Butyrate-producing Faecalibacterium prausnitzii suppresses natural killer/T-cell lymphoma by dampening the JAK-STAT pathway

Abstract

Background Natural killer/T-cell lymphoma (NKTCL) is a highly aggressive malignancy with a dismal prognosis, and gaps remain in understanding the determinants influencing disease outcomes. Objective To characterise the gut microbiota feature and identify potential probiotics that could ameliorate the development of NKTCL. Design This cross-sectional study employed shotgun metagenomic sequencing to profile the gut microbiota in two Chinese NKTCL cohorts, with validation conducted in an independent Korean cohort. Univariable and multivariable Cox proportional hazards analyses were applied to assess associations between identified marker species and patient outcomes. Tumour-suppressing effects were investigated using comprehensive in vivo and in vitro models. In addition, metabolomics, RNA sequencing, chromatin immunoprecipitation sequencing, Western blot analysis, immunohistochemistry and lentiviral-mediated gene knockdown system were used to elucidate the underlying mechanisms. Results We first unveiled significant gut microbiota dysbiosis in NKTCL patients, prominently marked by a notable reduction in Faecalibacterium prausnitzii which correlated strongly with shorter survival among patients. Subsequently, we substantiated the antitumour properties of F. prausnitzii in NKTCL mouse models. Furthermore, F. prausnitzii culture supernatant demonstrated significant efficacy in inhibiting NKTCL cell growth. Metabolomics analysis revealed butyrate as a critical metabolite underlying these tumour-suppressing effects, validated in three human NKTCL cell lines and multiple tumour-bearing mouse models. Mechanistically, butyrate suppressed the activation of Janus kinase-signal transducer and activator of transcription pathway through enhancing histone acetylation, promoting the expression of suppressor of cytokine signalling 1. Conclusion These findings uncover a distinctive gut microbiota profile in NKTCL and provide a novel perspective on leveraging the therapeutic potential of F. prausnitzii to ameliorate this malignancy. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information. The metagenomic sequencing data reported in this study are available at the China National Center for Bioinformation (CNCB)— National Genomics Data Center (NGDC) under BioProject accession number PRJCA010329, and the gut metagenomic data of public Korean NKTCL cohort can be accessed in the Sequence Read Archive database with accession number of PRJNA1043252. The RNA and ChIP sequencing data are available at the National Omics Data Encyclopedia (NODE) under Project ID of OEP005390, OEP004744, and OEP004746, respectively. All other data are available in the manuscript including its supplementary files or from the corresponding authors on reasonable request.