Growth rate alterations of human colorectal cancer cells by 157 gut bacteria

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.

A type VII secretion system of Streptococcus gallolyticus subsp. gallolyticus contributes to gut colonization and the development of colon tumors

“…The fact that TX20005 CS alone stimulated host cell proliferation whereas CS from the mutant did not suggest that Sgg stimulation of host cell proliferation is mediated by Sgg T7SS T05 -secreted proteins. This is consistent with a recent study showing that CS from several Sgg strains were able to directly promote HT29 cell proliferation in the absence of bacteria [ 75 ]. At the moment, it is unclear whether the Sgg T7SS T05 -secreted factor mediating cell proliferation is the same as the one that enhances Sgg adherence to host cells.…”

Streptococcus gallolyticus Increases Expression and Activity of Aryl Hydrocarbon Receptor-Dependent CYP1 Biotransformation Capacity in Colorectal Epithelial Cells

“…Furthermore, our unpublished pilot in APC min mice at 6 weeks shows no increase in tumor burden in these susceptible mice upon S. gallolyticus UCN34 colonization. These strain level effects on cell proliferation for a multitude of CRC-associated bacteria were recently also shown by us for Fusobacterium nucleatum and Clostridium species (Taddese et al, 2020). These combined data suggest effective long-term colonization with S. gallolyticus only when tumors are present and, more importantly, that strain level differences are important for the observed effects.…”

“…pasteurianus strains 992 and NTB7. A phylogenetic tree of these S. bovis strains was published in Taddese et al, 2020 ( Taddese et al, 2020 ). Other bacterial strains were E. faecalis 19433 ( ), Enterobacter cloacae NTB9, Staphylococcus lugdunensis NTB8, Salmonella typhimurium NTB6, Escherichia coli Nissle 1917, and E. coli NTB5 ( Boleij et al, 2011 ).…”

“…pasteurianus ( Kumar et al, 2017 ). Our recent report shows that cell proliferation increase or decrease depends on the S. bovis substrain and the CRC cell lines employed ( Taddese et al, 2020 ). This shows a complex relationship not only at strain level but also between CRC cells from different origin.…”

Microbial Community Profiling Distinguishes Left-Sided and Right-Sided Colon Cancer

“…The human gastrointestinal tract is colonized by complex and diverse commensal microbial communities that contribute to the health of the host (Price et al, 2015;Garrett, 2019). The gut has approximately 40 trillion microbes, the vast majority of which are present in the large intestine (colon and rectum) (Sender et al, 2016;Wong and Yu, 2019;Taddese et al, 2020), and 60-80% of the microbes have not been identified due to culture-related difficulties (Van Citters and Lin, 2005;Shen et al, 2010). Therefore, the colon is the main contributor to the total number of bacteria in the digestive tract.…”