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Webinar #6: The Gut Microbiome and Metabolic Syndrome

Guy Daniels
Onegevity

Listen and learn as Onegevity explores the latest research on the gut microbiome's impact on Metabolic Syndrome. From weight to blood sugar control, we point out what taxa and specific bacteria to look for in a Gutbio report and how it impacts you!


Slide 1 - Welcome back to another segment in our comprehensive series on the microbiome and how it relates to your health. I’m Guy Daniels, the head of medical education at Onegevity health, and today we’ll be diving into metabolic syndrome, part one. Part two will be on NAFLD and NASH. This webinar will touch upon obesity, type 2 diabetes, and vascular health. So let’s begin.


Slide 2 – The war on obesity in this country has been a complete failure. We have a broken system from top to bottom. The food supply, and how we choose to eat is primary among them. The concepts of counting calories and avoidance of fat hasn’t helped. Today, as a nation, almost ¾ of us are either overweight or obese. If I were to write another book, it would be entitled “stop counting calories.” It would address ill-founded approaches, and highlight factors never discussed, such as the omnipotent microbiome. Since I’m not writing another book, I’ll share a few thoughts within this webinar. We’ll start with this slide, and as you can see from the bar-graph to the right, there is significantly more Proteobacteria and Fusobacteria in these obese subjects. If you recall, both of these phyla, in particular, Proteobacteria, is a phylum I mention all of the time -- which is loaded with opportunistic pathogens, a term with which you should be familiar by now. This study is a bit of a rarity, as each taxa highlighted within this paper fell in place according to the bulk of the literature. There are almost always odd, contradictory, or outlier findings in every study. But here, in this rare occurrence, the data seems to line up with what we typically see. And if you recall, the two most typical findings within the microbiome are that F. prausnitzii is good, and Escherichia is bad. And that’s what we see here. Not only was F. prausnitzii significantly beneficially associated with BMI (which is to say weight), but this was also the case for blood sugar. Contrarily, but equally consistent, was the fact that Escherichia was significantly detrimentally associated with BMI and blood sugars. So you ask, what do the bacteria in my body have to do with my weight? It largely boils down to inflammation.


Slide 3 – Here, I want to highlight through a case study, the power of the microbiome, and something that is continuously being demonstrated in animal studies. As you know, I rarely reference animal studies, unless they highlight something remarkable, which we’ll later see in this webinar. And you probably recall me saying, that in numerous conditions, whether it’s dementia, depression, autism, metabolic syndrome or something else, when the microbiome from a human or animal, with the said condition, is transplanted into healthy control rodents, they then go on to manifest those symptoms and lab results. Well, here we have an example between two humans. In this instance, here we have a mother/daughter fecal transplant scenario. The mother had received numerous rounds of antibiotics for reasons which centered around a C. difficile infection. The antibiotics actually worsened the situation in the long term, which makes sense, as the number one cause for a C diff infection is antibiotic use, yes, think about that. So, it was decided that she would need a fecal transplant, which came from her daughter. Well, this woman, who had never been obese in her lifetime, went on to become obese following the FMT, as well as new symptoms such as constipation. Despite exercise and a supervised diet, she gained more weight, in line with her daughter’s weight. This highlights one aspect of what’s wrong with our approach to weight loss in this country. If you have a difficult time losing weight, maybe it’s in large part due to your microbiome, and your lifetime of experiences which has shaped it, from the mode of delivery, breast-feeding or lack thereof, antibiotic exposure, stress and of course diet. If you haven’t viewed my previous webinars, I touch upon all of these. And one, antibiotic exposure, we’ll touch upon again now.


Slide 4 – On this slide, we have two studies that are almost identical in design and results. These researchers took obese men who were prediabetic or had metabolic syndrome and subjected them to 7 days of therapy on either vancomycin or amoxicillin. The premise was to verify what had been shown, mostly in animal research, that antibiotic use can worsen metabolic syndrome. Of course, they took a baseline and follow-up fecal microbiome samples, and these samples showed almost identical outcomes. Only the vancomycin groups experienced significant reductions in a number of the most important taxa you keep hearing me mention, taxa such as clostridium clusters IV and XIVa, F. prausnitzii, and species from the important genera Coprococcus, Anaerostipes, and Clostridium.


