Vanessa Stadlbauer-Köllner, MD, is a professor and liver transplantation lead with the Department of Gastroenterology and Hepatology at the Medical University of Graz (Austria). Her research interests include hepatology, immunology, transplantation, microbiome, intestinal permeability, and probiotics.
Michelle Maddux, ND, received her doctorate of naturopathic medicine from Southwest College of naturopathic Medicine in Arizona. She has completed additional training in integrative and functional medicine, laboratory medicine, eating disorders, meditation, and mindfulness.
Dr. Michelle Maddux: So, your work focuses mostly on hepatology, immunology and the influence of the gut microbiome. It’s such a fascinating topic, yet it’s largely misunderstood by a lot of people. Would you begin by giving us just a little bit of an overview of how these functions—liver, immune, gut—work together in a healthy individual, as well as the potential repercussions of imbalances such as dysbiosis or microbiome imbalance?
Prof. Vanessa Stadlbauer-Koellner: Yes, of course. It’s really true, as you said, that this is a fascinating field. So, when I started research in the field of hepatology, I started from the disease part, seeing patients with lots of complications of liver cirrhosis. And then I started to be interested in immunology, and at a later stage it became apparent that the gut microbiome influences these conditions to a large extent. So, the gut microbiome, which is the sum of all the microorganisms that live in our intestines, plays a really large role in stabilizing the gut barrier. Usually when you are healthy, you have a diverse bacteria community that lives in the gut. They produce a lot of helpful substances that can be used by the body, but they also keep the barrier tight so the bacteria itself and toxic products of the bacteria, do not enter the bloodstream.
But in the case of diseases, when the gut microbiome is damaged, for example by toxic substances like alcohol, the intestinal barrier breaks down and substances from the gut microbiome can enter the body. And we have a very unique situation with the communication between our gut and liver. All the blood that is in our intestines gets collected in a large vein, and this portal vein goes directly to the liver. So, the liver doesn’t only get oxygenated blood from an artery, it also gets this nutrition and other substance-rich blood via the portal vein. Potential problematic substances like bacterial products can also enter the liver via the portal vein. When you are quite healthy, the liver can deal with that. The liver initiates an inflammatory reaction, and the problem is essentially solved.
But if you have a liver disease like liver cirrhosis, these bacterial products can enter the circulation. This can actually be measured when you draw a blood sample from a patient with such a condition; endotoxins can be found circulating in the blood, for example. This can then cause systemic inflammation or even infections leading to clinical problems. This concept of the microbiome, the gut barrier, the immune system and systemic effects is what we call the gut-liver axis.
Dr. Maddux: So that was a really wonderful and succinct summary of the gut-liver axis and the gut microbiome’s impact on it. You mentioned that 1 aspect of your work looked at cirrhosis and how manipulation of the gut microbiome through targeted probiotics can have a positive impact on liver function, as well as immune response and obviously gut microbial diversity and intestinal barrier integrity. You did a couple of studies: 1 in 2009 and 1 in 2020. What were the key takeaways from those studies?
Prof. Stadlbauer-Koellner: I have been working on complications of liver cirrhosis for a long time, even before 2009. So, I would like to start by drawing the whole picture. Initially I was very interested in understanding whether the immune system works well or not in liver cirrhosis. During a research stay abroad in London between 2006 and 2008, I studied neutrophil granulocytes. They are the first barrier of defense that helps our bodies fight pathogens. We found out that neutrophil granulocytes don’t really work well in liver cirrhosis. And then we did our first study using a single probiotic strain given to those patients via a milk drink, and saw a slight improvement in immune (neutrophil) function.
When I came back to Graz, Austria, I wanted to repeat the study in a larger setting as a placebo-controlled trial with a large number of patients. I had the chance to work together with Institute AllergoSan, and together with them, we developed a multispecies probiotic from the data from cell culture experiments and other analyses using strains that are likely to improve the gut barrier and immune function, and thereby help prevent liver complications. I planned and conducted this very large study with funding from an Austrian government agency. The study included 100+ patients with liver cirrhosis. They were treated for 6 months with a multispecies probiotic, which is available on the market as Omni-Biotic® Hetox.
