Background: Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to microbial infection. For decades, the gut microbiota was thought to play an important role in sepsis pathogenesis. However, the systemic and functional link between gut microbiota and sepsis has remained unexplored. Methods: To address this gap in knowledge, for the first time, we carried out systematic analyses on clinical stool samples from septic patients, including 16S rDNA sequencing, metabolomics and metaproteomics analyses. In addition, we performed fecal microbiota transplantation from human to mice to validate the roles of gut microbiota in sepsis progression. Findings: We found the composition of gut microbiota was significantly disrupted in septic patients compared with healthy individuals. Besides, the microbial functions were significantly altered in septic feces as identified by metabolomics and metaproteomics analyses. Interestingly, mice that received septic feces exhibited more severe hepatic inflammation and injury than mice that received healthy feces after cecal ligation and puncture. Finally, the abundance of some intestinal bacteria as well as certain metabolites was significantly co-related with plasma total bilirubin level in septic patients. Interpretation: Taken together, our data indicate that sepsis development is associated with the disruption of gut microbiota at both compositional and functional levels, and such enteric dysbiosis could promote organ inflammation and injury during sepsis. Funding: This study was supported in part by the award of Young Pearl Scholars of Guangdong province, the Natural Science Funds for Distinguished Young Scholar of Guangdong province (2016A030306043), and the funding from State Key Laboratory of Organ Failure Research (201804) to PC (Peng Chen), and the President Foundation of ZhuJiang Hospital, Southern Medical University to ZL. Declaration of Interest: The authors report no relationships that could be construed as a conflict of interest. Ethical Approval: All patients gave informed consent, and the Institutional Ethical Committee has approved the experimental design and study.