Bernd Schnabl, MD, on the Microbiome and NAFLD

In this video, Bernd Schnabl, MD, from the University of California, San Diego, School of Medicine, discusses his session titled “The Microbiome and Fatty Liver Disease,” which he presented at Harvard’s Nonalcoholic Fatty Liver Disease (NAFLD): Mechanisms and Novel Therapeutics symposium. 

Bernd Schnabl, MD, is a professor of medicine in the Department of Medicine, Division of Gastroenterology, and is the director of the San Diego Digestive Diseases Research Center at the University of California, San Diego, School of Medicine.

TRANSCRIPT:

I am Bernd Schnabl, a physician scientist in gastroenterology and hepatology. I'm a professor of Medicine at the University of California in San Diego. I'm also the Director of the San Diego Digestive Diseases Research Center.

I will talk about the gut microbiome in nonalcoholic fatty liver disease. I also will present this at the Harvard NAFLD Symposium. The liver communicates with the intestine via the portal vein, via the biliary system, but also via mediators in the systemic circulation. We have many bacteria, fungi, and viruses present in the intestine.

These microbes are very important because they maintain the homeostasis—the balance—in our liver. On the other hand, they can also serve as a source of pathogens and as a source of molecules that can now contribute to the development of fatty liver disease.

We know from clinical practice that only like 10% to 20% of the patients with nonalcoholic fatty liver disease develop progressive disease, such as steatohepatitis, fibrosis, and cirrhosis.

It is clear that beyond over nutrition, beyond increased caloric intake, there are factors present that contribute to this progression of disease. Changes in the gut microbiome, including microbial metabolism but also gut‑barrier dysfunction could represent co‑factors that now contribute to the progression of NAFLD toward NASH.

We know this for quite a long time now from experimental mouse models. For example, germ‑free mice, when they are fed a high‑fat diet, they are protected from obesity. They accumulate less fat in their body as compared to the conventional mice. This indicates that gut microbes, bacteria in the intestine contribute to the development of obesity of NAFLD.

We also know from fecal microbiota transfer studies from obese mice to germ‑free mice that mice that receive feces from obese mice in fact gain more weight and develop more fatty liver disease than germ‑free mice that receive feces from non‑obese mice.

What do we know now about patients with nonalcoholic fatty liver disease? How does their gut microbiome change?

There are several studies now published about describing the fecal‑gut microbiome using these 16S nonculture independent techniques to describe the gut microbiome in the feces from these patients. They were compared to patients with simple steatosis, healthy controls, but also with more severe NAFLD, such as NASH with fibrosis and cirrhosis.

Some results and especially the results from the smaller studies are inconsistent and sometimes, in fact, contradictory. The most consistent changes that were observed in these sequencing studies are in patients with NAFLD compared with healthy individuals or in patients with mild versus more severe NAFLD.

There seems to be especially an increase in the abundance of Proteobacteria. Proteobacteria are gram‑negative bacteria that are a source of LPS. We know that Enterobacteriaceae, Escherichia, and [indecipherable 4:02] are increased while other bacteria and families are decreased which includes Coprococcus, Eubacterium, and also Faecalibacterium prausnitzii.

This information has been now successfully also used to predict noninvasively the progressive disease in patients using mathematical modeling.

Beyond these descriptive changes in the gut microbiome, now how does the gut microbiome, in fact, contribute to the progression from nonalcoholic fatty liver disease? There are a couple of factors that I would like to describe.

The first one, which is commonly cited, is the gut‑barrier dysfunction or what we describe as an increased intestinal permeability. This describes that there is a dysfunction in the intestinal barrier so that the paracellular space in between the epithelial cells is loosened.

Now microbial products, such as LPS, can now translocate from the intestinal lumen to the liver, and then can reach the liver where they can cause progression of disease by increased inflammation but also hepatosteatosis. Interestingly, a recent meta‑analysis showed that in fact, only about 50% of the patients with NASH have increased intestinal permeability.

This is very clear that we have to probably move on from a generalized concept of gut‑microbiome contribution to nonalcoholic fatty liver disease and steatohepatitis to more a classification of subtypes of patients with nonalcoholic liver disease and NASH. A subtype by which how the gut microbiome contributes to the progression from a less-severe disease to a more progressive type of liver disease.

Other contributors how the gut microbiome causes progression of liver disease toward NASH and fibrosis include changes in bacteria metabolites such as, for example, such as production of new metabolites.

Recently there was a very elegant study that confirmed that bacteria in the intestine are able to produce endogenous ethanol. This endogenous ethanol will reach the liver via the portal vein, and then can contribute to the progression from nonalcoholic liver disease toward NASH and toward fibrosis.

What can we do now to restore the gut homeostasis? How can we use the gut microbiome as a treatment approach? There are two main concepts how we can do this.

The one is essentially to use additive approaches. In this case, you can use, for example, fecal‑microbiota transplantation where you are adding bacteria. You're adding essentially feces from a healthy donor to a diseased patient, or you can add probiotics, which are defined as living beneficial bacteria. You can add prebiotics, or you can add next‑generation biotics, which include engineered bacteria.

Fecal‑microbiota transplantation has gained a lot of attraction. Many diseased types nowadays ... Most recent studies actually did not show a decrease of the BMI in patients with obesity and with nonalcoholic fatty liver disease, though newer studies and larger studies are awaited to see whether there is any effect.

A large meta‑analysis recently also demonstrated that probiotics seem to be beneficial for NAFLD. However, most of the studies use different probiotic studies. They sometimes mix it with prebiotics. Again, there is no uniform treatment, a regimen that can be recommended at this point.

I have talked about the additive approaches that we can use to manipulate the gut microbiome to restore gut homeostasis. On the other hand, there are the subtractive approaches where we not try to add something to the gut microbiome but where we try to take something away, where we try to decrease the pathobionts, the bacteria that do some harm.

What approaches can we take here? We can obviously use antibiotics. They are mostly broad‑spectrum. You're not able to target single‑bacteria species. We have recently shown in a model of alcoholic liver disease at the preclinical stage that bacteriophages can infect [indecipherable 9:14] very precisely in the gut microbiome. They can eliminate certain bacteria that do harm to the liver and especially to the hepatocytes. Bacteriophages are viruses that can very specifically infect bacteria and lyse them from the inside. These are additive and subtractive approaches to restore gut homeostasis.

On the other hand, we can also use beneficial molecules from bacteria to restore gut homeostasis. Two approaches I want to briefly mention. One is we can use some bile acids. They are currently being tested whether or not as a direct bacterial product. Obeticholic acid is a bile acid analog, which has affinity to certain host receptors and has beneficial metabolic effect.

Other bacteria molecules that are in mediators that are produced by the bacteria of, for example, short‑chain fatty acids showed, when smaller studies have been conducted ... We also need to wait for more and larger studies before this can, in fact, enter the clinical‑trial stage and also the recommendation that this can be used in a larger population of patients with NAFLD.

Overall, NAFLD is characterized by changes in the gut microbiome. We have certain subtypes of patients that are probably more affected by the gut microbiome than others. In the future, we need to more classify these patients according to their subtype of the disease.

Whether they have, for example, increased intestinal permeability, whether they have changes in their short‑chain fatty acids, then we have to treat them more precisely and more personalized rather than treating the entire population of NAFLD patients with one‑fits‑all therapeutic approach.

I would like to thank you for listening and also for your attention.