We treated these patients for half a year, and then followed them for another half year. 50% of the patients got the probiotic intervention and the other patients got a placebo. In the end, we were very, very surprised that we were able to improve liver function during that time. That’s really a very unique finding, because you can’t usually improve liver function in liver cirrhosis with any kind of treatment. You can improve liver function when you take away the toxic stimulus that causes liver cirrhosis, like when you treat hepatitis C or hepatitis B, or when patients stop drinking, but there is no drug currently available that can improve liver function. So, we were very happy about this result. And we could also show that this multispecies probiotic improves neutrophil function and also monocyte function. But at that time, it was still very difficult to look at the composition of the gut microbiome in such a large study with 100 patients, at least in my facility.
So, it took a couple of years until we could use the samples from the same study to conduct an in-depth analysis of microbiome composition and function. What we found was that the probiotic really improves the composition of the gut microbiome. We found both the probiotic strains in these patients and improvements in the general structure of the gut microbiome. For example, we found an increase in bacterial strains that are able to produce short-chain fatty acids. And it is well known that short-chain fatty acids improve the gut barrier. So, this was the evidence for the clinical effect we saw in the first study, which made us very happy because we saw that it was not by chance, but really by modulating the gut microbiome.
Dr. Maddux: It’s very exciting to me when we have the ability to go back and re-analyze data with new technology. Technology, especially in the scientific community, is improving so very quickly. And so to be able to go back to that study and have an even greater understanding of the findings and see different findings that you just weren’t able to see before is really exciting to me. There are 2 additional studies that further piqued my interest about how the microbiome has an impact on these particular systems; 1 looked at glucose metabolism and lipid markers in patients with diabetes, which is such a huge and prevalent issue around the world. What were your findings in that particular study?
Prof. Stadlbauer-Koellner: In the diabetes study, we again did research on the same product: Omni-Biotic Hetox, together with a prebiotic. The reason for doing this is that in diabetes we see changes in the gut microbiome, in the gut barrier and in the immune system. So we came up with the hypothesis that the same product could be useful in this condition. And this was not only done by us. There were also 2 other studies, one from Poland and one from Saudi Arabia, who used the same product. We decided to go for a similar treatment duration, so we used 6 months of treatment. And it was again a placebo-controlled study. The patient took this probiotic and a prebiotic for 6 months, and we included an observation period afterwards. Compared with the placebo group, we had some very interesting findings.
We found additional improvement in glucose metabolism. All these patients were diabetic and received their normal diabetes treatment. But with the addition of the probiotic and prebiotic, we saw further improvement in glucose metabolism. We also found some improvement in lipid metabolism and the gut barrier. What was most striking to me was that although we told these patients not to follow any crash diets, or change their eating habits or physical activities in any significant way, the patients who took the probiotic lost 2.5 cm from their hip circumference. So, they didn’t lose weight, but they lost fat. And that’s of course a very interesting finding. As I said, the patients continued their normal treatment for diabetes and/or arterial hypertension. But it seems that adding this probiotic treatment can improve the effectiveness of these treatments. I think this is really important in a condition like diabetes, which affects millions of people worldwide.
Dr. Maddux: Yes, that’s a really interesting finding. Losing hip circumference is a really big deal. At least in the United States, we talk about the waist to hip ratio being such a key feature for increased cardiovascular and cancer risk. And so having a probiotic/prebiotic regimen that would actually help take centimeters off a waist circumference and a hip circumference, that’s a big deal, even if there isn’t necessarily a weight loss with it.
So, another study looked at the use of a targeted probiotic to offset the impact of long-term proton pump inhibitor (PPI) use. Again, PPIs are everywhere in the United States; they’re over-the-counter drugs. Anybody can buy them and start taking them. So, a lot of people use them. It would be exciting to understand whether a simple supplement could be of benefit in this particular population. What did your study find?
Prof. Stadlbauer-Koellner: Here again, we re-analyzed data from our cirrhosis cohort. One of my doctoral students did this work, and she found that when she looked at the gut microbiome composition, one of the strongest factors that explained the variation between patients was whether or not they took a PPI . And when we looked at this in more detail and found some shocking findings. We found that in patients with chronic diseases like liver cirrhosis, when they have to take a PPI, this causes a certain type of dysbiosis. We find oral bacteria in the stool microbiome that don’t normally belong there. Everybody has bacteria in his or her mouth, which is perfectly fine. We need them there, but they are usually killed by the stomach’s gastric acid when swallowed.
