Scholarlink

Background <p>A deeper understanding of the relationship between dysbiotic gut microbiota and liver tissue-level molecular and histopathological phenotypes in metabolic dysfunction-associated steatotic liver disease (MASLD) remains needed. We aimed to characterize the associations between gut microbial metabolic functions and treatment responses in participants with MASLD.</p> Methods <p>We performed a prespecified sub-analysis of a randomized controlled trial comparing the sodium–glucose cotransporter 2 inhibitor (SGLT2i) tofogliflozin and the sulfonylurea (SU) glimepiride in participants with MASLD and type 2 diabetes (ClinicalTrials.gov NCT02649465). Fecal whole-genome shotgun metagenomics, liver RNA sequencing, serum profiling, and histopathological assessments were integrated to investigate microbiota–host interactions.</p> Results <p>Microbial metabolic pathways, rather than taxonomic composition, differed significantly between participants with MASLD and healthy controls. Among the altered microbial pathways, amino acid metabolism emerged as a prominent functional category and was selected for further investigation. Pathways related to amino acid metabolism, particularly phenylalanine metabolism, exhibited opposing patterns: phenylalanine degradation was enriched in MASLD and positively correlated with liver fibrosis scores, whereas phenylalanine biosynthesis inversely correlated with fibrosis severity. Microbial phenylalanine degradation was positively associated with 28 hepatic pathways, including the non-alcoholic fatty liver disease (NAFLD) pathway, in which mitochondria-associated genes were core-enriched. Both SGLT2i and SU treatments improved NAFLD activity scores and altered microbial metabolic pathways without significantly changing microbial species composition. Notably, SGLT2i increased phenylalanine biosynthesis pathways, which were inversely associated with liver fibrosis.</p> Conclusions <p>Gut microbial amino acid metabolism, particularly phenylalanine metabolism, is closely linked to liver fibrosis and molecular pathways in MASLD. Modulation of microbial metabolic functions may represent a promising therapeutic strategy beyond changes in microbial composition.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 发表日期：

    2026年7月30日

查看全文
  • Kohei Yasuda,
  • Noriho Iida,
  • Yumie Takeshita,
  • Yusuke Masuo,
  • Masao Honda,
  • Toshinari Takamura,
  • Taro Yamashita

摘要

Background

A deeper understanding of the relationship between dysbiotic gut microbiota and liver tissue-level molecular and histopathological phenotypes in metabolic dysfunction-associated steatotic liver disease (MASLD) remains needed. We aimed to characterize the associations between gut microbial metabolic functions and treatment responses in participants with MASLD.

Methods

We performed a prespecified sub-analysis of a randomized controlled trial comparing the sodium–glucose cotransporter 2 inhibitor (SGLT2i) tofogliflozin and the sulfonylurea (SU) glimepiride in participants with MASLD and type 2 diabetes (ClinicalTrials.gov NCT02649465). Fecal whole-genome shotgun metagenomics, liver RNA sequencing, serum profiling, and histopathological assessments were integrated to investigate microbiota–host interactions.

Results

Microbial metabolic pathways, rather than taxonomic composition, differed significantly between participants with MASLD and healthy controls. Among the altered microbial pathways, amino acid metabolism emerged as a prominent functional category and was selected for further investigation. Pathways related to amino acid metabolism, particularly phenylalanine metabolism, exhibited opposing patterns: phenylalanine degradation was enriched in MASLD and positively correlated with liver fibrosis scores, whereas phenylalanine biosynthesis inversely correlated with fibrosis severity. Microbial phenylalanine degradation was positively associated with 28 hepatic pathways, including the non-alcoholic fatty liver disease (NAFLD) pathway, in which mitochondria-associated genes were core-enriched. Both SGLT2i and SU treatments improved NAFLD activity scores and altered microbial metabolic pathways without significantly changing microbial species composition. Notably, SGLT2i increased phenylalanine biosynthesis pathways, which were inversely associated with liver fibrosis.

Conclusions

Gut microbial amino acid metabolism, particularly phenylalanine metabolism, is closely linked to liver fibrosis and molecular pathways in MASLD. Modulation of microbial metabolic functions may represent a promising therapeutic strategy beyond changes in microbial composition.