Project description:Gut microbiota plays a crucial role in the pathogenesis of Alzheimer disease (AD). Here, we found that AD patients had significantly lower abundance of Agathobacter, which were negatively correlated with cognitive impairment. Animal experiments showed that Agathobacter rectalis (A. rectalis) supplementation increased beneficial commensal bacteria, significantly improved pathological damage, and suppressed microglial activation in APP/PS1 mice. We further demonstrated that butyric acid, a metabolite of A. rectalis, reduced microglial activation and pro-inflammatory factor production via Akt/ nuclear factor κB (NF-κB) signal pathway in vitro. Meanwhile, we revealed that A. rectalis effectively inhibited activation of microglia in the APP/PS1 mice by regulating Akt/ NF-κB pathway. This finding highlights the role of A. rectalis and its metabolite butyrate in mitigating neuroinflammation in AD by modulating the Akt/NF-κB pathway.
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.