Abstract
ABSTRACT Several bacteria in the human gut microbiome have been associated with colorectal cancer (CRC) by high-throughput screens. In some cases, molecular mechanisms have been elucidated that drive tumorigenesis, including bacterial membrane proteins or secreted molecules that interact with the human cancer cells. For most gut bacteria, however, it remains unknown if they enhance or inhibit cancer cell growth. Here, we screened bacteria-free supernatants (secretomes) and inactivated cells of over 150 cultured bacterial strains for their effects on cell growth. We observed family-level and strain-level effects that often differed between bacterial cells and secretomes, suggesting that different molecular mechanisms are at play. Secretomes of Bacteroidaceae, Enterobacteriaceae, and Erysipelotrichaceae bacteria enhanced cell growth, while most Fusobacteriaceae cells and secretomes inhibited growth, contrasting prior findings. In some bacteria, the presence of specific functional genes was associated with cell growth rates, including the virulence genes TcdA, TcdB in Clostridiales and FadA in Fusobacteriaceae, which both inhibited growth. Bacteroidaceae cells that enhanced growth were enriched for genes of the cobalamin synthesis pathway, while Fusobacteriaceae cells that inhibit growth were enriched for genes of the ethanolamine utilization pathway. Together, our results reveal how different gut bacteria have wide-ranging effects on cell growth, contribute a better understanding of the effects of the gut microbiome on host cells, and provide a valuable resource for identifying candidate target genes for potential microbiome-based diagnostics and treatment strategies.
Highlights
Over the past few decades, thousands of microbial species have been identified in the human gut microbiome
Reproducibility of growth rate alterations by bacterial cells and secretomes To identify alterations in the growth rates of colorectal cancer (CRC) cell lines by bacterial cells or their secreted pro ducts, inactivated cells or secretomes were added to five CRC cell lines with different mutational landscapes and one embryonic kidney cell line HEK293T
Over 150 human gut bacteria belonging to taxo nomic groups that have previously been associated with CRC were tested for their effects on cell growth of five CRC cell lines (HT29, Caco-2, HCT116, SW480, and HCT15) with different mutation landscapes representing commonly mutated genes in CRC, and one immortalized kidney cell line (HEK293T)
Summary
Over the past few decades, thousands of microbial species have been identified in the human gut microbiome. The bacterial composition on the affected intestinal mucosa changes in a process that is described by the bacterial driverpassenger model.[6,7] Bacterial drivers may facilitate the acquisition of hallmarks of cancer[8] in mucosal cells by generating DNA-damage, reducing the epithelial barrier function, and stimulating procarcinogenic immune responses. As the tumor microenvironment changes in the transition from adenoma to carcinoma, bacterial passengers compete with the drivers, further shifting the micro biome toward a CRC signature.[9,10] The newly acquired bacteria may in turn affect tumor development, by potential inhibiting, enhancing, or neu tral effects on tumor cell growth.[6] These CRC-
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