Conversely, but not surprisingly, there was a significant increase in Proteobacteria and the troublesome genus Enterococcus. So what we see here is consistency within the data. Of course, we have a long way to go in understanding the microbiome. However, we at Onegevity have put together the big pieces, while we finetune the rest. And through our expertise and hard work, we can share data with you that no one else can.


For example, if you take a look at the left side, you’ll see the vancomycin increased Lactobacillus plantarum in both studies, which would be interpreted as a negative outcome. But, L. plantarum is a popular probiotic, so how can this be? Well, we’ve just completed a thorough meta-analysis on the microbiome as it relates to metabolic syndrome, and what we found, is that the genus Lactobacillus, and at times certain species within, have an inordinate amount of negative associations when it comes to obesity and lab markers for metabolic syndrome. I know this may seem a little surprising, but if you recall, this was also the case for IBS, Crohn’s disease, and ulcerative colitis. So, if you use our convenient at-home test kit, and within the survey, you inform us that weight is a concern of yours, then we will make the appropriate recommendations to drive your microbiome in the proper direction. The other unique take-away from these two studies is that one antibiotic drove these unhealthy changes, and one didn’t at all.


Slide 5 – As you can see from the figure to the right, there is a clear association with the number of rounds of exposure to antibiotics and the development of type 2 diabetes. And in line with our previous slide, the relative risks are not the same for all antibiotics across the board. So again, this is yet another factor at play as to why someone may develop dysbiosis, and another, who would appear to have the same risk factors, does not.


Slide 6 – If you’re someone like in our case study, who was unsuccessfully on multiple rounds of antibiotics, or anyone with dysbiosis for that matter, is FMT therapy from a healthy donor worth considering? The short answer is no, not outside of research, but this research does shed more clues to the benefit of shifting one’s microbiome, as we can see here in this study. These researchers performed FMT on subjects with metabolic syndrome, re-using their own microbiome, the autologous group, or using the microbiome from lean subjects, the allogeneic group. They analyzed the microbiome of both groups before FMT and 6 weeks later after infusion into the metabolic subjects. They also measured for insulin sensitivity.

As you can see to the right, when a lean microbiome is infused into the gut of a metabolic syndrome patient, their insulin sensitivity significantly improves at the 6-week mark. These metabolic benefits were driven by the composition of the lean microbiome, which contained more of the key butyrate-producing taxa we continually discuss, in addition to cutting in half the amount of E. coli. Conversely, when the metabolic subjects received their own microbiome back via FMT, their E. coli count more than doubled. Although you can’t get FMT therapy outside of a research setting to treat obesity or type 2 diabetes, you can drive the necessary changes in your microbiome through precise recommendations, which brings us to this important point.


Slide 7 – This is from a systematic review of all the literature looking at the impact of FMT therapy on metabolic syndrome. They wound up only using three papers, one of which we just reviewed. The point I want to make from this slide is if you read the text to the left, you’ll see that the researchers from the 2017 paper went out to 18 weeks. And just like in our previous slide, FMT therapy improved a common blood marker associated with metabolic syndrome, in this case, HbA1c, which was not maintained out to 18 weeks. The point is this; you can introduce whatever good bacteria into your gut as you wish, but if you do not feed them the fuel they require to grow and reproduce, they will either die out or revert to undetectable or nearly so. So if you consider one person with gut problems, who eats a terrible diet, that so-called food, will not supply the good bacteria with what they need to survive and thrive, and on the other hand, it will contribute to dysbiosis. Had these subjects in this study, taken the appropriate prebiotics following their FMT therapy, I can virtually guarantee, the maintenance of a healthier microbiome and labs vs. at 18 weeks vs. day zero. So again, what we’re doing is making precise recommendations based on your analysis, and in doing so, driving your microbiome in the right direction, primarily with prebiotics. The other interesting point from this same 2017 paper, was that when they split the FMT groups into responders and non-responders, they found that the responders had significantly more Akkermansia muciniphila in their microbiome.


