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Kanaeva, V. A.

Publications and source records attributed to Kanaeva, V. A..

2 recordsLinked to original sources
bioRxiv2025

Non-Intestinal Microbial Signatures in Stool as Predictors of Cancer Immunotherapy Outcome

Despite the recognized role of the gut microbiome in modulating immune checkpoint inhibitor (ICI) efficacy, the ecological principles governing this relationship remain elusive. Moving beyond cataloging specific bacteria, we investigated whether general ecosystem properties determine clinical outcome. Through genome-resolved metagenomic analysis, we constructed a comprehensive catalog from 951 stool metagenomes and subsequently analyzed a curated subset of 624 samples from 11 multi-cancer cohorts. Our catalog comprises 3,816 non-redundant metagenome-assembled genomes (MAGs) and reveals key ecological determinants of ICI response. We found that clinical benefit is associated with an ecosystem dominated by prevalent, autochthonous taxa. A taxons prevalence in the population positively correlated with its association with positive outcome. Functionally, responder-associated microbes were enriched in genomic capacity for complex carbohydrate metabolism (including specialized mucin degradation) and amino acid biosynthesis. In contrast, non-response was characterized by enrichment of low-prevalence, exogenous (oral and food-derived) bacteria and a functional shift toward nucleoside metabolism, indicative of a dysbiotic state focused on replication. A log-ratio biomarker capturing this ecological shift provided generalizable predictive value across independent cohorts (mean AUC = 0.67 {+/-} 0.13). Our results support an ecological interpretation of the "Anna Karenina principle" in microbiomes: response is linked to a stable, functionally coherent microbial community, whereas non-response represents a destabilized state with high individual variability. This reframes the search for biomarkers from individual taxa to the assessment of ecosystem stability and metabolic competence, providing a foundation for microbiome-targeted strategies to improve cancer immunotherapy outcomes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/652660v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@f0c9edorg.highwire.dtl.DTLVardef@591c6eorg.highwire.dtl.DTLVardef@59863forg.highwire.dtl.DTLVardef@17c934d_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗
bioRxiv2023

Systemic Metabolic Depletion of Intestine Microbiome Undermines Melanoma Immunotherapy Effectiveness

Immunotherapy has proven to be a boon for patients grappling with metastatic melanoma, significantly enhancing their clinical condition and overall quality of life. A compelling connection was discovered between the composition of the intestinal microbiome and the effectiveness of immunotherapy substantiated in both animal models and human patients. Nonetheless, the precise biological mechanisms through which gut microbes influence melanoma treatment outcomes remain poorly understood. This study conducted a high-resolution metagenomic meta-analysis, employing cutting-edge bioinformatics techniques including genome-resolved metagenomics, strain profiling, comparative genomics, and metabolic reconstruction. According to the obtained results, the systemic metabolic depletion of the gut microbiome causes a lack of response to immunotherapy. Specifically, the presence of bacteria adept at utilizing polysaccharides, as well as those responsible for cobalamin, amino acids, and fatty acids production, decreased in patients who experienced unfavorable treatment outcomes. In contrast, patients who had successful outcomes after immunotherapy exhibited a prevalence of amino acids and cobalamin prototrophs, while autotrophy in these substances characterized the microbiomes of patients with unsuccessful outcomes. The metabolic reconstruction of short-chain fatty acid biosynthesis pathways did not differentiate bacteria linked to treatment outcomes based on their ability to produce acetate, butyrate, or propionate. However, the cobalamin-dependent Wood-Ljungdahl pathway of acetate synthesis was directly associated with immunotherapy effectiveness.

bioinformatics↗