Faecalibacterium Prausnitzii Confers a Protective Effect Against the Development of NKTCL

Over the last decade, increasing evidence has pinpointed the intimate interactions between gut microbiota and various diseases (Schupack DA et. al. Nat Rev Gastroenterol Hepatol. 2022). Notably, the “microbiota-gut-lymphoma axis” has emerged as a potential target for the clinical management of lymphoid neoplasms (Shi Z et. al. Clin Med Insights Oncol. 2021). However, gaps remain in understanding how gut microbes influence the survival outcomes of patients with Natural killer/T-cell lymphoma (NKTCL).

To identify key gut microbial species associated with NKTCL, we conducted fecal metagenomic sequencing on a discovery cohort consisting of 30 treatment-naïve NKTCL patients and 20 healthy controls (HCs). Through linear discriminant analysis effect size (LEfSe) analysis, 16 differentially abundant species were revealed, with 12 microbial taxa depleted and 4 enriched in NKTCL. Among them, Faecalibacterium prausnitzii showed the most significant reduction in the NKTCL group and stood out as the most abundant marker species identified by LEfSe analysis.

We subsequently investigated the correlations between these identified marker species and outcomes of NKTCL patients using univariable and multivariable Cox proportional hazards analyses. Our findings indicated that F. prausnitzii was the uniquely independent protective predictor for the survival of NKTCL patients. Specifically, decreased abundance of F. prausnitzii was significantly associated with poorer survival outcomes, including both the progression-free survival and overall survival, in NKTCL patients. Furthermore, patients with “Good” survival exhibited comparable abundances of F. prausnitzii as well as overall microbial compositions, as revealed by principal coordinate analysis, to those of HCs, in contrast to patients with “Poor” survival. Importantly, these results were substantiated upon inclusion of a validation cohort, which comprised 12 NKTCL patients and 13 HCs.

To determine whether F. prausnitzii could confer protective effects against NKTCL development, we established two syngeneic tumor-bearing models by challenging C57BL/6 mice with RMA and EL4 cells, respectively, which express essential markers, including CD3 epsilon, CD56, TIA1, and Granzyme B, for NKTCL identification (Wen et. al. EBioMedicine. 2023). In RMA-challenged mice, supplementation with live F. prausnitzii bacteria led to significantly reduced tumor burden, including decreased tumor volume, weight, and luminescence intensity, compared to control mice receiving sterile phosphate buffered solution and nonpathogenic Escherichia coli MG1655, respectively. Moreover, these tumor-suppressing effects were further confirmed in an EL4-challenged mouse model, where prophylactic treatment with F. prausnitzii significantly hindered tumor formation and improved survival rates in mice.

Altogether, this study shed light on the significant beneficial role of gut F. prausnitzii in NKTCL for the first time, underscoring its potential as a probiotic-centered therapeutic strategy for this disease.