Slide 8 – With that in mind, we take a look at a newly published paper using A. muciniphila in humans, a first. Up until now, we only had extensive animal data telling us, that when administered, this superstar would have an array of metabolic benefits. Now we see it in humans. It significantly improved insulin sensitivity, GGT, AST, and total cholesterol and showed more modest improvements in LDL, triglycerides body weight, and fat mass. When it comes to non-commercial scientific markers of inflammatory indicators, it also showed a significant reduction in serum LPS, that’s that component of gram-negative bacteria we’ve discussed before, which results in a significantly heightened immune and inflammatory response, as it’s a recognition of an invader. Not that these amazing results aren’t enough, but the really interesting thing about this is that most of these benefits were driven by the pasteurized version of A. muciniphila. As we know, we go through great lengths, from manufacturer to supplier, to retailer, to your shelf, to keep probiotics alive and well, so you can take them. Here we have quite the opposite. These bacteria had been pasteurized; they were dead. So how in the world is it that they were able to drive such great benefits then? You’ve heard me mention before that many bacteria possess both direct and indirect benefits. Here we have an example of a direct benefit. A muciniphila contains a protein called the Amuc1100 protein. Although not discussed and measured in this paper, many researchers before, have found that this protein interacts with some component of our gut wall, and triggers a long series of benefits, through various protein expressions. It is likely that this is primarily how these benefits were manifested --through pasteurized bacteria in this study. You can’t buy A. muciniphila off the shelf or anywhere online, but you can increase it through various supplements.


Slide 9 – This brings us to this mouse study I referenced earlier to highlight a couple of very interesting points. In this rather elaborate experiment, the researchers exposed one group of mice to 30 days of cold, and one remained at room temperature, the RT group. By some epigenetic modification, the mass of the intestines of the cold-exposed mice increased significantly, as you can see from O and P to the right. Villi and microvilli length and gut diameter all increased significantly, which leads to an increase in absorptive capacity. I’ll be you didn’t know that the morphology of the gut could change so dramatically. It makes sense, as the organism under these conditions of stress needs to harvest more energy from its food, to maintain body temperature. To go one step further, if you look to the highlighted E to the right, they transplanted the microbiome of the cold exposed mice, into room temperature control mice, and found that strikingly, the gut morphology differences were ultimately also transferred, which also showed prolonged intestinal transit time, proportional to the increase in the intestinal length of the corresponding animals. The other interesting component of this relates to our superstar friend, A. muciniphila. When they administered A. muciniphila to the cold transplanted microbiome, our superstar friend prevented the increased glucose absorption, transit time, and intestinal length. Albeit in an animal model, this illustrates several important, powerful features of the microbiome, and how adaptable it, and our body can be. The A. muciniphila here was alive, not pasteurized. Its benefits in the fight against obesity and diabetes were confirmed in our recent meta-analysis, and are derived from its direct benefits via the Amuc1100, its benefits as a non-invasive mucin-degrader, and it’s indirect benefits as a propionate producer. A. muciniphila is not a butyrate producer, but a gram-negative propionate producer. Although butyrate gets most of the attention, its 3-carbon cousin is highly beneficial, as we’ll now see. 


Slide 10 – Here, we have another slide with two similar studies. Both look at administering propionate to subjects. In the 2017 study, labeled B, you can see how the propionate group had a significant increase in energy expenditure, purely from the propionate, which increased lipid oxidation. The 2014 study shown in the show in C and D to the right, shows significant increases in two hormones called PYY and GLP-1, which we’ll get to in a second. Over 24 weeks, the novel propionate supplement significantly reduced weight gain, intra-abdominal adipose tissue distribution, meal size, intrahepatocellular lipid content, and prevented the deterioration in insulin sensitivity observed in the control group. Propionate is a highly beneficial SCFA, which you have to think of as a hormone. Whether you want one of the benefits above, or others like the potentiation of glucose-stimulated insulin release and the maintenance of β-cell mass through inhibition of apoptosis, propionate plays a large role in all things metabolic. It does this in a variety of ways, but two of the most recognized are due to the interaction with PYY and GLP-1, which are hormones secreted from certain cells in your colon. These two hormones play a large role in appetite regulation. So if you’re goal is to lose weight, but you’re always hungry, the generation of SCFAs, in particular, propionate, would be an excellent way to suppress your appetite to support weight loss. Propionate also interacts with another very powerful type of receptor in the body, GPR, which helps to regulate energy expenditure. The best way to increase the amount of propionate in your gut is to feed the bacteria which produce it. This is done by selecting for certain fibers, such as PHGG, which proportionately speaking, are more propionate-producing in general. What we would not do, is provide or feed Lactobacillus, a common mistake most everyone else will make, as a genus, it’s negatively associated with weight. We’d also try to feed our good friends in the genus Bifidobacterium, and in a genus I’ve barely mentioned before, that of Bacteroides, which has extensive positive associations in most all things metabolic.


