Gut Microbiome's Role in NAFLD and NASH: From Dysbiosis to Treatment

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• Microbiome and NAFLD/NASH Link
• Diet and Antibiotics Impact on Microbiome
• Auto-Brewery Syndrome Explained
• FMT for NASH Treatment
• Future Microbiome Research
• Full Transcript

Microbiome and NAFLD/NASH Link

Dr. Scott Friedman, MD, establishes a strong connection between the gut microbiome and non-alcoholic fatty liver disease progression. He explains that trillions of bacteria reside in the human intestine, collectively known as the microbiome. Research from both animal models and human studies indicates that specific microbiome compositions can influence NASH risk and progression.

Dr. Scott Friedman, MD, emphasizes compelling evidence that NASH can be transferred between experimental animals through microbiome transplantation. This transferability underscores the microbiome's significant role in disease development. However, he notes that researchers have not yet identified the specific bacterial components driving NASH pathogenesis.

Diet and Antibiotics Impact on Microbiome

Diet plays a crucial role in shaping the gut microbiome composition according to Dr. Scott Friedman, MD. He clarifies that multiple factors beyond diet influence our microbial inhabitants. Household environments significantly affect microbiome profiles, as first-degree relatives typically share similar bacterial communities.

Dr. Friedman presents a compelling theory about antibiotic exposure driving NASH emergence over the past 25 years. He notes that antibiotics enter our systems not only through medications but also through food sources. Farm animals receive antibiotics, and plants absorb them, creating pervasive exposure that may systematically alter population-wide microbiomes. These changes potentially increase energy retention and fat accumulation, leading to NAFLD and NASH development.

Auto-Brewery Syndrome Explained

Dr. Scott Friedman, MD, discusses the fascinating auto-brewery syndrome as an extreme example of microbiome-liver interaction. This rare condition involves specific gut bacteria, particularly a Klebsiella subspecies, that ferment carbohydrates to produce ethanol. The generated alcohol travels from the intestine through the portal vein directly to the liver, causing damage indistinguishable from alcoholic liver disease.

During his conversation with Dr. Anton Titov, MD, Dr. Scott Friedman, MD, emphasizes that while auto-brewery syndrome is rare, it demonstrates how bacterial metabolites can directly cause liver injury. This phenomenon explains why NAFLD historically resembled alcoholic liver disease, leading to initial diagnostic confusion. The syndrome provides concrete evidence that gut bacteria can produce liver-damaging substances without alcohol consumption.

FMT for NASH Treatment

Fecal microbiome transplantation has been attempted as a potential NASH treatment, according to Dr. Scott Friedman, MD. He reports that current evidence does not support FMT as a robust or effective therapy for non-alcoholic steatohepatitis. The transplantation may lack durability, with microbiomes often returning to their original state post-treatment.

Dr. Scott Friedman, MD, explains to Dr. Anton Titov, MD, that researchers might not be using the optimal microbiome compositions for transplantation. Despite current limitations, he maintains that the medical community should keep an open mind about FMT's potential. As understanding of bacterial composition and behavior deepens, selective microbiome manipulation may eventually show therapeutic benefits for NAFLD and NASH patients.

Future Microbiome Research

Dr. Scott Friedman, MD, expresses confidence that microbiome research will yield significant breakthroughs in NASH treatment. Academic investigators and commercial companies are actively working to identify the specific bacteria, viruses, and fungi that drive NASH progression. The ultimate goal involves developing therapeutic strategies to attenuate these harmful microbial components.

Dr. Friedman acknowledges the challenge of permanently altering established microbiomes during his discussion with Dr. Anton Titov, MD. He notes that microbiomes tend to return to their original steady-state even after intervention. Despite these challenges, he remains optimistic that deeper understanding of intestinal flora will lead to effective microbiome-based treatments for fatty liver disease in the future.

Full Transcript

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 the intestine, which collectively is known as the microbiome. 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. 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. 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. 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. Let's remember that it's not just the antibiotics that we may take for a cold or, better yet, for bacterial infection, which is more appropriate. It's also the antibiotics that may be in our food.

Farm animals are fed antibiotics. There are antibiotics exposed to plants and grains. 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.

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. 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?

Dr. Scott Friedman, MD: That's a very interesting and probably a rare circumstance. But there were 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?

Dr. Scott Friedman, MD: The reason is that when the disease first started to appear, it looked like alcoholic liver disease. 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. 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.

Dr. Anton Titov, MD: You mentioned already that fecal microbiome transplantation. Has FMT been tried to treat non-alcoholic steatohepatitis, NASH, and fatty liver disease?

Dr. Scott Friedman, MD: 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.

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.

So I would say that there's no convincing evidence yet that FMT is a widespread viable therapy for NAFLD or NASH. 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 or NASH treatment. We're just not there yet.