Colorectal cancer-associated <i>Streptococcus gallolyticus</i> : a hidden diversity expose

<i>Streptococcus gallolyticus</i> subsp. <i>gallolyticus</i> (<i>SGG</i>) is a bacterial pathogen implicated in bacteremia and endocarditis and is often associated with colon tumors in elderly individuals. The development of colorectal cancer (CRC) has been linked to intestinal dysbiosis, characterized by increased proportions of <i>SGG</i> and other intestinal microbes. In this study, we present the complete nucleotide sequence of five novel clinical isolates of <i>SGG</i> associated with colorectal cancer, revealing unexpected genetic diversity. Sequencing an additional 30 <i>SGG</i> clinical isolates provided a more comprehensive description of this genetic diversity. We did not identify a pathogenicity island specific to CRC-associated <i>SGG</i> isolates. Most of these human-derived <i>SGG</i> isolates exhibit resistance to multiple antibiotics. Our findings also offer additional insights into multilocus sequence typing (MLST), capsular loci, and pilus organization. Analysis of the repertoire of surface proteins reveals high potential for binding and foraging complex polysaccharides. Finally, comparative genomics with the phylogenetically closest non-pathogenic subspecies <i>S. gallolyticus</i> subsp. <i>macedonicus</i> confirmed that <i>SGG</i> pathogenicity-associated factors mostly rely on a large repertoire of surface proteins involved in host colonization, presence of C5a peptidase to avoid innate immunity, bile salt hydrolase to persist in the gut, and of specific bacteriocin and type VII-dependent effectors to colonize the host colon. Additionally, the presence of extracellular polysaccharides in <i>SGG</i> probably helps the bacterium survive in harsher conditions.IMPORTANCE<i>Streptococcus gallolyticus</i> subsp. <i>gallolyticus</i> (<i>SGG</i>) was the first intestinal bacterium associated with colorectal cancer. It is now widely accepted that colonic microbiota dysbiosis contributes to oncogenesis, with a higher relative abundance of several potentially pro-carcinogenic bacteria. For example, the oncogenic role of <i>Escherichia coli pks</i>+ and enterotoxinogenic <i>Bacteroides fragilis</i> in colorectal cancer has been well established, identifying the role of genetic loci encoding toxins. Through the sequencing and analysis of 11 clinical <i>SGG</i> isolates from CRC patients and comparisons with non-CRC isolates, we uncovered a significant diversity among CRC-associated strains. Our findings suggest that <i>SGG</i> association with CRC is complex and is not linked to a specific strain or pathogenicity island, thus highlighting the opportunistic and versatile nature of <i>SGG</i>.