Slide 11 – Another way someone would usually try to address weight loss is obvious, through exercise. Seemingly, however, most would prefer the diet-only approach, as exercise is hard work. I’m not going to delve into the act of exercise and what types and methods are best for weight loss, but I’ll simply relay the fact that exercise also contributes to changes within the microbiome, as we see on this slide. If we look up top at A, within the two circles are the obese subjects in blue and the controls in red. As you can see, the blue dots cluster together, as do the red dots. These clusters are related to similarity in microbiome populations. After 6 weeks of exercise, represented by B, you see the microbiome separation between obese and healthy controls become more similar, shown by the distribution of the dots. And what changes happened to the microbiome of the obese upon exercise? They had significant increases in many of the classic butyrate-producing healthy bacteria I keep mentioning, in all of these webinars. And following the 6 weeks of exercise, were 6 weeks of sedentary living, at which point all of these butyrate-producing bacteria significantly decreased.


Slide 12 – Another way to address your weight and metabolic concerns is through diet and supplementation of fibers, which is the bulk of our recommendations, similar to this Chinese study. Here, the researchers subjected 93 centrally obese people to a comprehensive diet and fiber supplementation program. The first 9 weeks had more supplementation, while the following 14 weeks were considering more of a maintenance program. In this one study, we’ll see many of the points I’ve brought up through these webinars. Through this massive increase in fiber and thereby the feeding of many highly beneficial bacteria, which can generate direct benefits and indirect benefits through the production of SCFAs, we see the following: a weight loss of almost 13 lbs. A decrease in gut permeability. In part, because of this, a significant decrease in serum LPS. Because of this, a significant decrease in key inflammation markers. And improvements in insulin sensitivity, lipid profiles, and blood pressure. And what taxa changed from all these fibers? If we look at highlighted A to the right, we see our old nemesis; the phylum Proteobacteria was significantly reduced. If we look below that to highlighted C, we see the key subclassified family within Proteobacteria, that of Enterobacteriaceae, was significantly reduced with the fiber. If we look to the right at highlighted D, we see key genera within Enterobacteriaceae within Proteobacteria, such as Escherichia, Shigella, Klebsiella, and Citrobacter all had significant decreases on the high fiber diet. These genera represent a fair number of the opportunistic pathogens from gram-negative bacteria, whose inflammatory-inducing LPS is 100 – 1000 times higher than that of other more innocuous gram-negative bacteria, such as those from Bacteroides. We also see increases in the keystone genus, Bifidobacterium, which is essentially universally beneficial. So with this, it’s now a good time to look at one new feature of our report.


Slide 13 – Here, we see our new keystone taxa report. The six taxa listed here, come up often in the literature, and often or almost always seem to play a critical role, in one direction or another, for most conditions. Several of these we’ve touched upon within this webinar, such as the ones we just discussed, Bifidobacterium and Proteobacteria. As you can see, the red is on the left side of Bifidobacterium, so you ideally want more, whereas the red is on the right side of Proteobacteria, in which case, more is bad. One taxa, Methanobacteria, which is actually from archaea, has red on both sides. If you recall from our IBS webinar, too much Methanbacteria has been strongly associated with constipation, whereas too little is associated with diarrhea. Within obesity, although you’d think Methanbacteria would worsen the condition, data generally shows the opposite. We see our superstar friends, F. prausnitzii, which is highly beneficial in every condition we’ve reviewed thus far, and A. muciniphila, also universally beneficial, but even more so in metabolic syndrome, than other conditions. So, of course, we want to maximize both of these keystone species. That leaves us with Prevotella, which up until now has had universally positive associations. But when it comes to metabolic syndrome, the data is evenly split as to whether it is beneficial. And so things brings up another learning point or two.


