Study Identifies Gut Microbiota Linked to HE Pathophysiology


Urease-positive Streptococcus salivarius was the most significantly abundant gut microbiota in patients with HE.

Certain gut microbiota are strongly associated with the pathophysiology of hepatic encephalopathy (HE), according to research published in Hepatology Communications.

HE is a neuropsychiatric complication as a result of liver cirrhosis (LC). While past research has suggested gut microbiota plays a role in the pathogenesis of HE, this has not been explicitly confirmed.

In this study, the authors analyzed how the gut microbial profile changed among patients with HE or decompensated LC, compared with patients with compensated LC and patients without any health complications.

The study included 26 patients with decompensated LC, 27 patients with compensated LC, and 26 healthy controls.

All participants were aged 50 and older, with a mean (range) age of 68.4 (52−85), 67.6 (54−81), and 61.4 (50−79) in the decompensated LC, compensated LC, and healthy control groups, respectively. All 3 groups also had slightly more men than women, and mean BMI was slightly higher in both LC groups compared with the control group.

In an effort to clarify which functional gut microbial species are associated with HE, the authors focused on patient responses to being treated with rifaximin (RFX), a nonabsorbable antibiotic used to treat HE. Patients who experienced reduced plasma ammonia levels after RFX were defined as responders, and patients who saw no decrease were defined as nonresponders.

The authors also collected fecal samples from all patient groups and compared their fecal gut microbial profiles using 16S ribosomal RNA gene amplicon and metagenomic sequencing, and identify the specific species using linear discriminant analysis effect size.

They found that urease-positive Streptococcus salivarius, which can produce ammonia, was the most significantly abundant gut microbiota in the group of patients with HE. The microbiota’s ability to increase levels of blood ammonia and brain glutamine was experimentally verified in mice.

Further, urease-negative Ruminococcus gnavus was also identified as a significantly abundant gut bacterium in patients with RFX-nonresponsive HE after RFX administration.

“Interestingly, R. gnavus enhanced urease activity of recombinant urease itself, implying that R. gnavus could amplify ammonia production of surrounding urease-positive microbiota,” the authors noted. “Furthermore, the sensitivity of S. salivarius and R. gnavus to RFX depended on conjugated secondary bile acid levels, suggesting a therapeutic potential of the combined use of secondary bile acid levels with RFX for enhancing the efficacy of RFX.”

According to the others, this may begin to explain why R. gnavus was found to be a dominant species among patients who were nonresponders, as these participants had plasma secondary bile acid levels much lower compared with responders.

According to the authors, targeting these identified bacteria is a potentially effective strategy to treat HE.

“In addition, although blood ammonia levels are generally thought to be unstable, future studies might be able to specify a new biomarker of HE through detailed characterization of specific gut microbiota, such as S. salivarius, identified here in patients with HE,” the authors concluded.


Yukawa-Muto Y, Kamiya T, Fujii H, et al. Distinct responsiveness to rifaximin in patients with hepatic encephalopathy depends on functional gut microbial species. Hepatol Commun. 2022;6(8):2090-2104. doi:10.1002/hep4.1954

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