Diet has emerged as a key impact factor for gut microbiota function. However, the complexity of dietary components makes it difficult to predict specific outcomes. Here we investigate the impact of plant-derived nanoparticles (PNP) on gut microbiota and metabolites in context of cancer immunotherapy with the humanized gnotobiotic mouse model. Specifically, we show that ginger-derived exosome-like nanoparticle (GELN) preferentially taken up by Lachnospiraceae and Lactobacillaceae mediated by digalactosyldiacylglycerol (DGDG) and glycine, respectively. We further demonstrate that GELN aly-miR159a-3p enhances anti-PD-L1 therapy in melanoma by inhibiting the expression of recipient bacterial phospholipase C (PLC) and increases the accumulation of docosahexaenoic acid (DHA). An increased level of circulating DHA inhibits PD-L1 expression in tumor cells by binding the PD-L1 promoter and subsequently prevents c-myc-initiated transcription of PD-L1. Colonization of germ-free male mice with gut bacteria from anti-PD-L1 non-responding patients supplemented with DHA enhances the efficacy of anti-PD-L1 therapy compared to controls. Our findings reveal a previously unknown mechanistic impact of PNP on human tumor immunotherapy by modulating gut bacterial metabolic pathways.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is intricately related to the reprogramming of host metabolism. However, existing studies have mainly focused on peripheral blood samples and barely identified specific metabolites that are critically involved in the pathology of coronavirus disease 2019 (COVID-19). In the current small-scale study, we performed metabolic profiling in plasma (n = 61) and paired bronchoalveolar lavage fluid (BALF) samples (n = 20) using parallel two-dimensional liquid chromatography–mass spectrometry (2DLC-MS). In addition, we studied how an identified metabolite regulates the immunopathogenesis of COVID-19. The results unveiled distinct metabolome changes between healthy donors, and moderate and severe patients in both plasma and BALF, indicating that locations and disease severity play critical roles in COVID-19 metabolic alteration. Notably, a vital metabolite, indoxyl sulfate, was found to be elevated in both the plasma and BALF of severe COVID-19 patients. Indoxyl sulfate selectively induced TNF-α production, reduced co-stimulatory signals, and enhanced apoptosis in human monocytes. Moreover, its levels negatively correlated with the strength of co-stimulatory signals and antigen presentation capability in monocytes of COVID-19 patients. Collectively, our findings suggest that the levels of indoxyl sulfate could potentially serve as a functional biomarker to monitor COVID-19 disease progression and guide more individualized treatment for COVID-19 patients.