Slide 14 – Here again, we have two studies, both finding that Prevotella appears to play a nefarious role in metabolic syndrome. From H on the left, we see from the 2016 Danish study, that the most prominent species within Prevotella, that or P. copri, was associated with insulin resistance. But how? It appears that their production of BCAAs could be the culprit. If you recall, the bacteria in our gut possess the genetic ability to make thousands of enzymes, and this can vary from bug to bug. Here we have a genus, which possesses the ability to make BCAAs via its metabolism. This makes sense, as we know that subjects from a Burkina Faso study, who consumed a very high fiber diet, and who had very high levels of Prevotella, had higher levels of BCAAs. Our data shows us that the BCAAs may not be the problem, but their parent compound BCAAs may be, as there’s a fair bit of data to suspect them in metabolic syndrome. But the Burkina Faso people don’t suffer from obesity, diabetes, and vascular disease. So is their high Prevotella really a problem? Likewise, in a southeast Asia study, again, a group with high Prevotella due to their native high fiber diet, they too don’t suffer from these maladies. Maybe another hint can come from the second study in this slide, where researchers looked into serum succinate. Succinate is a byproduct of both human and bacterial metabolism, and high serum levels have been linked to hypertension, heart disease, and type 2 diabetes. Succinate, like everything else in our incredibly complex stew of biochemistry, is a signaling molecule, and too many results in negative outcomes, and as you can see from the right side of this slide, it was detrimentally associated with all of these parameters of metabolic syndrome. And the family Prevotellaceae, which is mostly comprised of Prevotella, was associated with this increase in succinate, as it’s a succinate producer. But again, the high-fiber native subjects had high Prevotella but did not suffer from metabolic syndrome. The likely answer lies within the overall balance of the microbiome, which is a function of what you ingest. The high succinate subjects had high levels of succinate producers, but low levels of succinate consumers. This should sound similar to you, as we discussed this concept before with lactate. The high BCAA group would, in theory, have to consume more animal protein, as these amino acids come primarily from that source. The higher your fiber, the more you compensate for animal protein, and its potential detrimental metabolites, particularly in the distal colon. So, if you suffer from a condition, which we by now is in some large or small part related to your gut, you may have not only obvious problematic players in your gut, but an overall imbalance in metabolism, which includes producers vs consumers, something we can look at via the genetic blueprint of your microbiome.


Slide 15 – If we look at this Japanese study in diabetics, where incidentally, Prevotella had positive associations, and lactobacillus had negative associations, we see a significant increase in live bacteria in the blood of diabetic patients. This stands to reason, if we recall back to gut permeability, since peptides and proteins from food, and LPS from bacteria can make their way into our bloodstream, through a compromised GI tract, then why can’t bacteria? As you can imagine, this has systemic consequences, like everything else we cover.


Slide 16 – And so as we progress through obesity and the likely impending diabetes, we continue on a step further into the development of the vascular disease, with its possible acute outcomes. In this study, which looked at the microbiome, and its genetic metabolic capacity, 53 congestive heart failure subjects were compared to 41 healthy controls, and what they found was quite classic, reconfirming many of the points I’m trying to drive home. The healthy controls were enriched in our good friend F. prausnitzii, and the CHF subjects were enriched in the opportunistic pathogens from Streptococcus, Veillonella, and, most specifically, from the bad acting species, Ruminococcus gnavus, all names you’ve heard before. From a metabolic viewpoint, the microbial genes from the CHF patients were enriched in the ability to make the now-familiar, but detrimental LPS, and especially in a compound which is new to you, TMA, aka trimethylamine. As we see from C to the right, the key enzyme in the synthesis of TMA is expressed significantly higher in CHF, than that in the healthy controls. The result of this, you’ll see in time, in a whole webinar dedicated to TMAO, but for now, just know that there is a clear association between TMAO and vascular disease. The other finding reported here in D, is that the key enzyme to make butyrate is expressed significantly higher in the healthy controls, than in the CHF subjects. Once again, we see the benefits of this exceptional SCFA, which functions on many levels within the gut, and systemically to optimize one’s health. If your lab results show that you have a low metagenomic ability to make butyrate, one of our primary goals is to rectify that. 


