Project description:It is increasingly recognised that the gastrointestinal microbiota plays a critical role in human health and promising evidence is accumulating that with dietary strategies, of prebiotic intervention, microbiota imbalances can be corrected and host health improved. Several prebiotics are widely used commercially in foods including inulin, fructo-oligosaccharides, galacto-oligosaccharides and resistant starches and there is convincing evidence, in particular for galacto-oligosaccharides, that prebiotics can modulate the microbiota and promote the growth of bifidobacteria in the intestinal tract of infants and adults. In this study we describe the identification and functional characterisation of the genetic loci responsible for the transport and metabolism of purified galacto-oligosaccharides (PGOS) by our model bifidobacterial strain, B. breve UCC2003. We further demonstrate that the extracellular endogalactanase specified by several B. breve strains, including B. breve UCC2003, is essential for metabolism of PGOS components with a long retention time and high degree of polymerisation. These PGOS components are transported into the bifidobacterial cell via various ABC transport systems and sugar permeases where they are further metabolised to galactose and glucose monomers that feed into the bifid shunt. This research described here advances our understanding of GOS metabolism by bifidobacteria and for the future there is great potential for exploiting bifidobacterial beta-galactosidase to create targeted prebiotics that can enrich for selected Bifiobacteria sp. and other beneficial microbes among the gut microbiota.
Project description:The gut microbiome plays a critical role in enhancing the effectiveness of immune checkpoint blockade (ICB) therapy. Here, we demonstrate that oral supplementation with the prebiotics mannose slows tumor growth in immunocompetent mice in a manner dependent on the gut microbiota. This effect is associated with an increase in the abundance of Faecalibaculum. Mannose generates an immune-stimulatory tumor microenvironment (TME), characterized by a higher percentage of effector and memory CD8+ T cells, along with a notable immunoreactive gene expression signature. Crucially, mannose modulates the stemness program of CD8+ T cells and promotes the generation of progenitor exhausted CD8+ T cells (Tpex). Mechanistically, mannose enhances the production of the short-chain fatty acids (SCFA) propionate and butyrate by the gut microbiota. Administration of propionate and butyrate suppresses tumor progression and stimulates the expansion and differentiation of Tpex both in vivo and in vitro. Furthermore, mannose works synergistically with PD-1 blockade, resulting in tumor regression and enhanced differentiation of intratumoral Tpex into intermediate exhausted CD8+ T cells (Tex-int) and terminally exhausted CD8+ T cells (Tex-term). We also identified a gene signature related to mannose therapy that correlates with favorable responses to ICB across various cancers. Overall, our findings support the combination of mannose dietary supplementation with anti-PD-1 immunotherapy in treating ovarian cancer and suggest its potential for clinical application.
Project description:The gut microbiome plays a critical role in enhancing the effectiveness of immune checkpoint blockade (ICB) therapy. Here, we demonstrate that oral supplementation with the prebiotics mannose slows tumor growth in immunocompetent mice in a manner dependent on the gut microbiota. This effect is associated with an increase in the abundance of Faecalibaculum. Mannose generates an immune-stimulatory tumor microenvironment (TME), characterized by a higher percentage of effector and memory CD8+ T cells, along with a notable immunoreactive gene expression signature. Crucially, mannose modulates the stemness program of CD8+ T cells and promotes the generation of progenitor exhausted CD8+ T cells (Tpex). Mechanistically, mannose enhances the production of the short-chain fatty acids (SCFA) propionate and butyrate by the gut microbiota. Administration of propionate and butyrate suppresses tumor progression and stimulates the expansion and differentiation of Tpex both in vivo and in vitro. Furthermore, mannose works synergistically with PD-1 blockade, resulting in tumor regression and enhanced differentiation of intratumoral Tpex into intermediate exhausted CD8+ T cells (Tex-int) and terminally exhausted CD8+ T cells (Tex-term). We also identified a gene signature related to mannose therapy that correlates with favorable responses to ICB across various cancers. Overall, our findings support the combination of mannose dietary supplementation with anti-PD-1 immunotherapy in treating ovarian cancer and suggest its potential for clinical application.
Project description:The gut microbiome plays a critical role in enhancing the effectiveness of immune checkpoint blockade (ICB) therapy. Here, we demonstrate that oral supplementation with the prebiotics mannose slows tumor growth in immunocompetent mice in a manner dependent on the gut microbiota. This effect is associated with an increase in the abundance of Faecalibaculum. Mannose generates an immune-stimulatory tumor microenvironment (TME), characterized by a higher percentage of effector and memory CD8+ T cells, along with a notable immunoreactive gene expression signature. Crucially, mannose modulates the stemness program of CD8+ T cells and promotes the generation of progenitor exhausted CD8+ T cells (Tpex). Mechanistically, mannose enhances the production of the short-chain fatty acids (SCFA) propionate and butyrate by the gut microbiota. Administration of propionate and butyrate suppresses tumor progression and stimulates the expansion and differentiation of Tpex both in vivo and in vitro. Furthermore, mannose works synergistically with PD-1 blockade, resulting in tumor regression and enhanced differentiation of intratumoral Tpex into intermediate exhausted CD8+ T cells (Tex-int) and terminally exhausted CD8+ T cells (Tex-term). We also identified a gene signature related to mannose therapy that correlates with favorable responses to ICB across various cancers. Overall, our findings support the combination of mannose dietary supplementation with anti-PD-1 immunotherapy in treating ovarian cancer and suggest its potential for clinical application.