Jonathan Stine, MD, on the Impact of Exercise on NAFLD and Gut Dysbiosis

Jonathan Stine, MD, discusses a proof-of-concept study he and colleagues conducted on how nonalcoholic fatty liver disease (NALFD), including nonalcoholic steatohepatitis (NASH), and gut dysbiosis may be connected, and the positive impacts that exercise training can have on patients with NALFD and gastrointestinal diseases. 


Hughes A, Dahmus J, Rivas G, et al. Exercise training reverses gut dysbiosis in patients with biopsy proven nonalcoholic steatohepatitis: a proof of concept study, Clin Gastroenterol Hepatol. Published online ahead of print, August 31, 2020.  doi: j.cgh.2020.08.063.


Jonathan Stine, MD, is the research director of the Liver Center and an assistant professor of medicine and public health sciences at the Milton S. Hershey Medical Center of Pennsylvania State University in Hershey, Pennsylvania.


Dr. Jonathan Stine:   Good morning. This is Dr. Jonathan Stine. I am an Assistant Professor of Medicine and Public Health Sciences at the Pennsylvania State University, Milton S. Hershey Medical Center. I'm also the research director for the Penn State Liver Center.

Rebecca:  Thank you for joining us today, Dr. Stine. I appreciate you taking the time to talk with us.

Dr. Stine:  Of course. Thank you for having me Rebecca. The pleasure is all mine.

Rebecca:  Today we're going to be talking about some research that you have done into the effects of exercise on nonalcoholic fatty liver disease and particularly on ‑‑ I guess you'd call it the subset of that ‑‑ nonalcoholic steatohepatitis or NASH.

To begin with, the research article that I read that you prepared states that nonalcoholic fatty liver disease or NAFLD is the leading cause of liver disease worldwide. Why has NAFLD become so prevalent?

Dr. Stine:  Rebecca, that's a really great question. Over the past decade or so, we've seen an explosion in metabolic disease worldwide. In fact, 30% of the world's population does have what we call a nonalcoholic fatty liver disease. This really parallels what we're seeing with obesity and sedentary behavior as society becomes more advanced.

We consider nonalcoholic fatty liver disease to be the hepatic manifestation of the metabolic syndrome. It's not a surprise with what we see from an obesity standpoint. Most of our patients are unaware of their diagnosis. They have a test for another reason. Then they're told they have fatty liver disease.

Many patients won't develop symptoms for 20, 30, 40 years. Oftentimes, people go undiagnosed until they have end‑stage liver disease, which is very problematic.

Rebecca: You mentioned that gut dysbiosis is involved in causing nonalcoholic fatty liver disease to progress to the more severe condition of NASH. What's the mechanism behind the relationship between gut health and these liver diseases?

Dr. Stine:  The relationship between gut health and liver disease has gained a lot of attention over the past couple of years and does remain of great interest to physicians and scientists and like. As you've mentioned, NAFLD is really one condition where gut health plays an important role.

We generally think NAFLD, or the more severe type of NASH, develops in the setting of what we call a multi‑hit hypothesis.

With this hypothesis, we see multiple factors acting together on a person who's genetically predisposed to develop fatty liver disease. Well‑known hits or factors include hormones that come from adipose tissue, insulin resistance, genetic and epigenetic factors, nutritional factors, physical inactivity, and the area of our recent research focus, the gut microbiota.

We see this gut‑liver axis as this bidirectional relationship where the liver receives most of its blood flow from the intestines. As a result, it's constantly exposed to the microbiota and its products. In exchange, in the other direction the liver then supplies the GI tract with bile acids through the biliary system.

The reason this is important is each individual person, such as you or myself, has a very specific composition of their gut microbiota. Dysbiosis is what we define as a relative disturbance in this normal composition. This can occur when there's a loss of beneficial microbiota, an increase in pathologic microbiota, or even a decrease just in the overall variety.

Dysbiosis contributes to NAFLD through many different mechanisms. Personally, I'd like to categorize these as either inflammatory or metabolic. Some of the inflammatory changes are promoted by dysbiosis through changes and expression of some of the tight junction proteins.

This leads to disruption of the gut barrier, what we call leaky gut. Leaky guts then allows for bacteria to translocate. We see production of endotoxins and ultimately increased production of endogenous ethanol within the body.

