So microbiome and non-alcoholic fatty liver disease, including, NASH, non-alcoholic steatohepatitis. Dr. Anton Titov, MD.: What is the role of diet in gut microbiome dysbiosis in fatty liver disease, and in NASH? This is a very important and rapidly growing area. Let me start by saying that we all harbor trillions of bacteria in our intestine, which collectively is known as the microbiome. And everyone's microbiome is a little bit different. Nonetheless, there is growing evidence, both from animal models and from humans, that the nature of the microbiome may influence the propensity and risk of progression of NASH. We haven't really nailed down which bacteria specifically are the driving force that creates the risk for NASH. Dr. Scott Friedman, MD.: But there is strong evidence that you can transfer NASH from one experimental animal to the other by transplanting their microbiome. And in fact, there are some case studies where microbiome transplant has either conferred a risk or presence of NASH in patients or has attenuated the risk of NASH. So I would say we're at the stage now, where we are pretty certain there's a strong link between the microbiome and the risk of NASH. Dr. Scott Friedman, MD.: But we haven't identified the components of the microbiome sufficiently to use that as a therapeutic or to manipulate the microbiome in a way to treat NASH. Now, the diet certainly has a lot to do with the microbiome. Dr. Scott Friedman, MD.: But it's not just the diet. It's also the household one lives in, because typically, first-degree relatives who share a household also share the same microbiome. It may also be influenced by exposure to antibiotics. And let's remember that it's not just the antibiotics that we may take for cold or, better yet, for bacterial infection, which is more appropriate. It's also the antibiotics that may be in our food. So animals, farm animals are fed antibiotics. There are antibiotics exposed to plants and grains. And so, there's a theory that I think is very compelling. That suggests that one of the reasons NASH has begun to appear in the last 25 years is because we have systematically changed the population microbiome. Because of all this pervasive exposure to antibiotics that drives the emergence of different bacteria that may start to increase the risk that we retain energy, retain fat, and ultimately develop NAFLD and NASH. And so you know, one of the Holy Grails is to identify the classic or the absolute components of the microbiome that are driving NASH. Of course, then we hope to attenuate them or to change the microbiome. We're not there yet.

Dr. Scott Friedman, MD.: But there are both a lot of academic investigators as well as commercial companies that are hot on the trail of trying to identify the NASH-causative bacteria. Or it could be viruses or fungi as well. They're also part of the intestinal flora. We collectively identify those features that ultimately may be driving the emergence or the progression of NASH. And as I mentioned, to attenuate them therapeutically, it seems that the microbiome is very hard to change. So we have a relatively fixed microbiome, it can be influenced by antibiotics. Dr. Scott Friedman, MD.: But often, the microbiome, even when it changes, goes back to its original steady-state often, which is increasing the risk of NASH. Dr. Anton Titov, MD.: Professor Friedman, in one of your reviews, you mentioned the auto-brewery syndrome, the microbial fermentation of carbohydrates in the gut that actually gives an endogenous production of alcohol, which is then damaging to the liver. Could you please elaborate on that topic? That's a very interesting and probably a rare circumstance. Dr. Scott Friedman, MD.: But there was a couple of cases that have been described, including one very compelling detailed description from China. It described a particular bacterium, Klebsiella, a particular subspecies of Klebsiella. The bacteria generated ethanol, and that ethanol percolates from the intestine through the portal vein, which drains from the intestine into the liver and effectively injures the liver because of high levels of ethanol. Now, why is that tantalizing? Because remember that the name we currently use for the disease is non-alcoholic fatty liver disease. Dr. Anton Titov, MD.: Why do we call it non-alcoholic? The reason is that when the disease first started to appear, it looked like alcoholic liver disease. And in fact, patients were often thought to be surreptitiously drinking. And it took a few years to sort out that no, even though it looks like alcohol, it's non-alcoholic. Now, in the case of the auto-brewery syndrome, we don't think this is a major cause of NASH. Dr. Scott Friedman, MD.: But it does speak to the idea that in extreme circumstances, the bacteria in the intestine can lead to changes in the liver, in this case through ethanol. And so, this was one example. And perhaps there are a few others where bacteria are actually making a metabolite, in this case, ethanol that causes effectively alcoholic non-alcoholic liver disease. It means that patients are not drinking alcohol, but the bugs are making alcohol that's percolating into the liver and damaging it. You mentioned already that fecal microbiome transplantation. Has FMT been tried to treat non-alcoholic steatohepatitis, NASH, and fatty liver disease? It's been tried episodically. So far, there are no large studies that convincingly demonstrate that FMT or fecal microbiome transplantation is a robust and effective means of treating NASH. And I think it may well be that we're not necessarily using the right microbiome or that the microbiome transplantation isn't durable. It means that the bugs go back to what they were before. And so I would say that there's no convincing evidence yet that FMT is a widespread viable therapy for NAFLD / NASH. Dr. Scott Friedman, MD.: But I think the jury is very much still out. And as we dig deeper into understanding the composition and the behavior of bacteria in our intestines, I'm pretty confident we're going to start to see some inroads that show that selective, either FMT or manipulation of the microbiome will have a benefit as a NAFLD / NASH treatment. We're just not there yet.