If you don’t have a lot of gastric acid because you take an acid blocker, these bacteria can go further down into the intestinal gut microbiome. When you are perfectly healthy, this phenomenon is seen, but it’s probably not a huge deal. But when you have liver cirrhosis, these translocated certain oral bacteria (oralization) that cause this so-called oralization are associated with a higher risk for complications and even a higher risk for death. Because many people have to take PPIs and cannot discontinue them because they would get acid-related diseases of the stomach and other complications, we first think of treatment with an antibiotic. But that wouldn’t really help because we would kill millions of commensal bacteria in the process.
So, we had to come up with something else. Probiotics were next on our list as a potential solution. This is the published study that you’re referring to, in which we took a couple of probiotic strains and treated patients on a long-term PPI. We had some very interesting findings, but to be honest, we were not completely happy with the results. So that’s why this product will probably not come to the market at any time because we decided it was not good enough. We want more. But we can already show that with this product, we could improve gut permeability. So, in those patients who had increased zonulin levels, which is a marker of gut permeability, they showed a very nice decrease when they took the probiotic.
We also saw some improvement in liver function tests. What was very interesting was that we also saw an improvement in gastrointestinal symptoms. When you ask a patient who takes a PPI if they feel any side effects, they will hardly ever report anything. But when you then ask them to fill out a questionnaire at the study outset and after 3 months of taking the probiotic, we saw a huge increase in their gastrointestinal quality of life. So yes, we had some very good findings, but we were not happy enough with them. So, what we are currently doing is searching for a better targeted probiotic. And we are already quite advanced with this. From a huge number of probiotic strains, we identified a couple of strains that are really targeted against the bacteria that cause oralization. And now we are working together again with Institut AllergoSan to make a product and test it in a clinical setting.
Dr. Maddux: It’s exciting that you’re getting to develop a product as you’re improving quality of life. As knowledge of the gut-liver axis expands and hopefully becomes as large as knowledge of the gut-brain axis, I think there’ll be a lot more interest in this. In addition to this study, is there anything else that you or some of your colleagues are working on or have been recently published that gets you really excited?
Prof. Stadlbauer-Koellner: One topic that’s really, really interesting and what we have begun to study is microplastic particles. When you drink something out of a plastic bottle. or eat something that was wrapped in plastic, or when you use toothpaste, for example, you ingest microplastic particles. There was a study a few years ago from a colleague of mine, also a gastroenterologist in Vienna, who showed that these microplastics can be detected in the stool. This caused a lot of media interest at the time. And it also caught my interest. So I started reading and found out that from animal studies, it’s already known that microplastic causes changes in the gut microbiome.
When you feed mice microplastic, they develop changes in the gut microbiome. And when you look at this data, it looks like the microbiome of somebody who is obese, has cancer or has some other disease like diabetes. You see a loss in diversity of the microbiome and you see an increase in potentially pathogenic species.
On the other hand, there are also some studies completely outside of the medical field that showed certain bacteria are able to degrade microplastic. This was done at waste plants. They collected bacteria from waste sites and saw that there are certain types of bacteria that can really eliminate the plastic. What we are going to do now is find out whether microplastic really damages the human microbiome. And if yes, if we can find probiotic bacteria that can degrade these microplastics. This would be really, really cool because we can’t get rid of plastics and plastic packaging materials. It also has some advantages because it’s very light and you don’t need a lot of energy to transport things that are wrapped in plastic. So, it’s not our goal to say that microplastic is bad overall. But if microplastic really damages the human gut microbiome, I would like to find out if there is a possible solution with probiotics to get rid of these negative effects.
Dr. Maddux: That is really interesting and very exciting. I do read a lot about microplastics and I know a lot of people try to minimize plastic, but you’re right. It’s just not something that you can realistically completely avoid. And I never really thought about the environmental impact of making things all in glass, which is heavier to transport and so on and has potentially a larger environmental footprint. That’s a really great point. I love that study. I’m really excited to see what you guys find.
Prof. Stadlbauer-Koellner: We just started last month. It’ll take some time, but yes, we are also very excited and we really like this topic. And we think that this is something very important for the future.
Dr. Maddux: Well, Dr. Stadlbauer, thank you so very much for your time and for sharing the findings of some of your studies and for giving us a heads up about upcoming studies that we should pay attention to. I very much appreciate your time and you sharing your knowledge and expertise with us this morning.