Tofogliflozin alters amino acid metabolism in gut microbiota linked to hepatic transcriptomic signatures in MASLD.

In 30 seconds

This prespecified sub-analysis of a randomized controlled trial examined gut microbiota–liver associations in participants with MASLD and type 2 diabetes treated with tofogliflozin or glimepiride. Integrated stool metagenomics, liver RNA sequencing, serum profiling, and histopathology showed that microbial metabolic pathways differed between MASLD and healthy controls, while species composition did not significantly change with treatment. Phenylalanine degradation was enriched in MASLD and associated with greater fibrosis; tofogliflozin increased phenylalanine biosynthesis pathways, which were inversely associated with fibrosis.

Key findings

• Phenylalanine degradation was enriched in MASLD and positively correlated with liver fibrosis scores; phenylalanine biosynthesis was inversely correlated with fibrosis severity.
• Microbial phenylalanine degradation was positively associated with 28 hepatic pathways, including the NAFLD pathway, with mitochondria-associated genes core-enriched.
• Tofogliflozin and glimepiride both improved NAFLD activity scores and altered microbial metabolic pathways without significantly changing microbial species composition.
• Tofogliflozin increased microbial phenylalanine biosynthesis pathways, which were inversely associated with liver fibrosis.

Why it matters

The findings connect microbial function—not simply which species are present—with liver fibrosis and hepatic molecular signatures in MASLD. They suggest that amino acid metabolism, particularly phenylalanine pathways, may help explain microbiota–liver relationships and provide a focus for further mechanistic and therapeutic research.

What to keep in mind

This was a prespecified sub-analysis, and the reported microbiota–liver relationships are associations; they do not establish that microbial pathway changes cause changes in fibrosis.