You take the combination of these two things that we see chronic inflammation in the liver cells and activation of the macrophages, which ultimately lead to the development of NAFLD, the progression to NASH, the development of liver fibrosis, and potentially end‑stage liver disease.

Now, in addition to the inflammatory changes, we see some metabolic changes and dysbiosis lead to increased energy extraction of dietary energy by the gut microbiota. This leads to persons to gain weight. They develop increased adipose tissue.

We also see greater triglycerides and fatty acid synthesis and decreased cholesterol export from the liver. We see changes in bile acid homeostasis and different ways that the endocannabinoid system is modulating. This leads further to obesity development.

It's this cycle that is very difficult to break. Dysbiosis plays a very complicated but very important role in the development of fatty liver disease, as well as disease progression.

Rebecca:  I was going to say, the sounds like a very complex set of circumstances here that we're talking about when you've got genetic factors, you've got environmental factors, and they feed upon each other.

Dr. Stine:  Yes, absolutely. All these factors are very synergistic. Many of the multiple hits serve to even further this pro‑inflammatory cycle of damage to the liver cells and disease progression.

Rebecca:  Are people with IBD more likely to develop fatty liver disease? You mentioned the inflammatory process and the leaky gut. Some of these things are of course characteristic of IBD.

Dr. Stine:  Yeah. That's a really good question. There is some pathophysiologic overlay between leaky gut and inflammation. We know with fairly robust cross‑sectional evidence that patients who do have inflammatory bowel disease, and whether it's ulcerative colitis or Crohn's disease, doesn't really matter.

Either way, this overall grouping of patients does have increased prevalence rates of non‑alcoholic fatty liver disease, and perhaps some studies suggest they have increased prevalence rates of the more severe type with NASH.

Rebecca:  Interesting. Your report also noted that some previous studies have shown that exercise training can reverse gut dysbiosis in obese patients who don't have liver disease. Some animal models have shown that there are similar effects in subjects that do have NASH.

Have you been able through your research to determine why exercise has this effect on gut health?

Dr. Stine:  Unfortunately, at this point, we have not been able to determine exactly why exercise training does have this benefit on gastrointestinal health. What I would say and what we do know is that exercise training increases the diversity of the microbiome.

It leads to greater abundance of the beneficial microbes if you will and also has the potential to decrease some of the harmful microbes, which produce some of these pro‑inflammatory substances that worsen that cascade I was talking about earlier.

Various researchers have proposed different mechanisms to explain how exercise training leads to these favorable changes in the microbiota. These include a physiological increase in core body temperature during exercise, a reduction in intestinal blood flow, which may lead to more direct contact between the gut immune cells and the microbiome.

There also has been postulated that an increase in bile acid circulation and a potentially production of lactic acid during exercise can lead to alterations in the pH of the gastrointestinal system. All of these may lead to some of the benefit we see with the reversal dysbiosis.

Rebecca:  That's very interesting. What further research are you planning or do you think is required to clarify these interactions between gut health and liver disease and determine how best to prevent and manage NAFLD and NASH?

Dr. Stine:  Well, I think at this point, a lot of the physiological adaptation and change that we see with exercise is well described, but researchers haven't really examined some of these physiological changes in the context of the microbiome.

Whether or not exercise training will change the amount of leaky gut that we have or what clinically relevant events happened as a result of the physiological changes.

For example, does the reversal of dysbiosis in patients with NAFLD and NASH lead to events we can measure in the clinic? Does this correlate with reduction in fatty liver disease seen on a liver biopsy? Do we see resolution of NASH? Do we see improvement in liver fibrosis?

Are there lower rates of major adverse cardiovascular vascular events? In particular, there are several bacteria that are implicated not only in the development of fatty liver disease but also in the increased cardiovascular risk we see in this population.

Lastly, NAFLD patients have an increased risk of primary cancer, and certainly, there's a role for dysbiosis in the microbiota and oncogenesis in cancer development. Can we then take this study further into that field and examine that relationship and show its benefit?

Rebecca:  How can a practicing gastroenterologist or hepatologist apply what you've learned so far to helping their patients who may have symptoms of gut dysbiosis and also may have fatty liver disease? Any advice that they can take away from this that's practical in the everyday care for these patients?

Dr. Stine:  Yeah, this is always the million‑dollar question, Rebecca, with translational research. How do we take it from the bench to the bedside and enact change in our clinics?

