TY - JOUR

T1 - Biofilms and core pathogens shape the tumor microenvironment and immune phenotype in colorectal cancer

AU - Kvich, Lasse

AU - Fritz, Blaine Gabriel

AU - Zschach, Henrike

AU - Terkelsen, Thilde

AU - Raskov, Hans

AU - Høst-Rasmussen, Kathrine

AU - Jakobsen, Morten Ragn

AU - Gheorghe, Alexandra Gabriella

AU - Gögenur, Ismail

AU - Bjarnsholt, Thomas

N1 - Publisher Copyright: © 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.

PY - 2024

Y1 - 2024

N2 - Extensive research has explored the role of gut microbiota in colorectal cancer (CRC). Nonetheless, metatranscriptomic studies investigating the in situ functional implications of host-microbe interactions in CRC are scarce. Therefore, we characterized the influence of CRC core pathogens and biofilms on the tumor microenvironment (TME) in 40 CRC, paired normal, and healthy tissue biopsies using fluorescence in situ hybridization (FISH) and dual-RNA sequencing. FISH revealed that Fusobacterium spp. was associated with increased bacterial biomass and inflammatory response in CRC samples. Dual-RNA sequencing demonstrated increased expression of pro-inflammatory cytokines, defensins, matrix-metalloproteases, and immunomodulatory factors in CRC samples with high bacterial activity. In addition, bacterial activity correlated with the infiltration of several immune cell subtypes, including M2 macrophages and regulatory T-cells in CRC samples. Specifically, Bacteroides fragilis and Fusobacterium nucleatum correlated with the infiltration of neutrophils and CD4+ T-cells, respectively. The collective bacterial activity/biomass appeared to exert a more significant influence on the TME than core pathogens, underscoring the intricate interplay between gut microbiota and CRC. These results emphasize how biofilms and core pathogens shape the immune phenotype and TME in CRC while highlighting the need to extend the bacterial scope beyond CRC pathogens to advance our understanding and identify treatment targets.

AB - Extensive research has explored the role of gut microbiota in colorectal cancer (CRC). Nonetheless, metatranscriptomic studies investigating the in situ functional implications of host-microbe interactions in CRC are scarce. Therefore, we characterized the influence of CRC core pathogens and biofilms on the tumor microenvironment (TME) in 40 CRC, paired normal, and healthy tissue biopsies using fluorescence in situ hybridization (FISH) and dual-RNA sequencing. FISH revealed that Fusobacterium spp. was associated with increased bacterial biomass and inflammatory response in CRC samples. Dual-RNA sequencing demonstrated increased expression of pro-inflammatory cytokines, defensins, matrix-metalloproteases, and immunomodulatory factors in CRC samples with high bacterial activity. In addition, bacterial activity correlated with the infiltration of several immune cell subtypes, including M2 macrophages and regulatory T-cells in CRC samples. Specifically, Bacteroides fragilis and Fusobacterium nucleatum correlated with the infiltration of neutrophils and CD4+ T-cells, respectively. The collective bacterial activity/biomass appeared to exert a more significant influence on the TME than core pathogens, underscoring the intricate interplay between gut microbiota and CRC. These results emphasize how biofilms and core pathogens shape the immune phenotype and TME in CRC while highlighting the need to extend the bacterial scope beyond CRC pathogens to advance our understanding and identify treatment targets.

KW - Bacteroides fragilis

KW - biofilms

KW - Colorectal cancer (CRC)

KW - Fusobacterium nucleatum

KW - in situ hybridization, fluorescence

KW - sequence analysis, RNA

U2 - 10.1080/19490976.2024.2350156

DO - 10.1080/19490976.2024.2350156

M3 - Journal article

C2 - 38726597

AN - SCOPUS:85192859445

VL - 16

JO - Gut Microbes

JF - Gut Microbes

SN - 1949-0976

IS - 1

M1 - 2350156

ER -