Complex Interplay Among Gut, Liver, and Microbes Underlies Metabolic Changes in Chronic Hepatitis C

A team including researchers from NIDDK’s Intramural Research Program uncovered how complex metabolic changes in the gut, its microbes, and the liver mirror the state of diseases such as chronic hepatitis C, which could lead to the development of new treatments for liver disease. The gut, the microbes it houses, and the liver all play central roles in the body’s metabolism of nutrients and their by-products. Nutrients and microbial products absorbed in the gut travel directly to the liver through the portal vein before they are further metabolized and distributed throughout the body. Liver disease, such as that resulting from chronic infection with the hepatitis C virus, not only damages the liver through inflammation and fibrosis (scar tissue formation), termed cirrhosis in severe cases, but also disrupts metabolic processing by human cells and microbes.

Scientists selected chronic hepatitis C as a disease model in which to study how these complex metabolic and microbial changes correlate with the degree of liver disease. They recruited 23 men and women with chronic hepatitis C, either with or without cirrhosis present, to participate in a study at the NIH Clinical Center. Assessments included measures of human- and microbe-produced metabolites in blood samples from the portal vein and arm, liver biopsies, and fecal samples, taken initially and then 6 months after treatment with antiviral drugs to eliminate the viral infection. Over time, they found an anticipated uptick in immune activity and inflammation in these individuals, but also dampened gut-liver metabolism, particularly in utilizing fat for energy. Within the liver, these metabolic changes were localized to cellular structures called peroxisomes and mitochondria that handle inflammation-fighting antioxidants and energy production, and the changes persisted in cases of severe liver fibrosis even after the viral infection was cleared. Gut microbial activity was also altered with worsening liver disease, as microbes boosted fat production, reduced methane metabolism, and degraded the protective mucus lining the intestine, changing the mix of metabolites feeding into the liver and leaving both organs more vulnerable to inflammation.

These findings illustrate how the fates of gut and liver are intimately linked, and that multiple disruptions in cellular and microbial metabolism in these organs are associated with inflammation and disease severity in the setting of chronic liver disease, in this case due to hepatitis C infection. They offer clues for future exploration into disease processes and therapeutic remedies to counter these metabolic changes and slow disease progression.