At this point in time, there's really so much investigation and study we need to do as a scientific society to better understand the relationship between the microbiome and NAFLD and NASH. We're still a long way from making specific recommendations in the clinic with regards to what we do with this dysbiosis.

For example, we're not routinely recommending prebiotics or probiotics to improve NAFLD or NASH because no studies have really looked at any of the clinically important benefits with these medications.

However, I do see a potential for our research to identify and open the door for new treatments that do target microbiome manipulation, which could lead to creation of prebiotics or probiotics, which may ultimately lead to some of these improvements.

What I would say the main takeaway from our study is that we know that exercise, training, and lifestyle change works for patients with NAFLD and NASH when they lose weight. Unfortunately, only 10 percent of our patients will achieve the recommended amount of weight loss.

One of the main findings from our study that's important is we saw improvement in fatty liver disease and dysbiosis, independent of significant weight loss. When we're counseling patients, they're very frustrated when they're unable to lose the weight. They're very fixated on those numbers.

I think this study allows us to come back to them and say, "We understand that losing weight is difficult. However, exercise training will lead to additional benefits. It does improve your fatty liver disease and improves the function of your blood vessels. It may change the composition of the bacteria in your body, which may lead to more NAFLD. Ultimately we do see benefit, even if you don't lose the weight."

Rebecca:  That's really good news for people who are trying, but not really making much progress with losing weight, but exercising by itself has benefits, irrespective of weight loss.

Dr. Stine:  Yes. Many, many studies before us have shown that you can improve your body composition with exercise training, even if you don't lose any weight. You can shrink the amount of fat in your liver. You can reduce inflammation in your blood when you're measuring inflammatory markers.

There are some of these precursors before you see that end game with the major clinical change with liver biopsy or cardiovascular risk decreasing where we do see this benefit without weight loss well before some of those other things we see with continued lifestyle change and healthy behaviors.

Rebecca:  We've talked about exercise training, but we haven't been very specific about what kind of exercise. Have you come to any conclusions about that? About what types of exercise have the biggest impact.

Dr. Stine:  The good news for our patients is really any exercise is good. At this point, there are multiple recommendations from different societies. We tend to follow what the Department of Health and Human Services recommends, which is 150 minutes per week of moderate‑intensity exercise, which would be the equivalent of a brisk walk.

When I see patients in my office, I tell them, "When you do this exercise, you should still be able to have a conversation, in this day and age from six feet away, of course, or through a mask when you're walking with your exercise partner." or if they don't want to do the moderate intensity, they can do 75 minutes of vigorous exercise.

We do recommend a combination of aerobic exercise and then two additional strength training sessions. People have looked at the different modalities. They've compared aerobic exercise such as walking or running to strength training with lifting weights or doing bodyweight exercises to high‑intensity interval training.

No specific type of exercise has been shown to be better or worse in terms of improving patient's fatty liver disease. With our study, we focused exclusively on aerobic exercise, largely because this is the easiest thing for our research subjects to complete without having an injury during the exercise protocol.

Rebecca:  Well, this is very interesting. I look forward to finding out what's coming up next. Do you have research plans yourself that you're going to be undertaking and into this area anytime soon?

Dr. Stine:  Yeah, I would say this is really just the tip of the iceberg in terms of our investigation of some of the benefits of exercise. I will say our preliminary findings really further cemented the importance of using exercises medicine in our patients with NAFLD and NASH.

With all the attention on finding an effective pharmacologic treatment with medications, we cannot forget about the importance of lifestyle change. Moving forward, we look only not to validate these preliminary proof of concept findings with a large multicenter exercise‑based trial to confirm that exercise truly does reverse gut dysbiosis.

We also want to answer some of those mechanistic questions that still loom related to the physiological change we see with exercise training. We plan to measure leaky gut, as well as changes in gut pH, core body temperature, bile acids, circulation, and portal blood flow to the liver.

Ideally, we would like to still show some of the benefits of exercise training independent of weight loss. Those are the avenues that plan to take this study moving forward and hopefully more to come in the upcoming months to years from our my research group.

Rebecca:  We look forward to hearing about the results of your further research at a later date, and we really appreciate you taking the time to talk to us today. Thank you so much.

Dr. Stine:  You're welcome, Rebecca. Again, the pleasure was all mine. Thank you for having me.