What does that tell you? That perhaps a lot of the driving force with coronary disease and cardiovascular disease may actually be from inflammation.
They say here that “in this study, biologic therapy for moderate to severe psoriasis was associated with a reduced coronary inflammation assessed by perivascular FAI. This finding suggests that perivascular FAI measured by CCTA may be used to track response to interventions for coronary artery disease.
Diet & Coronary Artery Disease
Kyle: Speaking of coronary artery disease, someone who’s received a lot of attention about coronary artery disease and diet is Dr. Esselstyn. Can you tell us about his work?
Dr. Seheult: Yes, so Dr. Esselstyn is a cardiothoracic surgeon at the Cleveland Clinic. I mean, his job is to operate on people with coronary disease, and there was a number of patients of his that couldn’t get it, they were so sick. He was interested in this whole food, plant-based diet, and so he initiated this diet very strictly on a number of his patients who could not undergo surgery, and he followed them up three to five years later with angiograms and was able to show that cutting out all meat and actually cutting out oils — it was a very strict diet — he was able to show that he was able to cut down the amount of coronary events substantially in those patients that were adherent to the diet and actually showed very elegantly that there was an actual reversal of coronary disease in these coronary arteries.
Just remember that coronary heart disease treatment is coronary artery disease bypass surgery, or CABG. Here after three to five years, we actually had disease that reversed itself, so it was quite remarkable.
Kyle: I am not a vegetarian, but I do try to stick to unprocessed meats when I eat meat, and I took some solace in a big study that came out of Europe in 2013. Can you tell us about that study, and if there’s any new research that sheds light on this debate of unprocessed meat versus processed meat?
Dr. Seheult: Yeah, Kyle, so prior to this big European study, a couple of studies out of the United States had shown that both processed and unprocessed red meat could lead to increased all-cause mortality and cardiovascular mortality.
This European study, known as the EPIC study, was the largest study on diet and disease up to that point — over half a million people in 10 different countries in Europe. It was very heterogeneous, very widespread, and what their findings were, at odds with the United States findings, was that they only found an increased mortality in those who were consuming processed meats and not unprocessed meats, and so that led to a big debate about whether or not this was had to do with the processing the salts the other things that go into things like processed bacon, hotdogs, cold cuts, these sorts of things.
And so that was published in 2013, but there’s been some new light that’s been shed on that, ironically, also out of Europe in the UK Biobank study that just got published this year in 2021 in March, and I’d like to go into that in more detail. They looked at about half a million middle-aged adults recruited into the UK Biobank study between 2006 and 2010 with a mean follow-up of about eight years.
What they did again was looking at association, and so what they did is they looked at a number of different disease subgroups for both, in this case, unprocessed red and processed meat that was taken three times a week. And anything here that has a line that is completely on one side of this unity line means that it is statistically significant.
So what does both unprocessed red meat and processed meat together three times a week lead to? It leads to an association with ischemic heart disease. It leads to an association with cerebral vascular disease, specifically ischemic strokes. It leads to pneumonia, which is something that we hadn’t seen before and is interesting, considering our discussion with COVID-19. It also leads to diverticular disease, which is not surprising. It also leads to diabetes.
Once again, these are the same things that we saw with increased BMI, but the real question is, what do we see with just unprocessed meat just three times per week? Again, we still see an increased risk of ischemic heart disease. We still see an increased risk for pneumonia, which is very surprising but interesting, and not so surprising when you consider the Neu5Gc finding, it’s also associated with diverticular disease, and also again associated with diabetes.
When we looked at processed meat more than three times a week, again, ischemic heart disease. We see a small, very slight increased risk of venous thromboembolism, in terms of statistically significant but not quite, because the p-value is 0.06. Again, this pneumonia, increased risk is still there. We also see diverticular disease once again and once again diabetes.
What we haven’t talked about up until this point is poultry meat, which does not have Neu5Gc in it, but what it did show was that it is statistically significant, again, for ischemic heart disease. So even white meat, poultry meat is associated with ischemic heart disease. We can also see here that gastroesophageal reflux disease, and in fact gastritis and duodenitis, is associated with poultry meat consumption more than three times per week. We also see that gallbladder disease is associated, and also once again diabetes as well.
Risks & Benefits of Red Meat Consumption
Kyle: The data here suggests many potential negative associations between red meat and poultry consumption and different impacts on health. What about benefits?
Dr. Seheult: Yeah, well this is an associative study. What we saw across the board with meat, in general, was a reduction in iron deficiency anemia, which shouldn’t be surprising. There were some mixed results regarding red meat and poultry. With red meat, we saw a reduction in atrial fibrillation, atrial flutter, which is an irregular heartbeat, that disappeared when we looked at poultry.
So it was an interesting finding, and this led the authors to conclude that “our findings from this large, prospective study of British adults show that meat consumption is associated with higher risks of several common condition, but a lower risk of IDA.” That is iron deficiency anemia. “The higher risks are at least partially accounted for by higher BMI,” and that’s interesting. “And some of the associations remaining after adjusting for BMI or waist circumference may still be due to other aspects of adiposity. Additional research is needed to evaluate whether these differences in risk reflect causal relationships, and if so what proportion of incident cases for these different outcomes that could be prevented by decreasing meat consumption.”
So what they’re saying here is that a lot of the driving force for association was seen with BMI, although BMI did not explain a hundred percent of it, and I think that’s interesting, because we know that obesity has a vicious cycle associated with inflammation. And as we’ve just discussed, inflammation may be part and parcel with the antibodies against 5Gc.
Kyle: And I assume the results from this new UK Biobank study help support the hypothesis of Neu5Gc and inflammation, right?
Dr. Seheult: Yeah, well, because Neu5Gc is present in unprocessed meats, we would expect that if in fact Neu5Gc is causing inflammation, we should also pick up a signal in the unprocessed meats category as well as the processed meats, and that seems to be the case here.
So, in summary, certain diets are associated with outcomes. Sialic acid and the immune response offers a testable explanation for why red meat is associated with ischemic heart disease and cancer. And while more research is needed, there is an emerging picture that is developing.
I think the answers to some of these questions is going to be made known through this COVIDENCE UK Study, which is actually looking at dietary and lifestyle choices and the mortality with COVID-19, and I hope that there are more studies looking at this specifically.
Okay, thanks for joining us. And don’t forget to see all of our MedCram videos at our website MedCram.com. We’ll see you next time.