Project description:NK cells, as a type of key immune cell, play essential roles in tumor cell immune escape and immunotherapy. Accumulating evidence has demonstrated that the gut microbiota community affects the efficacy of anti-PD1 immunotherapy and that remodeling the gut microbiota structure is a promising strategy to enhance anti-PD1 immunotherapy responsiveness in advanced melanoma patients; however, the details of the mechanism remain elusive. In this study, we found that Eubacterium rectale (E. rectale) was significantly enriched in melanoma patients who responded to anti-PD1 immunotherapy and a high E. rectale abundance was related to longer survival in melanoma patients. Furthermore, administration of E. rectale remarkably improved the efficacy of anti-PD1 therapy and benefited the overall survival of tumor-bearing mice; moreover, application of E. rectale significantly recruited NK cells into the tumor microenvironment. Interestingly, conditioned medium isolated from an E. rectale culture system dramatically enhanced NK-cell function. Through GC-MS/ UHPLC-MS/MS-based metabolomic analysis, L-serine production was found to be significantly decreased in the E. rectale group; moreover, administration of an L-serine synthesis inhibitor dramatically increased NK-cell activation, which led to enhanced anti-PD1 immunotherapy effects. Mechanistically, supplementation with L-serine or application of the L-serine synthesis inhibitor affected NK-cell activation through Fos/Fosl. In summary, our findings reveal the role of bacteria-modulated serine metabolic signaling in NK-cell activation and provide a novel therapeutic strategy to improve the efficacy of anti-PD1 immunotherapy in melanoma.
Project description:The production of short-chain fatty acids by Firmicutes within the human gastrointestinal tract is recognized as critical for gut health and the progression of a range of disease states. Firmicutes lack many glycan-degrading pathways and instead derive a major proportion of their metabolic precursors from carbohydrates released by glycan-degrading generalists belonging to the Bacteroidota phylum and Bifidobacteriaceae family. Recently, it was shown that Eubacterium rectale, a widespread member of the Firmicutes belonging to the Clostridiales cluster XIVa, can grow on the unusual but ubiquitous plant-derived sugar sulfoquinovose (SQ) using a sulfoglycolytic sulfofructose transaldolase pathway. Here, we show that in addition to SQ, E. rectale can also grow on the SQ glycoside sulfoquinovosyl glycerol (SQGro). The 3D structure of the E. rectale sulfoquinovosidase shares strong structural conservation with SQases from gram-negative bacteria. Using sequence-similarity networks, we provide new biological context to a conserved domain of unknown function protein SftX belonging to DUF4867, which is conserved in the sulfoglycolytic sulfofructose transaldolase pathway and determine its 3D structure. Finally, with the aid of a synthetic mini-human microbiome reconstituted in germ-free mice, we show that an SQ dietary supplement can rescue E. rectale from population crashes that occur upon switching from a high-fibre to a low-fibre, high-fat diet. This suggests that SQ or SQGro has potential as a prebiotic for promoting the maintenance of this important SCFA-producing bacterium within the colonic microbiota.
Project description:<p>This study aimed to investigate the protective effects of non-fermented celery polysaccharides (NFCP), fermented celery polysaccharides (FCP), Eubacterium rectale (ER), and their combined intervention (ER+FCP) on Type 2 diabetes (T2D)-related kidney injury in a rat model, using untargeted urinary metabolomics and kidney function indices. We employed ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC–QTOF/MS) to analyze urinary metabolite profiles. Principal component analysis (PCA) demonstrated significant metabolic disturbances in the diabetic group (DM), while all intervention groups showed a shift towards a healthier metabolic profile, with ER and ER+FCP exhibiting the most pronounced improvements. Metabolic alterations in the intervention groups were further validated by differential metabolite analysis, with FCP inducing a larger number of significant changes compared to NFCP. The combined intervention (ER+FCP) showed synergistic effects, enhancing lipid metabolism, inflammation resolution, and the regulation of bile acids, all contributing to kidney protection. Inflammatory markers, oxidative stress, and histological analysis confirmed the efficacy of these interventions in mitigating kidney injury. Our findings highlight the potential of fermented celery polysaccharides and ER to provide enhanced protection against diabetic kidney disease through metabolic modulation and synergistic interactions.</p>
Project description:The adult human gut microbial community is typically dominated by two bacterial phyla (divisions), the Firmicutes and the Bacteroidetes. Little is known about the factors that govern the interactions between their members. Here we examine the niches of representatives of both phyla in vivo. Finished genome sequences were generated from E. rectale and E. eligens, which belong to Clostridium Cluster XIVa, one of the most common gut Firmicute clades. Comparison of these and 25 other gut Firmicutes and Bacteroidetes indicated that the former possess smaller genomes and a disproportionately smaller number of glycan-degrading enzymes. Germ-free mice were then colonized with E. rectale and/or a prominent human gut Bacteroidetes, Bacteroides thetaiotaomicron, followed by whole genome transcriptional profiling of both organisms in their distal gut (cecal) habitat as well as host responses, high resolution proteomic analysis of cecal contents, and biochemical assays of carbohydrate metabolism. B. thetaiotaomicron adapts to E. rectale by upregulating expression of a variety of polysaccharide utilization loci (PULs) encoding numerous glycoside hydrolase gene families, and by signaling the host to produce mucosal glycans that it, but not E. rectale, can access. E. rectale adapts to B. thetaiotaomicron by decreasing production of its glycan-degrading enzymes, increasing expression of selected amino acid and sugar transporters, and facilitating glycolysis by reducing levels of NADH, in part via generation of butyrate from acetate, which in turn is utilized by the gut epithelium. This simplified model of the human gut microbiota illustrates niche specialization and functional redundancy within members of major gut bacterial phyla, and the importance of host glycans as a nutrient foundation that ensures ecosystem stability.