Slide 17 – In yet another congestive heart failure study we see the impressive statement, which I’ll just read verbatim, that “Compared with normal control subjects, the entire CHF population had massive quantities of pathogenic bacteria and Candida such as Campylobacter, Shigella, Salmonella, Yersinia Enterocolitica, and Candida species.” As you would expect, along with this predominance of the opportunistic pathogens came intestinal permeability, inflammation, and heart manifestations, as measured by right atrial pressure, all of which were interrelated, as shown to the right. If we look at gut permeability alone, it was 78% higher in the CHF arm vs. control, and it got progressively worse as the CHF class increased. Also, take note of the opportunistic pathogens; there may be a new name or two there. It always doesn’t have to be E. coli; there is a long list of these bad players waiting for their opportunity to flourish under the right conditions. It so happens that these 4 bacterial genera fall within Proteobacteria, but there are many others that don’t. 


Slide 18 – To take vascular health a step further, this study looked at the bacterial diversity of atherosclerotic plaque as compared to the oral and gut of subjects with atherosclerosis vs. healthy controls. Interestingly, they found the potentially troublesome genera Veillonella and Streptococcus in almost all plaques, and that was correlated to their abundance within the oral cavity. The oral microbiome is quite different from the gut microbiome, which we’ve mostly been discussing — the microbiome changes as you descend the GI tract. As we’ve discussed, there are a variety of factors for this, such as oxygen availability, HCL, pancreatic enzymes, bile, and pH. However, like in SIBO, where you have bacteria able to crawl too far up the GI tract, here you have the same concept, but in a different direction, where someone with a compromised GI tract, say they take PPIs or H2 blockers or have pancreatic insufficiency, or something else, the normal mechanisms for keeping bacteria compartmentalized, is out of whack, and you can have bacteria descend the GI tract, so where in one location, they are a part of the normal environment, in another, they can be problematic. So, with these oral taxa making their way to the vascular plaque, the Veillonella and Streptococcus could have descended, and passed through the permeable wall of the GI tract, and taken up residence in the plaque. Similarly, if you look at A to the right, and the statement, you’ll see that the plaque had far more of the nefarious Proteobacteria than the oral or gut samples, as a percent of the population. Again, quite possibly gaining access to the vasculature via intestinal permeability, which they likely in part caused. 


Slide 19 – In the first of our review slides, we see the differences in fermentation between carbohydrates and protein as they relate to metabolic syndrome. Note the key that denotes the black lines as beneficial, and the grey as negative regulators. This is not to say we should consume no animal products, but for the general population, the likelihood that the ratio of animal protein to fermentable fibers is far too high. In the top left, we see the SCFAs, notably butyrate and propionate, for which I keep singing their praises. And on the upper right, you see some of the fermentation by-products from protein, many of which, but not all, are either directly harmful, harmful in a more metabolized form, or indicators of imbalance.


Slide 20 – In our last review slide, we visually see the short-chain fatty acids at work in metabolic syndrome from another angle. Here, I think you can gain an appreciation of how the SCFAs can support the individual metabolically. We see the GLP-1 and PYY I had mentioned earlier, and we here add the GPR41 and 43 proteins, which, when signaled by SCFAs, can have significant benefits. They are not only located along the GI tract, as this image implies but systemically as well. We’ll dive more into the GPRs in our next webinar, which brings us to our last slide.


Slide 21 – So in review, we hit on several topics. We reconfirmed findings from taxa with which you’re now becoming familiar. For example, taxa within proteobacteria can be problematic for one person’s depression, another’s IBD, and another’s metabolic syndrome. The genes of the person may be unique, their life experiences, reasonably unique, but the players in the gut remain the same. One person’s dementia can be another’s autoimmune, given the same general microbiome flaws.


As you can see from this slide, we hit on other concepts as well. If you haven’t seen my previous webinars, I suggest you give them a try, as we build on concepts as we progress. If you haven’t placed an order for one of our kits, send me an email at support@onegevity.com, and let me know what I can do better to support your optimal health. Until next time.