Bernd Schnabl, MD, is a practicing physician and associate professor at University of California San Diego. His research focuses on the cellular and molecular mechanisms that contribute to chronic liver disease.
The “leaky gut hypothesis” of liver disease is the idea that bacteria passing from the gastrointestinal tract to extraintestinal sites may contribute to disease onset and progression. But the role of the microbiota is not fully incorporated into this longstanding hypothesis.
In a recent review called “The Gut Microbiota and Liver Disease“, Schnabl and Llorente describe the latest ideas on how the intestinal microbiota contribute to liver disease. Evidence from Schnabl’s lab and others suggests that products generated from metabolic activities of the microbes, as well as interactions between microbes and host, influence disease susceptibility.
Schnabl spoke with GMFH editors about this topic.
What do we know about intestinal bacteria and liver disease?
We have known for a very long time that there is a so-called gut-liver axis.
It was reported almost 30 years ago that patients with liver disease have changes in the bacterial composition of the intestine. For example, patients with chronic alcohol abuse or alcoholic liver disease have intestinal bacterial overgrowth, particularly in the small intestine. That was published in 1984, and the results were found using regular culture techniques of aspirates from the small intestine.
Nowadays, we know that patients with nonalcoholic fatty liver disease [NAFLD] and nonalcoholic steatohepatitis [NASH], which is commonly associated with obesity, have changes in their microbiota. Changes are not only characterized by intestinal bacterial overgrowth, but there are also changes in the bacterial composition. With the advancement of our technology and especially with newer sequencing techniques, we can discriminate certain patterns of bacterial changes in the intestine. Patients with specific liver diseases have certain changes in their microbiome or microbial composition in the intestine, which is also called intestinal dysbiosis.
What is your understanding of how ‘leaky gut’ (intestinal barrier damage) contributes to liver disease?
Patients with liver disease have this leaky gut syndrome. This was published almost 20 years ago: if certain non-digestible marker molecules are orally administered to patients with liver disease, they passively absorb these markers to a higher degree than a normal, healthy person.
The gut leakiness is caused by damage to the barrier of the intestine that allows patients to passively absorb these marker molecules. Patients not only absorb exogenously-administered markers but also products and toxins that are derived from intestinal bacteria. Bacterial products like lipopolysaccharides (LPS), are able to translocate from the lumen of the gut to the bloodstream.
The liver is now the first organ to encounter all these toxic bacterial products because the liver is very tightly connected to the intestine via the portal circulation. All venous blood coming from the intestines reaches the liver via the portal circulation. The liver encounters increased amounts of microbial products in the setting of a leaky gut.
If translocation of bacterial products and toxins is blocked or neutralized in animals, liver disease can be prevented. We have different methods to achieve this. First, we can use non-absorbable antibiotics which decrease the amount of intestinal bacteria. Subsequently, fewer bacterial products are available that can now translocate to the liver and systemic circulation. Second, stabilization of the gut barrier will prevent liver disease. Third, if we use a genetically modified mouse that is unable to recognize or sense these bacterial products, it’s also resistant to liver disease.
What are promising therapies that could emerge from studying the microbiota in liver disease?
I think we are not there yet to use novel therapies as standard of care in routine clinical practice, but there are different and promising approaches which are being actively investigated in clinical trials.
There was a recent publication on probiotics. Probiotics are the “good” bacteria, and they have been shown to be very useful in preclinical animal models. The published study was a placebo-controlled trial with Lactobacillus rhamnosus GG, which is a very common bacterial probiotic strain. The research team used Lactobacillus rhamnosus GG in patients with cirrhosis, which is an end-stage liver disease. Probiotics reversed changes in the microbial composition in the intestine (dysbiosis) and lowered systemic LPS levels in cirrhotic patients.
There is a general concern whether probiotic bacteria — live organisms — can have adverse effects in cirrhotic patients and cause overt infections in the setting of a leaky gut. However, the authors of this study were able to show that lactobacilli appeared to be very safe in this cirrhotic patient population.
This is a very good example of the beneficial effects of probiotics: they restore the intestinal dysbiosis, stabilize the gut barrier, and stabilization of the gut barrier will then lower systemic levels of translocated microbial products like LPS. The trial was not long enough to see if there was also an improvement in the clinical severity and survival of these patients with liver cirrhosis.
What are the next steps in moving forward on probiotic treatments?
Before this actually can become standard of care, findings need to be confirmed in larger and longer clinical trials. Patients with cirrhosis have a very high mortality in the short term. We ultimately need to demonstrate that probiotics improve the clinical course and increase survival of patients with end-stage liver disease.
How might it be possible in the future to personalize treatments for liver disease patients?
Once the microbiome of larger patient cohorts has been sequenced, we can then associate certain microbiome composition patterns with clinical symptoms and disease outcomes. Patients with a different microbiota composition could be treated differently. This is the idea behind personalized medicine using a precision microbiome approach.
However, this requires not only to determine the composition of the intestinal microbiome, but we also need more information about the liver disease, intestinal, systemic and liver inflammation, prognosis, etc. This whole concept will allow us to stratify patient populations into different categories and then treat them on an individual basis. This will be a very good and useful approach for the future. Some patients might benefit from targeting the microbiome, while others need different therapeutic approaches.
As a researcher in this area, have you changed any aspects of your clinical practice?
I’m much less hesitant to use, for example, non-absorbable antibiotics over lactulose in patients with cirrhosis and hepatic encephalopathy. We have very good preclinical data suggesting that lowering the intestinal bacterial burden might have some clinical benefit for liver disease. Thus, non-absorbable antibiotics might not only improve hepatic encephalopathy in patients with end-stage liver disease, but liver disease might improve at the same time. However, this needs to be evaluated in larger clinical trials.
Chen P, et al. (2015) Dysbiosis-induced intestinal inflammation activates tumor necrosis factor receptor I and mediates alcoholic liver disease in mice. Hepatology. DOI: 10.1002/hep.27489
Llorente C & Schnabl B. (2015) The Gut Microbiota and Liver Disease. Cellular and Molecular Gastroenterology & Hepatology DOI: http://dx.doi.org/10.1016/j.jcmgh.2015.04.003
This interview has been edited for clarity and length.
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