Foundation France. GK is a scientific co-founder of everImmune, Samsara Therapeutics and Therafast Bio. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders.
The composition and metabolism of the human gut microbiota are strongly influenced by dietary complex glycans, which cause downstream effects on the physiology and health of hosts. Despite recent advances in our understanding of glycan metabolism by human gut bacteria, we still need methods to link glycans to their consuming bacteria. Here, we use a functional assay to identify and isolate gut bacteria from healthy human volunteers that take up different glycans. The method combines metabolic labeling using fluorescent oligosaccharides with fluorescence-activated cell sorting (FACS), followed by amplicon sequencing or culturomics. Our results demonstrate metabolic labeling in various taxa, such as Prevotella copri, Collinsella aerofaciens and Blautia wexlerae. In vitro validation confirms the ability of most, but not all, labeled species to consume the glycan of interest for growth. In parallel, we show that glycan consumers spanning three major phyla can be isolated from cultures of sorted labeled cells. By linking bacteria to the glycans they consume, this approach increases our basic understanding of glycan metabolism by gut bacteria. Going forward, it could be used to provide insight into the mechanism of prebiotic approaches, where glycans are used to manipulate the gut microbiota composition.
<div>Abstract<p>Several approaches to manipulate the gut microbiome for improving the activity of cancer immune-checkpoint inhibitors (ICI) are currently under evaluation. Here, we show that oral supplementation with the polyphenol-rich berry camu-camu (CC; <i>Myrciaria dubia</i>) in mice shifted gut microbial composition, which translated into antitumor activity and a stronger anti–PD-1 response. We identified castalagin, an ellagitannin, as the active compound in CC. Oral administration of castalagin enriched for bacteria associated with efficient immunotherapeutic responses (<i>Ruminococcaceae</i> and <i>Alistipes</i>) and improved the CD8<sup>+</sup>/FOXP3<sup>+</sup>CD4<sup>+</sup> ratio within the tumor microenvironment. Moreover, castalagin induced metabolic changes, resulting in an increase in taurine-conjugated bile acids. Oral supplementation of castalagin following fecal microbiota transplantation from ICI-refractory patients into mice supported anti–PD-1 activity. Finally, we found that castalagin binds to <i>Ruminococcus bromii</i> and promoted an anticancer response. Altogether, our results identify castalagin as a polyphenol that acts as a prebiotic to circumvent anti–PD-1 resistance.</p>Significance:<p>The polyphenol castalagin isolated from a berry has an antitumor effect through direct interactions with commensal bacteria, thus reprogramming the tumor microenvironment. In addition, in preclinical ICI-resistant models, castalagin reestablishes the efficacy of anti–PD-1. Together, these results provide a strong biological rationale to test castalagin as part of a clinical trial.</p><p><i>This article is highlighted in the In This Issue feature, p. 873</i></p></div>
<div>Abstract<p>Several approaches to manipulate the gut microbiome for improving the activity of cancer immune-checkpoint inhibitors (ICI) are currently under evaluation. Here, we show that oral supplementation with the polyphenol-rich berry camu-camu (CC; <i>Myrciaria dubia</i>) in mice shifted gut microbial composition, which translated into antitumor activity and a stronger anti–PD-1 response. We identified castalagin, an ellagitannin, as the active compound in CC. Oral administration of castalagin enriched for bacteria associated with efficient immunotherapeutic responses (<i>Ruminococcaceae</i> and <i>Alistipes</i>) and improved the CD8<sup>+</sup>/FOXP3<sup>+</sup>CD4<sup>+</sup> ratio within the tumor microenvironment. Moreover, castalagin induced metabolic changes, resulting in an increase in taurine-conjugated bile acids. Oral supplementation of castalagin following fecal microbiota transplantation from ICI-refractory patients into mice supported anti–PD-1 activity. Finally, we found that castalagin binds to <i>Ruminococcus bromii</i> and promoted an anticancer response. Altogether, our results identify castalagin as a polyphenol that acts as a prebiotic to circumvent anti–PD-1 resistance.</p>Significance:<p>The polyphenol castalagin isolated from a berry has an antitumor effect through direct interactions with commensal bacteria, thus reprogramming the tumor microenvironment. In addition, in preclinical ICI-resistant models, castalagin reestablishes the efficacy of anti–PD-1. Together, these results provide a strong biological rationale to test castalagin as part of a clinical trial.</p><p><i>This article is highlighted in the In This Issue feature, p. 873</i></p></div>
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