Dysbiosis of human tumor microbiome and aberrant residence of Actinomyces in tumor-associated fibroblasts in young-onset colorectal cancer

Abstract

Colorectal cancer (CRC) is the third most common form of cancer, and the incidence of sporadic young-onset colorectal cancer (yCRC) has been increasing. Microbiota residing in the tumor microenvironment are emerging tumor components. The colonic microbiome differs between patients with CRC and healthy controls; however, few studies have investigated the role of the tumor microbiota in disease diagnosis and tumorigenesis of yCRC. We performed 16S rRNA sequencing analysis to identify the microbiome in CRC and found that tumor microbial diversity decreased in yCRC. Proteobacteria and Firmicutes were the most abundant phyla in all CRC samples, and Actinomyces and Schaalia cardiffensis were the key microbiota in the yCRC group. Correlation analysis revealed that Actinomyces co-occurred with various pro-tumor microbial taxa, including Bacteroidia, Gammaproteobacteria, and Pseudomonas. An independent cohort was used to validate the results. The Actinomyces in CRC was co-localized with cancer-associated fibroblasts and activated the TLR2/NF-κB pathway and reduces CD8+ T lymphocyte infiltration in CRC microenvironment. This study suggests that tumoral microbiota plays an important role in promoting tumorigenesis and therefore has potential as a promising non-invasive tool and intervention target for anti-tumor therapy.

Identification of consensus head and neck cancer-associated microbiota signatures: a systematic review and meta-analysis of 16S rRNA and The Cancer Microbiome Atlas datasets

“…Lastly, Actinomyces did not significantly correlate with TME subtypes in our analysis. However, Actinomyces has been associated with young-onset colorectal cancers, showing a preferential localization with cancer-associated fibroblasts in the TME [108]. These findings underscore the importance of validating and understanding the underlying mechanisms through which these bacteria can modulate the TME in HNSC.…”

The Microbiome-TIME Axis: A Host of Possibilities

“…The effects of CAFs on the TIME are further complicated by microbiota. Recently, colonization with Actinomyces species has been associated with young-onset colorectal cancer [ 39 ]. Actinomyces have been shown to co-localize with and preferentially infect CAFs and impair CD8 + T cell infiltration by toll-like receptor 2 (TLR2) signaling ( Figure 1 ) [ 39 ].…”

“…Recently, colonization with Actinomyces species has been associated with young-onset colorectal cancer [ 39 ]. Actinomyces have been shown to co-localize with and preferentially infect CAFs and impair CD8 + T cell infiltration by toll-like receptor 2 (TLR2) signaling ( Figure 1 ) [ 39 ]. In mouse models, infection with H. pylori was found to differentiate fibroblasts into cells that possess CAF characteristics and secrete pro-inflammatory cytokines such as IL-6 ( Figure 1 ) [ 40 ].…”

Effects of chemotherapy and immunotherapy on microbial diversity in TME and engineered bacterial-mediated tumor therapy

“…Xu et al. ( 18 ) found microbiota differences between yCRC patients and patients with old-onset colorectal cancer(oCRC). 16S rRNA sequencing analysis revealed decreased tumor microbial α diversity in yCRC, suggesting the presence of microbial community dysbiosis in yCRC.…”